Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([C:10]#[N:11])=[N:8][CH:9]=1)=[C:2]=[S:3].[C:13]([C:15]1([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=2)[CH2:18][CH2:17][CH2:16]1)#N.C[OH:32].Cl>CC(N(C)C)=O.O>[C:10]([C:7]1[N:8]=[CH:9][C:4]([N:1]2[C:13](=[O:32])[C:15]3([CH2:18][CH2:17][CH2:16]3)[N:19]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[C:2]2=[S:3])=[CH:5][C:6]=1[CH3:12])#[N:11]
Reactant: CO
Reactant: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Reactant: Cc1cc(N=C=S)cnc1C#N
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C)c3)C(=O)C23CCC3)cc1F
Temperature: 65 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
A mixture of 5-isothiocyanato-3-methylpicolinonitrile (Intermediate 6, 2.9 g, 16.57 mmol) and 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide (Intermediate 21, 2.7 g, 11.05 mmol) in DMA was heated to 65° C. overnight. MeOH (50 mL) and HCl (2M, 70 mL) were added and the mixture was heated to 105° C. for 1 h then cooled to room temperature. Water was slowly added until a yellow solid precipitated and the mixture was stirred at room temperature for 3 h. The solid was filtered, washed with water, dissolved in DCM, dried over sodium sulfate, and absorbed on silica gel. Purification by column chromatography on silica gel eluting with 0 to 100% EtOAc/hexanes afforded a pale yellow solid. This solid was triturated in MeOH, filtered, and dried to afford 1.39 g (29%) of 4-(7-(6-cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, 1H), 8.40 (m, 1H), 8.06 (d, 1H), 7.75 (t, 1H), 7.43 (dd, 1H), 7.32 (dd, 1H), 2.73 (d, 3H), 2.59-2.53 (m, 2H), 2.52 (s, 3H), 2.44-2.23 (m, 2H), 1.91-1.88 (m, 1H), 1.52-1.48 (m, 1H). LCMS [M+1]+ 424.0.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[N:5][N:4]([CH3:9])[N:3]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O1CCCC1>[CH3:9][N:4]1[N:3]=[C:2]([NH:1][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])[C:6]([C:7]#[N:8])=[N:5]1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Cn1nc(N)c(C#N)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C#N)c(Nc2ccc(F)cc2[N+](=O)[O-])n1
Reaction time: 0.25 h

Procedure:
To a solution of 4-amino-2-methyl-1,2,3-triazole-5-carbonitrile (1.7 g) in tetrahydrofuran (35 ml) under nitrogen, was added sodium hydride (1.0 g; 50% oil dispersion) at room temperature. After 15 minutes, 2,5-difluoronitrobenzene(2.22 g) was added to the mixture, which was stirred overnight under nitrogen. The deep red solution was then quenched in ice/water/HCl and filtered to give an orange solid. The solid was chromatographed on a magnesium silicate column using dichloromethane; the purified product recrystallised from ethyl acetate-ethanol to give an orange crystalline solid, melting point 159°-160° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.CO>C(Cl)Cl.CCOCC>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:8])[CH:3]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CCNC(=O)C1
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1C=C(Nc2ccc(F)cc2)CCN1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
Piperidine-2,4-dione (I-59d: 10 g, 88.40 mmol) and 4-fluoroaniline (9.82 g, 88.40 mmol) were heated at 120° C. for 5 hours under argon atmosphere. The reaction was monitored by TLC (10% methanol in DCM). The reaction mass was cooled to room temperature, diluted with ether and stirred for 20 minutes. The solid precipitated was collected by filtration to afford 7 g of the product (38.46% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17](O)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:30]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:18])[NH2:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.6 %

Procedure:
To a solution of (S)-3-(4-benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic acid (5.00 g, 13.5 mmol) and 1-hydroxybenzotriazole monohydrate (2.50 g, 16.1 mmol) in N,N-dimethylformamide (50 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (3.10 g, 16.1 mmol) and 28% aqueous ammonia solution (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=2:1-1:1) to give tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-carbamoylethyl]carbamate (1.53 g, yield 31%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:13][OH:14]>>[CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=[N:13][OH:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCN1CCC(=O)CC1
Agent: Cl
Product: CCCCN1CCC(=NO)CC1

Procedure:
1-Butyl-4-piperidone oxime is prepared from 1-butyl-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH2:14])[CH:8]=1>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[S:1]([Cl:5])(=[O:3])=[O:2])[CH:10]=[CH:11][CH:12]=1
Reactant: C=Cc1cccc(Cl)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)/C=C/c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Sulfuryl chloride (3.2 mL, 38.5 mmol, 2 eq.) was added dropwise into a 2-neck mL round-bottomed flask containing 2.7 mL of DMF at 0° C. After stirring the mixture at room temperature for 30 min, 1-chloro-3-vinylbenzene (2.5 mL, 19.3 mmol, 1 eq.) was added and the reaction mixture was heated at 55° C. for 5 h. After the reaction mixture was cooled at room temperature, ice water was poured (20 mL) and the product was extracted three times from the aqueous phase with DCM. The resulting organic phase was washed once with water, brine and dried under Na2SO4. After the product was purified from the crude by flash column chromatography (5% EtOAc/hexanes), compound 1 (1.9785 g, 19.3 mmol) was obtained in a 44% yield. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=15.2 Hz, C═CH, 1H), 7.55 (s, ArH, 1H), 7.50 (dt, J=6.4, 2.2 Hz, ArH, 1H), 7.46-7.40 (m, ArH, 2H), 7.25 (d, J=15.1 Hz, C═CH, 1H). APT (100 MHz, CDCl3, δ): 143.47 (C═C8H), 135.59 (C5), 132.48 (C═C9H), 132.34 (C3), 131.19 (C1H), 130.71 (C2H), 128.77 (C4H), 127.40 (C6H). GC-MS m/z (% relative intensity, ion): 239.95 (2, M+4), 237.95 (13, M+2), 235.95 (19, M+), 201 (35, M+-Cl), 137 (100, M+-SO2Cl), 102(85), 75 (45), 51 (28). HPLC: 99.7% pure, retention time 4.98 min.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:10]1([C:8]2[S:7][N:6]=[C:5]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:9]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC#CCO
Reactant: CS(=O)(=O)c1nsc(C2CCCC2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(C2CCCC2)n1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
300 mg of 3-methylsulfonyl-5-cyclopentyl-1,2,4-thiadiazole and 99 mg of 2-butyn-1-ol were dissolved in 3 g of N,N-dimethylformamide, 62 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 155 mg of 5-cyclopentyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (3)).
Reaction SMILES: C[O:2][C:3]([CH:5]([P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].O[Li:24].O>CCO.CO.O>[Li+:24].[CH2:10]([O:9][C:7]([NH:6][CH:5]([P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[C:3]([O-:4])=[O:2])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: [Li]O
Solvent: O
Solvent: CCO
Solvent: CO
Product: COP(=O)(OC)C(NC(=O)OCc1ccccc1)C(=O)[O-]
Product: [Li+]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Z-α-phosphonoglycine trimethyl ester (1.6 g) was dissolved in EtOH (5 mL) and treated with a solution of LiOH.H2O (408 mg) in MeOH/H2O (5 mL/2 mL). The mixture was stirred at 0° C. for 30 min and the solvent was removed. The crude (1.5 g) was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl[C:12]1[CH:31]=[CH:30][C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[O:29]CC[O:26]3)[CH:20]=2)=O)=[CH:14][CH:13]=1.[NH:32]1CCCC(C(OC)=O)CC1.C(OC(C1CCN(CC2C=CC=C(NC(=O)C3C=CC(Cl)=CC=3)C=2)CC1)=O)C>>[CH3:1][C:2]1[CH:10]=[C:6]([C:7]([NH:32][C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:12]=2)[CH2:16][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]([OH:29])=[O:26])[CH2:20][CH2:19]2)=[O:8])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(C(=O)Cl)c1
Reactant: COC(=O)C1CCCNCC1
Reactant: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Agent: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Product: Cc1cncc(C(=O)Nc2cccc(CN3CCCC(C(=O)O)CC3)c2)c1

Procedure:
The title compound is prepared according to the reaction sequence 2.001a-2.001d described above using 5-methylnicotinoyl chloride instead of 4-chlorobenzoyl chloride as in 2.001a and rac-methyl azepane-4-carboxylate instead of ethyl isonipecotate as in 2.001c: LC-MS A: tR=0.48 min; [M+H]+=368.14.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]=O)=[CH:15][CH:16]=1.[BH4-].[Na+]>CCO>[CH2:1]([NH:8][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: COc1ccc(C=O)cc1
Reactant: C=CCCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCCCCCNCc1ccc(OC)cc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A solution of hept-6-enylamine (2.0 g, 13.4 mmol) and anisaldehyde (1.79 mL, 14.7 mmol) in EtOH (50 mL) was stirred at room temperature for 1 h. Then, NaBH4 (556 mg, 14.7 mmol) was added at 0° C. under nitrogen. The resulting solution was allowed to warm up to room temperature for 4 h. Then, the reaction mixture was partitioned between ice-cold water and CH2Cl2, washed with brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography (gradient AcOEt/CH2Cl2 0:1 to 2:8, then CH2Cl2/MeOH 9:1) to give 1.8 g (34%) of the title product 86 as a colorless oil: m/z=234 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[N:14][CH:13]=[C:12](Cl)[C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[N:14][CH:13]=[C:12]3[NH:18][N:19]=[C:10]([NH2:11])[C:9]=23)=[CH:6][CH:7]=1
Reactant: NN
Reactant: N#Cc1c(Cl)cncc1-c1ccc(N)cc1
Solvent: O
Product: Nc1ccc(-c2cncc3[nH]nc(N)c23)cc1
Temperature: 25 °C

Procedure:
The product from Example 1C (1.4 g) in hydrazine hydrate (10 mL) was heated at 110° C. for 3 hours, cooled to room temperature, and partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 8% methanol in CH2Cl2 to provide 0.5 g of the title compound as a yellow solid. MS (ESI(+)) m/e 225 (M+H)+.
Reaction SMILES: [I-].BrC1C=CC=C[N+]=1C.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].[C:15]1([CH2:21][C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:15]1([CH2:21][C:22]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)O
Reactant: O=C(O)Cc1ccccc1
Agent: C[n+]1ccccc1Br
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)OC(=O)Cc1ccccc1
Yield: 82 %

Procedure:
To a suspended toluene (2 ml) solution of 2-bromo-1-methylpyridinium iodide (720 mg, 2.4 mmol) was added a mixture of tert-butyl alcohol (148 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in toluene (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and tert-butyl phenylacetate was isolated in 82% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)Cl.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:25]([NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[C:40]3[CH2:46][CH2:45][NH:44][CH2:43][C:41]=3[N:42]=2)=[CH:33][CH:32]=1)=[O:29])[CH3:26].C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[C:3]([C:8]([N:44]2[CH2:45][CH2:46][C:40]3[C:39]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[N:38][C:37]([C:34]4[CH:33]=[CH:32][C:31]([NH:30][C:28]([NH:27][CH2:25][CH3:26])=[O:29])=[CH:36][CH:35]=4)=[N:42][C:41]=3[CH2:43]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2nccnc2Cl)C3)cc1
Reaction time: 3 h

Procedure:
3-Chloropyrazine-2-carboxylic acid (0.0648 g, 0.000409 mol) in dry Methylene chloride (1.50 mL, 0.0234 mol) was added N,N-Dimethylformamide (0.00200 mL, 0.0000258 mol) followed by Oxalyl chloride (0.040 mL, 0.00047 mol) dropwise. The reaction mixture was stirred for 3 hours then concentrated, added 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.102 g, 0.000267 mol), N,N-Dimethylformamide (1.80 mL, 0.0232 mol), and N,N-Diisopropylethylamine (0.180 mL, 0.00103 mol) and stirred overnight. The reaction mixture was filtered and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.76 (dd, J=5.6, 2.5, 1H), 8.70-8.60 (m, 2H), 8.17 (dd, J=39.6, 8.8, 2H), 7.47 (dd, J=23.6, 8.8, 2H), 6.17 (dd, J=13.2, 5.7, 1H), 4.79 (s, 1H), 4.42 (s, 1H), 3.91 (t, J=5.4, 1H), 3.80-3.66 (m, 4H), 3.54-3.41 (m, 5H), 3.19-3.05 (m, 2H), 2.81 (t, J=5.1, 1H), 2.69 (t, J=5.0, 1H), 1.06 (q, J=7.2, 3H). LC/MS-m/z+523.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:28])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].I[C:30]1[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=1>>[OH:27][C:24]([CH3:25])([CH3:26])[CH2:23][C@@:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:13][C:12](=[O:28])[N:11]([C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=3)=[CH:8][CH:7]=2)[CH3:10])[CH2:16][CH2:15]1
Reactant: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Reactant: O=c1cc(I)cc[nH]1
Product: C[C@@H](c1ccc(C#Cc2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-ethynylphenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 28 Step 3. LC-MS Method 1 tR=1.3 min, m/z=471 (M+1). 1H NMR (CD3OD) 7.44-7.28 (m, 8H), 6.97 (d, 2H), 6.64 (s, 1H), 6.44 (dd, 1H), 5.54 (q, 1H), 3.02 (dt, 1H), 2.49 (m, 2H), 2.21 (m, 1H), 2.15 (s, 2H), 1.53 (d, 3H), 1.26 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1)([CH3:3])[CH3:2].[I:21][CH3:22]>CC(C)=O>[I-:21].[CH:1]([C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N+:18]=1[CH3:22])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)c1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Solvent: CC(C)=O
Product: CC(C)c1cc(C(F)(F)F)ccc1C1=[N+](C)C(C)(C)CO1
Product: [I-]
Temperature: 55 °C
Yield: 89.3 %

Procedure:
To a solution of 2-(2-isopropyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro oxazole (step 1) (950 mg, 3.33 mmol) in 8.0 ml acetone was added) iodomethane (2.1 ml, 33.3 mmol). The mixture was heated in a 55° C. oil bath for 48 hours. The solvent was removed in vacuo. The solid was stirred in ether, filtered and dried to provide 1.27 g (89%) of the title compound as light yellow solid. MS (m/e): 300.4 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].Cl.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)=[CH:32][CH:31]=1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1ccc(CNC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid, Example 26, step 3, was reacted with methyl-4-(aminomethyl)benzoate hydrochloride and HBTU at 80° C., 2 h to give the title compound as a white solid. MS (m/e)=541.2 [M+H+].
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15]3[C:20]([CH:21]=[C:22]4[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][CH:5]=1)C.Cl.N1C=CC=CC=1.CN1CCCC1=O>O>[CH:16]1[C:15]2[C:20](=[CH:21][C:22]3[C:27]([C:14]=2[C:7]2[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([OH:3])=[CH:5][CH:6]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12
Temperature: 175 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
Under the nitrogen atmosphere, 9-(4-ethoxynaphthalen-1-yl)anthracene (87.1 g) as the fourteenth intermediate compound, pyridine hydrochloride (289.0 g) and 1-methyl-2-pyrrolidone (87 ml) were added to a flask, and stirred for 16 hours at 175° C. The reaction solution was cooled to room temperature, added with water, and washed while being heated. After suction filtration, the solid remained after dissolution was collected. The obtained solid was washed with methanol while being heated. It was then dissolved in heated chlorobenzene and subjected to suction filtration by using a Kiriyama funnel layered with silica gel. An appropriate amount of filtrate was distilled off under reduced pressure, and by adding heptane, re-precipitation was performed to give 4-(anthracen-9-yl)naphthalen-1-ol (74.3 g) as a fifteenth intermediate compound. The scheme is shown in the following “Reaction 26”.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].N1C=CC=CC=1>ClCCl>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Yield: 98.2 %

Procedure:
10.7 g (98.9 mmol) of ethyl chloroformate was added dropwise to a mixture of 15.0 g (94.2 mmol) of 2-fluoro-5-nitroaniline, 8.20 g (104 mmol) of pyridine and 150 ml of dichloromethane at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for one night. After the dichloromethane layer was separated out by adding water to the reaction mixture, the dichloromethane layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. Thereafter the dichloromethane was distilled off to obtain the crude product (crystals). The crude product was washed with hexane, thereby obtaining 21.1 g of the objective product (yield: 98%) in the form of ocher crystals.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O>N1C=CC=CC=1>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: OCCOC1C=CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOC2C=CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-(cyclohex-2-enyloxy)ethanol (intermediate BU) (0.3 g) in anhydrous pyridine was added TsCl (1.3 eq). The mixture was stirred at room temperature for 16 h, after which TLC showed the reaction was complete. The mixture was poured into water, extracted with EA, washed with water and brine, and dried with anhydrous Na2SO4. Solvent was removed and the residue purified by column chromatography to obtain intermediate BV (0.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:11]([SH:14])[NH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29]Br>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:11]3[S:14][CH2:28][CH2:29][N:12]3[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: COc1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
5-(3-Methoxy-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (630 mg, 2.22 mmol) was dissolved in dry DMF (22 mL) under nitrogen atmosphere. Solid potassium carbonate (1.5 g, 11.1 mmol, 5 eq) was added followed by 1,2-dibromoethane (0.192 mL, 2.22 mmol, 1 eq) and the suspension was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated to dryness to give 420 mg (61% over two steps) of crude 6-(3-methoxy-phenyl)-7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazole which was used without further purification in the following step.