Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][CH2:8][C:9]#[CH:10])[CH3:5])[CH3:2].C([Li])CCC.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][CH2:8][C:9]#[C:10][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH3:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#CCCOC(C)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C)OCCC#CC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The product from Example 31A (79.99 g, 0.563 mole) in tetrahydrofuran (1 L) was treated dropwise at −78° C. with n-butyllithium (2.5 M in hexane, 0.563 mole, 225 mL). The reaction mixture was stirred at −78° C. for 30 minutes and then benzyl chloroformate (0.563 mole, 80.4 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hours, allowed to warm to ambient temperature and stirred overnight. After quenching with water, ethyl acetate was added and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and concentrated. Flash chromatography of the residue (silica, hexane to hexane:ethyl acetate, 30:1 to 4:1) provided the title compound as a colorless oil (155.5 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[N:28][OH:29])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1cc(Cl)ccc1Cl)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(CC(=NO)c1cc(Cl)ccc1Cl)c1ccc(Br)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-bromo-phenyl)-1-(2,5-dichloro-phenyl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.4:1) as a white foam, MS (EI): m/z=463 ([M]+, 1Br).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:15][N:16]([C:19]([CH3:29])([CH3:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:17]=2[OH:18])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH3:37][O:38][CH2:39]Cl>CN(C)C=O.C(OCC)C>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:15][N:16]([C:19]([CH3:28])([CH3:29])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[C:17]=2[O:18][CH2:37][O:38][CH3:39])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COCCl
Reactant: CCCCCCc1ccc(-c2c(C(=O)OCC)nn(C(C)(C)Cc3ccc(C)cc3)c2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(-c2c(C(=O)OCC)nn(C(C)(C)Cc3ccc(C)cc3)c2OCOC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
152 mg (0.329 mol) of ethyl 4-(4-hexylphenyl)-5-hydroxy-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxylate was dissolved in 1.6 mL of N,N-dimethylformamide, mixed with 26 mg (0.65 mmol) of 60 wt % sodium hydride (suspended in mineral oil) and 0.050 mL (0.66 mmol) of chloromethyl methyl ether under cooling with ice successively and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether and washed with 1 M hydrochloric acid, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product (crude yield 174 mg).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[N:8]=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1Cl>>[Cl:6][C:7]1[N:8]=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: CC(C)(C)N
Product: CC(C)(C)Nc1c(Cl)cnnc1Cl

Procedure:
Following the general procedure of PREPARATION 41 and making non-critical variations but starting with t-butylamine (66.5 ml), and 3,4,5-trichloropyridazine, the title compound is obtained, NMR (300 MHz, CDCl3) 8.50, 5.09, and 1.55 δ.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH:25]([C:27]1[CH:32]=[CH:31]C(B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:1]3[CH:31]=[CH:32][C:27]([CH:25]=[O:26])=[CH:28][CH:29]=3)[C:10]=12
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1nn([C@H]2CC[C@@H](N3CCN(C)CC3)CC2)c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN(C2CCC(n3nc(-c4ccc(C=O)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 54.3 %

Procedure:
cis-3-Methyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.0 g, 6.80 mmol), 4-formylphenylboronic acid (1.22 g, 8.16 mmol), palladium tetrakistriphenyphosphine (0.47 g, 0.41 mmol) and sodium carbonate (1.73 g, 16.31 mmol) were mixed with ethylene glycol dimethyl ether (70 mL) and water (35 mL). The reaction mixture was heated at reflux overnight under nitrogen. Organic solvent was removed under reduced pressure and the aqueous layer was filtered and washed with water. After drying on the lyophilizer, the residue was purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase to give 4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde (1.55 g, 54%). 1H NMR (DMSO-d6) δ 1.60 (m, 2H), 1.72 (m, 2H). 2.07 (m, 2H), 2.15 (s, 3H), 2.22-2.46 (m, 1H), 4.83 (m, 1H), 7.88 (d, J=8.13 Hz, 2H), 8.07 (d, J=8.10 Hz, 2H), 8.21 (s, 1H), 10.11 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=420.2, Rt=0.70 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6](C)(C)[CH2:5][C:4]=2[N:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([C:15]#[C:16][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Reactant: C#Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1CCCc2nc(C#Cc3ccccc3)ccc21
Yield: 14.7 %

Procedure:
To a solution of 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one (0.2 g, 1.1 mmol) and ethynylbenzene (0.17 g, 1.6 mmol) in triethylamine (7 ml) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium (0.02 g, 0.062 mmol). The mixture was heated at reflux for 3 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.04 g, 15%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:18][C:19](=O)[CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](OC(C)(C)C)=[O:12])[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:18][CH2:19][CH2:20][CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(NC(=O)CC(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c1
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CC(CO)NCCC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
3-Methoxy-α-[(1-oxo-3,3-diphenylpropyl)amino]benzenepropionic acid, 1,1-dimethylethyl ester (1 eq, 1 mmole, 470 mg) was added portionwise to a mixture of lithium aluminum hydride (3 mmole, 3 ml of 1M in tetrahydrofuran) in tetrahydrofuran (5 ml) at 0° C. under argon. After the addition and the cessation of hydrogen evolution, the mixture was brought to reflux. The mixture was refluxed overnight, cooled to room temperature and quenched with solid sodium sulfate.10 water. The solids were removed by filtration through Celite, and the solvent was evaporated in vacuo to yield an oil which crystallized upon standing. The crystals were washed with hexanes/ether, collected, and dried to afford 299.9 mg of the title compound, melting point 89°-91° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[C:18]([C:23]([O:25]CC)=O)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11].[OH-].[Na+]>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([C:23]([NH:1][CH2:2][CH2:10][C:12]3[CH:29]=[CH:28][CH:15]=[CH:14][CH:13]=3)=[O:25])=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:28][CH:29]=1)=[O:11]
Reactant: CCOC(=O)c1nccnc1Oc1ccc(C(=O)c2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1ccc(Oc2nccnc2C(=O)NCCc2ccccc2)cc1)c1nc2ccccc2[nH]1

Procedure:
To the solution of ethyl 3-(4-(1H-benzo[d]imidazole-2 carbonyl)phenoxy)pyrazine-2-carboxylate (30 g, 77 mmol) in methanol (250 mL) was added aqueous NaOH solution (4.62 g, 115 mmol) in 50 mL of water. The reaction mixture was heated to reflux for 1 h. The reaction mixture was concentrated then diluted with water. The aqueous layer was washed with ethyl acetate and then acidified by addition of 2N HCl to pH 6. The precipitate was collected by filtration, dried to give the title compound as a light brown solid. MS [M+H]=351.2.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:31])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2[CH:27]=[C:28]([CH3:30])[CH3:29])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO>[CH3:29][C:28]([CH3:30])=[CH:27][C:18]1[C:19]([C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:31]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C(F)(F)F)c2C=C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=Cc1c(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cccc1C(F)(F)F
Temperature: 25 °C

Procedure:
2-[2-(2-Methyl-propenyl)-3-trifluoromethyl-benzoylamino]-indan-2-carboxylic acid ethyl ester (2) (100 mg, 0.32 mmol) is dissolved in EtOH (20 mL) and set to stir at RT. To this solution is added 5M KOH (2 mL). The reaction mixture is heated to reflux and stirred for 1 h. After concentration in vacuo, the resulting residue is dissolved in water (10 mL) and washed with EtOAc (20 mL). The phases are separated and the aqueous phase is acidified with concentrated HCl to pH 2. The aqueous phase is washed with 50 mL ether (3×). Organic phases are collected, concentrated to dryness, then the resulting residue is purified on an HPLC. The desired product (397) is obtained as white solid (40.0 mg, 43%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)=[CH:11][C:10]=1[Cl:30])=[O:5])C.[OH-].[Na+]>CO>[Cl:30][C:10]1[CH:11]=[C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)[CH:13]=[CH:14][C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1Cl
Yield: 86.1 %

Procedure:
A solution of enantiomerically enriched-(trans)-ethyl-2-[2-chloro-4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]cyclopropanecarboxylate (III-2f) (0.269 g, 0.64 mmol) and 0.75 mL of 15% aqueous sodium hydroxide in 8 mL of methanol was heated at reflux for 1.5 hours. Methanol was evaporated and the residue was dissolved in water and acidified with concentrated hydrochloric acid. The resulting suspension was extracted with dichloromethane, the organic phase was washed with water and dried over anhydrous sodium sulfate and the solvent evaporated to give 0.217 g (86% yield) of the title compound as a white solid. NMR (400 MHz, CDCl3) δ 7.32 (t, J=7.33 Hz, 2H), 7.28 (t, J=7.69 Hz, 1H), 7.09 (t, J=6.41 Hz, 1H), 7.06 (d, J=7.87 Hz, 1H), 6.98 (d, J=7.51 Hz, 2H), 6.99 (m, 1H), 6.90 (dd, J=7.87 Hz, 1.65 Hz, 1H), 6.80 (d, J=8.42 Hz, 1H), 6.61 (d, J=2.56 Hz, 1H), 6.40 (dd, J=8.42 Hz, 2.38 Hz, 1H), 4.26 (s, 2H), 2.66 (m, 1H), 1.70 (m, 1H), 1.60 (m, 1H), 1.33 (m, 1H). ES-MS m/z 394 (MH)+. [α]25,D=+170° (chloroform, c=1.2). Product was determined to be 98% ee by chiral SFC according to Method 1.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Sn:15](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:24]([Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C#N)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To 4-iodobenzonitrile (2.29 g, 10.0 mmol, 1.00 equiv) in THF (30 mL) at −40° C. was added iPrMgCl (2.0 M in Et2O, 5.50 mL, 11 mmol, 1.1 equiv). The reaction mixture was stirred for 1.0 hr at −40° C. before the addition of nBu3SnCl (3.91 g, 12.0 mmol, 1.20 equiv). After stirring for 1.0 hr at −40° C., the reaction mixture was warmed to 23° C. and quenched with saturated aqueous NH4Cl (30 mL), and Et2O (20 mL) was added. The phases were separated and the aqueous phase was extracted with Et2O (2×20 mL). The combined organic phases were washed with brine (50 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes to afford 3.14 g of the title compound as a colorless oil (80% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:38])[C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][C@H:15]2[NH:25][C:26]([C:28]2[CH:37]=[CH:36][C:35]3[CH2:34][NH:33][CH2:32][CH2:31][C:30]=3[N:29]=2)=[O:27])=[O:12])=[N:7][CH:8]=1.[CH2:39]=O>>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:38])[C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][C@H:15]2[NH:25][C:26]([C:28]2[CH:37]=[CH:36][C:35]3[CH2:34][N:33]([CH3:39])[CH2:32][CH2:31][C:30]=3[N:29]=2)=[O:27])=[O:12])=[N:7][CH:8]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)C(=O)Nc2ccc(Cl)cn2)[C@H](NC(=O)c2ccc3c(n2)CCNC3)C1
Reactant: C=O
Agent: Cl
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)C(=O)Nc3ccc(Cl)cn3)ccc2C1

Procedure:
In a manner similar to that employed in Example 18, the title compound was prepared from the compound obtained in Example 341 and formalin.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[NH2:12][CH2:13][CH:14]1[O:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[OH:22])[CH2:15]1.[BH4-].[Na+]>C(Cl)Cl.CO>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH2:7][NH:12][CH2:13][CH:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]([C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=5)[N:26]=[CH:25][CH:24]=4)[OH:22])[CH2:15]3)=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1ccc2nccc(C(O)CN3CCOC(CN)C3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2nccc(C(O)CN3CCOC(CNCc4ccc5c(c4)OCO5)C3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Activated 3A molecular sieve (3.485 g) and piperonal (0.172 g, 1.15 mmol) were added to a solution of 2-(2-aminomethyl-morpholin-4-yl)-1-(6-methoxy-quinolin-4-yl)-ethanol (0.365 g, 1.15 mmol) in DCM (10.5 ml) and methanol (3.5 ml). The mixture was stirred overnight at room temperature before sodium borohydride (0.112 g, 2.9 mmol) was added. The reaction mixture was stirred at room temperature for a further 2 hours, filtered over Hydromatrix (wetted with NaHCO3) and concentrated. The residue was purified by chromatography on silica gel (DCM:MeOH 9:1+1% NH4OH).
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][CH:20]2[CH:12]([NH:13][C:14]3[CH:15]=[C:16]([Cl:24])[C:17]([Cl:23])=[CH:18][C:19]=32)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)CO>O>[Cl:24][C:16]1[C:17]([Cl:23])=[CH:18][C:19]2[C@@H:20]3[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C@H:12]3[NH:13][C:14]=2[CH:15]=1
Reactant: O=C(c1ccccc1)N1CCC2Nc3cc(Cl)c(Cl)cc3C2CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Clc1cc2c(cc1Cl)[C@@H]1CCNCC[C@H]1N2
Temperature: 170 °C
Yield: 21.8 %

Procedure:
A mixture of 3-benzoyl-8,9-dichloro-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole (0.20 g, 0.55), potassium hydroxide (1.0 g, 17.8 mmol), and ethylene glycol (5 mL) was heated to 170° C. Upon the disappearance of starting material, the reaction was cooled to room temperature, diluted with H2O, and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography and prep HPLC to give the title compound (31 mg, 22%) as a tan solid. 1H NMR (d-MeOH) δ 8.54, 7.02, 6.63, 3.73, 3.08-2.88, 2.40, 2.17, 1.81, 1.65; IR (drift) 2934, 2916, 2866, 2850, 2831, 1627, 1608, 1569, 1481, 1466, 1372, 1365, 953, 775, 662 cm−1; HRMS (FAB) calcd for C12H14Cl2N2+H 257.0612, found 257.0619.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:38][CH3:39])[C:22]([Cl:40])=[CH:21][N:20]=1>>[Cl:40][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[O:38][CH3:39])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(OC)cc2C1
Yield: 27.7 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (100 mg, 0.43 mmol) and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (151 mg, 0.43 mmol) were coupled to provide 8-[5-chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (66 mg, 22%) as a pale yellow foam following flash chromatography on silica gel (0-5% MeOH-DCM); NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.03 (m, 1H), 7.64 (s, 1H), 7.39 (s, 1H), 7.20 (s, 1H), 6.80 (s, 1H), 6.60 (m, 2H), 3.92 (m, 10H), 3.73 (s, 2H), 3.40 (s, 2H), 3.29 (m, 4H), 2.78 (t, J=7 Hz, 2H), 1.20 (t, J=7 Hz, 3H); MS (m/e) 554 (M+1).
Reaction SMILES: CC[O-].[Na+].[CH2:5]([SH:9])[CH2:6][CH2:7][CH3:8].Cl[CH:11]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13][CH2:12]1>C(O)C>[CH2:5]([S:9][CH:11]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13][CH2:12]1)[CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCC(Cl)CCN1
Reactant: CCCCS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCSC1CCNC(=O)CC1

Procedure:
6.8 g (0.1 mol) of sodium ethylate and 9 g (0.1 mol) of butanethiol are initially introduced into 100 ml of ethanol, and 14.8 g (0.1 mol) of 5-chloro-azacycloheptan-2-one are added at room temperature. After the mixture has been boiled under reflux for 10 hours, the precipitated sodium chloride is filtered off under suction, the mother liquor is evaporated down in vacuo and the residue is distilled.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-])=O)[CH3:2]>CO.[Pd]>[NH2:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[CH2:1][CH3:2])[C:7]([OH:9])=[O:8]
Reactant: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C(=O)O)cc1N
Reaction time: 1 h
Yield: 70.7 %

Procedure:
4-Ethyl-3-nitrobenzoic acid (5.0 g, 27.4 mmol) was dissolved in methanol (50 ml) and a Pd-C catalyst (5%, 250 mg) was added thereto. The mixture was stirred under a hydrogen atmosphere from 0° C. to room temperature for 1 hr. After the completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with methyl t-butyl ether/hexane and dried to give the object compound (3.2 g, 70.6%).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)[N:5]=2.[CH:23]1(OC2N=C3C(N=CN3C3CCCCO3)=C(N)N=2)CCCC1>>[Br:1][C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]1[CH2:14][CH2:15][CH2:23][CH2:16]1)[N:5]=2
Reactant: Nc1nc(OC2CCC2)nc2c1nc(Br)n2C1CCCCO1
Reactant: Nc1nc(OC2CCCC2)nc2c1ncn2C1CCCCO1
Product: Nc1nc(OC2CCCC2)nc2c1nc(Br)n2C1CCCCO1

Procedure:
Prepared similarly to Intermediate 56 from 2-(cyclopentyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14]C1C=CC(N)=CC=1OC>>[Cl:14][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1cc(N)ccc1Cl
Product: COc1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-chloro-3-methoxy-phenylamine.