Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.Cl>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([CH3:14])[C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:1])[CH3:8]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)CC(=O)c1ccco1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)C(=O)c1ccco1
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a stirred solution of 5.0 g (27.4 mmol) ethyl beta-oxo-2-furanpropionate in 15 ml dry THF under argon at −78° C. was added dropwise 27.4 ml (27.4 mmol, 1M solution in THF) lithium bis(trimethylsilyl)amide and stirring continued for 15 minutes at −78° C. 5.44 ml (87.4 mmol) methyl iodide was then added dropwise and stirring continued for 30 minutes at −78° C., 2.5 hours at 0° C. and 20 hours at room temperature. The reaction mixture was poured into 100 ml 1M hydrochloric acid at 0° C. and the phases separated. The aqueous phase was extracted twice with ether and the combined organic extracts washed with brine, dried over sodium sulfate, and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/3) afforded 4.42 g (82%) (RS)-3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester as a yellow oil. EI-MS m/e (%): 196 (M+, 10), 168 ([M—C2H4]+, 6), 151 ([M—OEt]+, 7), 95 (100).
Reaction SMILES: [BH4-].[Na+].C1COCC1.[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:18])[CH3:17].Cl>CO>[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([OH:18])[CH3:17]
Reactant: CC(=O)c1ccc(Cl)cc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(Cl)cc1Br

Procedure:
Solid NaBH4 (354 mg, 9.4 mmol) was added to a 0° C., THF (5 mL) and MeOH (15 mL) solution of 1-(2-bromo-4-chlorophenyl)ethanone (1.8 g, 7.8 mmol). After 30 min 2N aqueous HCl was slowly added, and the resulting mixture was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [H-].[Na+].C(S)C.Cl[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16](C2C=C(Cl)C=CC=2Cl)[C@H](C)CCCBr)(=[O:15])=[O:14])=[CH:9][CH:8]=1>O1CCCC1>[C:10]1([S:13]([NH2:16])(=[O:15])=[O:14])[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](CCCBr)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCS
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of NaH (0.025 g, 1.03 mmol) in tetrahydrofuran (2 mL) was added ethanethiol (0.096 g, 1.54 mmol), followed by 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide (0.500 g 1.03 mmol) under nitrogen at 0° C. The reaction was stirred overnight at 22° C. The mixture was quenched with H2° (3 mL), extracted with ethyl ether (2×10 mL), dried over Na2SO4, and filtered. The organic solvent was concentrated under reduced pressure. Silica gel chromatography (1:9, ethyl acetate:hexanes) afforded 0.460 g of 4-chloro-N-[2,5-dichlorophenyl}-N-[4-(ethylthio)]-1-(R)-methylbutyl]benzenesulfonamide as a yellow oil in 59% yield. LC/MS 466.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:22]2([CH3:23])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[CH:18]([CH:20]=[O:21])[CH3:19])[C@H:13]2[C@@H:4]([C@:5]3([CH3:25])[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:24])[CH:7]=[CH:6]3)[CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C(Cl)Cl>[C:26]([O:1][C@@H:2]1[C@@:22]2([CH3:23])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[CH:18]([CH:20]=[O:21])[CH3:19])[C@H:13]2[C@@H:4]([C@:5]3([CH3:25])[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:24])[CH:7]=[CH:6]3)[CH2:3]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@H]2[C@@H](CCC3=CC(=O)C=C[C@@]32C)[C@@H]2CC[C@H](C(C)C=O)[C@@]12C
Reaction time: 5 h

Procedure:
12α-Hydroxypregna-1,4-dien-3-one-20-carbaldehyde (34.2 g) was dissolved in 300 ml of methylene chloride. To the solution were added 23.6g of acetyl chloride and 27.7 g of pyridine, and the mixture was stirred atroom temperature for 5 hours. To the reaction mixture was added 300 ml of methylene chloride, the resulting solution was washed in sequence with diluted hydrochloric acid and water, and dried over anhydrous magnesium sulfate. Low-boiling fractions were distilled off from the solution under reduced pressure. There was thus obtained crude 12α-acetoxypregna-1,4-dien-3-one-20-carbaldehyde as a viscous substance. This crude product was dissolved in 300 ml of benzene, 21.3 g of piperidine was added to the solution, and the resulting mixture was refluxed for 3 hours while removing the byproduct water azeotropically with benzene. Low-boiling fractions were distilled off from the thus-obtained reaction mixture. There remained crude 12α-acetoxy-22-(N-peridyl)bisnor-1,4,20(22)-cholatrien-3-one as a viscous substance, which was dissolved in 180 ml of pyridine. To the solution was added gradually at room temperature a mixture of 20.0 g of chromium trioxide and 250 ml of pyridine. After stirring the resulting mixture for one hour, 1 liter of benzene was added to the reaction mixture. The solid matter was filtered off, and diluted hydrochloric acid was added to the filtrate. After effecting benzene extraction to a sufficient extent, the benzene layer was washed in sequence with diluted hydrochloric acid and water. Low-boiling fractions were distilled off under reduced pressure, and the residue was purified by preparative liquidchromatography [column: Waters Associates' Prep LC/System 500, Prep PAK™500/SILICA; solvent system: isopropyl alcohol:n-hexan=20:80, v/v] to give 9.1 g of 12α-acetoxypregna-1,4-diene-3,20-dione as crystals. It has the following physical properties.
Reaction SMILES: [OH-].[Na+].[OH:3][C@H:4]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)=[C:13]([CH3:31])[CH:12]=1)[CH3:6].O.Cl>O1CCOCC1>[OH:3][C@H:4]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[C:13]([CH3:31])[CH:12]=1)[CH3:6]
Reactant: CCOC(=O)COc1ccc(-c2c(C)cc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OCCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc(C)c1-c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A 1 mol/L aqueous solution of sodium hydroxide (0.81 mL) was added to a mixture of ethyl (4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino]ethoxy}-2′,6′-dimethyl biphenyl-4-yloxy)acetate (0.16 g), water (1 mL) and 1,4-dioxane (2 mL), and the mixture was stirred at room temperature overnight. 1 mol/L hydrochloric acid (0.81 mL) was added to the reaction mixture, and the organic solvent was evaporated under reduced pressure. The precipitate was collected by filtration to afford the title compound (0.12 g) as a pale yellow amorphous. The structure and physical data were shown in table 1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11](Br)[C:12]([O:14]C)=[O:13])=[C:6]([CH3:17])[CH:5]=1)(=[O:3])[CH3:2].C[O-].[Na+].Cl.O>CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[C:6]([CH3:17])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(Br)Cc1ccc(C(C)=O)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(C=CC(=O)O)c(C)c1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 34.5 %

Procedure:
The obtained methyl 3-(4-acetyl-2-methylphenyl)-2-bromopropionate (2.79 g, 9.33 mmol) was dissolved in methanol (80 mL). The solution was cooled to 5° C. Sodium methoxide (1.51 g, 27.98 mmol) was added to the solution. The mixture was stirred at room temperature for 20 minutes, refluxed for 1 hour, cooled to room temperature, and acidized with 1N hydrochloric acid. Water (50 mL) was added to the mixture. The mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 657 mg of the desired compound as yellow crystalline product (yield 34%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:23]([CH3:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]=1[CH3:25].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][C:13]2[C:14]([CH3:25])=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][C:23]=2[CH3:24])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: CCOC(=O)c1cc(C)c(N)c(C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (0.78 g, 4.55 mmol) in CH2Cl2 (15 mL) at room temperature are added ethyl 4-amino-3,5-dimethyl-benzoate (0.878 g, 4.55 mmol) and N,N-diisopropylethylamine (1.98 ml, 11.36 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 3.25 ml, 5.46 mmol) is added via syringe. After 48 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes. After purification, the solid is triturated with 30% ethyl acetate in hexanes and filtered to give the title compound as a white powder (0.907 g, 57.5%). Mass spectrum (m/z): 347.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]=2[O:5][C:4](=O)[CH:3]=1.[NH3:16]>>[CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]=2[NH:16][C:4](=[O:5])[CH:3]=1
Reactant: Cc1cc(=O)oc2c1C(=O)CC(C)(C)C2
Reactant: N
Product: Cc1cc(=O)[nH]c2c1C(=O)CC(C)(C)C2

Procedure:
Prepared from 4,7,7-trimethyl-5,6,7,8-tetrahydro- cumarin-5-one and methanolic ammonia analogously to Example C(b).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].Br[CH:16]1[C:21](=O)[CH2:20][CH2:19][N:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17]1>CC(O)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[S:8][C:16]3[CH2:17][N:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:20][C:21]=3[N:9]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)N1CCC(=O)C(Br)C1
Reactant: NC(=S)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Product: CCOC(=O)N1CCc2nc(-c3ccncc3)sc2C1
Temperature: 25 °C
Yield: 20 %

Procedure:
Thioisonicotinamide (18 mmol) and calcium carbonate (200 mmol) were added to a solution of ethyl 3-bromo-4-oxopiperidine-1-carboxylate (5 g; 20 mmol) in 2-propanol (60 ml). The reaction mixture obtained was heated under reflux for 48 hours. The course of the reaction was monitored by thin layer chromatography. The reaction mixture was then cooled to 25° C. and filtered over Celite and the filter cake was washed several times with ethyl acetate. The organic phase was concentrated under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed successively with water and saturated sodium chloride solution. After the organic phase had been dried over sodium sulfate, the solvent was removed under reduced pressure. The crude product obtained was purified by column chromatography (30% ethyl acetate in hexane). The desired product was obtained in a yield of 20%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8]S(C)(=O)=O.[I:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1
Reactant: Oc1ccc(I)cc1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(I)cc2)c(Cl)c1

Procedure:
2 g of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester, 1.14 g of 4-iodophenol and 1.96 g of potassium carbonate are stirred for 24 hours at 50° C. in 20 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. The organic phase is washed with water and potassium carbonate solution and concentrated. Purification over silica gel yields 1,3-dichloro-5-(3,3-dichloro-allyloxy)-2-[3-(4-iodo-phenoxy)-propoxy]-benzene. 1H-NMR (CDCl3) 300 MHz: 2.28 (m, 2H), 4.13 (t, 2H), 4.22 (t, 2H), 4.58 (d, 2H), 6.10 (t, 1H), 6.71 (d, 2H), 6.81 (s, 2H), 7.55 (d, 2H)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCOCC1>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)=[CH:27][CH:28]=1
Reactant: Nc1ccc(COC2CCCCO2)cc1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=S)c1cnc(C)nc1Nc1ccc(COC2CCCCO2)cc1
Yield: 94.4 %

Procedure:
A solution of 4.25 g (18.26 mmol) of ethyl 4-chloro-2-methylthio-pyrimidine-5-carboxylate, 4.73 g (22.85 mmol) of 4-(tetrahydropyran-2-yloxymethyl)aniline and 6.4 ml (45.7 mmol) of triethylamine in sieve-dried 1,4-dioxan was heated at 60° C. for 4 hours. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (MgSO4) and evaporated to give a brown oil which was purified by flash chromatography on silica gel using1:4 ethyl acetate/hexane as eluent. Product containing fractions were combined and evaporated to give 6.68 g (90%) of ethyl 4-[4-(tetrahydropyran-2-yloxymethyl)phenyl]amino-2-methylthiopyrimidine-5-carboxylate as a yellow oil. [Mass spectrum (ESI) MH+ =404].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:8]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[CH2:9][C:10]([C:13]([F:16])([F:15])[F:14])(O)[N:11]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:8]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:11]=2)=[CH:4][CH:3]=1
Reactant: OC1(C(F)(F)F)CN(c2cc(Cl)ccc2Cl)C(c2ccc(Br)s2)=N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cn(-c2cc(Cl)ccc2Cl)c(-c2ccc(Br)s2)n1
Temperature: 120 °C
Yield: 64.3 %

Procedure:
The mixture of 2-(5-bromo-thiophen-2-yl)-1-(2,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazol-4-ol (822 mg, 1.8 mmol) and p-toluenesulfonic acid monohydrate (172 mg, 0.9 mmol) in 10 mL toluene was heated at 120° C. for 6 hrs. The solvent was removed, and the residue was redissolved into dichloromethane, then washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (hexane/EtOAc 85/15) to give an off-white solid (512 mg, 64% yield). 1H-NMR (400 MHz, CDCl3): δ 6.68 (d, 1H), 6.89 (d, 1H), 7.31 (dd, 1H), 7.47 (dd, 1H), 7.55 (d, 1H), 7.56 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(O)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.O=S(Cl)[Cl:25]>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1)[Cl:25]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C2(Cl)OC(=O)c3c(Cl)cccc32)n1

Procedure:
A mixture of 0.7 g of 7-chloro-3-hydroxy-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide, 30 ml of CCl4, 2 ml of SOCl2 and 4 drops of DMF are refluxed at 60° for 11/2 hrs. The mixture is then cooled, excess SOCl2 and CCl4 removed on a rotovaporator. The residue is diluted with 20 ml of CH2Cl2 and added to a stirred mixture of 10 ml of methanol and 2 ml of diethylamine. After 21/2 hrs the mixture is stripped on a rotovaporator to remove excess CH2Cl2 and methanol and the residue partitioned between CH2Cl2 (50 ml) and water (50 ml). The organic phase is separated, concentrated and the gummy residue flash chromatographed over silica gel using 80/20 hexane/ethyl acetate (500 ml), 60/40 hexane/ethyl acetate (500 ml) (28 fractions×50 ml). Fractions 18 to 20 yielded title compound a) and fractions 11 to 16 the compound b).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[NH:11][C:12](=[O:35])[C@@H:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:14]C(=O)C(O)C1CCCN1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:40].O1CCOCC1>ClCCl>[ClH:40].[CH2:1]([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[NH:11][C:12](=[O:35])[C@H:13]([CH2:31][CH:32]([CH3:33])[CH3:34])[NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](NC(=O)C(O)C1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
[2-Hydroxy-2-(N-t-butyloxycarbonylpyrrolidin-2-yl)acetyl]-D-leucylvaline benzyl ester (200 mg) was added to dry dichloromethane (1 ml) and 4N hydrochloric acid/dioxane (1 ml) was added to the solution under cooling with ice to conduct a reaction at room temperature for 1.5 h. The reaction liquid was concentrated under reduced pressure and the residue was washed with n-hexane and dried to give 2-hydroxy-2-(pyrrolidin-2-yl)acetyl]-D-leucylvaline benzyl ester hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2([OH:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[CH:5][N:4]=1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2([OH:18])[CH2:16][CH2:15][CH:14]([N:19]3[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=4)=[O:25])[CH2:20]3)[CH2:13][CH2:12]2)=[CH:5][N:4]=1
Reactant: COc1ncc(C2(O)CCC(=O)CC2)c(OC)n1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c(OC)n1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(2,4-dimethoxy-pyrimidin-5-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17](=[S:19])[NH2:18])=[C:4]2[CH2:3]1.[Cl:20][CH2:21][C:22](=O)[CH2:23]Cl>O1CCOCC1>[Cl:20][CH2:21][C:22]1[N:18]=[C:17]([C:16]2[N:15]=[CH:14][N:5]3[C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=4[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=23)[S:19][CH:23]=1
Reactant: O=C(CCl)CCl
Reactant: CN1Cc2c(C(N)=S)ncn2-c2ccccc2C1=O
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccccc2C1=O
Yield: 49.6 %

Procedure:
A yellow suspension of 8.60 g (0.0316 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide in 200 ml of dioxan was treated with 4.41 g (0.0347 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 3 hrs., cooled and filtered. The solution was boiled at reflux for a further 16 hrs., cooled and suction filtered. The product was recrystallized from hot acetonitrile. There were obtained 5.4 g (65%) of 3-(4-chloromethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals. An analytical sample could be obtained from the mother liquor after chromatography (silica gel, cyclohexane/ethyl acetate 1:1) and recrystallization (acetonitrile); m.p. 248-249°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([O:16][C:17]2[CH:25]=[CH:24][C:23]3[NH:22][C:21]([CH3:26])=[CH:20][C:19]=3[C:18]=2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:9]=1.[OH-].[Na+].CN(C)[CH:41]=[O:42]>>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([O:7][CH3:6])[N:9]=[C:10]([O:16][C:17]2[CH:25]=[CH:24][C:23]3[NH:22][C:21]([CH3:26])=[C:20]([CH:41]=[O:42])[C:19]=3[C:18]=2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:11]=1
Reactant: COc1cc(OC)nc(Oc2ccc3[nH]c(C)cc3c2C(=O)OCc2ccccc2)n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)nc(Oc2ccc3[nH]c(C)c(C=O)c3c2C(=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
0.46 ml of phosphorus oxychloride was dropwise added to 1.8 ml of N,N-dimethylformamide under cooling with ice, and the mixture was stirred for 30 minutes. Then, 2.3 g of benzyl 5-[(4,6-dimethoxypyrimidin-2-yl)oxy]-2-methylindol-4-carboxylate was dissolved in 10 ml of N,N-dimethylformamide, and the solution was dropwise added to the above mixture under cooling with ice. The mixture was stirred for 30 minutes, and then poured into ice water. An aqueous sodium hydroxide solution was added thereto for adjustment to pH9, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure, was crystallized from isopropyl ether to obtain 2 g (yield: 81.5%) of the desired compound. mp: 148°-149° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([O:20][CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.Cl.[NH2:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]([F:31])([F:32])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([O:20][CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:27])=[CH:24][CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(COc2cc(-c3ccc(OC(F)(F)F)cc3)cc3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(COc2cc(-c3ccc(OC(F)(F)F)cc3)cc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a DMF solution (2 mL) of the intermediate from Step D (35 mg, 0.08 mmol) was added tert-butyl β-alaninate hydrochloride (30 mg, 0.16 mmol) DIEA (0.06 mL, 0.35 mmol) and BOP (53 mg, 0.12 mmol). The solution was stirred at room temperature for ca. 30 minutes. The solution was then partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with aqueous 1N HCl (3×), brine; dried over MgSO4 and filtered to give tert-butyl N-{4-[({3-[4-(trifluoromethoxy)phenyl]-1-naphthyl}oxy)methyl]benzoyl}-β-alaninate. LCMS1 4.50 min. (M+H)=566. The tert butyl group was removed by treatment with 1/1 DCM/TFA for 1 hour. The crude acid was purified by reverse phase HPLC to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.57 (s, 1H); 8.31 (d, J=8.1 Hz, 1H); 7.92 (m, 1H); 7.89 (d, J=8.3 Hz, 2H); 7.82 (d, J=8.7 Hz, 2H); 7.70 (m, 3H); 7.56-7.49 (m, 2H); 7.39 (d, J=8.1 Hz, 2H); 7.24 (s, 1H); 5.46 (s, 2H); 3.69-3.65 (m, 2H); 2.68-2.66 (m, 2H). LCMS1 3.97 min. (M+H)=510