Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:4]2([CH2:42][O:41][C:7]3([CH2:12][CH2:11][CH:10]([N:13]4[C:18](=[O:19])[C:17]([CH2:20][C:21]5[CH:26]=[CH:25][C:24]([C:27]6[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=6)=[CH:23][CH:22]=5)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]5[N:38]=[CH:39][N:40]=[C:14]45)[CH2:9][CH2:8]3)[O:6][CH2:5]2)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].O1CCCC1>C(OCC)(=O)C>[OH:41][CH2:42][C:4]1([CH2:5][O:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:25][CH:26]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[CH2:3][CH2:2][CH2:1]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC2(CCC2)CO3)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CO)CCC3)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-{[4-(6,13-dioxadispiro[3.2.5.2]tetradec-10-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.7 g), sodium cyanoborohydride (1.3 g), boron trifluoride-diethyl ether complex (2.5 mL) and tetrahydrofuran (50 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.8 g, 47%).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:4]=2[CH2:3]1>[Pd].CO>[NH2:13][C:10]1[CH:11]=[CH:12][C:4]2[CH2:3][S:2](=[O:16])(=[O:1])[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=1
Reactant: O=C1NS(=O)(=O)Cc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)NS(=O)(=O)C2
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
A mixture of 3,4-dihydro-2,2-dioxo-6-nitro-4-oxo-1H-2,3-benzothiazine (267 mg, 1.1 mmol) and 10% palladium on carbon (26 mg, 10% (w/w)) in methanol (50 ml) was hydrogenated at 50 psi for 30 min. The mixture was then filtered, the solid washed with methanol and the filtrates evaporated in vacuo to give the title compound (239 mg, 100%) as a yellow solid. 1H NMR (360 MHz, D6-DMSO) δ 3.87 (2H, s), 5.11 (2H, brs), 6.59 (1H, dd, J=8.0 and 2.5 Hz), 6.88 (1H, d, J=8.0 Hz), 7.15 (1H, d, J=2.5 Hz). MS (FAB) 211 (M-1).
Reaction SMILES: [Na].[CH2:2]([O:9][N:10]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:11]1[CH2:12][CH2:13][C@H:14]2[C:19](O)=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH2:2]([O:9][N:10]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:11]1[CH2:12][CH2:13][C@H:14]2[CH2:19][OH:20])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C1N2C[C@@H](CC[C@H]2CO)N1OCc1ccccc1
Temperature: -10 °C
Yield: 99 %

Procedure:
The sodium salt of (2S, 5R)-6-benzyloxy-7-oxo-1, 6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid (II) (50 g, 0.16 moles, prepared as per the procedure described in Indian Patent Application No. 699/MUM/2013) was suspended in tetrahydrofuran (500 ml). To the suspension was added N-methyl morpholine (18.4 ml, 0.16 moles) under stirring. The reaction mixture was cooled to about −10° C. and ethyl chloroformate was added via addition funnel and stirred for 1 hour at about −10° C. To the reaction mixture was added NaBH4 (9.56 g, 0.25 moles) in lots under stirring. The reaction was monitored with the help of thin layer chromatography (TLC). After completion of reaction, water (500 ml) followed by ethyl acetate (500 ml) was added to the reaction mass. The reaction mixture was stirred for 30 minutes and the layers were separated. Organic layer was washed with brine (200 ml). The solvent was evaporated under vacuum to dryness to provide 43 g of (2S, 5R)-6-(benzyloxy)-2-(hydroxymethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1] octane (III) as a pale yellow oil (99% yield).
Reaction SMILES: Cl[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14]>>[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:18]2[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH:12]([CH3:11])[CH3:28])[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O[C@@H](CCl)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (1R)-2-chloro-1-phenylethanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 367.2 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[CH:7][CH:6]=1)C=C.Cl[C:15]1[CH:20]=CC=C[C:16]=1Cl>>[CH2:20]([C:13]1[C:5]([OH:4])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:15]=[CH2:16]
Reactant: C=CCOc1ccc2cn[nH]c2c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2cn[nH]c12
Yield: 60 %

Procedure:
A solution of the product from Step A (14.2 g, 82 mmol) in 1,2-dichlorobenzene (90 mL) was fluxed for 6 h and the reaction mixture was evaporated to a residue which was purified by chromatography (silica, EtOAc) to give a tan solid (8.59 g, 60%) that was used in the next step: LC/MS (+APCI) m/z 175 (M+H).
Reaction SMILES: CC([O-])=O.[Na+].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=O)[CH2:17][S:16](=[O:21])(=[O:20])[N:15]([CH3:22])[C:14]=2[CH:23]=1)=[O:9].Cl.[NH2:25][OH:26]>CCO>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[N:25][OH:26])[CH2:17][S:16](=[O:21])(=[O:20])[N:15]([CH3:22])[C:14]=2[CH:23]=1)=[O:9]
Reactant: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2=NO

Procedure:
NaOAc (3.66 g, 44.5 mmol) was added to an EtOH (100 mL) solution of 1-methyl-2,2,4-trioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazine-7-carboxylic acid methyl ester (4.00 g, 14.8 mmol) and hydroxylamine hydrochloride (1.55 g, 22.3 mmol). After heating at reflux for 4 days, it was evaporated, diluted with CH2Cl2 (400 mL), washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo. Crystallization from MeOH provided the title compound. MS (−APCI, m/z): 283 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][C:6]=1[C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[S:3][C:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][C:6]=1[C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:26]
Reactant: CCCCCCc1cc(C(=O)c2ccc(OC)cc2)c(N)s1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: CCCCCCc1cc(C(=O)c2ccc(OC)cc2)c(NC(=O)CCl)s1
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a solution of 28 g of 2-amino-3-(4-methoxybenzoyl)-5-hexylthiophene in 150 ml of chloroform is added 10 g of chloroacetyl chloride and the mixture is refluxed under heating with stirring for 2 hours. After cooling, the mixture is washed with 5% aqueous sodium hydrogencarbonate solution and sodium chloride solution, and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from ethanol to give 16.2 g of 2-chloroacetamido-3-(4-methoxybenzoyl)-5-hexylthiophene as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:26]1[CH2:28][CH2:27]1)[CH:9]([C:11]1[CH:12]=[C:13]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:25])[O:23][CH3:24])[C:14](Cl)=[N:15][CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](B1OC(C)(C)C(C)(C)O1)=[CH2:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[C:1]([O:5][C:6]([N:8]([CH:26]1[CH2:28][CH2:27]1)[CH:9]([C:11]1[CH:12]=[C:13]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:25])[O:23][CH3:24])[C:14]([CH:29]=[CH2:30])=[N:15][CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)NCCCc1cc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ncc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cc1CCCNC(=O)OC
Temperature: 85 °C
Reaction time: 17 h

Procedure:
to a solution of methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-chloropyridin-3-yl)propyl]carbamate (380 mg) in dimethoxyethane (8 mL) were added vinyl boronic acid pinacol ester (235 μL), 2M sodium carbonate (1.38 mL) and dichlorobis(triphenylphosphine)palladium (II) (65 mg), and the mixture was stirred at 85° C. for 17 hours. The reaction solution was cooled, and then an insoluble was filtered off through Celite, and to the filtrate was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1→1/4) to give methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-vinylpyridin-3-yl)propyl]carbamate [REx(113-6)] (282 mg) as a pale yellow oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([Br:13])[CH:9]=[CH:10][CH:11]=2)[C:6](=O)[CH2:5]1)(=O)C.BrBr.[CH2:17]([NH2:20])[CH2:18][NH2:19].C(N(CC)CC)C>C(Cl)Cl.CO>[Br:13][C:8]1[C:7]2[C:6]3[N:20]=[CH:17][CH:18]=[N:19][C:5]=3[NH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: NCCN
Reactant: CC(=O)N1CC(=O)c2c(Br)cccc21
Agent: BrBr
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1cccc2[nH]c3nccnc3c12
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
1-Acetyl-4-bromo-1,2-dihydro-indol-3-one (460 mg, 1.81 mmol) was dissolved in CH2Cl2 (8 mL). Bromine (111 μL, 2.2 mmol) was added slowly, and the reaction stirred for 20 min and then was concentrated in vacuo. The residue was dissolved in THF (8 mL). Ethylenediamine (244 μL, 3.6 mmol) was added, and the reaction stirred for 16 h at r.t. Triethylamine (2 mL) and MeOH (4 mL) were added, and the reaction stirred while left open to air for 24 h. The solution was concentrated in vacuo and purified by silica gel chromatography (8% MeOH/CH2Cl2) to provide the title compound as a red solid (248 mg, 55%). MS (ES) [m+H] calc'd for C10H6BrN3, 248, 250; found 248, 250.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[OH:25])[N:8]=2)[CH2:3]1.[CH:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:25])[C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(O)C1CC1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)C4CC4)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (100 mg, 0.295 mmol) in 10 mL DMF, at −2° C., was added cyclopropanecarboxylic acid (23 μL, 0.30 mmol), followed by the addition of triethylamine (82 μL, 0.59 mmol) and a solution of HATU (124 mg, 0.32 mmol) in 4 mL DMF. The mixture was warmed to room temperature and stirred for 1 h. Cold water was added to the reaction mixture which resulted in the formation of a precipitate which was collected by filtration and dissolved in CH2Cl2. The solution was then dried over MgSO4, filtered, and concentrated to afford N-((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide (80 mg, 66%) LC/MS: m/z 407.5 (M+H)+ at 2.08 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([N:8]([CH2:14][C:15]([F:23])([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)C.[OH-].[OH-].[Pd+2]>[CH:9]1([NH:8][CH2:14][C:15]([F:23])([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)C(F)(CC)CN(Cc1ccccc1)C1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C(F)(CC)CNC1CCCC1
Yield: 87.7 %

Procedure:
A solution of ethyl 2-((benzyl(cyclopentyl)amino)methyl)-2-fluorobutanoate (2.2 g, 6.8 mmol) in ethanol (20 mL) was hydrogenated with Pd(OH)2 (20%, 240 mg, 0.34 mmol) in presence of TFA (6.8 mmol) at atmospheric pressure for 20 h. The reaction mixture was filtered through celite. The filtrate was concentrated and diluted to EtOAc/H2O, aqueous layer was basified to pH=11-12 by 1N NaOH. The organic layer was then dried and concentrated to give the product (1.38 g, 88%) as light yellow liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (t, J=7.6 Hz, 3H) 1.31 (t, J=7.1 Hz, 4H) 1.41-1.94 (m, 9H) 2.88-3.08 (m, 3H) 4.26 (qd, J=7.12, 2.40 Hz, 2H). [M+H] calc'd for C12H22FNO2, 232. found 232.
Reaction SMILES: COC([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH:7]([CH2:17][CH:18]=[CH2:19])[C:6]1=[O:20])=O.[Cl-].[Li+]>CS(C)=O.O>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH2:5][C:6](=[O:20])[CH:7]([CH2:17][CH:18]=[CH2:19])[CH2:8]2
Reactant: C=CCC1Cc2cccc(OC)c2C(C(=O)OC)C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCC1Cc2cccc(OC)c2CC1=O
Temperature: 125 °C
Yield: 94.1 %

Procedure:
To a solution of 10.3 g (37.6 mmol) of 1,2,3,4-tetrahydro-8-methoxy-2-oxo-3-(2-propenyl)-1-naphthalene carboxylic acid methyl ester in 26.3 mL of DMSO and 1.1 mL of water was added 1.9 g (45.1 mmol) of lithium chloride. The reaction mixture was heated at 125° C. (bath temperature) for five hours. TLC analysis showed no starting material remaining. The mixture was cooled to room temperature and extracted with ethyl acetate (1 L). The organic layer was washed with 10% aqueous calcium sulfate (an efficient way of removing DMSO from organic layer), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by liquid chromatography on 800 g silica gel 60 (230-400 m), eluting with hexane-ethyl acetate (3:1), and collecting 40 mL fractions. Fractions 26-53 gave 7.65 g (94%) of pure title compound as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[C:25]1([CH:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:39]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][C:4]3([CH3:24])[CH2:8][C:7]4[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=4[O:5]3)[CH2:35][CH2:34]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCBr)O2
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCN1CCC(OC(c3ccccc3)c3ccccc3)CC1)O2
Temperature: 60 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
A suspension of tert-butyl [2-(2-bromoethyl)-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate (1.2 g), 4-(diphenylmethoxy)piperidine (0.85 g), and potassium carbonate (0.44 g) in N,N-dimethylformamide (20 mL) was stirred at 60° C. for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=98:2 to 95:5) to provide 1.6 g of the title compound. Yield 92%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]([CH3:12])[C:7]=1[C:8](=[O:11])[CH2:9][CH3:10].I[CH3:21].[OH-].[K+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:21][N:13]([C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[C:2]([CH3:1])[CH:3]=1)[C:14](=[O:19])[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CCC(=O)c1c(C)cc(NC(=O)OC(C)C)cc1C
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(=O)c1c(C)cc(N(C)C(=O)OC(C)C)cc1C
Temperature: 0 °C
Reaction time: 12 h
Yield: 93.8 %

Procedure:
Isopropyl N-(3,5-dimethyl-4-propionylphenyl)carbamate (2.63 g) and iodomethane (4.30 g) were dissolved in tetrahydrofuran (10 ml). The resultant solution was dropwise added to a solution containing potassium hydroxide (1.68 g) and tetra-n-butylammonium bromide (1.0 g). After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesiunm sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-methyl-N-(3,5-dimethyl-4-propionylphenyl)carbamate (Compound No. 40) (2.60 g) in a yield of 93.8%. nD20.0 1.5120.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[N:9]1[C:14]2[NH:15][C:16]3[CH:36]=[CH:35][CH:34]=[CH:33][C:17]=3[N:18]([C:20]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][C:23]=3[C:29]([F:32])([F:31])[F:30])=[O:21])[CH2:19][C:13]=2[CH:12]=[CH:11][CH:10]=1>CCCCCC>[CH3:3][C:4]1[CH:8]=[CH:7][N:6]([C:25]2[CH:26]=[CH:27][C:22]([C:20]([N:18]3[C:17]4[CH:33]=[CH:34][CH:35]=[CH:36][C:16]=4[NH:15][C:14]4[N:9]=[CH:10][CH:11]=[CH:12][C:13]=4[CH2:19]3)=[O:21])=[C:23]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[N:5]=1
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(C(F)(F)F)c2)n1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Sodium hydride (60% suspension in oil, 0.83 g, 20.8 mmol) was washed once with hexane, dried under nitrogen and resuspended in dry dimethylformamide (60 mL). 3-methyl pyrazole (0.90 mL, 11.2 mmol) was added in one portion. After the gas evolution subsided the stirring was continued at room temperature. The (6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-(4-fluoro-2-trifluoromethylphenyl)-methanone of Step B (3.6 g, 9.3 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) for 30 minutes. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 25% ethyl acetate in hexane provided 3.3 g of the desired product as a foam which crystallized by sonication from ethanol-hexane, m.p. 212-214° C. Further elution with 30% ethyl acetate in hexane yielded the more polar 5-methylpyrazole regioisomer of Example 6.
Reaction SMILES: CS(C)=O.[C-:5]#[N:6].[Na+].[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](Cl)=[N:16][O:17][CH3:18]>CCOCC>[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](=[N:16][O:17][CH3:18])[C:5]#[N:6]
Reactant: CON=C(Cl)c1ccccc1COc1cc(C)ccc1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Dimethyl sulfoxide (2 ml) and 95% sodium cyanide (0.21 g, 0.004 mol) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl chloride (0.60 g, 0.002 mol), and the mixture was stirred at 110° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetonitrile (0.45 g, 76.4%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(N)(=O)=O)cc1Br
Product: Cc1ccc(S(N)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-methylbenzenesulfonamide (Intermediate 152), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [ClH:1].Cl.C(OC([N:10]1[CH2:16][CH2:15][C:14](=[NH:17])[NH:13][CH2:12][CH2:11]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[ClH:1].[NH:17]=[C:14]1[CH2:15][CH2:16][NH:10][CH2:11][CH2:12][NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N=C1CCNCCN1
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Hydrogen chloride gas (2.0 g, 55 mmol) was bubbled into 15 mL of ethyl acetate at 0° C. over 3 min. 1-(tert-Butoxycarbonyl)-5-iminohexahydro-(1H)-1,4-diazepine hydrochloride (85 mg, 0.34 mmol ) was added and mixture was stirred at room overnight. Removal of solvent and hydrogen chloride in vacuo gave 60 mg (95%) of hexahydro-5-imino-(1H)-1,4-diazepine dihydrochloride as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][C:24]#[N:25].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:23]([C:24]#[N:25])([C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
To bis(2-chloroethyl)-carbamic acid tert-butyl ester (1.0 g, 3.8 mmol) and 2,4-dichlorophenyl acetonitrile (0.708 g, 3.8 mmol) in DMF (35 ml), NaH (95%) (0.258 g, 9.68 mmol) was added in one batch at 0° C. The solution was stirred for 10 minutes at room temperature. When foaming subsided, the solution was heated at 60° C. for 24 hours. It was then quenched with water at 0° C. and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed three times with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexane:ethyl acetate 4:1) yielded 0.620 g (45%) of the product as a syrup.