Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[S:8][CH2:9][C:10]([OH:12])=O.[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:24][N:23]([C:10](=[O:12])[CH2:9][S:8][C:3]2[N:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)CSc1ncccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CSc1ncccn1
Yield: 33.5 %

Procedure:
Proceeding as in Example 1, but substituting 2-(pyrimidin-2-ylthio)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 94, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(pyrimidin-2-ylthio)acetyl)pyrrolidine-2-carboxamide (10.9 mg, 33.5%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.92 (s, 1H), 8.59 (d, 2H), 7.53 (m, 2H), 7.27 (m, 2H), 7.23-7.15 (m, 8H), 6.93 (m, 2H), 4.47 (m, 1H), 4.09 (m, 2H), 3.78 (m, 1H), 3.39 (m, 1H), 2.68 (m, 3H), 1.93 (m, 2H). MS (EI) for C30H27FN4O3S. found 543.6 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:13])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].CC(O)=O>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:9]2[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCCC(=N)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCCc1nc(C(=O)OCC)cn1-c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 72 h
Yield: 24.6 %

Procedure:
To a solution of N-(4-chlorophenyl)butyrimidamide (compound 3, 3.5 g, 17.80 mmol), NaHCO3 (3.14 g, 37.38 mmol) in i-PrOH was added ethyl bromopyruvate (compound 4, 4.7 mL, 37.38 mmol) under N2. The reaction mixture was stirred at 85° C. for 72 hrs, then added AcOH (15 mL). After 4 hrs, the mixture was concentrated under reduced pressure. The residue was diluted with H2O, and extracted with CH2Cl2. The organic layer was washed with saturated NaHCO3 and 1N-HCl solution, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage Isolera™ FLASH Purification System was used for normal phase column chromatography with EtOAc and hexane) to provide the title compound (1.28 g, 25%) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 101.9 %

Procedure:
To a solution of tert-butyl-1-piperazinecarboxylate (5.0 g, 26.8 mmol) in DCM (100 mL) triethylamine (5.6 mL, 40.3 mmol) was added, the mixture was cooled down to 0° C. and isobutyryl chloride (4.2 mL, 40.3 mmol) was added. The reaction was allowed to warm up to room temperature and after 3 hours the reaction was complete. The mixture was washed with 50 mL of 0.4M Na2CO3 solution and then with 50 mL of saturated NH4Cl solution. The organic phase was dried over Na2SO4, filtered and the solvent removed under reduced pressure, affording 7.0 g of 4-isobutyryl-piperazine-1-carboxylic acid tert-butyl ester. The product was dissolved in 100 mL of DCM. H2SO4 (2.91 mL, 54.7 mmol) was added and the reaction left stirring for 16 hours. The precipitate formed was filtered affording 6.7 g of the titled compound (96%, yield)
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:9][C:10]1[CH:15]=[C:14](Br)[CH:13]=[C:12]([CH3:17])[C:11]=1[CH2:18][C:19]([O:21]C)=[O:20]>CN(C=O)C.[Cu]I>[CH3:17][C:12]1[CH:13]=[C:14]([O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:15]=[C:10]([CH3:9])[C:11]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: OCC(F)(F)F
Reactant: COC(=O)Cc1c(C)cc(Br)cc1C
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(F)(F)F)cc(C)c1CC(=O)O

Procedure:
18.05 g (451 mmol) of sodium hydride are initially charged in 500 ml of DMF. 41.05 g (410 mmol) of trifluoroethanol are added dropwise, after the evolution of gas has ended 15.63 g (82 mmol) of copper(I) iodide are added, a solution of 21.10 g (82 mmol) of methyl 2,6-dimethyl-4-bromophenylacetate in 100 ml of DMF is slowly added dropwise and the mixture is boiled at reflux for 2.5 h.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1.C(NC(C)C)(C)C.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1.Cl>ClCCl>[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:28]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: COC(=O)Cc1cccc(CN)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cccc(CNS(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3-aminomethyl-phenyl)-acetic acid methyl ester hydrochloride (from Preparation 18, 0.56 g) and diisopropylamine (2.2 mL) in 10 mL dichloromethane was added pyridine-3-sulfonyl chloride (from Preparation 2, 0.601 g, 2.83 mmol) and the reaction was stirred at room temperature for 16 h. Aqueous 1N HCl was added and the solution was washed with CH2Cl2. The organic solution was washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound. Purification via flash chromatography on silica gel (2:1 hexanes:EtOAc) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.71 (d, 1H), 8.04 (d, 1H), 7.37 (m, 1H), 7.05-7.24 (m, 4H), 5.87 (bs, 1H), 4.14 (s, 2H), 3.62 (s, 3H), 3.52 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9](=[O:25])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[NH:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)(C)(C)C.[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:33].[ClH:35].[NH2:7][CH:8]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[NH:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc[nH]c23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc[nH]c23)CC1
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-oxo-2-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL) and stirred for 4 hours. The solvent was removed to afford 2-Amino-3-(4-chlorophenyl)-1-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 385.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:16][CH2:15][CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:18][CH2:17][C:5]1=2)=[O:23]
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)c2ccc(F)cc2Cl)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.8 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.41 mmol), 2-chloro 4-fluoro benzoic acid (71.8 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55.22 mg, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated by rotary evaporation to obtain 2.93 mg of 2-chloro-4-fluoro-N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)benzamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 0.5 ml). 1H NMR (DMSO) 10.0 (bs, 1H), 8.6 (t, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.1-7.25 (m, 3H), 7.0 (d, 1H), 4.55-4.60 (m, 1H), 4.15-4.35 (m, 4H), 3.70-3.8 (m, 2H), 3.09-3.2 (m, 3H), 2.95 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCc1ccc2ccccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2ccc3ccccc3n2)n1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (157 mg, 0.83 mmol) and 2-but-3-ynyl-quinoline (150 mg, 0.83 mmol, Example 118(B)). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 127 mg (0.44 mmol, 53%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoline as an orange solid (M.P.=70.2-74.3° C.).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N)(=[S:16])C>C(O)C>[SH:16][CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(C)nc1CBr
Reactant: CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(C)nc1CS
Temperature: 95 °C

Procedure:
5 mmol of ethyl 4-(bromomethyl)-2-methyl-1,3-thiazole-5-carboxylate was dissolved in 50 ml of ethanol, then 5.5 mmol of thioacetoamide was added, and the temperature was heated up to 95° C. to carry out the reaction for 4 hours. The reacted liquid was cooled down to a room temperature. Ethanol was evaporated out and then purification was carried out using column separation method with solvents of ethylacetate and hexane, obtaining ethyl 4-(mercaptomethyl)-2-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[C:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][C:26](=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Reactant: C[Sn](C)(C)c1cncc(CCC(=O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cncc(CCC(=O)O)c2)CC1
Temperature: 90 °C
Yield: 73.3 %

Procedure:
A mixture of 3-trimethylstannyl-5-carboxyethylpyridine (0.298 g, 0.949 mmol) and 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.334 mL, 0.949 mmol) in dry THF (5 mL) was degassed with a stream of Ar bubbles for 10 min. To this solution was added bis(triphenylphosphine)palladium dichloride (0.033 g, 0.047 mmol) and then the reaction vessel was sealed and the mixture was heated at 90° C. (oil bath temperature) for 16 h. The cooled mixture was then evaporated to dryness and the residue chromatographed (SiO2/hexane-EtOAc, 7:3) to give the title compound (0.294 g, 73%) as a clear yellow oil:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30](Cl)=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.FC(F)(F)[C@H](C1C(N2C=CC(C)=N2)=[N:46]C(C)=CC=1)O>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:19][CH2:20]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[C:28]([N:34]3[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]3)=[N:46][C:30]([CH3:29])=[CH:31][CH:32]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: Cc1ccc([C@H](O)C(F)(F)F)c(-n2ccc(C)n2)n1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: Cc1ccc([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c(-n2ccc(C)n2)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (S)-2,2,2-trifluoro-1-(6-methyl-2-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)ethanol (Intermediate 20)
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([NH:7][C@H:8]([C:24]([OH:26])=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:6])[CH3:3].ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:43][N:44]([N:51]=O)C(N[N+]([O-])=O)=N>O1CCCC1>[N+:44](=[CH:43][C:24](=[O:26])[C@@H:8]([NH:7][C:5](=[O:6])[O:4][C:2]([CH3:1])([CH3:27])[CH3:3])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)=[N-:51]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)C=[N+]=[N-]
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-[(1,1-dimethylethoxy)carbonyl]--O-benzyl-L-tyrosine in dry tetrahydrofuran (90 ml) cooled at -20° C. to -25° C. was added isobutyl chloroformate (8.7 ml, 67.3 mmol) followed by 4-methylmorpholine (6.8 ml, 67.3 mmol) and the mixture was stirred for 20 minutes. The precipitate was filtered and washed with dry tetrahydrofuran. The filtrate was cooled to -5° C. and poured into a diazomethane in ether solution (prepared from 1-methyl-3-nitro-1-nitrosoguanidine (29.7 g, 202 mmol) as described in Example 1 (d) at 0° C. The resulting yellow solution was kept at 0° C. for 2.0 hours, then at room temperature overnight. Nitrogen was then bubbled through the solution for 30 minutes, the solution diluted with ethyl ether (500 ml) and then washed with water, saturated sodium bicarbonate, and brine, and dried over magnesium sulfate. Concentration in vacuo afforded a yellow residue which was triturated with hexane (500 ml) to give 24.5 g of (S)-[3-diazo-2-oxo-1-[[4-(phenylmethoxy)phenyl]methyl]propyl]carbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:17]=[CH:18]C(C)=[N+:20]([O-])[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:5]([O:4][CH2:1][C:2]1[CH:18]=[CH:17][C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:21][N:20]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Product: CC(=O)OCc1ccc(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 80 ml. of acetic anhydride stirred at 135°C. is added slowly 39.8 g. (0.185 mol) of the above N-oxide. The solution is stirred at this temperature for 30 minutes and then poured into 500 ml. of ice-water. After stirring the mixture for two hours it is extracted with a mixture of ethyl acetate and ether. The extract is washed with water, dried and evaporated to dryness. The residue is passed through an alumina column with ether as the eluent. Evaporation of the first fraction yields 2-acetoxymethyl-5-benzyloxypyridine as an oil.
Reaction SMILES: [NH2:1][C:2](SC)=[C:3]([N:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:32][C:33]([NH:35][CH2:36]CC)=O)(=[O:31])=[O:30])=[CH:19][CH:18]=1)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[CH3:42]OC>C(O)CO.S(=O)(=O)(O)O>[C:2]([CH:3]([N:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:32]=[CH:33][N:35]([CH3:36])[CH3:42])(=[O:30])=[O:31])=[CH:21][CH:22]=1)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:1]
Reactant: COC
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C(=O)OCC)=C(N)SC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: OCCO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1)C(C#N)C(=O)OCC
Reaction time: 1 h

Procedure:
200 mg of the product of Stage C of Example 3 were dissolved in 5 ml of dimethyl ether of ethylene glycol and 1 ml of concentrated sulfuric acid was added at ambient temperature. After stirring for one hour, water was added while cooling in an ice bath. Extraction was carried out with dichloromethane and the organic phases .were washed and dried. The solvent was evaporated under reduced pressure to obtain 180 mg of crude product which was crystallized from ethyl acetate to obtain 140 mg of the expected product melting at 130°-132° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=2)=[O:14])[CH3:11])=[CH:5][C:4]=1[C:19]([F:20])([F:21])[F:22])#[N:2]
Reactant: Nc1ccc(F)cc1
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Product: C[C@@H](C(=O)Nc1ccc(F)cc1)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)alanine and 4-fluoroaniline: 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.42 (m, 2H), 7.14 (d, J=2.5 Hz, 1H), 7.00-6.91 (m, 3H), 4.47 (q, J=7.0 Hz, 1H), 3.36 (m, 2H), 1.56 (d, J=7.1 Hz, 3H), 1.10 (m, 1H), 0.69 (m, 2H), 0.35 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][NH:6]2.[H-].[Na+].I[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][N:6]2[CH3:16]
Reactant: CI
Reactant: O=Cc1c[nH]c2cccc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a cold solution (0° C.) of 4-bromo-indole-3-carboxaldehyde (0.767 g, 3.4 mmol) in dry DMF (2 mL) was added NaH (60% dispersion in mineral oil, 173 mg, 4.37 mmol). The resulting mixture was stirred at 0° C. for 20 min. Iodomethane (0.8 mL, excess) was added to the reaction mixture in a drop wise fashion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was quenched with water and was extracted repeatedly from EtOAc. The combined organic extracts were washed with water (twice) and brine. After drying over magnesium sulfate, solvent was removed. The resulting solid was taken in hexane and sonicated for 30 min, filtered to provide the product, 4-bromo-1-methyl-indole-3-carboxaldehyde (0.687 g, 85% yield). A mixture of 4-bromo-1-methyl-indole-3-carboxaldehyde (109 mg, 0.45 mmol), phenyl boronic acid (85 mg, 0.69 mmol) in DMF (4 mL) was degassed (argon). To the mixture was added bis(triphenylphosphine)-palladium II chloride (25 mg, 0.035 mmol) followed by addition of 2M Na2CO3 solution (2 mL, 4 mmol) and the mixture was stirred under argon at 100° C. for 18.5 h and then at reflux for 3 h. The mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted repeatedly with ethyl acetate. The combined extract was washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, solvent was removed in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc 1:1). The desired product was isolated as syrup (79% yield). MS: 236, 238.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH:17]1([C:20]2[C:21]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[C:21]([N:30]3[CH2:35][CH2:34][N:33]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:16])=[CH:15][CH:14]=4)=[O:13])[CH2:32][CH2:31]3)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)[CH2:18][CH2:19]1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 81.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (241 mg) described in Preparation Example 16 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (271 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 87, the title compound (401 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1
Reactant: OCc1cccc(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cccc(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.BrCC1C=CC=C([C:28]([F:31])([F:30])[F:29])C=1>>[CH3:14][O:13][C:10]1[C:9]([O:15][CH3:16])=[CH:8][C:7]([S:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([C:28]([F:31])([F:30])[F:29])[CH:3]=2)=[CH:12][N:11]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Product: COc1cc(SCc2cccc(C(F)(F)F)c2)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using 1-(bromomethyl)-3-trifluoromethylbenzene instead of 1-(bromomethyl)-3-chlorobenzene.