Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@@H:19]([NH:20][C:21]([C:23]3[S:24][C:25]4[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:18][CH2:17][C@@H:16]([C:33]([O:35]C)=[O:34])[CH2:15]1)=[O:12])=[CH:5]2.[OH-].[Li+:38].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C@@H:19]([NH:20][C:21]([C:23]3[S:24][C:25]4[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:18][CH2:17][C@@H:16]([C:33]([O-:35])=[O:34])[CH2:15]1)=[O:12])=[CH:5]2.[Li+:38]
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@H]3CC[C@@H](C(=O)[O-])C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.8 %

Procedure:
The compound (1.20 g) obtained in Example 51 was dissolved in tetrahydrofuran (32 mL), and lithium hydroxide (60.8 mg) and water (4 mL) were successively added under ice cooling, followed by stirring at room temperature for 14 hours. The solvent was distilled away under reduced pressure to give the title compound (1.12 g).
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])=[O:3].[BH4-].[Na+]>C(O)C>[CH3:1][S:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[CH:13][CH:14]=1)=[O:3]
Reactant: CS(=O)CCOc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)CCOc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.1 g (5.18 mmol) 3-(2-methanesulphinyl-ethoxy)-benzaldehyde in 20 ml ethanol (anhydrous) is added NaBH4 (0.215 g, 5.7 mmol). The reaction mixture is stirred at room temperature for 0.5 h. Then it is poured onto water and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a colorless oil that is of sufficient purity for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5].[N:19]1([CH2:25][C:26]2[S:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:29]2[S:30][C:26]([CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:27][CH:28]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: Cc1cnccc1NC(=O)c1cc(Br)cnc1N
Product: Cc1cnccc1NC(=O)c1cc(-c2ccc(CN3CCOCC3)s2)cnc1N

Procedure:
Reaction of 2-amino-5-bromo-N-(3-methyl-pyridin-4-yl)-nicotinamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A21”; HPLC/MS: 0.97 min, [M+H]=410;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([OH:27])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:36]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([NH2:36])=[O:27])=[CH:15][CH:14]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(=O)O)ccc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(N)=O)ccc2c1=O
Yield: 94.6 %

Procedure:
A solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylic acid (0.59 g, 1.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g, 2.6 mmol) and 1-hydroxybenzotriazole ammonium salt (0.40 g, 2.6 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.56 g, 94.9%) as crystals.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17](OCC)(=[O:19])[CH3:18].CC(C)([O-])C.[K+]>CC(OC)(C)C>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([C:1](=[O:3])[CH2:2][C:17](=[O:19])[CH3:18])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(C)=O
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 2.27 g (10.0 mmol) of 4-acetyl-1-(tert-butoxycarbonyl)piperidine (from Step A), 1.95 mL (20.0 mmol) of ethyl acetate and 2.24 g (20.0 mmol) of potassium t-butoxide in 25 mL of MTBE was stirred at rt for 20 h. The reaction was quenched with 50 mL of 0.5 N KHSO4 and extracted with 150 mL of ether. The extract was dried over MgSO4 and concentrated. Flash chromatography on 70 g of silica gel using 20:1 v/v hexanes/acetone as the eluant afforded the title compound. The enol form predominated in CDCl3 solution: 1H NMR (500 MHz, CDCl3) δ 1.46 (s, 9H), 1.53 (dq, J=4.5, 12.5, 2H), 1.81 (app d, J=13.5, 2h), 2.07 (s, 3H), 2.44–2.33 (m, 1H), 2.72–2.79 (m, 2H), 4.18–4.28 (br s, 2H), 5.50 (s, 1H).
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>C(O)(C)(C)C>[N+:1]([C:4]1([CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2]
Reactant: C=CC(=O)OCC
Reactant: O=[N+]([O-])C1CCCCC1
Solvent: CC(C)(C)O
Product: CCOC(=O)CCC1([N+](=O)[O-])CCCCC1
Yield: 87 %

Procedure:
99.5 g of nitrocyclohexane was dissolved in 40 ml of t-butanol, and 83.4 ml of ethyl acrylate was added thereto in the presence of 7 ml of 40% Triton B. The mixture was reacted at room temperature to give 153 g (yield: 87%) of 1-nitro-l-(2-ethoxycarbonylethyl)cyclohexane. Then, 20 g of this substance was dissolved in ethanol and 3.6 g of Raney nickel was added thereto. The mixture was strongly stirred in the presence of hydrogen gas (70 kg/cm2), and then the Raney nickel was removed. The reaction solution was refluxed under heating for 5 hours. Then, ethanol was distilled off to give 8.0 g (yield: 62%) of 1-aza-2-oxospiro[4.5]decane8.0 g of this substance was dissolved in 30 ml of THF, and 3.6 g of LiAlH4 was added thereto. The mixture was reacted at room temperature for 15 hours to give 7.4 g (yield: 83%) of 1-azaspiro[4.5]decane.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C@H:29]1[CH2:34][C:33]2[C:35]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1>CN(C)C=O>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([C:35]2[C:33]3[CH2:34][C@H:29]([NH:28][C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:15][CH:14]=4)[CH2:30][O:31][C:32]=3[CH:38]=[CH:37][CH:36]=2)[CH2:40][CH2:41]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
A solution of 4-morpholinobenzoic acid (380 mg, 1.83 mmol; described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) and 1,1′-carbonyldiimidazole (310 mg, 1.92 mmol) in anhydrous N,N-dimethylformamide (12 mL) was stirred at 75° C. for 30 min. The mixture was allowed to cool after which a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (430 mg, 1.74 mmol) in N,N-dimethylformamide (8 mL) was added. The reaction mixture was stirred at room temperature for 3 days. Another portion of 1,1′-carbonyldiimidazole (57 mg, 0.35 mmol) was added, and the mixture was stirred for an additional 3.5 h. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 93:7+0.5% NH3) affording 513 mg (68% yield) of the title compound as a white solid: mp 210-212° C.; [α]22D −145° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 436 (65, M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:14]([CH3:13])(=[O:16])=[O:15])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.06 mmol) in dry THF (30 mL) was added NaH (246 mg, 6.12 mmol) at room temperature. The suspension was stirred for 30 min before addition of methanesulfonyl chloride (540 mg, 4.80 mmol). The solution was stirred at room temperature for another 30 min and poured into water (50 mL). The aqueous solution was extracted with ethyl acetate (2×30 mL), the combined organic layers were dried over MgSO4 and filtered, the filtrate was evaporated under vacuum to afford white solid (780 mg, 93%). The crude product was used directly for the next reaction. LC/MS: Rt 3.26 mis.; (m/e=275.0, 276.9 (M+H, M+2+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:30]([C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=1)(=[O:31])=[O:32])[C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: ClCCl
Product: CNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21
Yield: 68.9 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 11 from 7.03 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)indol-2-one and 5.73 g of 4-nitrobenzenesulfonyl chloride. Chromatography on silica using DCM as the eluent gives 7.76 g of the expected product after crystallization from iso ether. M.p.=220°-221° C.
Reaction SMILES: [Cl:1][Si:2]([Cl:5])(Cl)[Cl:3].[CH3:6][C:7]([Li])([CH3:10])[CH2:8][CH3:9]>C(OCC)C>[CH3:6][C:7]([Si:2]([Cl:5])([Cl:3])[Cl:1])([CH3:10])[CH2:8][CH3:9]
Reactant: [Li]C(C)(C)CC
Reactant: Cl[Si](Cl)(Cl)Cl
Solvent: CCOCC
Product: CCC(C)(C)[Si](Cl)(Cl)Cl
Reaction time: 1 h
Yield: 35 %

Procedure:
A two-liter four-necked flask equipped with a stirrer, a reflux cooling tube and a dropping funnel was charged in a nitrogen atmosphere with 85 grams (0.5 mol) of tetrachlorosilane and 500 ml of diethylether and then added with the droplets of 500 ml of 1,1-dimethylpropyllithium (1.0 M diethylether solution) as being stirred and cooled with ice over 2 hours. After completion of the addition, stirring was continued for another one hour at room temperature. The resulting mixture was filtered out in a nitrogen atmosphere and then purified by distillation thereby obtaining 36 grams (yield : 35%) of 1,1-dimethylpropyltrichlorosilane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:6]2)#[N:2].C1C(=O)N([Br:28])C(=O)C1>CC#N>[Br:28][C:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(C#N)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2cc(C#N)ccc2c1Br
Yield: 91 %

Procedure:
A solution of 140 (4.48 g, 18 mmol) and NBS (3.85 g, 21.6 mmol) in MeCN (80 mL) was stirred at reflux for 1 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2, washed with 10% aqueous Na2SO3, water, dried, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to give tert-butyl 1-bromo-6-cyano-2-naphthylcarbamate (141) (5.69 g, 91%): mp (iPr2O/hexane) 164-166° C.; 1H NMR [(CD3)2SO] δ 9.01 (s, 1H), 8.63 (d, J=1.5 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.93 (dd, J=8.9, 1.8 Hz, 1H), 1.50 (s, 9H). Anal. (C16H15BrN2O2) C, H, N, Br.
Reaction SMILES: [OH:1][C@H:2]([CH3:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]1[CH3:14].[OH-].[Na+].Cl>CO.C1COCC1>[OH:1][C@H:2]([CH3:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=[C:5]1[CH3:14]
Reactant: CCOC(=O)c1cn(C[C@@H](C)O)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)cn1C[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
(R)-Ethyl 1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate (2.474 mmol, 525 mg) was dissolved in methanol (1 ml) and THF (8 ml). NaOH 2 M (7.42 mmol, 3.71 ml) was added and the resulting mixture was stirred overnight at RT. The pH of the mixture was adjusted to about 5 with 1M HCl and the solvents were evaporated. Ethanol was added and the salts were removed by filtration. The filtrate was evaporated. 393 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.03 (m, 6H), 2.30 (s, 3H), 3.71-3.80 (m, 1H), 3.81-3.97 (m, 2H), 4.95 (bs), 7.67 (s, 1H).
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]1[C:8]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:7]([C:13]([O:15]CC)=[O:14])[CH:6]=[N:5]1.Cl>O.O1CCOCC1>[CH3:3][N:4]1[C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:7]([C:13]([OH:15])=[O:14])[CH:6]=[N:5]1
Reactant: CCOC(=O)c1cnn(C)c1S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc(C(=O)O)c1S(C)(=O)=O
Reaction time: 8 h
Yield: 64 %

Procedure:
Add a solution of LiOH (22 mg, 0.90 mmol) in H2O (1 mL) to a rapidly stirring solution of ethyl 1-methyl-5-(methylsulfonyl)-1H-pyrazole-4-carboxylate (175 mg, 0.75 mmol) in 1,4-dioxane (3 mL) at ambient temperature. Treat the reaction mixture with additional LiOH (5 mg, 0.21 mmol), and stir overnight. Acidify to pH 2 with 1 N HCl, and extract twice with CH2Cl2. Combine the organic layers, dry over MgSO4, filter, and concentrate under reduced pressure to yield the title compound as a white solid (98 mg, 64%). ES/MS m/z 202.9 (M−1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([Cl:15])[CH:6]=1.[NH4+:17].[OH-]>>[Cl:15][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([NH2:17])=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: [NH4+]
Reactant: COC(=O)Cc1cc(Cl)nc2ccccc12
Agent: [OH-]
Product: NC(=O)Cc1cc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-chloro-quinolin-4-yl)-acetic acid methyl ester (100 mg, 0.42 mmol) is suspended in 28% NH4OH (2.0 mL). The mixture is stirred at RT overnight. The solvent is evaporated to afford 2-(2-chloro-quinolin-4-yl)-acetamide as a solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[N:13][N+:14]([O-:16])=[O:15])[CH2:2]1.[H-].[Na+].[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>C(#N)C>[CH2:20]([C:19]([N:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:8]1=[N:13][N+:14]([O-:16])=[O:15])=[O:22])[CH3:21]
Reactant: O=[N+]([O-])N=C1NCCCN1CC1CCOC1
Reactant: CCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)N1CCCN(CC2CCOC2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
A mixture of 0.33 g of 1-[(tetrahydro-3-furanyl) methyl]-2-(nitroimino)hexahydropyrimidine, 0.07 g of sodium hydride (60%) and 10 ml of acetonitrile was stirred at 50° C. for 30 minutes. After this mixture was cooled on ice, 0.16 g of propionyl chloride was added dropwise thereto over 30 minutes, and the mixture was then stirred at room temperature for 2 hours. After the completion of reaction, insolubles were removed by filtration, and the filtrate was then concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (2:1 ethyl acetate/acetone) to obtain 0.08 g of 1-(ethylcarbonyl)-2-(nitroimino)-3-[(tetrahydro-3-furanyl)methyl]hexahydropyrimidine.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH2:30])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]3)=[C:16]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 3 h
Yield: 23.3 %

Procedure:
A solution of acryloyl chloride (0.044 mL, 0.54 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 93, 258 mg, 0.54 mmol) and DIPEA (0.103 mL, 0.59 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was suspended in CH3OH and filtered to give some of the title compound (67 mg). The filtrate was then concentrated in vacuo and purified by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2. Appropriate fractions were combined and concentrated in vacuo to give a solid which was suspended in CH3OH and collected by filtration to give more of the title compound (64 mg). The two batches of product were combined to give the title compound (131 mg, 46%) as a yellow solid; 1H NMR: 1.68-1.83 (1H, m), 2.04-2.16 (1H, m), 2.18 (6H, s), 2.63-2.77 (1H, m), 3.15-3.29 (3H, m), 3.35-3.46 (1H, m), 3.78 (3H, s), 5.66 (1H, dd), 6.16 (1H, dd), 6.49 (1H, dd), 6.54 (1H, s), 7.04 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 7.53 (1H, s), 8.23-8.4 (3H, m), 8.48 (1H, d), 9.34 (1H, s), 11.84 (1H, s); m/z: ES+ MH+ 532.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19](/[CH:22]=[C:23](/[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])\[C:24]#[N:25])[S:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:22]([C:19]2[S:20][CH:21]=[C:17]([Br:16])[CH:18]=2)[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cc(Br)cs1)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Br)cs2)C1(C#N)c1ccc(Cl)cc1F
Yield: 20.2 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(4-bromo-thiophen-2-yl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.7 g, 8 mmol) prepared in Example 70a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.9 g, 20%).
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>C(Cl)Cl.O>[N:13]1([C:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccccc21
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of di-tert-butylcarbonate (427.1 g, 1.96 mol) in CH2Cl2 (500 mL) was added dropwise at room temperature to a solution of indoline (212 g 1.78 mol) in CH2Cl2 (1000 mL). A solution of NaOH (85.3 g, 2.13 mol) in water (500 mL) was then added dropwise and the mixture was stirred overnight. The layers were separated and the organic layer was washed with 5% NaOH, brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure and the crude product was crystallized with petroleum ether, giving 324 g (68%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[NH:6][CH2:5][C:4]2=[CH:13][CH:14]=[CH:15][N:3]12.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([N:6]1[C:7]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[N:3]2[CH:15]=[CH:14][CH:13]=[C:4]2[CH2:5]1)(=[O:18])[CH3:17]
Reactant: CN1c2ccncc2NCc2cccn21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1Cc2cccn2N(C)c2ccncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 20 ml of acetic anhydride and 4.0 g of 10,11-dihydro-5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine was stirred at room temperature for two hours. The mixture was then evaporated, the residue dissolved in water, and the aqueous layer extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to afford 2.3 g of 11-acetyl-10,11-dihydro-5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine as an oil which solidified upon standing (mp 125°-130° C.). The solid was dissolved in ethanol and acidified with an ethanol solution of maleic acid. Dilution with diethyl ether precipitated 2.25 g (31.4%) of the corresponding maleate, mp 139°-141° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH2:10][CH:11]=O)=[CH:8][CH:7]=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14].[C:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1c(CC=O)cccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(CCNc2ccc(C(C)(C)C)cc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the aldehyde (Step B, 0.51 g, 2.3 mmol, 1 eq) and CH2Cl2 (30 mL) was added 4-t-butyl-aniline (0.36 mL, 2.3 mmol, 1 eq) and NaBH(OAc)3 (1.5 g, 6.8 mmol, 3.0 eq). The mixture was stirred at RT for 18 h then quenched with H2O. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give an orange oil. Purification by silica flash chromatography gave the desired compound as a yellow-orange foam. MS m/e 357 (M+H)+. Calc'd for C20H24N2O4-356.42.