Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.Cl[CH2:15][S:16]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:15][S:16]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:18].[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:15][S:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:18])=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: O=[N+]([O-])c1cccc(OCCCl)c1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(OCCCl)ccc1CS(=O)(=O)c1cccc2ccccc12
Product: O=[N+]([O-])c1cccc(OCCCl)c1CS(=O)(=O)c1cccc2ccccc12
Reaction time: 5 h

Procedure:
A mixture of 1-(2-chloro-ethoxy)-3-nitrobenzene (1.12 g, 5.6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (1.6 g, 6.72 mmoles) was stirred in THF (50 mL) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (16.8 mL, 16.8 mmoles) over a half an hour period. Temperature was allowed to rise to −40° C., and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off-white solid (0.9 g, 2.24 mmoles), and 1-[4-(2-chloro-ethoxy)-2-nitro-phenylmethanesulfonyl]-naphthalene (0.79 g, 2.1 mmoles).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:23])[C:16]([C:18](OCC)=[O:19])=[CH:17][N:11]3[CH:10]3[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]3)[CH:14]=1.O.[NH2:25][NH2:26]>CO>[OH2:19].[F:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:23])[C:16]([C:18]([NH:25][NH2:26])=[O:19])=[CH:17][N:11]3[CH:10]3[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]3)[CH:14]=1
Reactant: CCOC(=O)c1cn2c3c(cc(F)cc3c1=O)C1CCCCC12
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1cn2c3c(cc(F)cc3c1=O)C1CCCCC12

Procedure:
2 g of ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate was dissolved in 80 ml of methanol, and 5 ml of hydrazine hydrate was added thereto. The mixture was then heated while refluxing. The precipitated yellow needle crystals were separated by filtration, and recrystallized from ethanol to obtain 1.7 g of 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carbohydrazide monohydrate.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]([OH:18])[C:16]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:31])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[Cl:30][C:25]1[CH:24]=[C:23]([C:16]2([C:19]([F:21])([F:20])[F:22])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:32])=[O:5])=[C:8]([CH3:31])[CH:9]=3)[CH:17]2[OH:18])[CH:28]=[C:27]([Cl:29])[CH:26]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2O)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example 12.1) (500 mg) in dichloromethane (20 ml) was added trifluoroacetic acid (“TFA”) (4 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. To the reaction mixture was diluted with water and the phases were separated. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was suspended in diisopropyl ether/pentane (1:3). The solids were isolated by filtration and washed with pentane to give 4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (395 mg) as a white solid. M.p. 215-217° C. 1H-NMR (CDCl3, 400 MHz): 7.98 (d, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.52 (s, 2H), 7.40 (s, 1H), 5.76 (s, 1H), 2.61 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[BH4-].[Na+]>COCCOCCOCCOC>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOCCOC
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Temperature: 25 °C

Procedure:
Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 130 mmoles) from Step (1) is dissolved in the first distillate from the above Step (a) mixture and cooled to −75° C.±20° C. Sodium borohydride (6 g) as a solution in 75 mL triglyme is added slowly. After the addition, the reaction mixture is warmed to 25° C. The reaction mixture is quenched by the addition of 8 g acetic acid (and optionally 20 mL methanol) and concentrated by vacuum distillation—saving the distillate. The residue is dissolved in a mixture of water (100 mL) and ethyl acetate (200 mL), the layers separated, and the organic layer is concentrated by vacuum distillation. The residue is dissolved with 200 mL methanol and 10 mL acetic acid and concentrated by vacuum distillation. The residue is dissolved with 200 mL methanol and concentrated by vacuum distillation. The residue is dissolved with 200 mL methanol and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in crude [R—(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:33])C(=O)C1.NC1N=C2C(C(C3C=CN=CC=3)=C(C3C=CC(F)=CC=3)N2)=CC=1Br>>[Br:33][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=1)=[C:7]2[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1cccc(-c2[nH]c3ccccc3c2-c2ccncc2)c1
Agent: Nc1nc2[nH]c(-c3ccc(F)cc3)c(-c3ccncc3)c2cc1Br
Product: FC(F)(F)c1cccc(-c2[nH]c3ccc(Br)cc3c2-c2ccncc2)c1

Procedure:
3-(4-Pyridyl)-2-(3-trifluoromethylphenyl)indole was treated with NBS in the same manner as 6-amino-5-bromo-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole to afford the title compound: Mass Spectrum (CI) 417 (MBr81-H).
Reaction SMILES: [C:1]1([P:7]2(=[O:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.F[B-](F)(F)F.[O:31]=[N+:32]=[O:33]>C(OCC)C>[C:1]1([P:7]2(=[O:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:16]2[CH:17]=[CH:18][C:19]([N+:32]([O-:33])=[O:31])=[CH:20][CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P1(c2ccccc2)c2ccccc2CN1c1ccccc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(N2Cc3ccccc3P2(=O)c2ccccc2)cc1
Temperature: 26 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Under a static nitrogen atmosphere, a solution of 1,2-diphenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.0 g, 0.0033 mol) in 10 ml. of methylene chloride was dropwise added to a constantly stirred suspension of nitronium tetrafluoroborate (0.47 g, 0.0035 mol) in 25 ml. of methylene chloride while maintaining the temperature between -5° C. and 5° C. The reaction mixture was stirred for 3 hours at 26° C. and then added to 40 ml. of ice water. The layers were separated and the aqueous layer was extracted with methylene chloride. The methylene chloride layers were combined, dried over magnesium sulfate, and concentrated in vacuo to yield a residue which was purified on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was slurried in diethyl ether to yield 1-phenyl-2-(4-nitrophenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.9 g, 78% yield) as a yellow solid having a melting point of 255°-257° C. and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1>O1CCCC1>[NH2:12][C:3]1[C:2]([Cl:1])=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: Cc1nc2cc(Cl)c([N+](=O)[O-])cc2o1
Solvent: C1CCOC1
Product: Cc1nc2cc(Cl)c(N)cc2o1
Reaction time: 1.5 h

Procedure:
Compound (2), (30 g), was dissolved in tetrahydrofuran (150 mL), and Raney-Nickel which had been pre-washed with water (×3) and tetrahydrofuran (×3), was added. The mixture was then hydrogenated at room temperature and 50 psi of hydrogen. The reaction is complete in approximately 1.5 hours. After this period, the catalyst is filtered off and the solution concentrated under reduced pressure. The residue is triturated with heptane, cooled and the solid filtered off. Yield 22 g.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:32](=[O:34])[CH3:33]
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 μL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of acetyl chloride (52 μL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound (86 mg, 36%). 1H NMR (400 MHz, CDCl3) δ Shows rotomers 7.19-7.13 (2d, 2H), 6.91-6.88 (d, 2H), 4.05-4.02 (m, 2H), 3.85-3.80 (m, 2H), 3.56-3.45 (m, 4H), 2.67-2.65 (m, 2H), 2.60-2.56 (m, 4H), 2.32-1.96 (several multiplets, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][P:20](N(CC)CC)[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:18])([CH3:17])[CH3:16].N1C=NN=N1.ClC1C=CC=C(C(OO)=[O:44])C=1.S(=O)(O)[O-].[Na+]>ClCCl>[P:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])([O:14][CH2:13][CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:12]1)=[O:44]
Reactant: OCC1CC(c2ccc(Br)cc2)=NO1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OCC1CC(c2ccc(Br)cc2)=NO1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
[3-(4-Bromophenyl)-4,5-dihydroisoxazol-5-yl]methanol (2.5 g, 9.8 mmol) was dissolved in dichloromethane (100 ml). To this solution, di-tert-butyl-N,N-diethylphosphoroamidite (3.3 ml, 11.7 mmol) and 1H-tetrazole (1.2 g, 17.6 mmol) were added sequentially. After 1.5 h stirring at room temperature, the solution was cooled to 0° C. and m-chloroperbenzoic acid (70%; 3.6 g, 14.7 mmol) was added. After 1.5 h the reaction was warmed to room temperature; a sodium bisulfite solution was added and the mixture stirred about 5 min. After diluting with dichloromethane, the aqueous layer was extracted with dichloromethane (2×), and the combined organics were washed with saturated sodium bicarbonate solution, brine, and dried over magnesium sulfate. The crude residue was purified by chromatography on silica gel using 0-5% methanol in dichloromethane as the eluent, resuliting in 4.1 g of the desired product.
Reaction SMILES: Cl.[NH:2]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)[NH2:3].[C:16](OC(=O)C)(=O)[CH3:17].C(=O)(O)[O-].[Na+]>>[CH3:16][C:17]1[N:5]2[CH2:6][C:7]3[C:8]4[C:9]([NH:14][CH:15]=3)=[CH:10][CH:11]=[CH:12][C:13]=4[C:4]2=[N:2][N:3]=1
Reactant: NNC1=NCc2c[nH]c3cccc1c23
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nnc2n1Cc1c[nH]c3cccc-2c13

Procedure:
5-Hydrazino-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrochloride (50 mg), described in Example 8, is heated at reflux with 3 ml of acetic anhydride for 2 hours. The mixture is cooled and then poured into a saturated solution of sodium bicarbonate. The resulting precipitate is collected and then dissolved in methanol. This solution is rendered acidic by the addition of HCl in ether. The mixture is treated with charcoal and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[CH:14][C:6]1=2.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[O:20])=[CH:17][CH:16]=3)=[CH:14][C:6]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 53 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (50 mg) was reacted with (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 8 to give the title compound as a pale yellow solid (53% yield). M.p. 143-144° C., LCMS: m/z=518.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.48-1.58 (m, 1H), 1.87-2.15 (m, 4H), 2.17-2.22 (m, 3H), 2.55-2.64 (m, 4H), 2.83-2.89 (m, 1H), 3.12-3.23 (m, 1H), 3.42-3.50 (m, 2H), 3.60-3.64 (m, 2H), 4.40-4.49 (m, 3H), 5.07 (bs, 1H), 6.76 (s, 1H), 6.86-7.09 (m, 3H), 7.41 (d, J=8.1 Hz, 2H), 7.45-7.52 (m, 2H), 7.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:30]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(F)c(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc(F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Yield: 85.4 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-5-fluoro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (93.7 mg, 0.220 mmol) was dissolved in acetonitrile (6.6 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (115 mg, 0.880 mmol), acetic acid (0.252 mL, 4.40 mmol) and sodium triacetoxyborohydride (163 mg, 0.77 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-5-fluoro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (102 mg, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:27]([O:29]C)=O)[C:11]3[NH:25][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[C:12]=3[N:26]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:27]([NH2:31])=[O:29])[C:11]3[NH:25][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[C:12]=3[N:26]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1nc(N3CCOCC3)ccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1nc(N3CCOCC3)ccc12
Yield: 19 %

Procedure:
A solution of methyl 2-(3-chlorophenyl)-7-(4-morpholinyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylate (50 mg, 0.12 mmol) in a solution of 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated at 80° C. for 48 hr. Filtration gave 2-(3-chlorophenyl)-7-(4-morpholinyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxamide (10 mg, 0.022 mmol, 19% yield) as a yellow solid. MS (ESI) m/z 408 (M+H). 1H NMR (DMSO-d6) δ ppm 10.97 (s, 1H), 8.53 (br. s., 1H), 8.19-8.44 (m, 4H), 7.88 (br. s., 1H), 7.41-7.63 (m, 2H), 6.87 (br. s., 1H), 3.56-3.88 (m, 8H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:18]N1C(=O)CCC1=O.CCOC(C)=O.C1CCCCC1>CC#N>[Cl:18][C:10]1[C:11]([NH2:15])=[CH:12][N:13]=[N:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=1
Reactant: Nc1cnnc(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Nc1cnnc(-c2cccc(C(F)(F)F)c2)c1Cl
Yield: 52.1 %

Procedure:
6-[3-(Trifluoromethyl)phenyl]-4-pyridazinamine (2.0 g, 0.0084 mole, Compound No. 4) and N-chlorosuccinimide (0.61 g, 0.004 mole) were refluxed under N2 in CH3CN (50 mL) for 1.5 h. After this time no starting material was present by TLC. The mixture was partitioned between EtOAc/water. The organic layer was extracted again with water, dried (MgSO4), filtered and evaporated to give a crude oil. The oil was chromatographed on a Prep-500 using EtOAc/cyclohexane (9:1) to give a crude solid. The solid was recrystal-lized from EtOAc/cyclohexane to give 5-chloro-6-[3-(trifluoromethyl)phenyl]-4-pyridazinamine (0.57 g, 50% yield, Compound No. 35) as a tan solid.
Reaction SMILES: CN[N+]([O-])=O.S(=O)(=O)(O)O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN([N+]([O-])=O)[C:20]1[C:25]([N+]([O-])=O)=[CH:24][C:23]([N+]([O-])=O)=[CH:22][C:21]=1[N+]([O-])=O>>[C:12]1([NH:11][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CN(c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-])[N+](=O)[O-]
Agent: CN[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: c1ccc(Nc2ccccc2)cc1

Procedure:
Methylnitramine decomposes explosively in contact with concentrated sulfuric acid. It is evolved when aniline reacts with tetryl; a diphenylamine derivative is produced simultaneously. Methylnitramine reacts with picryl chloride to form tetryl.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(N(CC)CC)C.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(#N)C.ClCCl>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:18]
Reactant: Nc1cc[nH]n1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: O=C(Nc1cc[nH]n1)c1ccccc1F
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To a solution of 1H-pyrazol-3-amine (249 mg, 3 mmol, Aldrich) in acetonitrile (10 ml) was added triethylamine (0.836 ml, 6.0 mmol, Aldrich) and the stirred solution cooled in an ice-water bath. A solution of 2-fluorobenzoyl chloride (0.358 ml, 3.0 mmol, Alfa Aesar) in acetonitrile (10 ml) was added dropwise. The mixture was stirred under nitrogen and allowed to warm slowly to ambient temperature overnight. The solvent was concentrated in vacuo. The residue was partitioned between ethyl acetate (˜50 ml) and water approximately 50 ml). The phases were separated and the aqueous phase washed with further ethyl acetate (2×approximately 30 ml). The combined organic layers were filtered through a hydrophobic frit and the filtrate concentrated in vacuo to give the crude material (0.64 g). The sample was loaded in dichloromethane and purified on silica 70 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound as a colourless solid (342 mg); LCMS: (System 4) MH+=206, tRET=1.50 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([O:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39])[CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=1[O:35][CH2:33][CH3:34])=[O:31]
Reactant: CCOc1ccccc1CN
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Reactant: O=C(Br)CBr
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)c(OC)c2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:5][OH:6])[CH3:2].[CH:20](O)=O>>[CH2:1]([N:3]([CH3:20])[CH:4]([CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:5][OH:6])[CH3:2]
Reactant: CCNC(CO)CCOc1cccc2ccccc12
Reactant: O=CO
Product: CCN(C)C(CO)CCOc1cccc2ccccc12

Procedure:
2-(ethylamino)-4-(1-naphthyloxy)-1-butanol, described in Example 6, with formic acid, followed by reduction, gives 2-(ethylmethylamino)-4-(1-naphthyloxy)-1-butanol, and
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([CH:10](N)[CH:11]2[NH2:15])[C:8]=1[C:17]([O-:19])=[O:18])(=[O:4])[CH3:3].Cl[CH2:21][O:22][C:23](=[O:36])[C@H:24]([CH:33]([CH3:35])[CH3:34])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CN(C)C=[O:40]>C(OCC)(=O)C>[C:29]([O:28][C:26]([NH:25][CH:24]([CH:33]([CH3:35])[CH3:34])[C:23]([O:22][CH2:21][O:19][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:40])=[O:18])=[O:36])=[O:27])([CH3:32])([CH3:31])[CH3:30].[NH2:25][CH:24]([CH:33]([CH3:35])[CH3:34])[C:23]([O:22][CH2:21][O:19][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:40])=[O:18])=[O:36]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(N)C(N)C2SC1
Reactant: CN(C)C=O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(N)C(C)C)N2C(=O)C(N)C2SC1
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)N2C(=O)C(N)C2SC1
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-amino-8-amino-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, which is prepared by the general procedure described in W. German Offen. 2,236,620, are mixed in 100 ml of dimethyl formamide and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water with aqueous bicarbonate and again with water. The organic layer is dried over magnesium sulfate, filtered, and evaporated to dryness to give 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the amine protecting group is removed by standard procedures to give the title product.