Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)CC)C.[CH2:8]([O:15][CH2:16][C:17](Cl)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][CH2:16][C:17]([NH2:3])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Product: NC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Starting with the 3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenyl]-5-hydroxymethyl-oxazolidin-2-one which was formed as an intermediate in Example 3, the procedure of Example 1 was repeated to produce an azide compound in a yield of 90%. The azide compound (1.5 g) was reduced with triphenylphosphine/tetrahydrofuran/water by the same method as in Example 10 to provide a primary amine compound. The amine compound and triethylamine (1.2 ml) were added to dry dichloromethane (20 ml) and benzyloxyacetyl chloride (1.20 g) was subsequently added at 0° C. The reaction mixture was stirred overnight at room temperature and the resulting precipitate was filtered off. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (methanol/dichloromethane=5/95) to afford a benzyloxyacetamide compound (2.7 g) in a yield of 100%. The benzyloxyacetamide compound (1.9 g) was dissolved in a mixed solvent consisting of methanol (30 ml) and dichloromethane (5 ml). To the solution, 10% palladium hydroxide/carbon (340 mg) was added and the mixture was stirred for 2 days under 3 atm hydrogen atmosphere. The palladium hydroxide was filtered off and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol/dichloromethane=7/93) to afford an α-hydroxyacetamide compound (780 mg) in a yield of 49%. To a tetrahydrofuran solution (10 ml) of the α-hydroxyacetamide compound (530 mg), p-toluenesulfonyl fluoride (450 mg) and tetrabutylammonium fluoride (1.0M tetrahydrofuran solution; 3.3 ml) were added and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/acetone=2/3) to afford a monofluoroacetamide compound (562 mg) in a yield of 100%. To 10 ml of an acetone solution of the monofluoroacetamide compound, p-toluenesulfonic acid monohydrate (580 mg) and water (3 ml) were added and the mixture was heated under reflux for 2.5 h. The reaction mixture was cooled to room temperature, neutralized with solid sodium hydrogencarbonate, and concentrated under vacuum. Water was removed by azeotropy with toluene and the residue was purified by silica gel column chromatography (hexane/acetone=1/1) to afford the title compound (408 mg) in a yield of 81%.
Reaction SMILES: [H][H].C([O:10][C:11]1[C:12]([O:30]CC2C=CC=CC=2)=[CH:13][C:14]2[C:15](=[N:22][O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:16]3[CH2:21][CH:17]3[O:18][C:19]=2[CH:20]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:10][C:11]1[C:12]([OH:30])=[CH:13][C:14]2[C:15](=[N:22][O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:16]3[CH2:21][CH:17]3[O:18][C:19]=2[CH:20]=1
Reactant: [H][H]
Reactant: CN(C)CCCON=C1c2cc(OCc3ccccc3)c(OCc3ccccc3)cc2OC2CC12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)CCCON=C1c2cc(O)c(O)cc2OC2CC12
Yield: 45.1 %

Procedure:
In 20 ml of ethyl acetate was suspended 48 mg of 10% palladium-on-carbon. After displacing the atmosphere with hydrogen by suction, 240 mg of the compound obtained in Example 11 was added to the suspension, and the mixture was stirred at room temperature for 5 hours in a hydrogen stream (atmospheric pressure). The reaction mixture was worked-up in the same manner as in Example 2 to obtain 67.0 mg (41.5%) of the titled compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[NH:6][C:5]2=[O:13].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:23].[K+]>O.O1CCCC1.C(OCC)(=O)C>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[I:23])[C:5](=[O:13])[NH:6][C:7]2=[O:12]
Reactant: Nc1cc2c(cc1Cl)C(=O)NC2=O
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)c2cc(I)c(Cl)cc21
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of 96.1 mmol 5-amino-6-chloroisoindoline-1,3-dione (commercial, CAS: 5566-48-3) in 170 ml water was added dropwise at 10° C. a solution of 11 ml concentrated sulfuric acid in 50 ml water. After cooling the mixture to 5° C., a solution of 120 mmol sodium nitrite in 40 ml water was added dropwise and stirring continued at 0° C. for 90 min. A solution of 327 mmol potassium iodide in 80 ml water was then added dropwise over 40 min while maintaining the reaction temperature between 0 and 5° C. The reaction mixture was then warmed to room temperature and subsequently heated at 35° C. for 45 min and then 60° C. for 30 min before being recooled to room temperature and diluted with tetrahydrofuran/ethyl acetate (1/2). The phases were separated and the organic phase washed sequentially with aqueous sodium thiosulphite and brine and then dried over sodium sulfate and concentrated in vacuo. The residue was resuspended in 300 ml dichloromethane, stirred for 10 min at room temperature, and the resulting crystals collected by filtration to yield the title compound as a light brown solid. MS (m/e): 308.9 ({37Cl}M+, 35%), 306.9 ({35Cl}M+, 100%).
Reaction SMILES: COC[C@@H]1[C@H](/C=C/C(/C)=C/C(O)=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1.[CH2:30]([O:32][CH2:33][C@H:34]1[C@H:36](/[CH:37]=[CH:38]/[C:39](/[CH3:46])=[CH:40]/[C:41]([O:43]CC)=[O:42])[C@@:35]1([CH3:61])[C:47]1[CH:56]=[CH:55][C:54]2[C:53]([CH3:58])([CH3:57])[CH2:52][CH2:51][C:50]([CH3:60])([CH3:59])[C:49]=2[CH:48]=1)[CH3:31]>>[CH2:30]([O:32][CH2:33][C@H:34]1[C@H:36](/[CH:37]=[CH:38]/[C:39](/[CH3:46])=[CH:40]/[C:41]([OH:43])=[O:42])[C@@:35]1([CH3:61])[C:47]1[CH:56]=[CH:55][C:54]2[C:53]([CH3:58])([CH3:57])[CH2:52][CH2:51][C:50]([CH3:60])([CH3:59])[C:49]=2[CH:48]=1)[CH3:31]
Reactant: CCOC[C@H]1[C@H](/C=C/C(C)=C/C(=O)OCC)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 87 %

Procedure:
Following a procedure similar to that for the preparation of Compound 20a but using Compound 18b as the starting material afforded the title compound (31 mg, 87% yield) as a white solid:
Reaction SMILES: [CH3:1][C@@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[C@H]1[C@H](O)C[C@H]2C(C)(C)[C@@H]1C2.C[C@@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@H]4CC[C@H]3[C@@H]2CC1)CCCC(C)C.C[C@@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@@H]4CC[C@H]3[C@@H]2CC1)CCCC(C)C>>[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@@H](C)O
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C[C@H]1[C@H](O)C[C@@H]2C[C@H]1C2(C)C
Product: CCCCCC[C@H](C)O

Procedure:
(R)-2-octanol (6a), Example 13: (1S, 2S, 3S, 5R)-(−)-isopinocampheol (7a), Example 14: (IR, 2R, 3R, 5S)-(−)-isopinocampheol (8a), Example 15: β-cholestanol (9a) and Example 16: (α-cholestanol (10a).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].CS([C:12]1[N:13]=[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[N:17]=1)(=O)=O.O>CN(C=O)C>[O:22]=[C:19]1[N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[N:17]=[C:12]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:13]=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:15]=2[CH:21]=[CH:20]1
Reactant: CS(N)(=O)=O
Reactant: CS(=O)(=O)c1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of methylsulfonamide (200 mg, 2 mmol, 4 eq) in DMF (2 mL) was added NaH (80 mg, 2 mmol, 60% dispersion in mineral oil, 4 eq) and the reaction mixture was stirred for 30 min at 23°. To this solution was added a solution of 2-methanesulfonyl-4,8-diphenyl-8H -pyrido[2,3-d]pyrimidin-7-one (190 mg, 0.5 mmol) in DMF (1 mL) and the mixture was heated to 50°. After 1 h, H2O (10 mL) was added and then Et2O (10 mL), the layers were separated, and the organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and the solvent was evaporated. The yellow residue was then purified by Flash chromatography to afford N-(7-oxo-4,8-diphenyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-methanesulfonamide (101 mg, 51% yield). 1H-NMR (CDCl3) δ 2.82 (s, 3H), 6.69 (d, 1H, J=9.8 Hz), 7.31 (m, 2H), 7.59 (m, 8H), 7.91 (d, 1H, J=9.8 Hz), LC MS (m/e)=393 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1[C:31]([CH:36]=O)=[N:32][CH:33]=[CH:34][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:36][C:31]2[C:30]([CH3:29])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NCc2ncccc2-c2ccccc2)CC1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1-c1ccccc1)C1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B: Reaction of the above amine and 3-methyl-2-pyridinecarboxaldehyde in CH2Cl2 with NaBH(OAc)3 gave {4-[(3-methyl-pyridine-2-ylmethyl)-(3-phenyl-pyridin-2-ylmethyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 0.86 (q, 2H, J=10.8 Hz), 1.14 (q, 2H, J=11. Hz), 1.41 (s, 9H), 1.58 (d, 2H, J=11.7 Hz), 1.85 (s, 2H), 1.91 (s, 3H), 2.11 (s, 1H), 2.21 (s, 1H), 3.19 (br s, 1H), 3.80 (s, 2H), 3.84 (s, 2H), 4.23 (br s, 1H), 7.00 (dd, 1H, J=7.4, 5.1 Hz), 7.21-7.30 (m, 7H), 7.49 (dd, 1H, 7.8, 1.5 Hz), 8.25 (d, 1H, J=3.9 Hz), 8.53 (dd, 1H, J=4.8, 1.8 Hz). Conversion to the HBr salt using General Procedure D gave COMPOUND 259 as a pale yellow solid. 1H NMR (D2O) δ 1.29-1.48 (m, 4H), 1.90 (d, 2H, J=10.2 Hz), 2.02 (d, 2H, J=9.6 Hz), 2.37 (s, 3H), 2.66 (br t, 1H, J=8.1 Hz), 3.09 (br s, 1H), 4.12 (s, 2H), 4.35 (s, 2H), 7.42 (d, 2H, J=4.5 Hz), 7.59 (s, 3H), 7.81 (t, 1H, J=6.6 Hz), 8.01 (t, 1H, J=6.3 Hz), 8.28 (d, 1H, J=7.8 Hz), 8.45 (d, 1H, J=7.8 Hz), 8.51 (d, 1H, J=5.7 Hz), 8.77 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 14.56, 17.18, 25.80, 29.46, 49.67, 50.80, 51.86, 60.40, 126.08, 126.54, 129.68, 130.35, 133.97, 137.79, 138.70, 140.93, 141.18, 148.35, 148.41, 150.54, 151.18. ES-MS m/z 387 [M+H]+. Anal. Calcd. for C25H30N4.3.3HBr.2.2CH3OH: C, 45.12; H, 5.86; N, 7.74; Br, 36.42. Found: C, 45.22; H, 5.69; N, 7.97; Br, 36.19.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]([F:32])([O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[CH:21]([F:23])[F:22].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([O:24][C:20]([F:19])([F:32])[CH:21]([F:22])[F:23])[CH:26]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC(F)(F)C(F)F)c1
Yield: 72.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 300 mg of 3-(1,1,2,2-tetrafluoroethoxy)aniline, and 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 300 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydro pyrimidin-2-yl]-N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:43]([OH:45])=[O:44])[CH2:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]4([C:43]([OH:45])=[O:44])[CH2:42][CH2:41][CH2:40][O:39][CH2:38]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: C=CC1(C(=O)O)CCCOC1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)CCCOC4)cc3n2)N1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (600 mg, 1.122 mmol), 3-vinyl-tetrahydro-pyran-3-carboxylic acid (175.3 mg, 1.122 mmol), tri(o-tolyl)phosphine (68.3 mg, 0.224 mmol) and triethylamine (0.47 mL, 3.366 mmol) in 1,4-dioxane (15 mL) was degassed by bubbling nitrogen through for 5 minutes then warmed to 50° C. and treated with tris(dibenzylideneacetone)dipalladium(0) (102.7 mg, 0.112 mmol). After stirring at 100° C. for 45 minutes the reaction was cooled to room temperature, filtered through a pad of Celite, which was rinsed with ethyl acetate. The volatiles were removed in vacuo to provide crude title compound as an orange foam that was used without further purification. LCMS (m/z) 610.2 [M+H], Tr=1.97 min.
Reaction SMILES: [CH:1]1([S:4][C:5]([F:18])([F:17])[C:6]2([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])[CH2:8][O:7]2)[CH2:3][CH2:2]1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:1]1([S:4][C:5]([F:18])([F:17])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])([OH:7])[CH2:8][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(C2(C(F)(F)SC3CC3)CO2)c(F)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
To a solution of 2-[(cyclopropylthio) (difluoro)-methyl]-2-(2,4-difluorophenyl)oxirane (5.0 g, 0.017 mol) in DMSO (70 ml), 1,2,4-triazole (3.48 g, 0.05 mol) and potassium carbonate (6.95 g, 0.05 mol) were added, followed by stirring at 55° C. for 1.5 hours. After the completion of the reaction, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether—ethyl acetate, whereby 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (2.35 g, yield: 32%) was obtained as colorless crystals.
Reaction SMILES: O1CCCC1.[CH2:6]([C:13]1[S:14][CH:15]=[C:16](Br)[N:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:19]([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[CH2:20][C:21]#[CH:22]>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.[Cu](I)I.C(N(CC)CC)C>[CH2:6]([C:13]1[S:14][CH:15]=[C:16]([C:22]#[C:21][CH2:20][CH2:19][N:23]2[C:27](=[O:28])[C:26]3[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]2=[O:33])[N:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1csc(Cc2ccccc2)n1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1csc(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
Under a nitrogen atmosphere, 9 ml of tetrahydrofuran, 1.02 g of the 2-benzyl-4-bromothiazole obtained in the above described stage, and 2.3 ml of triethylamine were added to 143 mg of dichlorobis(triphenylphosphine)palladium, 38 mg of copper iodide, and 0.80 g of N-(3-butynyl)phthalimide. The obtained mixture was stirred under reflux for 4 hours. After completion of the stirring, the reaction solution was cooled to a room temperature, and a solid was then filtrated. The filtrate was concentrated, and the residue was then purified by column chromatography (Wako Gel C-200; toluene:ethyl acetate=9:1), so as to obtain 1.00 g of a phthalimide compound.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:6]=[C:5]([C:13]([O:15]C)=[O:14])[CH:4]=[CH:3]1.[OH-].[Li+].[CH3:19]O>O>[CH3:19][C:6]1[N:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[C:2](=[O:1])[CH:3]=[CH:4][C:5]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccc(=O)n(-c2nccs2)c1
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)ccc(=O)n1-c1nccs1
Temperature: 75 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
After 680 mg (2.88 mmol) of methyl 6-oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylate was dissolved in 12 mL of methanol and 4 mL of water, 207 mg (8.64 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 75° C. for 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, and aqueous HCl was then added to the reaction solution to titrate until pH 2 was reached. The resulting solid compound was filtrated to obtain a target compound (Actual yield: 466 mg, Percent yield: 73%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:13][CH:14]=2.Br[CH2:26][C:27]([N:29]([CH2:36][CH3:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>C(Cl)(Cl)Cl.O>[CH2:36]([N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27](=[O:28])[CH2:26][N:16]1[C:15]2[C:10](=[N:11][C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:13][CH:14]=2)[N:9]([CH3:8])[C:17]1=[O:18])[CH3:37]
Reactant: CCN(C(=O)CBr)c1ccccc1
Reactant: Cn1c(=O)[nH]c2cnc(-c3ccccc3)nc21
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)ncc21)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
to a mixture of about 60% sodium hydride (oily) (1.4 g) and dimethylformamide (70 ml) is added 7,9-dihydro-9-methyl-2-pheny-8H-purin-8-one (7.0 g) in portions at 0-5° C., and the mixture is stirred at 0° C. for one hour. To the mixture is added dropwise 2-bromo-N-ethyl-N-phenylacetamide (8.3 g) at the same temperature. After the addition, the mixture is stirred at room temperature for three hours. To the reaction mixture are added water and chloroform. The chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform) and recrystallized from ethanol to give the desired compound (10.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:33][C:34]1[C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:12]1)=[O:40]
Reactant: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(C)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 68 (175 mg, 0.40 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (110 mg, 0.48 mmol) using Method D to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-:21].[Na+]>Cl>[O:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:10]2[N:11]=[CH:12][N:13]=[C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:21])[CH:7]=3)[CH:9]=2)[CH2:16][CH2:17]1
Reactant: Fc1cc(-c2cc(NC3CCOCC3)ncn2)ccn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=c1cc(-c2cc(NC3CCOCC3)ncn2)cc[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
6-(2-Fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (2.50 g, 9.11 mmol) was dissolved in 1M HCl (50 mL) and heated to 90° C. The mixture was agitated overnight, cooled and neutralized with 1M NaOH (50 mL). The resulting slurry was cooled to 5° C., and the solids were filtered off, washed with ice cold water and dried in vacuo to give 4-(6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (2.46 g, 9.03 mmol, 99.1% yield) as a solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16](=[O:18])[CH3:17].C(OCC)(=O)C>CN(C)C=O>[O:18]=[C:16]([CH3:17])[CH2:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 25.0 g of diethyl malonate in 5 ml of dimethylformamide was added dropwise under ice-cooling over 20 minutes to a suspension of 6.55 g of sodium hydride in 90 ml of dimethylformamide. The reaction fluid was stirred for an hour under ice-cooling, to which a solution of 17.3 g of chloroacetone in 5 ml of dimethylformamide was added, and the mixture was stirred for an hour under ice-cooling and for 6 hours at room temperature. Ethyl acetate was added to the reaction fluid and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate. An oily matter obtained by concentrating the organic layer under a reduced pressure was distilled under vacuum to obtain 14.8 g of diethyl 2-oxopropylmalonate as a yellow oily matter.
Reaction SMILES: [ClH:1].[C:2]([NH:10][CH2:11][C:12]([OH:14])=O)(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C(Cl)Cl>[ClH:16].[C:2]([NH:10][CH2:11][C:12]([Cl:1])=[O:14])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N=C(NCC(=O)O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N=C(NCC(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To benzimidoylaminoacetic acid hydrochloride (2.2 g., 10 m moles) in 40 ml. of dry methylene chloride is added 2.5 g. (12 m moles) of phosphorous pentachloride, and the reaction mixture allowed to stir overnight at room temperature. The product is filtered, washed successively with methylene chloride (50 ml.), chloroform 2× 75 ml.) and hexane (50 ml.) and dried in vacuo, 2.5 g. (99% yield).