Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)#[N:2].C([Li])CCC.[CH3:20][N:21]1[C:25]([Cl:26])=[C:24]([C:27](Cl)=[O:28])[C:23]([Cl:30])=[N:22]1.Cl>C1COCC1>[CH3:20][N:21]1[C:25]([Cl:26])=[C:24]([C:27]([OH:28])=[C:3]([C:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:7][CH:8]=2)[C:1]#[N:2])[C:23]([Cl:30])=[N:22]1
Reactant: N#CCc1csc(-c2ccccc2)n1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(Cl)c(C(O)=C(C#N)c2csc(-c3ccccc3)n2)c1Cl
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
0.72 g of 4-cyanomethyl-2-phenylthiazole was dissolved in 10 ml of dry THF, and 4.6 ml of n-butyl lithium (1.56 M hexane solution) was dropwise added thereto at −60° C. or lower in an argon atmosphere. After the resulting product was stirred at −60° C. or lower for 20 minutes, 0.84 g of 1-methyl-3,5-dichloropyrazole-4-carbonyl chloride as dissolved in 3 ml of dry THF was dropwise added thereto at −60° C. or lower. Then, the resulting product was gradually heated, and stirred for 4 hours at room temperature. The reaction mixture was poured into ice water, acidified with diluted hydrochloric acid, extracted with ethyl acetate, and washed with saturated saline. The resulting product was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain the intended product from the fraction eluted with chloroform. The resulting product was crystallized and washed with diethyl ether to obtain 0.8.6 g of 3-(1-methyl-3,5-dichloropyrazol-4-yl)-2-(2-phenylthiazol-4-yl)-3-hydroxyacrylonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Br:10]C1CC(C(C)C)CCC1=O>>[Br:10][CH:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][CH2:5]1
Reactant: CC1(C)CCCCC1=O
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: CC1(C)CCCC(Br)C1=O

Procedure:
The bromination of 2,2-dimethyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][Br:20])[CH:8]=[CH:7]2
Reactant: Cc1ccc2cccc(Br)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cccc(Br)c2n1

Procedure:
To a solution of 2 (2.5477 g, 11.47 mmol) in carbon tetrachloride (40 mL) was added NBS (2.2461 g, 12.62 mmol) and a little bit of AIBN followed by refluxing overnight under UV light. The mixture was filtered to remove the solid and concentrated to give a yellow solid. Purification by chromatography (hexanes/DCM 80:20) yielded a white solid.(1.33 g, 39%) 1H NMR (400 MHz CDCl3) δ8.16 (1H, d, J=8.4 Hz), 8.05 (1H, d, J=7.2 Hz), 7.78 (1H, d, J=7.6 Hz), 7.65 (1H, d, J=8.4 Hz), 7.41 (1H, t, J=7.6 Hz), 4.78 (3H, s); 13C NMR (300 MHz CDCl3) δ158.3, 144.7, 138.0, 133.9, 128.9, 127.7, 127.6, 125.1, 122.4, 34.6; EIMS, m/z 299/300/301 (M/M+1/M+2).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-chloro-5-trifluoromethylpyrimidine. ESI-MS (m/z): 461 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11](I)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]>>[C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=3)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(=O)N1c2ccc(I)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1
Product: CC(=O)N1c2ccc(-c3cccc(S(C)(=O)=O)c3)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1

Procedure:
rac-cis-1-Acetyl-2,3-bis-(4-chloro-phenyl)-6-(3-methanesulfonyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-1-acetyl-2,3-bis-(4-chloro-phenyl)-2,3-dihydro-6-iodo-1H-imidazo[1,2-a]pyridin-5-one with 3-(methylsulfonyl)phenylboronic acid The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 553.11; the expected mass is 552.1. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:38]=[N:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cncc(C(F)(F)F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Yield: 38.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (83 mg, 0.19 mmol) was treated with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine (130 mg, 0.47 mmol, prepared according to J. Aebi et al US 20090048238 19 Feb. 2009), sodium carbonate (2M, 350 μl, 0.70 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (15 mg, 0.02 mmol) according to the method described in Example 3 to give 37 mg (39% yield) of the title compound. Purity 99%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[C:13]([Cu])#[N:14].[C-]#N.[Na+]>CN(C=O)C>[C:13]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 105 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
28 g (0.1 mol) of methyl 4-hydroxy-3-iodobenzoate 2 dissolved in 100 mL of DMF was treated with 9.92 g (0.11 mol) of CuCN and 0.49 g (0.11 mol) of NaCN. The system was flushed with nitrogen after which the mixture warmed to 105° C. and stirred to 18 h. The mixture was allowed to cool to room temperature, and any precipitates were removed via filtration and washed with EtOAc. The combined organics were diluted with 200 mL of water and then extracted with EtOAc (2×200 mL). The combined layers were dried over sodium sulfate, filtered and evaporated to dryness. After drying under vacuum, the resulting 18 g (100% yield) of 3 was characterized by LCMS and HNMR.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][N:37]2[CH3:40])=[CH:33][CH:32]=1)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:39]=[C:38]4[C:34]([CH:35]=[CH:36][N:37]4[CH3:40])=[CH:33][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2ccc(C=O)cc21
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cn1ccc2ccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc21

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-formy-1-methylindole to the procedure of step 1, Example 66. MS (ESI) m/z 522.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:17])[S:7](=[O:16])(=[O:15])[C:8]2[CH:14]=[CH:13][S:12][C:9]=2[C:10]=1[OH:11])([O:3]C)=O.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[S:7](=[O:16])(=[O:15])[N:6]([CH3:17])[C:5]=1[C:1]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:3]
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2sccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sccc2S1(=O)=O

Procedure:
1.9 G. of 3-carbomethoxy-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide are suspended together with 0.9 g. of 2-aminothiazole in 250 ml. of absolute xylene and heated to reflux for 7 hours, by which means 150 ml. of xylene are slowly distilled off. The residual xylene is then evaporated in vacuo. The crystalline residue is recrystallized from ethanol. There is obtained 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of melting point 217° C. (decomposition).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[C:12]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:31](OCC)=[O:32]>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[C:12]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[C:11]2[CH:31]=[O:32])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccc(F)cc2)c2cnccc21
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(-c2ccc(F)cc2)c2cnccc2n1S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
35.2mg (0.lmM) of the product of Step 4, above, in 4ml of absolute THF is cooled to -40° to -50°. To this is then slowly added 0.075ml (0.12mM) of n-butyllithium (1.6M in hexane) and the mixture stirred for 1 hour at -40° to -50°. 0.1 ml (1.2mM) of ethyl formate is added with stirring for 2 hours at -40° to -50°. The mixture is quenched with aqueous ammonium chloride and extracted with ethyl acetate. The resulting solution is dried over Na2SO4 and evaporated to dryness. The resulting product is applied to prep plates in CH2Cl2 /CH3OH (98:2) and the bands eluted with ethyl acetate to give the title product of this step as a yellow gum.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][NH:32][CH3:33])[CH3:28]>C(Cl)Cl>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][N:32]([CH3:33])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:28]
Reactant: CCN(CC)CCNC
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCN(C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq) is dissolved in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1.0 ml; 7.42 mmol; 5.00 eq) followed by N,N-diethyl-N′-methylethylenediamine (1.2 ml; 7.42 mmol; 5.00 eq) are added. After 1 hour at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (20) as a beige solid (570 mg; 89%).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=[N:9][OH:10])[CH2:5][CH2:4]1.P([O-])(O)(O)=O.[K+].[C-:17]#[N:18].[K+]>O>[OH:10][NH:9][C:6]1([C:17]#[N:18])[CH2:7][CH2:8][N:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: [C-]#N
Reactant: CON1CCC(=NO)CC1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Product: CON1CCC(C#N)(NO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-methoxy-piperidin-4-one oxime (240 g, 1.66 mol) and potassium dihydrogen phosphate (792.9 g, 5.83 mol) in water (200 ml) at 0-5° C. was added a solution of potassium cyanide (195.1 g, 3.0 mol) in water (200 ml) dropewise (caution!). The reaction mixture was stirred at room temperature overnight (stoppered flask), treated with another portion of potassium dihydrogen phosphate (79.3 g, 0.58 mol) and further stirred at room temperature over another night. The mixture was flushed with nitrogen, the semi-solid removed by filtration and dissolved in ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, all organic layers combined, washed with water and brine, dried over sodium sulfate and concentrated. The residue was triturated with cold diethyl ether, filtered and dried. Yield: 230.8 g of 4-hydroxyamino-1-methoxy-piperidine-4-carbonitrile as a tan solid, mp 130-131° C.
Reaction SMILES: [C:1]([C:3]1([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].S(=O)(=O)(O)[OH:23].[OH-].[Na+]>O>[C:1]([C:3]1([NH:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:23])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)N1CCC(C#N)(Nc2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(Nc2ccc(F)cc2)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
127.5 parts of ethyl 4-cyano-4-(4-fluorophenylamino)-1-piperidinecarboxylate are added dropwise to 360 parts of concentrated sulfuric acid (exothermic reaction: temperature rises to 50° C.). Upon completion, the whole is stirred overnight at room temperature. The reaction mixture is poured onto crushed ice and 250 parts of water are added. The whole is alkalized with sodium hydroxide solution at a temperature of 40°-50° C., whereupon the product is precipitated. It is filtered off, washed with water and taken up in boiling trichloromethane. The latter is washed twice with water, dried and evaporated, yielding 82.1 parts of less pure ethyl 4-carbamoyl-4-(4-fluorophenylamino)-1-piperidinecarboxylate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(O)(C)C.C(OC(C)C)(C)C>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: Cc1c(SCCCC2NCCc3ccccc32)ccnc1CSc1ccncc1
Yield: 36 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 1,2,3,4-tetrahydroisoquinoline, chromatography on silica gel and subsequent crystallization from isopropanol/diisopropyl ether gives the title compound; m.p. 190-192° C.; yield 36% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:13])([F:12])[F:11])[C:7]=1[CH:8]=[CH2:9].[CH3:28][C:29]1(C)[C:33](C)([CH3:34])OB(C2C=CC=CC=2)O1>>[NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:12])([F:13])[F:11])[C:7]=1[C:8]1[CH:34]=[CH:33][CH:29]=[CH:28][CH:9]=1
Reactant: C=Cc1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Product: COc1nc(-c2nnc([C@](C)(O)C(F)(F)F)o2)c(N)c(-c2ccccc2)c1C(F)(F)F

Procedure:
The title compound was prepared analogously to (S)-2-(5-(3-Amino-6-methoxy-5-(trifluoromethyl)-4-vinylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Example 14.0 step 1) by replacing 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane with 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane;
Reaction SMILES: N12CCN(CC1)CC2.C([Li])CCC.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[C:21](=[O:23])=[O:22]>C(OCC)C>[F:14][C:15]1[C:16]([C:21]([OH:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccnc1
Reactant: O=C=O
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1ncccc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 1,4-diazabicyclo[2.2.2]octane (1.15 g, 10.3 mmol) in diethylether (50 ml) is added n-butyllithium (2.6M in hexane) (3.95 ml, 10.3 mmol) at −78° C. The reaction mixture is stirred at −20° C. for 1 h followed by the addition of a solution of 3-fluoro-pyridine (1.00 g, 10.29 mmol) in diethylether (30 ml) at −78° C. The yellow suspension is stirred at −60° C. for 1 h and then cooled to −78° C. followed by the addition of excess dry ice. The resulting solution allowed to warm to to −10° C. over 20 min. The precipitate is filtered and the residue is washed with ether which yields pure 3-fluoro-pyridine-2-carboxylic acid (1.20 g, 8.51 mmol, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10](=O)[CH3:11])=[C:5]([CH3:14])[CH:4]=1.C(O)(=O)C.[NH2:19][CH2:20][C:21]([NH2:23])=[O:22].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:23][C:21](=[O:22])[CH:20]=[N:19][C:10]=2[CH3:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: NCC(N)=O
Reactant: COc1ccc(C(=O)C(C)=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2[nH]c(=O)cnc2C)c(C)c1
Temperature: -10 °C
Reaction time: 72 h

Procedure:
C9 (4.0 g, 21 mmol) and glycinamide acetate (2.79 g, 20.8 mmol) were dissolved in methanol (40 mL) and cooled to −10° C. Aqueous sodium hydroxide solution (12 N, 3.5 mL, 42 mmol) was added, and the resulting mixture was slowly warmed to room temperature. After stirring for 3 days, the reaction mixture was concentrated in vacuo. The residue was diluted with water, and 1 N aqueous hydrochloric acid was added until the pH was approximately 7. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was slurried with 3:1 ethyl acetate/heptane, stirred for 5 minutes, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: ethyl acetate) provided the product as a tan solid that contained 15% of an undesired regioisomer; this material was used without further purification. Yield: 2.0 g. LCMS m/z 231.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.14 (d, J=8.2 Hz, 1H), 6.82-6.87 (m, 2H), 3.86 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[C:7](=[O:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].C(O)C>>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Solvent: CCO
Product: CCC1(C)CC(O)C(C)C(C)(CC)N1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 118.2 g (0.6 mol) 2,6-diethyl-2,3,6-trimethyl-4-oxopiperidine in 1000 ml ethanol 18.2 g (0.4 mol) sodium borohydride are added in portions and the temperature is kept below 30° C. Subsequently the solution is stirred for 2 hours at 50° C. Ethanol is distilled off, 500 ml water are added to the residue which is subsequently extracted several times with CH2Cl2. The extract is dried over Na2SO4 and the solution is filtered. After removing the solvent 116 g (97%) 2,6-diethyl-2,3,6-trimethyl-4-hydroxypiperidin are obtained as yellowish liquid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S:5]([CH2:4][CH2:3][CH2:2][N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])(=[O:7])=[O:6])=[CH:9][CH:10]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=S(=O)(CCCCl)c1ccc(Cl)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A solution of 17.8 g (0.07 mole) of 1-chloro-3-(p-chlorophenylsulfonyl)propane and 15.2 g (0.082 mole) of potassium phthalimide in 300 ml of dimethylformamide was stirred at 90°-110° C. for 2 hr and then quenched in water. The mixture was extracted with methylene chloride and the methylene chloride layer dried over magnesium sulfate. Diethylether and hexane were added and the solution stored at 0° C. overnight. The crystalline product was recrystallized from methylene chloride diethyl ether to give a white crystalline product, m.p. 187.5°-188.5° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:37]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:37][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:16][CH:15]=3)[CH2:26][CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccccn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (220 mg) in N,N-dimethylformamide (5 mL) was added ammonium acetate (190 mg), and the mixture was stirred at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio) to give a crude product. The obtained crude product was subjected to basic silica gel column chromatography, and the title compound (95 mg, yield 45%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 437 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=1)([O-:11])=[O:10].Cl>O>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2cccc(O)c2)cc1

Procedure:
A mixture of 32.4 g (0.3 mol) of m-aminophenol and p-nitrofluorobenzene (0.15 mol) was boiled under reflux for 10 days in 400 ml of water and then poured into dilute hydrochloric acid, followed by extraction with ethyl acetate, washing 2 to 3 times with dilute hydrochloric acid and then concentrated. The deposited crystals were washed with hot benzene, cooled and then filtered. The yield was 26 g and the melting point was 158°-160° C.