Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(=O)[CH2:2][SH:3].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18](Br)[C:15]=1C=O.Cl>CS(C)=O>[Br:13][C:14]1[C:15]2[CH:18]=[CH:19][S:3][C:2]=2[CH:1]=[C:20]([CH3:22])[CH:21]=1
Reactant: Cc1cc(Br)c(C=O)c(Br)c1
Reactant: COC(=O)CS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Br)c2ccsc2c1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
Methyl thioglycolate (0.060 ml) and potassium carbonate (190 mg) were added to a solution of 2,6-dibromo-4-methylbenzaldehyde (153 mg) in dimethylsulfoxide (1.7 mL), and the reaction solution was stirred at 120° C. for 7 hours. The reaction solution was neutralized with 2 M hydrochloric acid, extracted with ethyl acetate, and washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. A 5 M aqueous sodium hydroxide solution (0.8 ml) was added to a solution of the resultant residue in a mixture of THF-methanol (1:1) (3.2 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, and washed successively with 2 M hydrochloric acid and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. Silver carbonate (30 mg) and acetic acid (0.005 ml) were added to a solution of the resultant residue in dimethylsulfoxide (1.1 mL), and the reaction solution was stirred at 120° C. for 6 hours. The reaction solution was diluted with ethyl acetate, and washed successively with an aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 4-bromo-6-methylbenzo[b]thiophene.
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:24])(=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1.[N+:25]([O-])([OH:27])=[O:26]>O>[N+:25]([C:21]1[CH:20]=[CH:19][C:17]2[C:18]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[S:15](=[O:24])(=[O:23])[C:16]=2[CH:22]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: O=S1(=O)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Temperature: 4 °C

Procedure:
To a mixture of acetic acid (77 ml) and sulphuric acid (77 ml) was added dibenzothiophene-5,5-dioxide (35.0 g), and the mixture cooled to 4° C. Addition of a total of 197 g. (131 ml) fuming nitric acid was begun, but in a short time the resulting paste became too thick to stir efficiently, and a further 77 ml. acetic acid was added. Local heating due to inefficient stirring was observed to occur, but the temperature of the reaction mixture was maintained at 4° C. as far as was possible. When the addition was complete (ca. 20 min.), the mixture was stirred at 4° C. for a further 30 min., and then poured into water. The crude nitrocompound was filtered off and recrystallised from dimethylformamide, m.p. 259° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:7]1([CH2:23][O:24][CH3:25])[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1)=[O:5])[CH3:2].[OH-].[NH4+].[H][H]>[Pd].CO>[CH3:25][O:24][CH2:23][C:7]1([N:6]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:4](=[O:5])[O:3][CH2:1][CH3:2])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)N(c1ccccc1)C1(COC)CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N(c1ccccc1)C1(COC)CCNCC1
Yield: 81.4 %

Procedure:
A solution of 14.2 parts of (phenylmethyl) 4-[(ethoxycarbonyl)phenylamino]-4-(methoxymethyl)-1-piperidinecarboxylate and 1.8 parts of ammonium hydroxide in 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 75 parts of trichloromethane. The solution is washed twice with water, dried, filtered and evaporated, yielding 7.9 parts (81.4%) of ethyl [4-(methoxymethyl)-4-piperidinyl]phenylcarbamate as a residue.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(O)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-Hydroxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: COC.C1(O)C=CC=CC=1.[ClH:11].Cl.[CH3:13][N:14]([CH2:16][CH:17]1[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30]C)[CH:25]=2)([OH:23])[CH2:21][CH2:20][N:19]([C:32]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:18]1)[CH3:15].[H-].C([Al+]CCCC)CCC>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C>[ClH:11].[ClH:11].[CH3:15][N:14]([CH2:16][CH:17]1[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)([OH:23])[CH2:21][CH2:20][N:19]([C:32]2([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:18]1)[CH3:13]
Reactant: COc1cccc(C2(O)CCN(C3(c4ccccc4)CCCCC3)CC2CN(C)C)c1
Agent: CCCC[Al+]CCCC
Agent: COC
Agent: Cl
Solvent: CCO
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)CC1CN(C2(c3ccccc3)CCCCC2)CCC1(O)c1cccc(O)c1
Reaction time: 12 h

Procedure:
The synthesis instructions are described analogously to Example 6, except for the last step. The methyl ether was then cleaved into the phenol. To that end, 0.5 g (1.2 mmol.) of the free base of compound (6) was dissolved in 5 ml of toluene, and 10 ml of dibutylaluminium hydride solution (1.5 M in toluene) were added at 0° C. and under a nitrogen atmosphere. After 12 hours' stirring, the batch was hydrolysed with 5 ml of ethyl acetate and 5 ml of ethanol, the solvent was removed in vacuo, the residue was dissolved in methyl ethyl ketone, and 1.0 ml of trimethylsilyl chloride was added thereto. The yield of (11) was 71 mg (0.15 mmol., 12%). The compound melted between 245 and 248° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].B([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]([C:6]1[CH:9]=[C:2]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[CH:3]=[N:4][CH:5]=1)#[N:8]
Reactant: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
Reactant: N#Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
5-bromonicotinonitrile (8.8 g, 48.08 mmol), 2-(4-boronophenyl)-2-methylpropanoic acid (example 21b) (11.50 g, 52.89 mmol) and K2CO3 (13.3 g, 96.16 mmol were dissolved in a mixture of DME (120 mL) and water (30 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (2.7 g, 2.40 mmol) was added. The reaction mixture was heated to reflux for 16 hr then cooled to room temperature, and evaporated under reduced pressure. The residue was diluted with aq. 0.5 N NaOH (100 mL) and stirred for about 30 min., and then the mixture was extracted with ether (30 mL×3) The aqueous layer was cooled to 0° C., acidified with 2 N HCl, and then extracted with EtOAc. The combined organic layers were washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane, filtered and dried to give 9.4 g of 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid as a white solid in 73% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:20]=1[C:9]1[NH:10][C:11]3[C:12]([CH3:19])=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=1[CH2:7]2.[B].C1NCCOC1.Cl.[OH-].[Na+]>O.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:20]=1[C@H:9]1[NH:10][C:11]3[C:12]([CH3:19])=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C@H:8]1[CH2:7]2
Reactant: COc1cc(C)c2[nH]c3c(c2c1)Cc1cccc(C)c1-3
Agent: Cl
Agent: [B]
Agent: [Na+]
Solvent: O
Solvent: C1COCCN1
Solvent: C1COCCO1
Product: COc1cc(C)c2c(c1)[C@H]1Cc3cccc(C)c3[C@H]1N2
Yield: 92.3 %

Procedure:
16 ml dioxane, 1.3 g (4.9 mmol) 5,10-dihydro-4,6-dimethyl-8-methoxyindeno[1,2-b]indole and 1.98 g (19.6 mmol) morpholineborane were added to a round bottom flask. 4 ml hydrochloric acid (conc.) was added dropwise during stirring of the solution. The reaction mixture was refluxed for 1 hour. 8 ml (6M) hydrochloric acid was added and the solution was refluxed for 30 min. After the solution had reached room temperature, 50 ml water was added. The mixture was made basic with NaOH(aq) until pH 9. The product was extracted with dichloromethane two times. The organic phase was dried with Na2SO4 and the solvent was evaporated. The product was subjected to chromatography in dichloromethane. The isolated product was dissolved in acetonitrile, a saturated solution of HCl(g) in ether was added and the product precipitated as the hydrochloride salt and was removed by filtration. 1.2 g (82.2%) of product was isolated. 1H NMR (CDCl3):2.33 (3H,s), 2.48 (3H, s), 2.95 (1H, dd), 3.56 (1H, dd), 3.77 (3H, s), 4.44 (1H, ddd), 5.71 (1H, d), 6.78 (1H, s), 6.93 (1H, s), 7.11-7.17 (2H, m), 7.30 (1H, d).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N+](=CP(=O)(OC)OC)=[N-].[CH3:16][O:17][C:18]1([O:40][CH3:41])[CH2:23][CH2:22][C:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:27]=2)([CH:24]=O)[CH2:20][CH2:19]1.C(O)(=O)C>O1CCCC1>[CH3:41][O:40][C:18]1([O:17][CH3:16])[CH2:19][CH2:20][C:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[CH:27]=2)([C:24]#[CH:1])[CH2:22][CH2:23]1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: COP(=O)(C=[N+]=[N-])OC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(OC)(OC)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a solution of potassium t-butoxide (0.155 g, 1.38 mmol) in dry tetrahydrofuran (5 mL) under an argon atmosphere at -78° C. was added a solution of dimethyl (diazomethyl)phosphonate (ca. 88% pure, 0.24 g, 1.38 mmol). After 0.25 h, a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethyl ketal (0.42 g, 1.15 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the mixture was allowed to stir at -78° C. under an argon atmosphere for 5 h. Aqueous acetic acid was added, the mixture was concentrated, partitioned between methylene chloride and water and extracted twice. The organic extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, provided an oil (0.13 g, 32%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)#[N:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C#N)cc1
Yield: 45.9 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)lactate (1.01 g), which is the product of Reference example 1(b), 4-cyanophenol (481 mg), triphenylphosphine (1.06 g) and solution of diethylazodicarboxylate in toluene (40%, 0.73 ml) and the reaction mixture was treated to afford the desired compound (619 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([CH:11]([OH:15])[CH:12]([CH3:13])[CH3:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)C(C)C)oc2cccc(F)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C(C)C)oc2cccc(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
1-(4-Fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.4 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (20 mL) and methanol (2 mL), and sodium borohydride (90%, 0.53 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (2 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (1.4 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=2)[C:9]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:8]1[CH3:28])=[O:4].C([O-])=O.[NH4+]>[Pd].CO.O1CCCC1>[C:18]([CH2:17][CH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C:8]([CH3:28])=[C:9]2[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: COC(=O)CCn1c(C)c(Cc2cccnc2)c2cc(/C=C/C(=O)O)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCn1c(C)c(Cc2cccnc2)c2cc(CCC(=O)O)ccc21
Temperature: 60 °C
Yield: 88.1 %

Procedure:
A mixture of (E)-3-[1-(2-methoxycarbonylethyl)-2-methyl-3-(3-pyridylmethyl)-1H-indol-5-yl]-2-propenoic acid (2.02 g), 10% palladium on carbon (0.20 g) and ammonium formate (1.68 g) in methanol (20 ml) and tetrahydrofuran (20 ml) was heated at 60° C. for 4 hours and then cooled and filtered. The residue was washed with methanol, and the filtrate and washings were combined and evaporated. The residue was triturated with dilute acetic acid to give a gummy solid. The solid was filtered off and boiled with ether to give the title compound as a crystalline solid (1.79 g), m.p. 144°-146° C. Found: C,69.60; H,6.20; N,7.16. C22 H24N2O4 requires: C,69.45; H,6.36; N,7.37%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:8][CH:7]([CH2:24][CH3:25])[C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:8][CH:7]([CH2:24][CH3:25])[C:6]1=[S:31]
Reactant: CCC1N=C(c2ccccc2Cl)c2cc(F)ccc2N(C(C)(C)C(=O)OC)C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCC1N=C(c2ccccc2Cl)c2cc(F)ccc2N(C(C)(C)C(=O)OC)C1=S

Procedure:
A mixture of 0.01 mole of 7-fluoro-5-(o-chlorophenyl)-2,3-dihydro-α,α-dimethyl-3-ethyl-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated. The residue thus obtained is chromatographed on silica gel and eluted to give 7-fluoro-α,α-dimethyl-3-ethyl-5-(o-chlorophenyl)-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][N:5]([CH3:6])[C:23]([CH2:22][O:21][C:18](=[O:20])[CH3:19])=[O:24]
Reactant: CNCc1ccccc1Br
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N(C)Cc1ccccc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-N-methyl benzylamine (CAS#698-19-1, 0.57 mL, 3.89 mmol) in THF (10 mL) at 0° C. is added triethylamine (0.98 mL, 1.03 mmol) followed by acetoxyacetylchloride (0.63 mL, 5.86 mmol). The reaction is permitted to warm to room temperature and after two hours the reaction is quenched with saturated aqueous NaHCO3 and diluted with ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-hexanes, 1:4 to 3:2) to provide acetic acid [(2-bromo-benzyl)-methyl-carbamoyl]-methyl ester; MS: (ESI) m/z 300.1, 302.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:30])[C:28]#[CH:29]>O>[CH2:27]([O:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[C:28]#[CH:29]
Reactant: C#CCO
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#CCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 100 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of 2-propyne-1-ol was stirred while heating at 100° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.20 g of 2-(3-(2-propyne-1-yloxy)pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 73”).
Reaction SMILES: C(O)C.[O:4]=[C:5]1[O:10][CH2:9][C@H:8]2[C@:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7]2.[BH4-].[Na+].Cl>C(OCC)(=O)C>[OH:4][CH2:5][C@@:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C@H:8]1[CH2:9][OH:10]
Reactant: CCOC(=O)[C@]12C[C@H]1COC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@]1(CO)C[C@H]1CO
Temperature: 10 °C
Yield: 44.4 %

Procedure:
In a reactor, ethanol (82.4 L) followed by ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (10.3 kg, 64.6 mol) were added and cooled to 10° C. Sodium borohydride (1.85 kg, 51.7 mol) was added in lots over a period of 1 hour by maintaining the reaction temperature between 10-15° C. The reaction temperature was raised to 20-25° C. and maintained for 1 hour. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 0-5° C. The pH of the reaction mass was adjusted to 7.0 using 1.5 N aqueous HCl at 0-5° C. during 1 hour. Ethyl acetate (34.0 L) was added to the reaction mass and the solid was filtered. The clear filtrate was distilled under reduced pressure at 40-45° C. to remove most of the solvent and the concentrate was dissolved in dichloromethane (103.0 L). The dichloromethane layer was washed with water (2×10.5 L). The aqueous layer was re-extracted with dichloromethane (3×10.5 L). The dichloromethane layers were combined and washed with brine (1×15.0 L). The organic layer was collected and distilled to remove most of the solvent at 40-45° C. under reduced pressure. The concentrate was passed over silica gel 60-120 mesh plug column using petroleum ether followed by 100% ethyl acetate as eluent to afford 5.0 kg (47.4%) of the title compound (2c).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:25]=[O:26])C>C1COCC1>[Si:5]([O:8][C:9]1[C:10]([F:16])=[C:11]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH:25]=[O:26])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)ccc1F
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
A 500 mL round bottom flask was charged with 90.A (8.60 g, 35.2 mmol) and THF (70 mL) and cooled to −78° C. under N2. To the cold solution was added sec-butyllithium (1.4 M in cyclohexane) (available from Aldrich) (27.7 mL, 38.7 mmol) dropwise. The mixture was stirred for 30 minutes, and to it was added DMF (4.09 mL, 52.8 mmol) dropwise. The mixture was stirred for 30 minutes at −78° C., warmed to room temperature over 30 minutes, quenched with 1 N HCl, and diluted with EtOAc. The organic layers were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 90.B (5.71 g, 59.6% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].CN(C)CCN(C)C.C([Li])CCC.[Br:27]CCBr>C1COCC1>[Br:27][C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: BrCCBr
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 25 g (140 mmol) of the product from Step A and 52.2 mL (350 mmol) of redistilled N,N,N′,N′-tetramethylethylenediamine in 350 mL of dry THF under nitrogen at −78° C. was slowly added via cannula 140 mL (350 mmol) of n-butyllithium (2.5N in hexane). The reaction mixture was stirred at −78° C. for 30 min then at −10° C. for 90 min. The reaction mixture was then cooled to −78° C. and 30.2 mL (350 mmol) of 1,2-dibromoethane was slowly added. The mixture was stirred at −78° C. for 30 min, at −10° C. for 90 min then quenched with saturated aqueous ammonium chloride solution. A 600 mL portion of ethyl acetate was next added and the mixture was washed sequentially with water and saturated aqueous brine (400 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanes gradient) to give the title compound. 1H NMR (500 MHz, CDCl3): δ 9.54 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.86 (br s, 1H), 7.51 (d, J=5.3 Hz, 1H), 1.39 (s, 9H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10]>P(=O)(O)(O)O>[CH3:6][C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:2][C:1]([OH:5])=[O:4]
Reactant: O=CC(=O)O
Reactant: CCC(=O)CC
Agent: O=P(O)(O)O
Product: CCC(=O)C(C)=CC(=O)O

Procedure:
Prepared from glyoxylic acid (16.1 g, 0.18 mol), 3-pentanone (45.6 g, 0.63 mol) and orthophosphoric acid (30 ml). 1H n.m.r. δ (CDCl3) 1.23, t J 7.2 Hz, 3H, CH3; 2.56, s, 3H, CH3; 2.76, q J 7.2 Hz, CH2; 6.55, s, CH.