Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[CH2:13][C@H:12]1[C:26](O)=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>N1C=CC=CC=1>[CH3:40][C:37]([O:36][C:34]([C:33]1[CH:41]=[CH:42][C:30]([NH:29][C:26]([C@@H:12]2[CH2:13][C@H:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)[CH2:15][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[O:27])=[CH:31][CH:32]=1)=[O:35])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)N1CCN([C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C2)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
To a solution of the compound prepared in Example 4 (0.20 g, 0.40 mmol) and 2-methyl-2-propanyl 4-aminobenzoate (0.154 g, 0.80 mmol) in pyridine (50 mL) was added 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.630 mg 3.2 mmol) at 0° C. The reaction was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the resulting residue diluted with dichloromethane (20 mL). This solution was washed with brine, dried and concentrated. Purification by flash chromatography (silica gel, 40 g, 20-80% ethyl acetate/hexanes) gave the title compound (0.185 g, 65%) as a white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][N:16]=[CH:17]2)=O)(C)(C)C.[ClH:22].CO>>[ClH:22].[CH:17]1[C:18]2[C:13](=[C:12]([NH:11][CH2:10][CH2:9][NH2:8])[CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][N:16]=1
Reactant: CC(C)(C)OC(=O)NCCNc1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: NCCNc1cccc2cnccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 27 (287 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (252 mg) as light yellow powdery solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])/[CH:5]=[CH:6]/[C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2)[CH3:2].C1COCC1>[C].[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2)[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(-c2ccccc2)c2cc(C)c(C)cc2c(=O)n1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1c(-c2ccccc2)c2cc(C)c(C)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
A mixture of the compound (1.0 g) obtained in Step 2, 10% palladium-carbon (300 mg), THF (15 ml) and ethanol (15 ml) was stirred for 1.5 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off. From the filtrate was distilled off the solvent. The residue was dissolved in ethyl acetate, which was washed with 2N-HCl, an aqueous solution of sodium hydrogencarbonate and water, successively, followed by drying (MgSO4). The solvent was distilled off to leave 3-(1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenylisoquinolin-3-yl)propionic acid ethyl ester as colorless crystals (0.85 g).
Reaction SMILES: [N+]([C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O.N([O-])=[O:15].[Na+]>[OH-].[Na+].[Cl-].[Na+].O.[C].[Pd]>[OH:15][C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1c(O)cccc1C(=O)O
Temperature: 40 °C
Reaction time: 9 h

Procedure:
3-Nitro-2-methyl benzoic acid (90.5 g, 0.500 mol) was dissolved in 1.0 mol/L aqueous solution (500 ml) of sodium hydroxide. 10% Palladium-carbon (4.5 g) was added and the mixture was stirred under a hydrogen atmosphere (2-3 atm) for 9 hours at 40° C. The catalyst was filtered off and conc. sulfuric acid (94.0 ml) was added under ice-cooling. An aqueous solution of sodium nitrite (35.0 g, 0.500 mol/150 ml) was added over one hour while stirring the mixture at riot more than 6° C., and after the dropwise addition, the mixture was heated at 65° C. for 1.5 hours. The inner temperature rose to 57° C. in an hour. The reaction mixture was cooled to room temperature, and saturated brine (300 ml) was added. The mixture was extracted with ethyl acetate (700 ml). The organic layer was washed with saturated brine (200 ml) and dried over magnesium sulfate. The solvent was distilled away to give 3-hydroxy-2-methyl benzoic acid as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]([O:21][CH3:22])([CH3:20])[C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].N1CCCCC1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([C:13](=[O:19])[C:12]([O:11][CH3:10])([O:21][CH3:22])[CH3:20])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC(=O)C(C)(OC)OC
Reactant: O=Cc1ccccc1Cl
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccccc1Cl)C(=O)C(C)(OC)OC
Yield: 112.6 %

Procedure:
A mixture of 2-chlorobenzaldehyde (2.81 g), methyl 4,4-dimethoxy-3-oxovalerate (3.81 g) and piperidine (0.2 ml) in benzene (20 ml) was refluxed under azeotropic dehydration for 7.5 hours. A small amount of benzene was added to the reaction mixture and the resultant solution was washed with water and dried over magnesium sulfate. The solvent was removed from the solution to give a reddish oil (7.04 g) of methyl 2-(2-chlorobenzylidene)-4,4-dimethoxy-3-oxovalerate. The mixture of the oily product (6.39 g) obtained above and methyl 3-aminocrotonate (2.33 g) was heated at 132° C. for 3.5 hours, allowed to stand and then dissolved in ethyl acetate. The resultant solution was washed with water and an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed from the solution under reduced pressure to give a viscous and brown oil (8.28 g). This oil was subjected to column chromatography on silica gel with an eluent (a mixture of 20 parts of benzene and one part of ethyl acetate by volume) to give an oily substance (5.26 g). This substance was dissolved in a mixture of ethyl acetate and diethyl ether and the solvent was removed under reduced pressure to give colorless powder (1.0625 g). This powder was recrystallized from a mixture of n-hexane and ethyl acetate to give faint yellow granules of dimethyl 2-methyl-4-(2-chlorophenyl)-6-(1,1-dimethoxyethyl)-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 145° to 146° C.
Reaction SMILES: CC1(C)O[C:6](=O)[CH2:5][C:4](=O)[O:3]1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1>>[OH:3][C:4]1[C:13]2[C:12](=[CH:22][CH:21]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[N:11]=[CH:6][CH:5]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc2nccc(O)c2c1

Procedure:
In a manner similar to that described in Example 58, Part A., 10 g (69 mmol) of 2,2-dimethyl-1,3-dioxan-4,6-dione and 11.4 g (69 mmol) of ethyl 4-aminobenzoate were tranformed into the title product: yield 10.86 g (72%); m.p. 233°-234° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:24])=[N:8][N:9]2[C:14]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][C:12]([CH3:23])=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+].C(#N)C.FC(F)(F)C(O)=O>O1CCOCC1>[CH:17]1([CH2:16][O:15][C:14]2[N:9]3[N:8]=[C:7]([CH3:24])[C:6]([C:4]([OH:5])=[O:3])=[C:10]3[CH:11]=[C:12]([CH3:23])[CH:13]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1c(C)nn2c(OCC3CCCCC3)cc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC2CCCCC2)n2nc(C)c(C(=O)O)c2c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A solution of 220 mg (0.469 mmol, 71% pure) of 7-(cyclohexylmethoxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 119A in 4 ml of dioxane was admixed with 2 ml of 2 N sodium hydroxide solution. The resulting mixture was stirred at 100° C. for 15 h. The solvent was drawn off under reduced pressure and acetonitrile (5 ml) was added to the residue, and then trifluoroacetic acid (2 ml) was added dropwise. The resulting precipitate was filtered off and dried under reduced pressure, which gave 110 mg (74% of theory, 95% pure) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[CH:19](=[N+:26]([CH3:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:19]([N:26]([CH3:28])[CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2cc3ccccc3[nH]2)cc1Cl
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(-c2ccc(F)c(Cl)c2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(3-chloro-4-fluorophenyl)-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31](F)([F:33])[F:32])[CH:26]=1.BrC1C=CC(C2C3C(=O)CCCC=3N(C3C=CC=C(C(F)F)C=3)C(=O)N2)=C(S(C)(=O)=O)C=1>>[F:33][CH:31]([F:32])[C:27]1[CH:26]=[C:25]([N:3]2[C:4]3[CH2:5][CH2:6][CH2:7][C:8](=[O:24])[C:9]=3[CH:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[S:20]([CH3:23])(=[O:22])=[O:21])[NH:11][C:2]2=[O:1])[CH:30]=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: CS(=O)(=O)c1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)F)c2)C2=C1C(=O)CCC2
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)F)c2)C2=C1C(=O)CCC2

Procedure:
The title compound is prepared in analogy to 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methyl sulfonyl)benzonitrile (example 18), using 4-(4-bromo-2-(methylsulfonyl)phenyl)-1-(3-(difluoromethyl)phenyl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (intermediate 36) as starting material. Yield: 185 mg; ESI mass spectrum [M+H]+=472; Retention time HPLC: 0.93 min (Z012_S04).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([S:18][CH3:19])=[N:11][C:12]([CH3:17])=[CH:13][C:14]=1[S:15][CH3:16].[CH2:20]1C[O:23][CH2:22][CH2:21]1>O>[CH3:19][S:18][C:10]1[C:9]([NH:8][C:22](=[O:23])[CH:21]=[CH2:20])=[C:14]([S:15][CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Nc1c(SC)cc(C)nc1SC
Reaction time: 14 h
Yield: 44 %

Procedure:
Triethylamine (277 mg, 2.75 mmol) was added to a solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (500 mg, 2.50 mmol) in THF (10 ml), then a solution of acryloyl acid chloride (225 mg, 2.50 mmol) in THF (3 ml) was gradually dropped thereinto and the mixture was stirred for 14 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution and dried over anhydrous sodium sulfate, the solvent was evaporated therefrom and the resulting crystals were recrystallized from chloroform-ethyl acetate-hexane to provide 276 mg (yield 44%) of N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acrylamide as colorless powdery crystals.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[C:14]([CH2:15][CH2:16][NH:17][C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])=[CH:13][N:12]=[CH:11]2)=[CH:7][CH:6]=1)#[N:4].CCN(CC)CC.[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42]([N:22]2[CH2:23][CH2:24][CH2:25][C@H:20]([C:18](=[O:19])[NH:17][CH2:16][CH2:15][C:14]3[N:10]([CH2:9][C:8]4[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:27][CH:26]=4)[CH:11]=[N:12][CH:13]=3)[CH2:21]2)=[O:43])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@H]2CCCNC2)cc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@H]2CCCN(C(=O)N(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3(S)-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine dihydrochloride (Example 11, Step E) (0.346 g, 0.843 mmol) was dissolved in CH2Cl2 (10 mL), treated with Et3N (0.587 mL, 4.2 mmol) and diphenylcarbamoyl chloride (0.390 g, 1.686 mmol) and stirred at ambient temperature for 1 hr. The reaction mixture was concentrated to dryness, partitioned between EtOAc and satd NaHCO3 soln, the organic layer separated, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound after purification on a silica gel column eluting with 0-2% MeOH/CH2Cl2. Anal. calculated for C32H32N6O2.0.95 H2O: C, 69.91; H, 6.22; N, 15.29; Found C, 69.97; H, 6.15; N, 14.80.
Reaction SMILES: [H-].[Na+].C#CCN1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)[CH2:8][CH2:7]1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>C1COCC1>[CH3:24][N:25]([CH3:29])[C:26](=[O:27])[O:23][C:20]1[CH:21]=[CH:22][C:13]([CH2:12][N:9]2[CH2:8][CH2:7][CH:15]([CH2:14][C:13]#[CH:12])[CH2:11][CH2:10]2)=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: C#CCN1CCN(Cc2ccc(O)c3ncccc23)CC1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCC1CCN(Cc2ccc(OC(=O)N(C)C)c3ncccc23)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a suspension of NaH (24 mg, 0.6 mmol 1.2 equiv) in anhydrous THF, HLA20 (140 mg, 0.5 mmol, 1.0 equiv) was added under Ar at 0° C. The resulting mixture was stirred for 20 min at 0° C. A solution of dimethyl carbamoyl chloride (1.1 equiv) in anhydrous THF was added, and the stirring was continued for 24 h at room temperature. After evaporation of the solvent, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried with NaSO4. Evaporation of the solvent gave a crude product that was purified by RP HPLC.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][SH:8])[C:3]([O:5][CH3:6])=[O:4].CO.F[C:12](F)(F)COP(OCC(F)(F)F)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>ClCCl>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH3:1])[CH2:7][S:8][CH3:12]
Reactant: COC(=O)C(C)CS
Reactant: FC(F)(F)COP(OCC(F)(F)F)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)CSC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of methyl 2-methyl-3-mercaptoproponate (1.34 g, 10 mmol) and methanol (0.42 g, 10 mmole) is added to a mixture of bis(2,2,2-trifluoroethoxy)triphenylphosphorane (11 mmole) [prepared in situ from triphenylphosphine (12 mmole) and sodium 2,2,2-trifluoro ethoxide (24 mmole) in dry diethyl ether (20 ml)] in dichloromethane (20 ml). After 20 hours stirring at room temperature the mixture is poured into water and extracted with ether. The ether extract is washed with 5% aqueous sodium hydroxide and dried over magnesium sulfate. The solution is evaporated, solids removed by filtration and the oily residue purified by vacuum distillation yielding methyl-3-methylthio-2-methylpropanoate.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].[C:15]([O:19][CH3:20])(=[O:18])[CH2:16][SH:17]>>[CH3:20][O:19][C:15](=[O:18])[CH2:16][S:17][CH2:2][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:14])[C:9]=2[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: COC(=O)CS
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Product: COC(=O)CSCc1c(O)ccc2c1CCCC2=O
Temperature: 40 °C
Yield: 52.1 %

Procedure:
5-Chloromethyl-6-hydroxy-1-tetralone (315 mg, 1.5 mmol) and methyl thioglycolate (2.0 mL, 22 mmol) were combined in a septum capped round bottomed flask and heated to 40° C. overnight. The excess methyl thioglycolate was removed in vacuo and the pot residue was purified by silica gel chromatography (Rf=0.18, hexanes/ethyl acetate/acetic acid, 58:40:2) to give 219 mg (52%) of the desired compound as a colorless glass: 1H NMR (CDCl3) δ 2.02 (p, 2H, J=6.01 Hz); 2.50 (t, 2H, J=6.01 Hz); 2.89 (t, 2H, J=6.01 Hz); 3.19 (s, 2H); 3.64 (s, 3H); 3.85 (s, 2H); 6.79 (d, 1H, J=8.7 Hz); 7.83 (d, 1H, J=8.7 Hz); 8.59 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[O:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of 2-chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidine-6-carbaldehyde (78 mg, 0.29 mmol) and 2-piperidin-4-ylpropan-2-ol (50 mg, 0.35 mmol) in DCE (3 mL) was stirred at ambient temperature for 45 min. Sodium triacetoxyborohydride (93 mg, 0.44 mmol) was added and the mixture stirred for 2 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 98:2 to 95:5) to afford the title compound as a tan solid (110 mg, 96%). LCMS (Method H): RT=2.33 min, M+H+=395.
Reaction SMILES: C(C1C=C(CC)[NH:5][C:4]=1[CH:10]=[O:11])C.[CH3:12][CH:13]([C:15](=O)[CH2:16][C:17](=O)[CH:18]([CH3:20])[CH3:19])[CH3:14]>>[CH:13]([C:15]1[CH:16]=[C:17]([CH:18]([CH3:20])[CH3:19])[NH:5][C:4]=1[CH:10]=[O:11])([CH3:14])[CH3:12]
Reactant: CC(C)C(=O)CC(=O)C(C)C
Reactant: CCc1cc(CC)c(C=O)[nH]1
Product: CC(C)c1cc(C(C)C)c(C=O)[nH]1

Procedure:
The procedure was the same as the one for the preparation of 3,5-diethylpyrrol-2-carboxaldehyde except starting with 2,6-dimethyl-3,5-heptanedione.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:32]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(F)cc2F)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]-malonate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b)
Reaction SMILES: [C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([SH:18])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:23])(=O)=O>[OH-].[Na+].O>[C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([S:18][CH3:23])[N:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1ccccc1)c1nc(S)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc([N+](=O)[O-])c(C(=O)c2ccccc2)n1

Procedure:
150 grams of 2-benzoyl-3-nitro-6-mercaptopyridine were dissolved in a solution of 45 grams of sodium hydroxide in 2.5 liters of water and hereto there was added dropwise at 35° C. with stirring 90 ml. of dimethyl sulfate. Then the composition was stirred for one hour at 40° C. After cooling the precipitated crystals were filtered off with suction and recrystallized from 1.8 liters of methanol.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([OH:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:51](Cl)([O:53]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH:13]2[O:38][C:51](=[O:53])[N:15]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=3[O:36][CH3:37])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol (31.9 mg, 0.0551 mmol) in CH2Cl2 (5 mL) at 0° C. was added DIPEA (67 μL, 0.386 mmol), followed by triphosgene (8.2 mg, 0.0276 mmol). The reaction was stirred at 0° C. for 30 minutes. The reaction was then poured into saturated NaHCO3 (15 mL) and the mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography (20% EtOAc/hexanes) afforded 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one. Rf=0.32 (25% EtOAc/hexanes). LCMS=606.3 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) (atropisomers present in 1:1 ratio, doubling of some peaks) δ 7.90 (s, 1H), 7.77 (s, 2H), 7.57-7.62 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.27 (m, 1H), 6.98 (s, 1H), 6.93 (dd, J=8.4, 3.2 Hz, 1H), 5.42-5.53 (m, 1H), 4.15-4.59 (m, 2H), 3.72 & 3.73 (2 singlets, 3H), 3.05-3.65 (m, 2H), 2.88 (m, 1H), 1.19-1.23 (m, 6H).