Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=[N:58][C:53]2[CH:54]=[CH:55][CH:56]=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCC1>CN(C=O)C>[CH:53]1([NH:58][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH:12]=[CH:11][C:10](=[O:42])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:34][CH2:33][CH:32]([N:35]5[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]5)[CH2:31][CH2:30]4)[N:17]=3)[CH:20]=2)[CH2:54][CH2:55][CH2:56]1
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC2CCC2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and cyclobutanamine (7.04 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (24.8 mg, 72%). LC-MS m/z 627 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26](CC)[C:27](=O)[C:28](F)(F)F)[CH2:24][CH3:25])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][CH2:27][CH3:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(CC)C(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}-N-ethyl-2,2,2-trifluoroacetamide (131 mg, 0.245 mmol) in ethanol (5.0 mL) was added sodium tetrahydroborate (28 mg, 0.74 mmol) at room temperature. The mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on NH-silica gel eluting with a 30-80% ethyl acetate/n-hexane gradient mixture to give the title compound (35.4 mg, 0.081 mmol, 33%) as a colorless solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:26])[C@@:10]([OH:25])([CH3:24])[C@@H:11]([CH2:22][OH:23])[NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:8][C@@H:9]([CH3:26])[C@@:10]([OH:25])([CH3:24])[C@@H:11]([CH2:22][OH:23])[NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CCCCC(=O)N[C@H](CO)[C@@](C)(O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CCCCC(=O)N[C@H](CO)[C@@](C)(O)[C@H](C)N

Procedure:
Meanwhile, the t-butoxycarbonyl group was removed from 412 mg (1.1 mmole) of 4(S)-t-butoxycarbonylamino-3(S)-hydroxy-6-methylheptanoyl-L-isoleucinol with 6N hydrogen chloride in dioxane, as described in Example 1(b), to yield 4(S)-amino-3(S)-hydroxy-6-methylheptanoyl-L-isoleucinol hydrochloride. This product was dissolved in 5 ml of dimethylformamide, and the resulting solution was added to the above-mentioned hydrazide solution, and the mixture was stirred at 4° C. for 7 days. The solvent was distilled off under reduced pressure. Water was added to the residue, and the oily substance produced was extracted with ethyl acetate. The organic extract was washed with 1N hydrochloric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous sodium sulfate. It was then condensed by evaporation under reduced pressure. The syrupy residue was purified by silica gel preparative thin layer chromatography, using a 5:1 by volume mixture of chloroform and methanol as the developing solvent. The active fractions extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, dried, and then condensed by evaporation under reduced pressure. On adding diethyl ether to the residues, the condensate solidified, and this was finely ground and then collected by filtration to yield 402 mg of the title compound as a colorless powder melting at 206°-212° C., [α]23 -95.0° (C=0.3, methanol).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:14][C:15](=[O:31])[CH2:16][C@@H:17]([CH2:29]I)[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[C:10]([O:14][C:15](=[O:31])[CH2:16][C@@H:17]([CH2:29][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)C[C@@H](CI)NC(=O)OCc1ccccc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiophenol (0.15 ml) in N,N-dimethylformamide (6 ml) was added NaH (58 mg) under ice cooling. After stirring at room temperature for 30 minutes, N-(benzyloxycarbonyl)-3(S)-iodomethy-β-alanine tert-butyl ester (0.6 g) was added and stirred for additional 1 hour. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% (EtOAc/n-hexane) to give N-(benzyloxycarbonyl)-3(S)-phenylthiomethy-β-alanine tert-butyl ester (0.64 g) as an pale yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1>O>[Cl:3][CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1
Reactant: O=S(Cl)Cl
Reactant: O=c1c2ccccc2ncn1CCO
Solvent: O
Product: O=c1c2ccccc2ncn1CCCl
Temperature: 85 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
This thionyl chloride (1,095 mL, 15 mmol) was added to 3-(2-hydroxyethyl)quinazoline-4 (3H)-one (2.0 g, 10.52 mmol) in a reactor, forming a white suspension that heated spontaneously to 85° C. The reaction medium was kept at this temperature under agitation for thirty minutes, after which it was left to cool to about 40° C. Next, 50 mL of water was added, forming a pinkish suspension, which was kept under agitation for two hours. The product was then vacuum filtered and washed with three portions of 10 mL of an ethanol/water mixture (50% v/v), yielding 3-(2-chloroethyl)quinazoline-4 (3H)-one as a pale white solid (1.8 g, 8.63 mmol, yield=82%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:12][C:11]=2[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:12][C:11]=2[CH:26]([OH:31])[C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ncc3F)c(C(=O)C(C)(C)C)c2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(COc2ccc(-c3cc(OC)ncc3F)c(C(O)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 1-(2-(5-fluoro-2-methoxypyridin-4-yl)-5-((4-methoxybenzyl)oxy)phenyl)-2,2-dimethylpropan-1-one (270 mg) in methanol (5 mL) was added sodium borohydride (50 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (255 mg) as a white amorphous solid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=2)[N:10]=[C:9]([O:18][CH3:19])[C:8]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.[CH3:28][C:29]1[C:34]([C:35]([C:37]2[N:41]([CH3:42])[N:40]=[N:39][CH:38]=2)=[O:36])=[CH:33][CH:32]=[C:31]([CH3:43])[N:30]=1.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:35]([C:34]3[C:29]([CH3:28])=[N:30][C:31]([CH3:43])=[CH:32][CH:33]=3)([C:37]3[N:41]([CH3:42])[N:40]=[N:39][CH:38]=3)[OH:36])[CH:15]=2)[N:10]=[C:9]([O:18][CH3:19])[C:8]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(C)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C)cc1
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.47 mL, 1.2 mmol) was added dropwise to a stirring solution of 4-chloro-6-iodo-2-methoxy-3-(4-methylbenzyl)quinoline (500 mg, 1.2 mmol, Intermediate 22: step c) in tetrahydrofuran (9 mL) at −78° C. After 2 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (255 mg, 1.2 mmol, Intermediate 19: step b) in tetrahydrofuran (2 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 15 minutes, water (5 mL) and ethyl acetate (50 mL) were added and the biphasic mixture was poured into saturated aqueous sodium chloride solution (15 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (6 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with 100% hexanes initially, grading to 100% ethyl acetate provided the title compound as a white foam. MS (ESI): mass calcd. for C29H28ClN5O2, 513.2. m/z found, 514.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:13]>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O-:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3].[Na+:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc([O-])cc1
Yield: 91 %

Procedure:
4-tert-Butylphenol (98 g, 0.650 mol) was charged into a 2 L three-necked round bottom flask equipped with a mechanical stirrer, a dropping funnel, and a condenser. The flask was purged with nitrogen gas and a solution of 26.7 g of sodium hydroxide (0.650 mol) in 820 mL of water was added to the flask. The stirred reaction mixture was heated at 50° C. until 4-tert-butylphenol was completely dissolved. In this way, 4-tert-butylphenol was reacted with sodium hydroxide to form sodium 4-tert-butylphenolate. The solution of sodium 4-tert-butylphenolate in water was then cooled to 20° C. and 350 mL of dichloromethane was added to the solution. The organic layer obtained in step two, which contained 0.325 mol of the perfluoropropane-1,3-di(sulfonyl halides), was dropwise added to the reaction mixture for 2 hours under nitrogen atmosphere. The reaction mixture was stirred at 20° C. for 12 hours and transferred to a separatory funnel. The upper water layer was separated from the lower organic (dichloromethane) layer. The water layer was then washed by 300 mL of ethyl acetate. The water layer was 953 g. 19F-NMR analysis (using hexafluoroglutaric acid as a reference) showed that the water layer contained 0.295 mol of sodium perfluoropropane-1,3-di(sulfinate). The yield was 91%. 19F-NMR (in D2O); δ −122.9 (s, 2F, CF2), −129.8 (s, 4F, CF2S) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[C:22]6[CH:28]=[CH:27][NH:26][C:23]6=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1.[H-].[Na+].I[CH3:35]>CN(C=O)C.CO>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[C:22]6[CH:28]=[CH:27][N:26]([CH3:35])[C:23]6=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8]2=[O:30])[C:4]([CH3:31])=[N:3]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5[nH]ccc5c4)cc3c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(ccn5C)c4)cc3c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of a new batch of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 36, 45.4 mg, 0.111 mmol) in 1.5 ml anhydrous DMF was treated with 55% NaH in oil (6.0 mg, 0.138 mmol). The reaction mixture was stirred for 20 min at rt, then was added iodomethane (0.009 ml, 138 mmol). The reaction mixture was stirred for 1.5 h at rt. The RM was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.62 min (Method A); M+H=424 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.38-8.36 (m, 1H), 8.18-8.16 (m, 1H), 8.13-8.09 (m, 1H), 8.06-8.04 (m, 1H), 7.99-7.95 (m, 1H), 7.60-7.58 (m, 1H), 7.57-7.55 (m, 1H), 6.54-6.51 (m, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH3:31])[C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[O:13])[CH2:7][CH2:6]1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:12](=[O:13])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:32])[CH2:6][CH2:7]3)[CH3:31])[CH:20]=2)=[CH:27][CH:26]=1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
After adding 20% palladium hydroxide-carbon (50 mg) to a solution of 1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methyl-3-[4-(4-nitrophenoxy)pyridin-2-yl]urea (186 mg) in tetrahydrofuran (5.0 ml), the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered. The filtrate was concentrated to provide the title compound (121 mg, 69.8%) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])O2)=[CH:5][CH:4]=1.C(N(CC)C(=O)C1C=CC=CC=1C(O)C1C=CC(N(C)C)=CC=1)C.[CH2:44]([N:46]([CH2:50][CH3:51])[CH2:47][CH2:48][NH2:49])[CH3:45]>[Cl-].[Zn+2].[Cl-]>[CH2:44]([N:46]([CH2:50][CH3:51])[CH2:47][CH2:48][N:49]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:19])=[CH:8][CH:7]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18])[CH3:45]
Reactant: CCN(CC)CCN
Reactant: CN(C)c1ccc(C2OC(=O)c3ccccc32)cc1
Agent: CCN(CC)C(=O)c1ccccc1C(O)c1ccc(N(C)C)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccc(N(C)C)cc1

Procedure:
To a solution of 0.32 g of Compound A and 1.41 g of Compound B in 10 ml of N,N-diethylethylenediamine was added 0.15 g of anhydrous zinc chloride. After heating at reflux for 2.5 hours in a nitrogen gas atmosphere, the mixture was concentrated under reduced pressure. To the residue were added 15 ml of methylene chloride and 50 ml of water, and pH of the mixture was adjusted to 1 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 30 ml of methylene chloride was added to the aqueous layer. The pH was adjusted to 12 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent, ethyl acetate:hexane:triethylamine=10:20:1). A major fraction was concentrated under reduced pressure to give 1.13 g of 2-(2-diethylaminoethyl)-3-(4-dimethylaminophenyl)isoindolin-1-one (Compound 18).
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4][CH2:3]1.C(OC1C=C(C)C(NC(=O)C)=CC=1C)(=O)C.[CH3:35][C:36]1[C:44]([OH:45])=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[N:39][NH:40]2>>[CH3:35][C:36]1[C:44]([O:45][C@H:3]2[CH2:2][CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4]2)=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[N:39][NH:40]2
Reactant: Cc1c(O)ccc2[nH]ncc12
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: CC(=O)Nc1cc(C)c(OC(C)=O)cc1C
Product: Cc1c(O[C@H]2CCC[C@H](N)C2)ccc2[nH]ncc12

Procedure:
The following compound of Example 410 was synthesized by carrying out reactions according to the methods described in Example 385 and Example 327, except for using the trans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained in Example 323, (a) and the 4-methyl-1H-indazol-5-ol obtained in Example 402, as starting materials.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[C:15]([C:18]1[CH:19]=[C:20](/[CH:23]=[C:24]2\[C:25](=[O:35])[NH:26][C:27]3[C:32]\2=[C:31](I)[C:30]([F:34])=[CH:29][CH:28]=3)[NH:21][CH:22]=1)(=[O:17])[CH3:16].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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.[Cu]I>[C:15]([C:18]1[CH:19]=[C:20](/[CH:23]=[C:24]2\[C:25](=[O:35])[NH:26][C:27]3[C:32]\2=[C:31]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:30]([F:34])=[CH:29][CH:28]=3)[NH:21][CH:22]=1)(=[O:17])[CH3:16]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#C[C@@H]4CCCN4)c32)c1
Reaction time: 2 h

Procedure:
Using Method C above, (S)-N-Boc-2-Ethynyl-pyrrolidine (220 mg, 1.13 mmol) (Example 87B) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (150 mg, 0.38 mmol) (Example 90B) using (Ph3P)4Pd (44 mg, 0.04 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 7 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-5% MeOH in CH2Cl2 gradient. The intermediate that resulted from this process was dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.3 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. The (S)-(Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after silica gel column with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 56 mg, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)=[N:8][CH:7]=1)=[O:5])[CH3:2].O.NN.C(O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][NH2:21])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(CN2C(=O)c3ccccc3C2=O)c2c(OC)cc(OC)cc12
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(CN)c2c(OC)cc(OC)cc12
Temperature: 40 °C
Reaction time: 4 h
Yield: 123.5 %

Procedure:
To a solution of 1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (1.22 g, 2.90 mmol) in 80 mL of absolute ethanol hydrazine monohydrate (1.59 g, 31.8 mmol) was added and the mixture was stirred under a nitrogen atmosphere at 40° C. After 4 h, the reaction was cooled to room temperature, and the phthalhydrazide precipitate was removed by filtration, rinsing with ethanol. The filtrate was concentrated under reduced pressure to give 1.04 g of crude 1-aminomethyl-6,8-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester, which was used directly the next step. H1-NMR (DMSO): δ, 8.84 (s, 1H), 7.81 (d, 1, J=2.4 Hz), 6.76 (d, 1H, J=2.3 Hz), 4.36 (q, 2H, J=7.13), 4.32 (s, 2H), 3.95 and 3.88 (s, 3H each), 1.35 (t, 3H, J=7.2 Hz); MS: APCI (M+H) calc'd for C15H18N2O4+H 291.3; found 291.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(Cl)c1OC
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(Cl)c1OC

Procedure:
1-(5-(3-Chloro-4,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(3-chloro-4,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (70% EtOAc/hexanes) gave the product as a pale yellow solid (0.051 g, 12% yield). MS: m/z 469.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[O:14][C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7]=2[C:6]([C:16]2[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:5][CH:4]=1.CC1C=CC(S(O[CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[C:15]2[O:14][C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[CH2:8][C:7]=2[C:6]([C:16]2[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[N:19]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[N:20]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1ccc(C2=NNC(=O)C2(C)C)c2c1OC1(CCCC1)C2
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C6) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B6*HCl)