Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(O)CC(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c(N2CCN(c3cccc(Cl)c3)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), 1-(3-chlorophenyl)piperazine hydrochloride (118.8 mg; 0.51 mmol) and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up; yield: 51 mg (29%), crystals;
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=3[F:19])=[C:2]([NH2:1])[N:3]=2)[CH2:30][CH2:31]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: COc1ccc(F)c(F)c1C(=O)c1ccc(Cl)nc1N
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3c(OC)ccc(F)c3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 39) and ethyl4-amino-1-piperidine carboxylate (Aldrich 96%) using the procedure described in Step B. Example 6. HRMS, observed: 435.1841, Calcd for (M+H)+: 435.1839.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][C:26]([O:29][CH3:30])([CH3:28])[CH2:25][N:24]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>CN(C=O)C>[CH3:30][O:29][C:26]1([CH3:28])[CH2:25][N:24]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22][N:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[N:20]=2)[CH2:27]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)C1
Solvent: CN(C)C=O
Product: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
To a solution of tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate (265 mg, 0.53 mmol) in DMF (15 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (610 mg, 2.63 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with brine, extracted with DCM (100 mL×3), and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford tert-butyl(±)-6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (264 mg, 85%). MS (ESI) m/z: 587 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[C:22]([CH2:21][C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:31](=[O:34])[CH2:32][CH3:33])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)#[N:23]
Reactant: CCC(=O)Cl
Reactant: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile (9.5 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol) in methylene chloride (1 mL) was added propanoyl chloride (3.0 μL, 0.035 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.1 mg, 9.9%). LCMS calculated for C20H24N5OS (M+H)+: m/z=382.2. Found: 382.1.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([C:25]([CH3:27])=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].CC1C=CC=C(C)N=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:27])[N:12]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 130 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a mixture of 5.0 g of 3-[(2,6-difluorobenzyl)oxy]pyridin-2-amine, 4.1 ml of ethyl 2-chloroacetoacetate, 3.5 ml of 2,6-dimethylpyridine, and 50 ml of toluene was stirred at 130° C. for 24 hours. After leaving to be cooled to room temperature, the reaction mixture was washed with water, a 1 M aqueous sodium hydroxide solution, a 10% aqueous citric acid solution, and a saturated aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to obtain 5.47 g of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][C:13]([OH:15])=[O:14])[CH2:3]1.[Mn]([O-])(=O)(=O)=[O:17].[K+]>O.[OH-].[Na+]>[C:13]([CH2:12][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:11][C:2](=[O:1])[C:3]1=[O:17])([OH:15])=[O:14]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C(O)CN1CC(=O)Nc2ccccc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Yield: 66.6 %

Procedure:
To a solution of 3.0 g (15 mmol) 1,2,3,4-tetrahydro-3-oxoquinoxaline-1-acetic acid in 50 ml water was added gradually a solution of 4. 0 g (25 mmol) potassium permanganate in aqueous sodium hydroxide (4%, w/v) and the mixture was refluxed for 4 h. The reaction mixture was cooled, filtered and the filtrate acidified with concentrated hydrochloric acid to pH 2.5. The precipitate was filtered off and washed with water to give 2.2 g (69%) 1-carboxymethylquinoxaline-2,3(1H,4H)- dione. M.p. >300° C. 1H-NMR (DMSO-d6): 12.0 (1H, broad s), 7.2 (4H, s), 7.0-5.0 (1H, broad s), 4.9 (2H, s).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([Si:7]([CH3:10])([CH3:9])[CH3:8])[S:5][CH:6]=1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]4[C@:34]([C:36](OC)=[O:37])([CH2:35][C:26]=3[CH:25]=[N:24]2)[CH2:33][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:30]4)=[CH:19][CH:18]=1.O>CCOCC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]4[C@:34]([C:36]([C:2]5[N:3]=[C:4]([Si:7]([CH3:10])([CH3:9])[CH3:8])[S:5][CH:6]=5)=[O:37])([CH2:35][C:26]=3[CH:25]=[N:24]2)[CH2:33][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:30]4)=[CH:19][CH:18]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: C[Si](C)(C)c1nc(Br)cs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2csc([Si](C)(C)C)n2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
A solution of 4-bromo-2-(trimethylsilyl)thiazole (304 μl, 1.784 mmol) in dry ether (2 mL) was added to a solution of butyllithium (2.5 M in Hexanes) (731 μl, 1.828 mmol) in dry ether (1 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (250 mg, 0.585 mmol) in dry ether (5 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at −78° C. then slowly warmed to −50° C. over 2 hours. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as a pale yellow foamy solid (76 mg). LCMS (Method F, ES-API): RT 2.65 min, m+H=553.3.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][CH2:22][C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][CH2:22][C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:24]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (3.5 g, 28 mmol) was added dropwise to a solution of 2-chloro-N4-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}quinoline-3,4-diamine (9.0 g, 23.5 mmol) and anhydrous triethylamine (10.0 mL, 35.3 mmol) in anhydrous dichloromethane (75 mL) at 6° C. After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (2.0 g) was added. After the reaction was stirred for another 30 minutes, it was still incomplete, and additional ethoxyacetyl chloride (2.0 g) was added. The stirring was continued for an additional 30 minutes, and the work-up procedure described in Part A of Example 19 was followed to provide 11.12 g of N-[2-chloro-4-({2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}amino)quinolin-3-yl]-2-ethoxyacetamide as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[C:10]([NH:13][C:14]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][NH:25][CH3:26])[CH2:16][CH2:15]1)(=[O:12])[CH3:11].Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].CCCl>C(Cl)Cl>[ClH:33].[C:10]([NH:13][C:14]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][O:22][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][N:25]([CH3:26])[C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:18][CH2:19]1)(=[O:12])[CH3:11]
Reactant: CNCC(OCCN1CCC(NC(C)=O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1(c2ccccc2)CCN(CCOC(CN(C)C(=O)OCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C

Procedure:
0.41 ml of triethylamine is added to a solution of 0.5 g of the compound obtained in EXAMPLE 11, step B), in 10 ml of DCM, the mixture is then cooled to 0° C. and 0.14 ml of benzyl chloroformate is added dropwise. The reaction mixture is washed twice with water, dried over MgSO4 and concentrated under vacuum. The residue is chromatographed on silica gel H using DCM and then a DCM/MeOH mixture (94/6; v/v) as the eluent. The product obtained is taken up with DCM, acidified to pH 1 by the addition of hydrochloric ether and concentrated under vacuum to give 0.39 g of the expected hydrochloride after crystallization from iso ether. M.p.=135° C.
Reaction SMILES: O.[OH-].[Na+].[NH2:4][CH2:5][CH2:6][OH:7].[F:8][C:9]([F:15])([F:14])[S:10](Cl)(=[O:12])=[O:11]>CC(C)=O>[F:8][C:9]([F:15])([F:14])[S:10]([NH:4][CH2:5][CH2:6][OH:7])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)(NCCO)C(F)(F)F

Procedure:
In a mixed solvent prepared from 100 ml of water and 50 ml of acetone and containing 3.2 g of sodium hydroxide, 3.7 g of 2-aminoethanol was reacted with 12.5 g of trifluoromethanesulfonyl chloride at room temperature for 12 hours. The solvent was evaporated from the resultant reaction mixture by vacuum distillation. To the residue was added 50 ml of chloroform. The sodium chloride generated was removed by filtration. The resultant chloroform solution was distilled under vacuum to obtain 2-trifluoromethanesulfonamidoethanol. A 10 g portion was taken out of this reaction product and dissolved in 100 ml of acetone. Thereto was added dropwise 12.0 g of thionyl chloride over a period of 3 minutes. Subsequently, 10 ml of an aqueous solution containing 2.06 g of sodium hydroxide was added thereto dropwise to react the reactants at 55° C. for 12 hours. The solvent was removed from the resultant reaction mixture, and 100 ml of water was added to the residue. After this mixture was stirred, 100 ml of diethyl ether was added to conduct extraction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](I)[CH3:22].Cl>O.CN(C)C=O>[CH2:21]([N:13]1[CH2:12][C:11]2([CH2:17][CH2:18][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[O:15][C:14]1=[O:16])[CH3:22]
Reactant: O=C1NCC2(CCN(Cc3ccccc3)CC2)O1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CC2(CCN(Cc3ccccc3)CC2)OC1=O

Procedure:
A mixture of 16.5 g 8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 6.6 g, 50% suspension of sodium hydride in mineral oil, 15 g ethyl iodide and 70 ml N,N-dimethylformamide is heated at 90° for one hour. The mixture is poured into 150 ml water and the resulting mixture acidified with 10 N hydrochloric acid. The mixture is extracted with two 100 ml portions of hexane. The aqueous layer is basified with sodium hydroxide and extracted with three 75 ml portions of dichloromethane. Removal of solvent in vacuum affords a residue which when crystallized from heptane gives 3-ethyl-8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 105°-106°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]=[N+:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][N:12]2[CH2:13][CH:14]=[CH:15][CH2:16][CH2:17]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(N=[N+]1C=CC=CC1)Nc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(F)cc1)NN1CC=CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of N-[[(4-fluorophenyl)carbamoyl]-imino]pyridinium ylide (1.04 g) and sodium borohydride (2.55 g) in ethanol (100 ml) was stirred at ambient temperature for 16 hours. Excess of sodium borohydride was decomposed with water, and the resulting mixture was evaporated. The residue was extracted with chloroform (20 ml×3). The combined organic extract was washed with water, dried over magnesium sulfate and evaporated to give crystalls. Recrystallization from diisopropyl ether gave N-[[(4-fluorophenyl)-carbamoyl]amino]-1,2,3,6-tetrahydropyridine (0.60 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH2:19]([CH:21]([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22])[CH3:20].CO>CCCCCCC>[CH3:28][C:26]1[O:25][N:24]=[C:23]([CH:21]([NH:22][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:19][CH3:20])[N:27]=1
Reactant: CCC(N)c1noc(C)n1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: CCC(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1noc(C)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-ethyl-5-methyl-1,2,4-oxadiazole-3-methanamine hydrochloride (1:1) (CAN 111997-68-3) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 98.5%, 357.1925 (M+H)+, αD20 (MeOH)=+36.7°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[C:16]([SH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C>[F:14][C:13]1[CH:12]=[C:11]([C:15]2[C:16]([S:21][C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:9][C:8]=1[C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Clc1ncccn1
Reactant: Nc1ncc(-c2ccc(-c3ccccc3S)cc2F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(-c3ccccc3Sc3ncccn3)cc2F)cn1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A solution of 4′-(2-aminopyrimidin-5-yl)-5′-fluorobiphenyl-2-thiol (300 mg, 1.00 mmol), 2-chloropyrimidine (229 mg, 2.00 mmol), PPh3 (262 mg, 1.00 mmol) and TEA (0.38 mL) in DMF (10 mL) was stirred at 120° C. under a N2 atmosphere over-night. The reaction mixture was then cooled to rt, concentrated to dryness, and the residue subjected to FCC purification to give the title compound (170 mg, 45%). MS (ESI): mass calcd. for C20H14FN5S, 375.10; m/z found, 375.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 2H), 8.56 (d, J=4.9, 2H), 7.79-7.73 (m, 1H), 7.63-7.56 (m, 2H), 7.55-7.48 (m, 2H), 7.33-7.24 (m, 2H), 7.21 (t, J=4.9, 1H), 6.23 (s, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCOCCBr
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(C2(CN3CCOCC3)CCOCC2)ccc1OCCCN1CCCC1
Temperature: 60 °C
Yield: 35.6 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (207 mg, 0.65 mmol) and bis(2-bromoethyl)ether (82 μL, 1.3 mmol) in anhydrous acetonitrile (10 mL) was added potassium carbonate (180 mg, 1.3 mmol). The mixture was heated to 60° C. overnight then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (97:3) with 10% NH3 to give the title compound (90 mg, 23% yield).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[N:59]1([CH2:65][CH2:66]O)[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:66][CH2:65][N:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(NCCc1ccccc1O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: OCCN1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(NCCc1ccccc1OCCN1CCCCC1)c1ccc(Oc2ccc(F)cc2)cc1
Yield: 69 %

Procedure:
200 mg (0.516 mmol) of 4-(4-fluorophenoxy)-N-[2-(2-hydroxyphenyl)ethyl]benzene-sulfonamide are reacted in 20 ml of THF with 230 mg (0.878 mmol) of triphenyl-phosphine, 141 μl (0.774 mmol) of DEAD and 0.165 ml (1.239 mmol) of 2-piperidin-1-ylethanol in analogy to the method described under 3C, resulting in the title compound in a yield of 69%.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([Si](C(C)C)(C(C)C)C(C)C)[C:14]2=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)OCc3ccccc3)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
Into a Round bottom flask was added compound 21 (250.0 mg, 0.0006118 mol) and Tetrahydrofuran (5.0 mL, 0.062 mol) and Tetra-n-butylammonium fluoride (190 mg, 0.00073 mol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage to give product 22 (55 mg).
Reaction SMILES: Cl.C([N:9]1[C:13]([CH2:14][CH2:15][CH:16]([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[CH3:23][C:21]1[CH:22]=[C:17]([CH:16]([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)[CH2:15][CH2:14][C:13]2[N:9]=[CH:10][NH:11][CH:12]=2)[CH:18]=[C:19]([CH3:24])[CH:20]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(C(CCc2cncn2Cc2ccccc2)c2cc(C)cc(C)c2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)cc(C(CCc2c[nH]cn2)c2cc(C)cc(C)c2)c1

Procedure:
2,0 g of 1-benzyl-5-[3,3-bis(3,5-dimethylphenyl)propyl]-1H-imidazole hydrochloride is hydrogenated in the mixture of 30 ml of 2N hydrochloric acid and 10 ml ethanol at 80° C. Pd/C (10%) as catalyst. When the uptake of hydrogen ceases, the reaction mixture is cooled, filtered and evaporated to dryness. Water is added and the mixture is made alkaline with sodium hydroxide. The product is then extracted to ethylacetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The residue is the product as base and it is made to its hydrochloride salt in ethyl acetate using dry hydrochloric acid. Yield 0,6 g. M.p. of the product is 101°-105° C.