Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=O)[CH:23]=[CH:24][C:25]=1[Cl:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][CH2:28][NH:12][C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(CCN[C@@H]2CCCC[C@@H]2N2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(±)-cis-2-(1-pyrrolidinyl)cyclohexylamine (5 gm) was combined with pyridine (1.2 gm), chloroform (200 ml), 3,4-dichlorophenylacetic acid (9.15 gm), and dicyclohexylcarbodiimide (12.3 gm) and the mixture was stirred for 12 hr at room temperature. The mixture was filtered, the precipitate was washed with ether (100 ml) and the filtrate and ether wash were combined. The organic solution was diluted with ether (200 ml) and extracted with 10% citric acid in water (300 ml). The acid layer was washed with ether (2×200 ml), then treated with excess concentrated aqueous ammonia until basic. The resulting mixture was extracted with methylene chloride (2×200 ml) and the combined organic extracts were washed with water (2×50 ml) and concentrated on a rotary evaporator. The resulting white solid was combined with tetrahydrofuran (25 ml) and added dropwise to a solution of AlH3 in tetrahydrofuran (76.2 ml of a 0.665M solution) at room temperature. After the addition, the mixture was poured into 15% NaOH and the resulting mixture was extracted with ether (3×100 ml). The ether was removed on a rotary evaporator and the residue was dissolved in ethanol (100 ml). The ethanol was removed on a rotary evaporator and the residue was converted to the hydrogen bromide salt which was recrystallized from ethanol. Analytical data are reported in Table I.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]#[C:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=O)C.[NH2:26][NH2:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:27]([C:14]3[CH:15]=[CH:16][C:11]([CH3:9])=[CH:12][CH:13]=3)[N:26]=[C:7]([CH2:6][CH:5]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[C:4]([OH:3])=[O:25])[CH:8]=2)=[CH:16][CH:15]=1
Reactant: NN
Reactant: CCOC(=O)C(CC#CC(=O)c1ccc(Br)cc1)c1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 121.8 %

Procedure:
3-[5-(4-Bromo-phenyl)-1-β-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester. To a solution of 6-(4-bromo-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl ester (7.5 g, 19 mmol) in THF (40 mL) was added hydrazine (4.5 g, 28 mmol, 1.5 equiv) and Cs2CO3 (9.0 g, 28 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (30 mL), and a satd aq solution of cesium carbonate (50 mL) was added. The resulting aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with satd aq NaHCO3 (50 mL) then brine (50 mL), and dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (5.5 g, 58%). TLC (silica gel, 3:7 EtOAc/hexanes): Rf=0.35. MS (ESI): mass calculated for C28H27BrN2O2, 502.13; m/z found, 503/505 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=10.7 Hz, 2H), 7.25-7.01 (m, 10H), 6.17 (s, 1H), 4.19-4.03 (m, 3H), 3.52 (dd, J=14.7, 9.6 Hz, 1H), 3.09 (dd, J=14.7, 6.0, 1H), 2.35 (s, 6H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]2)=[N:23][CH:24]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl

Procedure:
2-{5-Chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide was prepared from 1-(4-amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide in an analogous manner to Example 276. Product isolated as an off-white solid (557 mg, 88%). m.p.=160-163° C.; LCMS (m/e) 581 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 9.10 (s, 1H), 8.45 (d, 1H, J=8.3 Hz), 8.08 (s, 1H), 7.97 (t, 1H, J=2.0 Hz), 7.61-7.54 (m, 1H), 7.42-7.20 (m, 3H), 7.10-6.97 (m, 2H), 4.87-4.77 (m, 1H), 3.88-3.77 (m, 1H), 3.60-3.40 (m, 2H), 3.27-3.01 (m, 2H), 2.65 (s, 3H), 2.10-1.98 (m, 2H), 1.85-1.73 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([O:17][C:18](=O)[CH:19]=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=2)[C:18](=[O:17])[CH:19]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Cl)c(C(F)(F)F)c2)[nH]1
Reaction time: 8 h

Procedure:
67 g of 4-chloro-3-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 46.1 g of β-amino-β-ethoxyacrylic acid ethyl ester and g of p-toluenesulphonic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the residue, which solidified, was filtered off and recrystallised from ethanol. The product was the compound identified above. Melting point: 132°, 25 g (30%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:19]1[C:20](OS(C(F)(F)F)(=O)=O)=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:20]1[C:19]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]2[CH3:12])=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=2)[N:21]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (2,4-difluorophenyl)boronic acid (218.9 mg, 1.39 mmol) in dioxane (5.0 mL) and water (3 drops) was added (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (300 mg, 0.69 mmol), K3PO4 (293 mg, 1.38 mmol) and Pd(PPh3)4 (39.97 mg, 0.03 mmol) with stirring for 1 hour at 95° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (192.0 mg, 70%)
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>CCOCC>[Cl:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:3])=[O:8]
Reactant: O=C(O)c1ccccc1Cl
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccccc1Cl
Temperature: 0 °C
Yield: 72.4 %

Procedure:
An excess solution of diazomethane in ether was added to an ice-cooled and stirred solution of o-chlorobenzoic acid (7.6 g, 48.6 mmol) in 50 ml of ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl o-chlorobenzoate (6.0 g, 35.2 mmol, yield 72.4%, b.p. 92°-93° C./7 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:32]=[C:33]([CH:36]=[O:37])[S:34][CH:35]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:31]4[N:32]=[C:33]([CH:36]=[O:37])[S:34][CH:35]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(C=O)n1
Reactant: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1nc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)cs1
Yield: 44 %

Procedure:
Prepared according to Procedure B from (4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (2 g, 4.56 mmol), 4-(tributylstannyl)thiazole-2-carbaldehyde (1.84 g, 4.56 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.74 g, 20 mol %) heated at reflux overnight (18 hrs) in dioxane (50 ml). The cooled solution was filtered through a plug of Celite®, concentrated and triturated with iso-hexane (3×20 ml). The resultant solid was purified via flash column chromatography on silica gel, eluting with 5% methanol in chloroform. The purified product was isolated as a yellow solid (0.85 g, 44%). δH [2H6] DMSO 10.10(1H, s), 9.30(1,bs), 8.90(1H, s), 8.50(2H, s&d), 8.45(1H, d), 8.20(1H, d), 7.40(5H, bm), 7.10(4H, 2d), 6.80(1H, d).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:21]1[C:25]2[N:26]=[CH:27][N:28]=[CH:29][C:24]=2[C:23](I)=[CH:22]1)([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]1([C:37](=[N:44][C:45]2[CH:46]=[N:47][CH:48]=[C:49]([CH:56]=2)[C:50](N(OC)C)=[O:51])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][C:10]([N:21]1[C:25]2[N:26]=[CH:27][N:28]=[CH:29][C:24]=2[C:23]([C:50]([C:49]2[CH:48]=[N:47][CH:46]=[C:45]([N:44]=[C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:56]=2)=[O:51])=[CH:22]1)([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncnc21
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Product: CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 7-[2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methylethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 114) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Preparation 23) to afford the title compound as a yellow foam in 69% yield, 1.76 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:29])=[CH:4][C:5]([Cl:28])=[C:6]([C:8]2[C:9](=[O:27])[N:10]([CH2:25][CH3:26])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[Cl:28][C:5]1[C:6]([C:8]2[C:9](=[O:27])[N:10]([CH2:25][CH3:26])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)[CH:12]=3)=[CH:7][C:2]([NH:1][C:43]([NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])=[C:3]([F:29])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCN(C)C3)cc21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC3CCN(C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.3 %

Procedure:
To a solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-1,6-naphthyridin-2(1H)-one (500 mg, 1.20 mmol) and pyridine (140 mg, 1.8 mmol) in DCM (20 mL) was added phenyl isocyanate (215 mg, 1.8 mmol). The mixture was stirred at RT overnight, concentrated, and purified by prep-HPLC separation to give 1-(4-chloro-5-(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (53 mg, 8.4% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.53 (d, J=11.2 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.28-7.23 (m, 3H), 6.98-6.95 (m, 1H), 6.35 (s, 1H), 4.39 (s, 1H), 4.11-4.09 (m, 2H), 2.77-2.71 (m, 1H), 2.65-2.61 (m, 1H), 2.44-2.36 (m, 2H), 2.26 (s, 3H), 2.23-2.20 (m, 1H), 1.68-1.62 (m, 1H), 1.64 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][CH:4]=1)#[CH:2].I[C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][CH:4]=[C:3]2[C:1]#[C:2][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)=[C:26]([C:38]([F:39])([F:40])[F:41])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cncc2c(N)cccc12
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cncc2c(N)cccc12

Procedure:
The title compound can be synthesized from 4-ethynylisoquinolin-8-amine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 1. 4-ethynylisoquinolin-8-amine is prepared from 4-bromoisoquinolin-8-amine and ethynyitrimethylsilane according to the 2 steps procedure described in example 1.
Reaction SMILES: [CH:1]1([C:5](Cl)=O)[CH2:4][CH2:3][CH2:2]1.C1(P(=[CH:27][C:28](=[O:30])[CH3:29])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>O1CCCC1.[Pd]>[CH:1]1([CH:5]=[CH:27][C:28](=[O:30])[CH3:29])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C1CCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(=O)C=CC1CCC1

Procedure:
10 parts of cyclobutylcarboxylic acid chloride in tetrahydrofuran is hydrogenated over 10% palladium on carbon catalyst, to provide cyclobutylcarboxaldehyde. 25 parts of triphenylphosphoranylidene-2-propanone and 6.3 parts of the cyclobutylcarboxaldehyde in 60 parts by volume of benzene under nitrogen are refluxed for 8 hours. The solvent is removed by evaporation under reduced pressure to provide 4-cyclobutyl-3-buten-2-one.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.3 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (0.67 g, 2.01 mmol) in DCM (25 ml), were sequentially added triethylamine (0.84 ml, 6.04 mmol) and benzoyl chloride (0.28 ml, 2.42 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The crude was taken up with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-phenylacetate (310 mg; 42% yield).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:24])([CH3:23])[C:5](=[O:22])[CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][NH:13]C(=O)C(F)(F)F)=[CH:10][CH:9]=1>CO>[CH3:3][C:4]([CH3:24])([CH3:23])[C:5](=[O:22])[CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)COc1ccc(CNC(=O)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)COc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
Add 5N aqueous NaOH (15 mL) to a solution of N-[4-(3,3-dimethyl-2-oxo-butoxy)-benzyl]-2,2,2-trifluoro-acetamide (552 mg, 1.74 mmol) in methanol (10 mL) and stir for 2 h at ambient temperature. Extract the mixture with DCM three times. Dry the combined organic extracts over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (92:8) to give the title compound as a colorless oil (337 mg, 87%). MS (ES+) m/z: 205 (M+H—NH3)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[C:23](=[O:29])[N:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: Cn1cccc(CBr)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
3-Bromo-4-nitro-1H-indazole (Preparation B; 0.49 g, 2.04 mmol) was dissolved in dimethyl formamide (5 mL). Potassium carbonate (1.13 g, 8.15 mmol) was added followed by 3-(bromomethyl)-1-methylpyridin-2(1H)-one (0.41 g, 2.04 mmol). The mixture was stirred at ambient temperature for two days. The mixture was diluted with ethyl acetate (8 mL) and concentrated under vacuum to give a dark solid which was dried overnight under high vacuum. This material was dissolved in ethyl acetate (80 mL) and washed with water (40 mL). The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum to give a green solid. This material was triturated with diethyl ether and the solids were collected by filtration and dried under high vacuum to give 3-((3-bromo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one as a beige solid (552 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[C:40]([O:43][CH:44](Br)[CH3:45])(=[O:42])[CH3:41]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([O:12][CH2:45][CH2:44][O:43][C:40](=[O:42])[CH3:41])=[O:11]
Reactant: CC(=O)OC(C)Br
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOC(=O)[C@@H](c1ccc(F)cc1F)N1C(=O)[C@@H](C2Cc3ccccc3C2)NC(=O)[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoic acid (example 22) (0.130 g) was stirred in anhydrous DMF (1 mL) and anhydrous potassium carbonate (0.020 g, 0.5 eq.) was added. The mixture was stirred at room temperature for 1 hour then cooled to −10° C. (ice-salt bath). The heterogeneous mixture was treated with 1-bromoethyl acetate (0.120 mL, excess) and stirred for 3.5 hours keeping the bath temperature between −10 and −5° C. It was then partitioned between DCM and 1M HCl aq. (20 mL each). The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure to give a purple gum; this was purified by SPE cartridge (5 g, silica eluted with (i) cyclohexane x2, (ii) DCM x2, (iii) diethl ether x2, (iv) ethyl acetate x2, (v) methanol x2 to give I -(acetyloxy)ethyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate (0.081 g) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.I[C:11]1C=CC=CC=1C=O>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:11]
Reactant: O=Cc1ccccc1F
Reactant: O=Cc1ccccc1I
Product: C=Cc1ccccc1F
Yield: 20 %

Procedure:
The substantially same method as described in Preparation Example 284 was conducted, except that 2-fluorobenzaldehyde (Aldrich No. F4807) was used instead of 2-iodobenzaldehyde (Preparation Example 63) to obtain the title compound (1.82 g, yield 20˜40%).
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)C=O.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH2:1]([S:13]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([Cl:33])=[O:19])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCS(=O)(=O)c1ccccc1C(=O)Cl
Temperature: 25 °C

Procedure:
The o-dodecanesulfonylbenzoic acid (30.0 g, 0.084 mol) was dissolved in 100 ml of methylene chloride, then 0.5 ml of N,N-dimethylformamide was added, and they were stirred at room temperature. Then 12 ml of oxalyl chloride was added dropwise over 15 min, and after the addition the reaction mixture was stirred for 1 hour. The reaction solution was concentrated, to obtain o-dodecanesulfonylbenzoyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N+:22]([O-])=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH2:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Temperature: 50 °C

Procedure:
To a solution of the product from Step A (2.07 g, 5.72 mmol) in 20 mL of ethanol was added stannous(II) chloride (4.32 g, 22.8 mmol). The solution was heated to 50° C. for 45 minutes hour, then cooled to room temperature. The solution was poured into 2 mL of concentrated sulfuric acid, then heated to 90° C. for 30 minutes. After cooling, the solution was concentrated in vacuo, basified with 20% NaOH solution, and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as a brown oil.