Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>O1CCOCC1.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 55.8 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.052 g, 4.074 mmol) in 1,4-dioxane (16 ml), lithium hydroxide monohydrate (0.160 g, 3.81 mmol) was added and stirred for approximately 1.2 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydro pyranyloxy)cyclopentyl]heptanate (2) (0.902 g, 2.26 mmol) in 1,4-dioxane (3 ml) and water (0.57 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, approximately half of the solvent was evaporated under reduced pressure. Ethyl acetate and water were added to the residue and the solution was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 36 g; ethyl acetate:hexane=1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300SP: 6 g; ethyl acetate:hexane=1:4) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.671 g; 1.26 mmol; yield: 55.9%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH:21][NH2:22])=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1cn2c(C)c(CC)c(OC)nc2n1
Solvent: CCO
Solvent: O
Product: CCc1c(OC)nc2nc(C(=O)NN)cn2c1C
Yield: 86 %

Procedure:
A solution of 10.0 g of ethyl 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxylate (published UK Patent Application No. 2,128,989) and 20 ml of hydrazine hydrate in 150 ml of ethanol was refluxed for 4 hours. Most of the ethanol was evaporated and 100 ml of water were added. The resulting precipitate was filtered, washed with water, then ether and dried under vacuum over P2O5 to obtain 8.15 g of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carbohydrazide (86% yield) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.P(OCC)(OCC)(OCC)=O.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:3]1[CH:4]=[C:5]([NH:8][C:36]([NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: Nc1ccc(O)c(-c2nc3ccccc3s2)c1
Reactant: O=C=Nc1ccccc1
Solvent: CCOP(=O)(OCC)OCC
Product: O=C(Nc1ccccc1)Nc1ccc(O)c(-c2nc3ccccc3s2)c1

Procedure:
The procedure to prepare this compound was the same as that described for preparing the compound of Example 5 except that 1 gram of the 2-(2′-hydroxy-5′-aminophenyl)benzothiazole compound (prepared in Step B of Example 5), 18.6 g of triethyl phosphate and 0.55 g of phenyl isocyanate were used. The desired compound of Formula (VII) was obtained in a yield of 0.76 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1CC[C:17]2N(C3N=CC(F)=CN=3)N=N[C:16]=2[C@H:15]1[CH3:30])=[O:13].Cl.CCN(CC)CC.ClC1C(C(F)(F)[F:50])=CC=CC=1C(Cl)=O>C1COCC1>[CH3:30][C@@H:15]([NH:14][C:12](=[O:13])[C:3]1[CH:4]=[C:5]([F:50])[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[Cl:1])[C:16]#[CH:17]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: C[C@@H]1c2nnn(-c3ncc(F)cn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#C[C@@H](C)NC(=O)c1cc(F)cc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To the suspension of (R) but-3-yn-2-amine.HCl salt (10 g, 94.7 mmol, 1.0 equiv.) in THF (150 mL), Et3N (27.5 mL, 199 mmol, 2.1 equiv.) and (2-chloro-3-(trifluoromethyl)benzoyl chloride (23.1 g, 94.7 mmol, 1.0 equiv.) were added sequentially at 0° C. The reaction mixture was then stirred at room temperature for 16 hours. The precipitate was filtered off and washed with THF. The filtrate solution was concentrated and re-dissolved in EtOAc. The EtOAc solution was washed with saturated NaHCO3 and brine, dried over Na2SO4, concentrated. Trituration of the crude product from EtOAc/hexanes afforded the title compound (23 g, 83.8 mmol, 88%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 7.82-7.75 (dd, J=7.9, 1.6 Hz, 1H), 7.73-7.66 (dd, J=7.7, 1.6 Hz, 1H), 7.48-7.41 (dd, J=8.2, 7.3 Hz, 1H), 6.35-6.02 (d, J=7.9 Hz, 1H), 5.09-4.90 (dqd, J=8.1, 6.9, 2.3 Hz, 1H), 2.47-2.20 (m, 1H), 1.58-1.54 (d, J=6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.7, 137.9, 132.5, 129.4 (q, JC—F=31.5 Hz), 129.1, 129.0 (q, JC—F=5.2 Hz), 127.1, 122.5 (q, JC—F=273.4 Hz), 83.2, 71.2, 37.8, 22.1. HRMS-ESI (m/z): [M+H]+ calcd for C12H10ClF3NO, 276.0398. found, 276.0390.
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>CO>[NH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([O:21][CH3:1])=[O:20]
Reactant: Cc1cc(N)c2cnn(-c3cccc(C(=O)O)c3)c2c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc(-n2ncc3c(N)cc(C)cc32)c1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
Acetyl chloride (1000 mL, 11.5 mol) was added slowly to cold methanol (10.84 L at 0±3° C.), under an atmosphere of nitrogen, while maintaining the temperature below 5° C. The reaction mixture was stirred for a further 35 min at 0±3° C. and then 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoic acid (1084.2 g, 4.06 mol) was added. The reaction mixture was heated at reflux for 2.5 h and then the volume was reduced by distillation to approximately half the volume. Isopropyl acetate (10.84 L) was added maintaining the temperature at above 50° C. and the temperature held at 60° C. for 1 hour. The solution was cooled to 0° C. over a period of 3 hours and aged at 3±3° C. for a further ca. 10 hours. The precipitate was filtered and washed with a mixture of chilled isopropyl acetate:methanol (ca. 10:1, 3.26 L at 3±3° C.) and then chilled isopropyl acetate (2.1 L at 3±3° C.). The solid was dried in vacuo at 55° C. to afford the title compound as its hydrochloride salt (933.2 g): LCMS: tRET=3.20 min; MH+=282.min. A proportion of this material (874.1 g, 2.76 mol) in a mixture of water (5.28 L) and 2-methyltetrahydrofuran (8.7 L) was treated with sodium hydroxide (1M, 2720 mL then 2M, 13 mL) (until pH=7 is reached). The organic phase was separated and washed with water (6.1 L) and the aqueous layer extracts back extracted with 2-methyltetrahydrofuran (4.4 L). The combined organic extracts were evaporated to near dryness and then toluene (4.4 L) was added and the mixture evaporated to afford the title compound (767.4 g).
Reaction SMILES: [NH2:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([C:10](=[O:12])[CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].C(=O)([O-])O.[Na+].[Br:28][CH:29]([CH3:33])[C:30](Br)=[O:31]>C1(C)C=CC=CC=1.O>[C:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[C:2]([NH:1][C:30](=[O:31])[CH:29]([Br:28])[CH3:33])[S:13][C:5]=2[CH2:6]1)(=[O:12])[CH3:11]
Reactant: CC(Br)C(=O)Br
Reactant: CC(=O)N1CCc2c(sc(N)c2C(=O)c2ccccc2Cl)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CCc2c(sc(NC(=O)C(C)Br)c2C(=O)c2ccccc2Cl)C1
Temperature: 60 °C

Procedure:
13.3 g of toluene and 3.66 liters of water were added to 600 g of 2-amino-3-(2-chlorobenzoyl)-6-acetyl-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine, to which 301 g of sodium hydrogencarbonate was further added. While heating to 60° C., 301 ml of 2-bromopropionyl bromide was dropped into the solution. Further, 170 g of sodium hydrogencarbonate and 170 ml of 2-bromopropionyl bromide were added in order to complete the reaction. After cooling down to room temperature, 500 g of sodium hydrogencarbonate was added, after which the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate, followed by combination with the organic phase, washing with water and drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant solid matter was washed with ether to obtain 800 g of the intended product. 1H-NMR(90 MHz, CDCl3) δ: 1.7-2.4(m,2H), 1.99(d, J=7.2 Hz, 3H), 2.06 and 2.12(each S, total 3H), 3.25-3.7(m,2H), 4.41(q, J=7.2 Hz, 1H), 4,4-4.8(m,2H), 7.0-7.5(m,4H)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:31]1[CH:32]=[CH:33][C:28]([C:24]2[CH:23]=[C:22]([C:21]3[CH2:20][C:19](=[O:35])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:27]=[CH:26][CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M17) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (176 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4](O)[CH3:5].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]([Cl:14])[CH3:5]
Reactant: CC(O)c1c(F)cccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)c1c(F)cccc1Cl
Yield: 92.6 %

Procedure:
2-chloro-6-fluoro-alpha-methylbenzyl alcohol of (B) (45.1 g, 0.26 mol) is dissolved in chloroform (70 ml), and thionyl chloride (61.5 g, 0.52 mol) is added over a period of 30 minutes. The resultant mixture is refluxed for 16 hours. Excess thionyl chloroform are then removed on a rotary evaporator, resulting in pure title product (46.2 g, 92.6%).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].C[N+:24](C)(C)[CH2:25][C:26]1C=CC=C[CH:27]=1.C(#N)C=C>C1C=CC=CC=1>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:26]([CH3:27])[C:25]#[N:24])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CCCCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: [OH-]
Solvent: C=CC#N
Solvent: c1ccccc1
Product: CCCCCCc1ccc(N=Nc2ccc(OC(C)C#N)cc2)cc1

Procedure:
In 2 ml of benzene, 0.4 g of 4-hexyl-4'-hydroxyazobenzene and a catalytic amount of trimethylbenzylammonium hydroxide were dissolved. To the resultant solution, 8 ml of acrylonitrile was slowly added. The resultant mixture was heated for 22 hours and then subjected to vacuum distillation for expulsion of the solvent. The residue of the distillation was extracted with benzene. Then, it was purified by silica gel column chromatography, to obtain 0.25 g of 2-[4-(4-hexylphenylazo)phenoxy]propanenitrile. This compound was converted to a corresponding carboxylic acid by hydrolysis with acetic acid containing hydrochloric acid. The carboxylic acid was converted into an acid chloride with thionyl chloride. The aminated quartz plates were treated with the acid chloride in the same manner as in Example 18. The absorption spectrum of the quartz plates indicated that the plates had azobenzene bonded thereto. A sandwich cell was produced by interposing the same mixed such a manner that the direction of rubbing perpendicularly intersected. When this cell was exposed alternately to an ultraviolet light and a visible light, it showed a reversible change in transmittance, indicating a change in the arrangement of liquid crystals between the homeotropic mode and the twisted mode.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1)=[O:4].C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CC#N>[O:4]=[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1)[C@@H:2]([NH:1][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cccc(-c2ccncc2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2ccncc2)c1
Yield: 15.1 %

Procedure:
To a flask with (S)-2-amino-3-(4-fluorophenyl)-N-(3-(pyridin-4-yl)phenyl)propanamide (200 mg, 0.6 mmol) was added CH3CN as solvent, N-ethyl-N-isopropylpropan-2-amine (0.15 mL, 0.89 mmol) and tert-butyl 2-bromoacetate (0.097 mL, 0.66 mmol) and was heated at 55 degree for 5 hours. Reverse phase purification on HPLC followed by silica gel purification afforded 39 mg (15%) 34.4. 1H NMR (400 MHz, MeOH) δ ppm 8.50-8.68 (m, 2H) 7.88-7.99 (m, 1H) 7.61-7.75 (m, 2H) 7.55-7.60 (m, 1H) 7.42-7.52 (m, 2H) 7.23-7.31 (m, 2H) 6.97-7.04 (m, 2H) 3.53 (t, J=6.85 Hz, 1H) 3.29 (s, 2H) 3.05-3.12 (m, 1H) 2.95-3.03 (m, 1H) 1.43 (s, 9H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)c1ccc(CC(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-tert-butyl-phenyl acetic acid (5.0 g, 26.04 mmol) in DMF (30 mL) at rt were added Cs2CO3 (12.72 g, 39.06 mmol) and benzyl bromide (4.89 g, 28.6 mmol). The reaction mixture was stirred for overnight at room temperature and then the reaction mixture was heated at 100° C. for 1 h and cool to rt. The solvent was removed under reduced pressure and poured into cold 1 N HCl (50 mL). The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure, dried under vacuum. (4-tert-butyl-phenyl) acetic acid benzyl ester was obtained as a yellowish liquid. (5.96 g, 81%): 1H NMR (300 MHz, CDCl3): δ 7.37-7.33 (m, 7H), 7.25 (dd, J=5.4, 13.2 Hz, 2H), 5.14 (s, 2H), 3.65 (s, 2H), 1.32 (s, 9H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:9]2[CH2:10][CH2:11][C:12](=[O:13])[N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[S:25])=[CH:19][CH:18]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: O=C1CCNN1c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1CCN(C(=S)Nc2ccc(Cl)cc2)N1c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 47.8 %

Procedure:
Under a dry argon atmosphere a solution of 1.6 grams (0.008 mole) of 2-(4-chlorophenyl)-3-pyrazolidinone in 13 ml of tetrahydrofuran was added dropwise to a stirred mixture of 0.4 gram (0.009 mole) of sodium hydride (55% oil suspension, oil removed by washing with hexane) in 8 ml of dry tetrahydrofuran while at room temperature. After complete addition, the reaction mixture was heated at 50° C. until gas evolution ceased, then cooled to room temperature. A solution of 1.4 grams (0.008 mole) of 4-chlorophenyl isothiocyanate in 8 ml of tetrahydrofuran was added to the reaction mixture and the resultant mixture stirred at room temperature for 14 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture and the total extracted with ethyl acetate. The organic extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The solvent was removed by distillation under reduced pressure leaving a solid residue. The solid was purified by recrystallization from ethanol to afford 1.4 grams of 1-(4-chlorophenyl)thiocarbamoyl-2-(4-chlorophenyl)-3-pyrazolidinone (mp 121°-124° C.).
Reaction SMILES: F[C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClC1C=CC2[S:18][C:17]([SH:19])=NC=2C=1>>[F:9][C:8]1[C:2]2[S:18][C:17]([SH:19])=[N:4][C:3]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: Nc1cccc(F)c1F
Product: Fc1cccc2nc(S)sc12
Temperature: 90 °C

Procedure:
The title compound was prepared from 2,3-difluoroaniline as described for 5-chloro-2-mercaptobenzothiazole except that in the first step the reaction mixture was heated to 90° C. for 4 h.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3=[CH:13][N:14]=[C:15]([C:17]4[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[CH:16]=[C:11]3[C:10]([C:25](=[O:31])[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:9]2)[CH:5]=[C:4]([CH2:32][CH3:33])[N:3]=1.[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3=[CH:13][N:14]=[C:15]([C:17]4[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[CH:16]=[C:11]3[C:10]([CH:25]([OH:31])[CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[CH:9]2)[CH:5]=[C:4]([CH2:32][CH3:33])[N:3]=1
Reactant: CCc1cc(-n2cc(C(=O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cc(-n2cc(C(O)C(CC)CC)c3cc(-c4c(C)cccc4C)ncc32)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[1-(2-chloro-6-ethyl-pyrimidin-4-yl)-5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one (150 mg, 0.32 mmol) in a (4:1) mixture EtOH—H2O (4 mL) at −30° C., NaBH4 (70 mg, 1.8 mmol) is added, and the mixture is allowed gradually warm up to room temperature at which the reaction is maintained for 2 h. The mixture is concentrated under reduced pressure, and an aqueous saturated Rochelle's salt solution (10 mL) is added. The resulting suspension is stirred at room temperature for 1 h, and the product is extracted with DCM. The obtained solution is washed with brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue on silica gel (hexane-EtOAc, 1:1) gives 1-[1-(2-chloro-6-ethyl-pyrimidin-4-yl)-5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-ol as colorless oil.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2]>C(O)(=O)C.[Pt](=O)=O>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: CC(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1

Procedure:
A mixture of (±)-cis-1-methylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 0.55 g, in glacial acetic acid is hydrogenated with platinum dioxide at 50 pounds per square inch (PSI). Concentration, dilution with ethyl acetate and bicarbonate wash, followed by washing with brine and drying provides 250 mg of (±)-cis-1-methylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate. MS 260.1, 244.1
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.CN([CH:25]=[O:26])C>C1COCC1>[Br:13][C:14]1[C:15]([CH:25]=[O:26])=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(C=O)c(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine in THF (0.1M) at 0° C. was added n-BuLi (1.1 eq.). The solution was stirred for 30 min and then was cannulated in a solution of commercially available 5-bromo-2-methoxypyridine in THF (0.1M) at −78° C. The resulting solution was stirred at −78° C. for 30 min then DMF (1.5 eq.) was added. Final reaction mixture was allowed to warm to 0° C. before it was quenched with saturated aqueous NH4Cl and then extracted with EtOAc. The organic extract was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) afforded the desired compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[N:11]\[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13].C1COCC1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[NH:11][S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13]
Reactant: CC(C)(C)[S@](=O)/N=C1\CCc2c(Br)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N[C@H]1CCc2c(Br)cccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred suspension of crude (S,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide IND INT-9 in toluene (250 mL) under N2 was added anhydrous THF (250 mL) and the reaction mixture was cooled to −78° C. Sodium borohydride (26.8 g, 710 mmol) was added in four portions over 30 min (internal temperature maintained below −65° C.). The reaction mixture was stirred at −78° C. for 30 min before it was warmed to room temperature over 1 h and continued to stir for additional 1 h. The reaction mixture was filtered through Celite pad to remove Ti salts. The filtrate was treated with EA (500 mL), saturated sodium potassium tartrate (200 mL), and brine (50 mL) and the mixture stirred at room temperature overnight. The mixture was filtered through a celite pad and the filtrate dried over MgSO4. The crude product was obtained by concentration to dryness gave 46 g (61%) of (S)-N-((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide IND INT-11 as an off-white solid which was used in the next experiment without purification. LCMS-ESI (m/z) calculated C13H16BrNOS: 313.0; found 314.0 [M+H]+, tR=3.84 min.