Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:5][C:6]=1[CH:7]=[O:8].[CH3:19][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[O:5][C:6]=1[CH:7]([OH:8])[CH3:19]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde (1.32 g, 5.16 mmol) and 50 mL tetrahydrofuran is stirred at 0° C. Methyl magnesium bromide (2.2 mL, 6.71 mmol, 3M) is added dropwise and the resulting mixture is allowed to stir at room temperature 30 min. The reaction is not complete, so an additional amound of methyl magnesium bromide (1 mL, 3 mmol) is added and the reaction stirred an additional 1 hr at room temperature. The mixture is cooled on an ice/water bath and aqueous ammonium chloride (10 mL) is added. The product is extracted with three 75 mL portions of ethyl acetate, the combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography eluting with a mixture of 1:1 hexanes:ethyl acetate to afford 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol as an ivory solid, 1.12 g, 80%. MS (M++1) 272.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C@@:6]1([C:11]([OH:13])=[O:12])[CH2:10][CH2:9][CH2:8][NH:7]1.[CH3:14]O>>[ClH:3].[CH3:5][C@@:6]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9][CH2:8][NH:7]1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: C[C@@]1(C(=O)O)CCCN1
Product: COC(=O)[C@]1(C)CCCN1
Product: Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of anhydrous MeOH (65 mL) at 0° C. was added thionyl chloride (9.03 mL, 124 mmol) slowly over a 5 min period. 2-Methyl-(L)-proline (Bachem AG, Cat. No. F-3440, Bubendorf, Switzerland) (4.0 gm, 31 mmol) was added in one portion. The reaction was stirred at 0° C. for 5 min and then warmed to rt. The reaction was then heated to 70° C. overnight. The reaction was cooled and the solvent removed to yield 2-methyl-(L)-proline, methyl ester hydrochloride as a white solid (5.72 gm).
Reaction SMILES: [Li+].[OH-].[C:3]([NH:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Cl>O1CCOCC1>[C:3]([NH:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc(Oc2ccc(NC(C)=O)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.6 %

Procedure:
Aqueous LiOH (1M, 3.12 mL) is added to a suspension of methyl 4-(4-acetamidophenoxy)benzoate (445 mg, 1.6 mmol) in dioxane (6 mL). The reaction is stirred for 90 minutes at room temperature. Concentrated HCl (1.5 mL) is added to lower the pH to less than 6 and the resulting precipitate is collected by filtration. The filter cake is washed with water then dried to give 4-(4-acetamidophenoxy)benzoic acid (337 mg, 80%). MS for C15H13NO4 (ESI) (M−H)− m/z 270.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:11]=1[NH2:12].CC(C)([O-])C.[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:12][C:11]2[C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=[CH:16][C:10]=2[CH3:9])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc([N+](=O)[O-])c1Nc1ncc(Br)cn1
Temperature: 130 °C
Yield: 30.8 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (1.5 g, 7.89 mmol) and 2-methyl-6-nitroaniline (800 mg, 5.26 mmol) in N,N-dimethylformamide (10 mL) in a sealed tube was added potassium tert-butoxide (1.76 g, 15.78 mmol), and the mixture was heated under microwave at 130° C. for 2 hrs. LCMS showed the reaction was completed. The reaction was cooled to RT, quenched with water (20 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were separated, combined, washed with water (50 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=10:1) to afford the title compound as a yellow solid (500 mg, 31%). MS (ES+) C11H9BrN4O2 requires: 309, 311. found: 310, 312 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:8][C:6]1[CH:5]=[C:4]([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Clc1ccccc1
Reactant: Cc1cc(C)cc(O)c1
Product: Cc1cc(C)cc(Oc2ccccc2)c1
Yield: 60 %

Procedure:
Following General Procedure C (140° C., 30 hours), 3,5-dimethyl-phenol (183 mg, 1.5 mmol) is coupled with chlorobenzene (102 μL, 1.0 mmol) to give 60% 1,3-dimethyl-5-phenoxybenzene.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:29])([O:26]CC)[O:23]CC)[P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:31]>C(O)C>[Na+:31].[C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[P:22](=[O:23])([OH:29])[O-:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(=O)(OCC)C(NCCCCSc1ccccc1)P(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(OCC)C(NCCCCSc1ccccc1)P(=O)([O-])O
Yield: 35 %

Procedure:
To a solution of tetraethyl 4-(phenylthio)butylaminomethylenebisphosphonate (2.5 g) in ethanol (20 ml) was added a solution of sodium hydroxide (450 mg) in ethanol (20 ml). The mixture was heated under reflux for 4 hours and concentrated under reduced pressure. The residue was dissolved in water and the solution was subjected to column chromatography on Amberlite CG-50 (H+ form) and eluted with water to obtain diethyl 4-(phenylthio)butylaminomethylenebisphosphonate monosodium salt (810 mg). The resultant was recrystallized from methanol-hexane, m.p. 143°-145° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:23])[CH3:22])[C@@H:16]([CH3:24])[CH2:15][NH:14]2.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>ClCCCl>[C:21]([N:17]1[C:18]2[C:13](=[CH:12][C:11]([Br:10])=[CH:20][CH:19]=2)[N:14]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:15][C@@H:16]1[CH3:24])(=[O:23])[CH3:22]
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
N,N-Diisopropylethylamine (0.973 mL, 5.57 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.500 g, 1.858 mmol) and isopropyl chloroformate (1.0 M in toluene, 2.79 mL, 2.79 mmol) in 1,2-dichloroethane (10.0 mL), and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.558 g, 85%) as an off-white solid. MS (ESI, pos. ion) m/z 355, 357 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:29](Cl)(=[O:31])[CH3:30].O>[N+](C1C=CC=CC=1)([O-])=O>[CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]2[CH:7]=[C:8]([C:29](=[O:31])[CH3:30])[CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCCCC1(CCCC)c2cc(C(C)=O)ccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
After 7.0 g of 9,9-di-n-butyl-2-nitrofluorene (5) (21.7 mmol) was dissolved in 200 ml of anhydrous nitrobenzene and 5.77 g of anhydrous aluminum chloride (43.4 mmol) was added thereto, the reaction mixture was heated to 45° C., and a solution in which 3.40 g of acetyl chloride (43.3 mmol) was dissolved in 40 ml of anhydrous nitrobenzene was slowly added thereto for 1 hour, followed by stirring at 65° C. for 1 hour. Thereafter, the reaction mixture was cooled to room temperature, 100 ml of distilled water was added thereto and stirred for about 30 minutes, followed by extracting the product with 200 ml of dichloromethane. The extracted organic layer was sequentially washed with 100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of distilled water. Then, a solid product obtained by drying the recovered organic layer over anhydrous magnesium sulfate and distilling a solvent under reduced pressure was dispersed in a small amount of ether and stirred at room temperature for 30 minutes, followed by filtering and drying, thereby obtaining 5.44 g of 1-(9,9-di-n-butyl-7-nitrofluorene-2-yl)-ethanone (6) (68.7%) as a light yellow product.
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10].S(=O)(=O)(O)O.O.[OH-].[Na+].C(#[N:22])C>>[NH2:22][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: O[C@@H]1Cc2ccccc2[C@H]1O
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 0 °C
Yield: 63 %

Procedure:
Trans-1,2-indandiol (1.5 g) was dissolved in acetonitrile (25 mL) cooled to 0° C., and concentrated sulfuric acid (1.1 mL) was added. The mixture was gradually warmed to 20° C. and aged to 3 hours. Water (2 mL) was added and the mixture heated to reflux. Concentrated aqueous sodium hydroxide was added to adjust the pH to 12. The resulting solid was removed by filtration to provide an aqueous acetonitrile solution of cis-1-amino-2-indanol (1.02 g, 63% yield).
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[NH:12][CH2:13][C:14]1[N:18]([CH3:19])[C:17]([SH:20])=[N:16][N:15]=1.[CH3:21]I>ClCCl>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH3:4])[C:6]=1[NH:12][CH2:13][C:14]1[N:18]([CH3:19])[C:17]([S:20][CH3:21])=[N:16][N:15]=1
Reactant: CI
Reactant: Cc1cccc(C)c1NCc1nnc(S)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CSc1nnc(CNc2c(C)cccc2C)n1C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.7 g (0.0419 mol) sodium hydroxide is 125 ml water was added in one portion, 10.4 g (0.0419 mol), 3-(2,6-dimethylphenylaminomethyl)-4-methyl-5-mercapto-1,2,4-triazole. After a homogeneous solution was obtained, 6.2 g (0.044 mol) methyl iodide was added dropwise. The reaction mixture was then diluted with 50 ml dichloromethane and vigorously stirred for 0.5 hour. The reaction mixture was diluted with another 100 ml dichloromethane and the organic layer was separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a solid residue. The solid was triturated with ethyl ether to give the product as a colorless solid. The product is tabulated in Table I as Compound No. 14-A.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=O)[N:6]=1)([CH3:4])[CH3:3].NCCC(O)=O.[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36]>>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:19])([CH3:21])[CH3:20])[N:8]=[C:7]([CH:22]=[C:34]2[S:30][C:31](=[O:36])[NH:32][C:33]2=[O:35])[N:6]=1)([CH3:1])[CH3:4]
Reactant: O=C1CSC(=O)N1
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Agent: NCCC(=O)O
Product: CC(C)(C)c1nc(C=C2SC(=O)NC2=O)nc(C(C)(C)C)c1O
Yield: 23.9 %

Procedure:
4,6-Bis-(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxaldehyde (0.5 g, 1.5 mmoles) is treated with β-alanine (0.27 g, 3.1 mmoles) and 2,4-thiazolidinedione (0.22 g, 1.8 mmoles) according to the procedure of Example 6 to give 0.12 g (25%) of 5-[[4,6-bis-(1,1-dimethylethyl]-5 hydroxy-2-pyrimidinyl]methylene]-2,4-thiazolidinedione. MP=229°-232° C. dec.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]3[CH:24]=[CH:25][N:26]=[C:14]23)=[C:4]([F:27])[CH:3]=1.[Cu][C:29]#[N:30].Cl>[Fe](Cl)Cl.CS(C)=O>[C:29]([C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[N:15]3[CH:24]=[CH:25][N:26]=[C:14]23)=[C:4]([F:27])[CH:3]=1)#[N:30]
Reactant: CS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Br
Reactant: N#C[Cu]
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1C#N
Temperature: 160 °C

Procedure:
A mixture of 8-(4-bromo-2-fluoro-5-methylsulfonylaminophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (3.0 g), copper(I) cyanide (0.86 g) and dimethyl sulfoxide (30 ml) was heated for 7 hours at 160° C. under nitrogen atmosphere. After cooled to room temperature, the mixture was added with iron(II) chloride (0.8 g) and 6N hydrochloric acid (1.5 ml), and then stirred for 30 minuets at room temperature. The reaction solution was poured into ice water, and the thus obtained solid was filtered off and washed with ethyl acetate. The solid was dissolved into acetonitrile and then a portion adjacent to the original point of the short column of silica gel was removed. The eluate was concentrated to such an extent that any crystal did not precipitate, added with alumina (5.0 g) for column chromatography and stirred for 15 minuets. The alumina was filtered off, washed with a small amount of acetonitrile and then eluted with an acetonitrile solution (30 ml) containing triethylamine (5%) and water (5%). The eluate was distilled off under reduced pressure and the residue was added with ethyl acetate (10 ml), water (20 ml) and 6N hydrochloric acid (10 drops), followed by stirring vigorously to obtain a solid, which was then filtered off. The thus obtained solid was washed with water and ethyl acetate, and dried to give the compound of interest (0.6 g) as a white solid.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].[Br:11]Br.C(N(CC)CC)C.C(OCC)C>ClCCl>[Br:11][C:4]([C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])=[C:2]([CH3:3])[CH3:1]
Reactant: BrBr
Reactant: CCCCC(=O)C=C(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)C(Br)=C(C)C

Procedure:
To a magnetically stirred and ice-cooled solution of 2-methyl-oct-2-en-4-one (9.30 gram, 63 mmol) in dichloromethane (90 ml) was slowly added bromine (3.23 ml, 33 mmol; dissolved in 10 ml dichloromethane) and the resulting mixture was stirred for 10 minutes. To the obtained mixture was slowly added triethylamine (13.10 ml, 94.5 mmol: dissolved in 25 ml dichloromethane). The resulting mixture was allowed to attain room temperature and stirred for 1 hour and subsequently stirred for 16 hours at 40° C. The obtained mixture was washed with 1N HCl (100 ml), dried over MgSO4, filtered and concentrated in vacuo to give crude 3-bromo-2-methyl-oct-2-en-4-one. Sepacore (40×300 mm column) separation (Gradient: first eluant: petroleum ether (40-60); second eluant: petroleum ether (40-60)/diethyl ether=98/2 (v/v)); third eluant: petroleum ether (40-60)/diethyl ether=95/5 (v/v)) gave 3-bromo-2-methyl-oct-2-en-4-one (Intermediate IIIc-1) pale-yellow oil (11.80 gram, 77% yield). 1H-NMR (400 MHz, CDCl3) δ 0.92 (t, J=7.2 Hz, 3H), 1.29-1.39 (m, 2H), 1.56-1.66 (m, 2H), 2.00 (br s, 6H), 2.78 (t, J=7.4 Hz, 2H).
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:41])([CH:39]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH3:38])[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([S:8][C:9]([CH3:41])([CH2:39][N:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH3:38])[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:30])=[O:31])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(C=O)SCc3ccccc3)cc2c1
Reactant: C1CSCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(CN3CCSCC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a mixture of N-[2-(benzylthio)-2-methyl-3-oxopropyl]-5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (1.56 g) and 1,2-dichloroethane (50 mL) was added thiomorpholine (1.31 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.66 g) was added, and the reaction mixture was stirred overnight at room temperature. Aqueous sodium bicarbonate was added, and the mixture was extracted with 1,2-dichloroethane. The extract was washed with saturated brine, dried over sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (998 mg, yield 56%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12](OC(Cl)(Cl)Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([N:6]=[C:12]=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cc(Cl)cc1F
Solvent: Cc1ccccc1
Product: O=C=Nc1c(F)cc(Cl)cc1F

Procedure:
40 g of 4-chloro-2,6-difluoroaniline were dissolved in 300 ml of absolute toluene. With stirring, 100 ml of trichloromethyl chloroformate were added dropwise at 20° C. The mixture was slowly heated to reflux. After three and half hours, the mixture was concentrated and the resulting isocyanate was used directly for the synthesis of intermediate 3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])O[C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].CO.[CH3:21][NH2:22].Cl>O.C(O)(=O)C>[CH3:21][N:22]1[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(-c2ccccc2)oc(C)cc1=O
Reactant: CN
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)n(C)c(C)cc1=O
Reaction time: 18 h

Procedure:
3.8 g of 3-methoxycarbonyl-6-methyl-2-phenyl-4-pyrone, 33.3 ml of methanol, 13.3 ml of 40% aqueous methylamine and 2 ml of glacial acetic acid are mixed in a stoppered flask at room temperature and stored for 18 hours. The reaction mixture is then poured into approximately 100 ml of water and the pH is adjusted to 5 (addition of dilute HCl). Extraction with methylene chloride (3×50 mls) and evaporation of the organic siolvent yields 3.0 g of methyl 1,6-dimethyl-2-phenyl-4-oxonicotinate as a crystalline solid. mp (methylene chloride/ether)=226°-228° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][CH:11]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][N:33]([CH2:35][C@H:36]3[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]3)[CH:34]=2)[N:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:23]3[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]4[CH:31]=[N:32][N:33]([CH2:35][C@H:36]5[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]5)[CH:34]=4)[N:24]=3)[CH2:16][CH2:17]2)=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Reactant: Fc1ccccc1Oc1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(Oc6ccccc6F)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(2-fluorophenoxy)-2-(piperazin-1-yl)pyrimidine HCl salt (27 mg, 0.1 mmol), (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)-morpholine-4-carboxylate (40 mg, 0.1 mmol) and diisopropylethylamine (25 mg, 2.0 mmol) in dioxane (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was directly evaporated and used in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:22](C)=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16](O)[CH3:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:24])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[CH2:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(CNc2cccn3c(C(C)O)c(C)nc23)c1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=Cc1c(C)nc2c(NCc3c(C)cccc3C)cccn12
Yield: 141.8 %

Procedure:
A mixture of 1-[8-(2,3-dimethylbenzylamino)-2-methylimidazo[1,2-a]pyridine-3-yl]-1-ethanol (0.2 g, 0.65 mmol) and p-toluenesulfonic acid (0.029 g, 0.15 mmol) in benzene (40 ml) was refluxed for 20 h with Dean-Stark water separation. The solvent was evaporated under reduced pressure, the residue was solved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride:ethyl acetate (10:1) gave 0.062 g (33%) of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S([O-])([O-])=O.[Na+].[Na+].[C:27](=O)(O)[O-].[Na+].IC>O>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15]([CH3:27])(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc2c(cc1S(C)(=O)=O)CCN(C(C)=O)CC2
Temperature: 70 °C

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (18 g, 0.056 m) was added in portions to a mixture of sodium sulfite (8.8 g, 0.069 m) and sodium bicarbonate (10.8 g, 0.115 m) in water (36 ml) stirred at 70° C. There was a vigorous evolution of gas after each addition. The mixture was stirred for fifteen minutes, treated with iodomethane (8.5 ml, 0.136 m) and refluxed for forty-five minutes. The mixture was partitioned between methylene chloride and water. The methylene chloride phase was washed with water, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 159°-162° C.