Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)[C:2]#[CH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[C:14]([CH3:21])[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:6](=[O:8])[CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:19]2=[S:20])=[C:14]([CH3:21])[CH:13]=1
Reactant: C#CCNCC(=O)OCC
Reactant: Cc1cc(Cl)ccc1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN1CC(=O)N(c2ccc(Cl)cc2C)C1=S
Temperature: 25 °C
Yield: 26.6 %

Procedure:
A mixture of ethyl N-propargylaminoacetate (10.0 g), 4-chloro-2-methylphenylisothiocyanate (12.9 g), triethylamine (7.1 g), and methylene chloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1 N HCl (100 mL), then with water. The organic layer was dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid was collected by filtration. Recrystallization from Hexane-EtOAc afford the title compound (5.2 g) as yellow solid, m.p. 99°-102° C. Anal. Calcd. for. C13H11N2O Cl S: C, 56.01; H, 3.98; N, 10.05. Found: C, 55.61; H, 3.83; N, 10.0. Mass spectrum (EI, M.+) m/z 278.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[N+:20]([O-])=O)/[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>C(O)(=O)C.O.C(OCC)(=O)C.[Fe]>[NH2:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1/[CH:12]=[C:8](\[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)/[C:9]([OH:11])=[O:10]
Reactant: O=C(O)/C(=C/c1ccc(Cl)cc1[N+](=O)[O-])c1ccc(Br)cc1
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(Cl)ccc1/C=C(/C(=O)O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
To a 50° C. solution of 135 g of (2E)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid from Step 1 in 1.2 L of acetic acid and 80 mL of water, was added 98 g of iron (powder) portion wise maintaining the temperature below 50° C. The mixture was stirred 2 hrs at 50° C., cooled down to room temperature, diluted with ethyl acetate (1 L) and filtered through a plug of celite. Water (1 L) was added, the layers were separated and the organic layer was washed 2 times with water, brine, dried over magnesium sulphate and volatiles were removed under reduced pressure. Residual acetic acid was removed by the addition of 1 L of H2O to the crude mixture, the solution was filtered and washed with an additional 1 L of H2O and finally the solid was dried under high vacuum to afford 130 g of (2E)-3-(2-amino-4-chlorophenyl)-2-(4-bromophenyl)acrylic acid.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[C:6]1([CH:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: O=C(O)C(Nc1ccccc1)c1ccccc1
Yield: 97 %

Procedure:
α-Bromophenylacetic acid (5.01 g, 23.2 mmol.) is dissolved in aniline (25 mL, 274 mmol) and the mixture reacted in a closed vessel under MW irradiation at 120° C. for 5 minutes (LC-MS monitoring: complete conversion). Dichloromethane (DCM) (100 mL) is added to the reaction mixture and the resulting solid is filtered; 2M Na2CO3 (50 mL) is added to the solution, and the aqueous layer is washed with DCM (3×100 mL). The aqueous layer is acidified with 12N HCl (36 mL), and the title compound is recovered as racemic mixture by filtration (5.1 g, 97% yield, white solid).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: NCCCO
Product: O=C(NCCCO)c1cc2ccccc2s1
Yield: 52.3 %

Procedure:
2-Benzothiophenecarboxylic acid (5.0 g, 28.05 mmol) and 3-amino-1-propanol (2.57 ml, 33.66 mmol) were coupled according to the procedure of Example 22 to provide 3.45 g (52.3% yield) of the desired product as an orange solid. Electrospray Mass Spec: m/z 235.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:32])(=[N:27][C:28](=[O:31])[NH:29][CH3:30])=[O:26])=[CH:21][CH:20]=1>>[CH3:30][NH:29][C:28]([N:27]=[S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:20][CH:21]=1)([CH3:32])=[O:26])=[O:31]
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CNC(=O)N=S(C)(=O)c1ccc(N)cc1
Product: CNC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Yield: 23.5 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (164.5 mg, 0.61 mmol) with (RS)—S-(4-aminophenyl)-N-(methylcarbamoyl)-S-methylsulphoximide (126 mg, 0.55 mmol) according to procedure 5c, the desired product is obtained in 23.5% yield (60 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2[N:23]2[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]2)[CH2:5][CH2:4]1.CO>[Pd].C1COCC1>[F:31][C:2]([F:1])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2[N:23]2[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]2)[CH2:5][CH2:4]1
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1c(N)cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F

Procedure:
The sub-title compound is prepared in analogy to procedure 6b from (R)—N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3-fluoro-pyrrolidinyl]-3-fluoro-4-methylamino-5-nitro-benzoic acid amide (230 mg, 0.51 mmol), Pd/C (20 mg), MeOH (15 mL), THF (5 mL) and 3 bar H2-atmosphere. Yield: 215 mg.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:6][CH2:7][C:8](=[O:13])[N:9]([CH3:12])[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:2]2[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]3[O:6][CH2:7][C:8](=[O:13])[N:9]([CH3:12])[C:10]=3[N:11]=2)=[CH:29][N:30]=1
Reactant: CN1C(=O)COc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)COc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 120 °C
Yield: 71.6 %

Procedure:
A mixture of 2-chloro-8-methyl-4-morpholin-4-yl-8H-pyrimido[5,4-b][1,4]oxazin-7-one (100 mg, 0.35 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (116 mg, 0.53 mmol), Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) and sodium carbonate (1.0 mL, 1.0 mmol, 1M aqueous solution) in acetonitrile (4 mL) was degassed then heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 120 as a white solid (86 mg, 71%). LCMS: RT=3.04 min, [M+H]+=344. 1H NMR (400 MHz, CDCl3): δ 9.14 (2H, s), 5.25 (2H, broad s), 4.62 (2H, s), 3.81 (8H, s), 3.49 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[Li+].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH3:28])[C:8](=[O:26])[C:9]=1[N:10]2[S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCCC3=O)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCC(C)C3=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 328.9 %

Procedure:
5,6-Dichloro-9-tosyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 5b) (0.15 g, 0.036 mmol) was dissolved in dry THF, cooled to −78° C. and LiHMDS (0.8 mL, 0.88 mmol, 1M solution in THF) was added dropwise. The reaction mixture was slowly warmed to 0° C. and stirred for an additional 30 min. The reaction mixture was cooled to −78° C. and MeI (0.05 ml, 0.88 mmol) was added slowly, and the reaction mixture was slowly, warmed to room temperature and stirred for 4 h. The reaction was cooled to 0° C. and quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2×50 ml). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material obtained was purified by column chromatography using [EtOAc-hexane (1:9) as eluant] to afford the title compound (0.05 g, 32%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.22 (d, J=8.5 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.54 (d, J=9 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 3.55-3.49 (m, 1H), 3.22-3.15 (m, 1H), 2.68-2.64 (m, 1H), 2.42 (s, 3H), 2.27-2.22 (m, 1H), 1.95-1.87 (m, 1H), 1.25-1.17 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])(C)C)=[O:10].[BH4-].[Na+].O.[C:19](OCC)(=O)[CH3:20]>CO>[OH:8][CH:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][CH2:12][CH2:15][CH2:19][CH3:20])=[O:10])[CH:2]([CH3:1])[CH2:7]1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCOC(=O)N1CCC(O)CC1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (0.94 g, 4.41 mmol) in methanol (5 mL) was added sodium borohydride (0.22 g, 5.73 mmol) and the reaction was stirred at room temperature for 1 h. Water was added slowly, followed by ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product as a mixture of four stereoisomers, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C@H:11]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)[CH2:12]2)[CH3:9])=[CH:4][C:3]=1[O:26][CH3:27].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C@H:11]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=3)[CH2:12]2)[CH3:9])=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COC(=O)c1ccc([C@@H]2CC[C@H](N[C@H](C)c3ccc(F)c(OC)c3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc([C@@H](C)N[C@H]2CC[C@@H](c3ccc(C(=O)O)cc3)C2)ccc1F

Procedure:
Methyl 4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxyphenyl)ethyl]amino]-cyclopentyl]benzoate (preparation 33) (89 mg) in methanol (1 mL) was treated with 2M NaOH at r.t. for 2 h. After removal of the solvent in vacuo, 2M acetic acid was added to pH 4. The resulting precipitate was collected on a filter, washed with water and dried to afford the title compound. 1H NMR (300 MHz, DMSO) δ 7.78 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.2 Hz, 3H), 7.10 (dd, J=11.5, 8.3 Hz, 1H), 6.89 (ddd, J=8.2, 4.5, 1.9 Hz, 1H), 3.85-3.73 (m, 4H), 2.98-2.82 (m, 2H), 2.14-2.01 (m, 1H), 1.97-1.54 (m, 4H), 1.36 (td, J=11.7, 8.9 Hz, 1H), 1.25 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([C:35]3([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)=[S:3].Br[CH2:48][C:49](OCC)=[O:50]>CCO.C1COCC1.C(Cl)(Cl)Cl>[O:50]=[C:49]1[CH2:48][S:3][C:2]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[N:12]=[C:13]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[NH:17][C:16]5[N:24]=[CH:25][CH:26]=[CH:27][C:15]=5[N:14]4[C:28]=3[C:29]3[CH:34]=[CH:33][C:32]([C:35]4([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])[CH2:36][CH2:37][CH2:38]4)=[CH:31][CH:30]=3)=[CH:9][CH:10]=2)=[N:1]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC(N)=S)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC5=NC(=O)CS5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 70 °C
Yield: 91.7 %

Procedure:
To a solution of tert-butyl {1-[4-(2-{4-[(aminocarbonothioyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (53 mg, 0.083 mmol) in EtOH (2 mL), THF (1 mL) and CHCl3 (1 mL) was added ethyl bromoacetate (0.01 mL, 0.09 mmol). The reaction was heated at 70° C., 1.5 h. The reaction mixture was cooled to room temperature, then concentrated. Purification by column chromatography (SiO2, 50% to 100% EtOAc in hexane) gave the title compound as a yellow solid (51 mg, 91%). 1HNMR (CDCl3) 400 MHz δ: 8.16 (d, J=8.0 Hz, 1H), 8.02-8.01 (m, 1H), 7.62-7.61 (m, 2H), 7.40-7.35 (m, 2H), 7.32-7.29 (m, 1H), 7.20-7.13 (m, 3H), 7.05-7.04 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.80-6.78 (m, 1H), 6.60 (dd, J=8.0, 4.6 Hz, 1H), 6.36 (br s, 1H), 5.18 (br s, 1H), 3.90-3.88 (m, 2H), 2.54-2.52 (m, 4H), 2.16-2.12 (m, 1H), 1.92-1.90 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH2:5][C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:12])[CH:5]=[CH:6]2
Reactant: CC1CC(=O)c2cccc(Br)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1C=Cc2cccc(Br)c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 116 g (0.52 mol) of 4-bromo-3-methylindan-1-one in 950 ml of a mixture of THF-methanol (2:1, vol.) 38.3 g (1.02 mol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 1000 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 1500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 2 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The product was isolated by vacuum distillation (bp 104-108° C./5 mm Hg). Yield 100 g (93%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)N=Cc2cccc(Cl)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=S1(=O)NCc2cccc(Cl)c21
Temperature: 0 °C
Yield: 97.4 %

Procedure:
A suspension of 17.9 g of 7-chloro-1,2-benzisothiazole-1,1-dioxide in 180 ml of absolute ethanol was cooled to 0° C. and treated with 3.33 g of sodium borohydride at such a rate that the temperature remained below 5° C. The mixture was warmed to room temperature for 30 minutes, recooled to 0° C. and treated with glacial acetic acid to destroy excess hydride. The mixture was concentrated to dryness, the resulting solid suspended in water, filtered, washed with water and dried in vacuo at 50° C. for 16 hours to give 17.6 g of the title compound as a white powder, m.p. 159°-161°0 C.
Reaction SMILES: [CH3:1][N:2](C=O)C.C1COCC1.CN(C)[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][CH:21]=2)[NH:16][CH:15]=1.[C-]#N.[K+]>O>[N+:23]([C:19]1[CH:18]=[C:17]2[C:22]([C:14]([CH2:13][C:1]#[N:2])=[CH:15][NH:16]2)=[CH:21][CH:20]=1)([O-:25])=[O:24]
Reactant: CN(C)Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Yield: 36 %

Procedure:
To a mixture of DMF (35 mL) and Mel (74.6 g, 0.53 mol) in water (35 mL) and THF (400 mL) was added dimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine (23 g, 0.105 mol). After the reaction mixture was refluxed for 10 min, potassium cyanide (54.6 g, 0.84 mol) was added and the mixture was kept refluxing overnight. The mixture was then cooled to room temperature and filtered. The filtrate was washed with brine (300 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (7.5 g, 36%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:15]([O:14][C:12](=[O:13])[CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2])([CH3:18])([CH3:17])[CH3:16]
Reactant: N#Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccccc1C#N
Yield: 92.7 %

Procedure:
2-Cyanophenol (107.1 g) is dissolved in acetone (1000 ml) and is added t-butyl bromoacetate (200.0 g). Furthermore, potassium carbonate (141.6 g) is added, and then the reaction solution is heated under reflux for 2 hours. After allowing to cool, the insoluble materials are removed by filtration, and then the insoluble materials are washed with acetone several times. The filtrate and the washing are combined, concentrated under reduced pressure and treated with diisopropyl ether azeotropically. The resulting residue is crystallized from n-hexane-diisopropyl ether (5/1) (600 ml), and then stirred under ice-cooling. The precipitates are collected by filtration, washed with cold n-hexane-diisopropyl ether (10/1) (600 ml) several times and dried to give the title compounds (194.5 g).
Reaction SMILES: [OH-].[K+].[CH2:3]([CH:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CO>[CH2:3]([CH:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC1CCC(=O)C1CCCCCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC1CCC(=O)C1CCCCCCC(=O)O
Yield: 27.4 %

Procedure:
A potassium hydroxide (15 g, 0.27 mole) solution in methanol (30 ml) is added with a solution of ester (VIII) (50 g, 0.16 mole) in methanol (120 g). The reaction mixture is refluxed for 2 hours. It is then cooled and concentrated under reduced pressure, poured into water (200 ml) and acidified with conc. hydrochloric acid. It is then extracted with ethyl acetate (3×100 ml). The acid (IX) (13 g) is obtained. Yield=27%.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:17]=2[Cl:16])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: Clc1cccc(CBr)c1Cl
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1cccc(Cl)c1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 73 and 2,3-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](B2OC(C)(C)C(C)(C)O2)=[C:7]([NH:9]C(=O)OC(C)(C)C)[CH:8]=1.Br[C:27]1[C:28]([C:33]#[N:34])=[N:29][CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.CO.ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2=[C:27]3[C:28](=[C:33]([NH2:34])[N:9]=[C:7]2[CH:8]=1)[N:29]=[CH:30][CH:31]=[CH:32]3
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: N#Cc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)nc(N)c1ncccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from step 3) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene/ethanol (10:1, 0.23 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and anhydrous potassium carbonate (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% methanol in dichloromethane to give a semipure solid, which was then recrystalized in ethyl acetate, filtered, and dried to give a pure solid. 1H NMR (acetone d-6): δ 8.91 (d, 1H), 8.82 (d, 1H), 8.33 (d, 1H), 7.76-7.79 (dd, 1H), 7.07 (s, 1H), 6.96 (d, 1H), 6.6 (br, 2H), 3.90 (s, 3H). LRMS [M+H]=226.1
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([C:1]([Cl:23])=[O:2])=[CH:5][CH:6]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:11]1=[O:12]
Reactant: O=C(O)c1ccc(N2C(=O)CCc3ccccc32)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(N2C(=O)CCc3ccccc32)cc1

Procedure:
To a solution of 1-(4-carboxyphenyl)-3,4-dihydrocarbostyril (0.2 g) in chloroform (5 ml) is added thionyl chloride (0.8 ml) and the mixture is refluxed with heating for 1 hour. Then, chloroform and thionyl chloride are distilled off under reduced pressure to give 4-(3,4-dihydrocarbostyril-1-yl)benzoic acid chloride.