Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][C:7]1[CH:28]=[CH:27][C:10]2[N:11]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][C:16]([O:18]CC)=[O:17])[CH:12]=[N:13][C:9]=2[CH:8]=1)=[O:5]>Cl>[NH2:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][C:7]1[CH:28]=[CH:27][C:10]2[N:11]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[N:13][C:9]=2[CH:8]=1)=[O:5]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3N)ccc21
Agent: Cl
Product: Nc1ccccc1C(=O)Nc1ccc2c(c1)ncn2C(CC(=O)O)c1ccccc1

Procedure:
A solution of ethyl 3-{5-[(2-aminobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (15 mg, 35 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 72 hours. The solution was then evaporated in vacuo, and the residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.75 min, MH+ 401].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O>[Pd].C([O-])([O-])=O.[Ca+2].CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CO
Product: CN[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
The mixture of 4-(3,4-Dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine (10 gm), 5% Pd/CaCO3 (grade-21, 0.6 gm), water (2 ml) and methanol (150 ml) is taken in a hydrogenation flask and then subjected to hydrogenation under a hydrogen pressure of 0.5 Kg at 20-35° C. for 3 hours 30 minutes. The catalyst is removed by filtration and the solvent is evaporated completely under vacuum to obtain cis-(±)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine. (cis-(±):trans-(±): 99.8:0.2).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][C:10]1[C:14](B2OC(C)(C)C(C)(C)O2)=[C:13]([CH3:24])[O:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Br:8][C:6]1[CH:7]=[C:2]([C:14]2[C:10]([CH3:9])=[N:11][O:12][C:13]=2[CH3:24])[CH:3]=[N:4][CH:5]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1cncc(Br)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 3,5-dibromopyridine (0.20 g, 0.85 mmol) in 1,4-dioxane (8 mL) and H2O (0.55 mL) under nitrogen was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.13 g, 0.93 mmol), and potassium carbonate (0.35 g, 2.5 mmol). The reaction mixture was degassed with nitrogen for 15 min. (1,1′-Bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (62 mg, 0.08 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 95° C. for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was transferred to a separation funnel and the aqueous layer extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide 4-(5-bromopyridin-3-yl)-3,5-dimethylisoxazole (0.15 g, 71%) as a white solid. LCMS Method T: retention time 1.52 min, [M+1]=253.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15](Cl)=[O:16])[CH2:12][C:11]2([Cl:14])[Cl:13])=[CH:6][CH:5]=1)[CH3:2].[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][OH:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][O:29][C:15]([C:10]1([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH2:12][C:11]1([Cl:14])[Cl:13])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: CCOc1ccc(C2(C(=O)Cl)CC2(Cl)Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCOc1ccc(C2(C(=O)OCc3ccc(F)c(Oc4ccccc4)c3)CC2(Cl)Cl)cc1
Yield: 85.2 %

Procedure:
5.87 g (0.02 mole) of (±)-1-(4-ethoxyphenyl)-2,2-dichlorocyclopropane-1-carboxylic acid chloride and 4.36 g (0.02 mole) of 3-phenoxy-4-fluoro-benzyl alcohol were dissolved in 100 ml of anhydrous toluene, and 3 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20° to 25° C., while stirring. The reaction mixture was then stirred at 25° C. for a further 3 hours. It was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.1 g (85.3% of theory) of (±)-1-(4-ethoxy-phenyl)-2,2-dichlorocyclopropane- 1-carboxylic acid 3-phenoxy-4-fluorobenzyl ester were obtained as a yellow oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=O)[CH2:8]2)=[CH:4][CH:3]=1.Cl.[NH2:16][CH2:17][C:18]#[C:19][CH3:20].O1CCCC1>C(N(CC)CC)C>[Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:8][C:9]3[N:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:10]=3[C:11](=[O:13])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(=O)CC(c2ccc(Cl)s2)C1
Reactant: CC#CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1C(=O)CC(c1ccc(Cl)s1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of 5-(5-chloro-2-thienyl)cyclohexane-1,3-dione (2.2 g), 1-amino-2-butyne hydrochloride (1.0 g) and tetrahydrofuran (40 ml) was added triethylamine (0.96 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled. Insoluble materials were filtered off, and under reduced pressure, the solvent was evaporated. The residue was stirred at 250° C. for 3.5 hours, cooled and purified with silica gel column chromatography (EtOAc/hexane) to give oil of 7-(5-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.79 g).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:22])[CH:11]=[C:12]([CH:19]([F:21])[F:20])[N:13]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:16]1([CH2:15][N:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:22])[CH:11]=[C:12]2[CH:19]([F:21])[F:20])[CH2:17][CH2:18]1
Reactant: [H][H]
Reactant: O=c1cc(C(F)F)n(CC2CC2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1cc(C(F)F)n(CC2CC2)cc1O
Yield: 83.3 %

Procedure:
A mixture of 5-benzyloxy-1-cyclopropylmethyl-2-difluoromethyl-1H-pyridin-4-one (3.0 g, 9.82 mmol) and 10% Pd/C (300 mg) in methanol (90 mL) was subjected to hydrogenation in a Parr apparatus under a 15 psi hydrogen pressure for 27 min. Work-up as described above for the cyclopropyl derivative, afforded the title product (1.76 g, 83% yield) after vacuum oven drying. HPLC purity (peak area percent) of the title compound is 99.5% at λ=288 nm using HPLC Method 1 as described above.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[CH3:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([CH3:33])=[CH:35][CH:36]=3)[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: Cc1ccc(C(=O)NCCCN(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)S(C)(=O)=O)cc1

Procedure:
Compound 2 was coupled with 4-methylbenzoic acid following procedure K. LC-MS showed the product had the expected M+H+ of 574. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.0 (d, 2H) 7.65 (d, 2H) 7.50 (d, 2H) 7.2 (m, 3H) 7.0 (m, 3H), 6.7 (d, 2H), 4.4 (s, 2H), 3.45 (t, 2H), 3.2 (d, 4H), 3.0 (s, 3H) 2.7 (t, 2H), 2.45 (s, 3H), 1.8 (m, 2H).
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([I:28])[CH:30]=4)[CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:12](=[O:27])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=Cc1cccc(I)c1
Reactant: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCNCC2
Agent: Cl
Product: COC(=O)CCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1cccc(I)c1)CC2

Procedure:
Reductive amination using methyl 4-[4-(cyclohexylamino)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-1-yl]butanoate dihydrochloride and 3-iodo-benzaldehyde using a similar procedure as described in the preparation of intermediate I.1.d.1. LRMS (M+1)=567.3.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26]CC=C)=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30](OC1C=CC(Cl)=CC=1N)[CH:31]=[CH2:32]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH2:32][CH:31]=[CH2:30])[C:20]=3[OH:26])=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCOc1ccc(Cl)cc1N
Reactant: C=CCOc1ccc(Cl)cc1NC(=O)Cc1ccc(OC)c(OC2CCCC2)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(Cl)cc(NC(=O)Cc2ccc(OC)c(OC3CCCC3)c2)c1O

Procedure:
A solution of N-(3-cyclopentyloxy4-methoxyphenyl-acetyl)-2-allyloxy-5-chloroaniline (33 grams, 0.079 mol) in 330 millimeters of diphenyl ether was heated at 180° for 6.5 hours. This reaction mixture was combined with a second reaction mixture containing N-3-cyclopentyloxy-4-methoxyphenylacetyl)-2-allyloxy-5-chloroaniline and 250 milliliters of diphenyl ether which had been heated at 180° for 20 hours.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7](=[O:25])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[CH:17]4)[C:11]([CH3:23])=[C:10]([F:24])[CH:9]=2)[CH2:5][CH2:4]1.[CH2:26]([N:33]1[CH2:38][CH2:37][O:36][CH:35]([CH2:39]Cl)[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:33]1[CH2:38][CH2:37][O:36][CH:35]([CH2:39][N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]4[CH:13]=[C:8]([CH:9]=[C:10]([F:24])[C:11]=4[CH3:23])[C:7]([NH:6][CH:3]4[CH2:4][CH2:5]4)=[O:25])=[CH:22][CH:21]=3)[CH:17]=[N:18]2)[CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC2CN(Cc3ccccc3)CCO2)c1
Yield: 4.7 %

Procedure:
The procedure for Example 1 was followed using sodium hydride (60% in mineral oil, 19.4 mg), N-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide (Intermediate 3, 100 mg) and 4-benzyl-2-(chloromethyl)morpholine (87.6 mg) in DMF (5 ml) to give the crude product (70 mg) A portion (10 mg) was subjected to preparative HPLC to give the title compound as a white solid (7.6 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Br:12])=[CH:8][C:9]=2[F:11])[NH:4][C:3]=1[C:13]([NH2:15])=[O:14].[O:16]=[C:17](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[Br:12][C:7]1[CH:8]=[C:9]([F:11])[C:10]2[C:2]3[NH:1][C:17](=[O:16])[NH:15][C:13](=[O:14])[C:3]=3[NH:4][C:5]=2[CH:6]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1[nH]c2cc(Br)cc(F)c2c1N
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)c2[nH]c3cc(Br)cc(F)c3c2[nH]1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
15.4 g (56.6 mmol) 3-amino-6-bromo-4-fluoro-1H-indole-2-carboxylic acid amide was suspended in 300 ml dioxan and after the addition of 7.5 ml (61.8 mmol) diphosgene the suspension was refluxed for 2 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was subsequently sucked off. 12.5 g (74%) 7-bromo-9-fluoro-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 296, 298 [M−H]−
Reaction SMILES: C1(P(CCC)C2C=CC=CC=2)C=CC=CC=1.[OH:17][CH:18]1[CH:23]([C:24]2[CH:29]=[CH:28][C:27](OS(C(F)(F)F)(=O)=O)=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:19]1.C(N(CC)CC)C.[C]=O>CN(C)C=O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC(C)(C)C.O>[OH:17][CH:18]1[CH:23]([C:24]2[CH:29]=[CH:28][C:27]([C:38]([O:40][CH3:41])=[O:39])=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)C(O)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCP(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
An autoclave is initially charged under argon with 58 ml of N,N-dimethylformamide, 42 ml of methanol, 0.347 g of diphenylphosphinopropane and 0.189 g of palladium(II) acetate. The reaction mixture is stirred at room temperature over 20 minutes. Subsequently, 7.73 g of tert-butyl 3-hydroxy-4-(4-trifluoromethanesulphonyloxyphenyl)piperidine-1-carboxylate and 3.75 g of triethylamine are added and the autoclave is charged with 5 bar of carbon monoxide. The reaction mixture is subsequently stirred at 70° and 5 bar of pressure over 3 hours. Subsequently, the reaction mixture is cooled and a solution of palladium(II) acetate (0.095 g) and diphenylphosphinopropane (0.175 g) in 29 ml of N,N-dimethylformamide and 21 ml of methanol is added. The reaction mixture is subsequently stirred at 70° and 5 bar of carbon monoxide for a further 3 hours. The reaction solution is cooled and stirred with 200 ml of water and 250 ml of tert-butyl methyl ether. The phases are separated and the aqueous phase is extracted once more with 250 ml of tert-butyl methyl ether. The organic phases are combined and concentrated by evaporation to dryness. The title compound is obtained as a colourless solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane); Rt=4.15.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].C([O-])(=O)C.[NH4+]>CCOC(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(=Cc1c[nH]c2cc(F)ccc12)[N+](=O)[O-]
Yield: 86 %

Procedure:
6-Fluoro-3-(2-nitropropenyl)-1H-indole was prepared by combining 6-fluoroindole-3-carboxaldehyde (485 mg, 2.97 mmol), nitroethane (6.0 mL), and ammonium acetate (250 mg, 3.27 mmol). The reaction solution was allowed to reflux 2 hours. The reaction solution was diluted with EtOAc (100 mL), washed with H2O (50 mL×2), partitioned, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 560 mg (86% yield) of 6-fluoro-3-(2-nitropropenyl)-1H-indole; 1H NMR (CDCl3) δ 11.03 (1H, br s), 8.41 (1H, s), 7.63 (1H, dd), 7.50 (1H, s), 7.06 (1H, dd), 6.92 (1H, t), 2.44 (3H, s); TLC (SiO2 plate, 100% DCM) Rf=0.7.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:42](=[O:43])[C:41]2[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=2[CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1F
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1c(F)cccc1NC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 3-fluoro-2-methylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-fluoro-2-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (84%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.68 (d, J=6.6 Hz, 1H), 7.51-7.37 (m, 2H), 7.33-7.13 (m, 5H), 7.11-6.97 (m, 2H), 6.89 (d, J=7.8 Hz, 1H), 6.58 (s, 1H), 6.39 (s, 1H), 5.16-5.02 (m, 2H), 4.85 (d, J=9.4 Hz, 1H), 4.70 (d, J=9.4 Hz, 1H), 4.47 (t, J=8.8 Hz, 2H), 2.93 (t, J=8.8 Hz, 1H), 2.21-2.14 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 167.8, 162.8, 161.6, 161.2, 159.6, 142.8, 138.3, 138.2, 136.1, 134.6, 132.7, 131.0, 129.1, 128.5, 127.9, 127.1, 127.0, 126.9, 124.2, 123.6, 122.7, 121.1, 126.9, 120.3, 119.6, 113.0, 112.7, 109.7, 92.9, 80.4, 72.6, 65.4, 57.4, 41.4, 28.8, 15.6, 10.4, 10.3; MS (ES+) m/z 543.1 (M+23).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:20])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]2.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[C:25](O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]4)[N:20]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:33])[CH3:34]
Reactant: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 120 °C
Yield: 58.1 %

Procedure:
A solution of Ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D52) (2.04 g, 7.38 mmol), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (1.743 g, 8.12 mmol), EDC (2.123 g, 11.08 mmol) and HOBT (1.357 g, 8.86 mmol) in N,N-Dimethylformamide (DMF) (25 ml) was stirred overnight then heated at 120° C. during 4 hours. The mixture was dissolved in EtOAc then washed with water and NaHCO3 and purified by flash chromatography, eluting with EtOAc/iso-Hexane 10-90% then 10-30%. The solvent was evaporated to give (1.95 g) of white solid. MS (ES): C23H2335ClN4O4 requires 454; found (MH+) 455.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH2:22][OH:23]>CO>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[N:22][OH:23])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Reactant: NO
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C=NO)cnc32)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.150 g, 0.498 mmol) in MeOH (10 mL) was added hydroxylamine (50% solution in water, 0.061 mL, 1.0 mmol). The reaction mixture was heated to about 45° C. After about 2 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to provide the crude 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde oxime as a tan solid. LC/MS (Table 2, Method a) Rt=2.15 min; MS m/z: 317 (M+H)+. To a solution of the crude oxime in THF (20 mL) was added AcOH (0.285 mL, 4.98 mmol) followed by zinc dust (<10 micron, 0.130 g, 1.99 mmol). After a further 2 h, additional AcOH (0.285 mL, 4.98 mmol) and zinc dust (<10 micron, 0.130 g, 1.99 mmol) were added to the reaction mixture. After about an additional 2 h, additional AcOH (0.285 mL, 4.98 mmol) and zinc dust (<10 micron, 0.130 g, 1.99 mmol) were added to the reaction mixture. After about 15 h, the reaction mixture was diluted with DCM (about 5 mL) and filtered. The filtrate was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered, treated with HCl (4 M in 1,4-dioxane, 1 mL) and concentrated under reduced pressure to provide (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride: LC/MS (Table 2, Method a) Rt=1.64 min; MS m/z: 303 (M+H)+. To a suspension of the crude amine hydrochloride in DCM (10 mL) was added TEA (0.208 mL, 1.49 mmol) followed by cyclohexanecarbonyl chloride (0.101 mL, 0.747 mmol). After about 30 min, the reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude amide was purified by silica gel chromatography eluting with a gradient of 40-80% EtOAc in DCM to provide N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide as a tan solid (0.081 g, 39% over 2 steps). LC/MS (Table 2, Method a) Rt=2.40 min; MS m/z: 413 (M+H)+.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:18]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:20]=[N:19]1>>[Cl:17][C:16]1[C:11]2=[N:10][CH:9]=[C:3]([C:1]3[NH:2][N:20]=[N:19][N:18]=3)[C:4](=[O:5])[N:12]2[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C#N)=CNc1ncccc1Cl
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Product: O=c1c(-c2nnn[nH]2)cnc2c(Cl)cccn12
Yield: 44 %

Procedure:
The title compound (m.p. 313°-315° with decomposition, 44% yield) was prepared from ethyl 2-cyano-3-(3-chloro-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)4H-pyrido[1,2-a]pyrimidin-4-one in Example 2 of U.S. Pat. No. 4,122,274.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[CH:37]=[O:38])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCCCCC.O1CCCC1>[OH:38][CH:37]([C:36]1[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: O=Cc1ccccc1CCCCCCCCc1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (4.8 ml, 0.03 mole) in tetrahydrofuran/hexane (100 ml, 1/1) was cooled to 60° C. and n-butyllithium (2.5M solution in hexane, 13.6 ml, 0.03 mole) was added. This solution was stirred for 10 minutes followed by addition of t-butyl acetate (4.6 ml, 0.03 mole). The mixture was stirred for an additional 10 minutes followed by dropwise addition of a solution of 2-(8-phenyloctyl)benzaldehyde (10 gm, 0.03 mole) in tetrahydrofuran (25 ml). The whole was stirred first for 30 minutes at -50° C. and then for 30 minutes at 20° C. The reaction mixture was poured into aqueous acid and extracted twice with diethyl ether. The combined extracts were washed with 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography on silica gel using hexane-ethyl acetate (95/5) to elute gave the product as an oil. 90 MHz NMR (CDCl3) δ 1.29-1.52 (12H,m) 2.52-2.78 (6H,m) 5.39 (1H,dd) 7.10-7.60 (9H,m).