Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:73]=[CH:72][C:15]([O:16][CH2:17][C:18]3([O:42][C:43](=[O:71])[CH:44]([NH:60]C(OCC4C=CC=CC=4)=O)[CH2:45][CH2:46][CH2:47][CH2:48][NH:49]C(OCC4C=CC=CC=4)=O)[CH2:23][CH2:22][N:21]([C:24]4[N:33]=[C:32]5[C:27]([C:28](=[O:40])[C:29]([C:37]([OH:39])=[O:38])=[CH:30][N:31]5[CH:34]5[CH2:36][CH2:35]5)=[CH:26][C:25]=4[F:41])[CH2:20][CH2:19]3)=[C:14]([F:74])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]>[OH-].[Pd+2].[OH-]>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:73]=[CH:72][C:15]([O:16][CH2:17][C:18]3([O:42][C:43](=[O:71])[CH:44]([NH2:60])[CH2:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH2:19][CH2:20][N:21]([C:24]4[N:33]=[C:32]5[C:27]([C:28](=[O:40])[C:29]([C:37]([OH:39])=[O:38])=[CH:30][N:31]5[CH:34]5[CH2:36][CH2:35]5)=[CH:26][C:25]=4[F:41])[CH2:22][CH2:23]3)=[C:14]([F:74])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(N)CCCCN)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 94 mg 7-[4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-(2,6-bis-benzyloxycarbonylamino-hexanoyloxy)-piperidin-1-yl]-1-cyclo-propyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (MW: 1024.05, 0.091 mmol) and 20 mg of palladium hydroxide 20% on activated carbon in 20 ml of a 6/3/1 dichloromethane/methanol/water mixture was stirred at room temperature under hydrogen for four hours. The catalyst was filtered off using a glass fibre filter paper. The solvents were evaporated under reduced pressure and the residue dissolved in 10 ml methanol. The solution was diluted with 20 ml water while a white solid precipitated. The solid was collected and dried. Yield: 29 mg, 43%. MS: 757.0 (M+H)+, 755.2 Method ESI+, ESI−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([N:8]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:9]C(OCC1C=CC=CC=1)=O)([CH3:7])[CH3:6])[CH3:2].CCN(CC)CC.[SiH](CC)(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[C:5]([N:8]([C:20](=[O:29])[C:21]1[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([CH3:27])[CH:26]=1)[NH2:9])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)N(N)C(=O)c1cc(C)cc(C)c1
Yield: 160.7 %

Procedure:
Into a flask containing 1.5 g (0.0036 mol, 80% pure) of 2-[N′-benzyloxycarbonyl-N-(3,5-dimethyl-benzoyl)-hydrazino]-2-methyl-propionic acid ethyl ester, was added 20 mL of dry CH2Cl2, 1.5 mL of Et3N, and 1.27 g (0.010 mol) of Et3SiH. While stirring, small portions of a total of 0.010 g of Pd(OAc)2 was added and the reaction was stirred for 2 hours at room temperature. To the reaction mixture was added 100 mL of CH2Cl2 and some MgSO4 to aid in the filtration/removal of the Pd product. The CH2Cl2 solution was shaken with saturated NH4Cl, CH2Cl2 dried, and evaporated to yield 1.61 g of 2-[N-(3,5-dimethyl-benzoyl)-hydrazino]-2-methyl-propionic acid ethyl ester. The product was purified by chromatography, elution with 21-24% ethyl acetate in hexane. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.045 (s 2H), 7.0 (s 1H), 4.4 (s, 2H), 2.324 (s 6H), 2.236 (s 3H), 1.487 (s, 6H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:23][CH:24]([CH3:27])[CH2:25][NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:10]1([CH:8]([OH:9])[CH:7]([NH:26][CH2:25][CH:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:27])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CC(CN)OCc1ccccc1
Product: CC(CNC(c1ccccc1)C(O)c1ccccc1)OCc1ccccc1
Temperature: 140 °C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 2-benzyloxypropylamine (2.48 g, 0.015 mol) was heated at 140° C. for 6 hours and then allowed to stand at ambient temperature for 12 hours. The solidified reaction mixture was triturated with petroleum ether and filtered to obtain 2.72 g of a solid. Mass spectral analysis showed starting materials present. Recrystallization from isooctane gave 2.16 g (60%) of the product as a white solid; mp 114°-119° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:27])=[C:24]([F:26])[F:25]>CN(C)C=O>[F:27][C:23](=[C:24]([F:26])[F:25])[CH2:22][CH2:21][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:3][C:2]([F:16])([F:1])[F:17])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: FC(F)=C(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(SC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(SC(F)(F)F)cc1
Yield: 16.9 %

Procedure:
Using 0.50 g of (4-(trifluoromethylthio)benzyl)malononitrile, 10 ml of N,N-dimethylformamide, 86 mg of sodium hydride (60% in oil), and 0.74 g of 4-bromo-1,1,2-trifluoro-1-butene, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(3,4,4-trifluoro-3-butenyl)-2-(4-(trifluoromethylthio)benzyl)malononitrile (the present compound (54)).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl>>[CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A mixture of ethyl 4-[(methylsulfonyl)amino]benzoate (Lumma, W. C. et al. J. Med. Chem. 1987, 30, 758-763) (2.43 g, 0.01 mol) in 1N sodium hydroxide (22 mL, 0.022 mol) was stirred at room temperature for 24 h and then at 48° C. for 24 h. The mixture was acidified with concentrated hydrochloric acid to give a white precipitate which was separated by filtration. The cake was washed with water, dried, and recrystallized with ethanol-water to give 1.4 g (65%) of the title compound as white flakes, mp 248° C.
Reaction SMILES: O[N:2]=[CH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([C:32]4[C:23](=[CH:24][C:25]5[O:30][CH2:29][CH2:28][O:27][C:26]=5[CH:31]=4)[O:22][CH2:21]3)[C:13]2=[O:33])=[CH:7][N:6]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.C(=O)(O)[O-].[Na+]>[N:4]1[CH:3]=[N:2][N:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]4([C:32]5[C:23](=[CH:24][C:25]6[O:30][CH2:29][CH2:28][O:27][C:26]=6[CH:31]=5)[O:22][CH2:21]4)[C:13]3=[O:33])[CH:9]=[CH:10][C:5]=12
Reactant: O=C1N(Cc2ccc(NC=NO)nc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1N(Cc2ccc3ncnn3c2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a cooled (0° C.) suspension of N′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide (0.22 g, 0.5 mmol) in tetrahydrofuran (7 mL) was slowly added trifluoroacetic anhydride (0.08 mL, 0.54 mmol). The mixture was stirred at ambient temperature for 3 h, diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers was washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 50% to 65% gradient of ethyl acetate in hexanes to afford 1′-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.11 g, 54%) as a colorless solid: mp 207-209° C.; 1H NMR (300 MHz, DMSO-d6) δ8.65 (s, 1H), 8.37 (s, 1H), 7.82-7.77 (m, 1H), 7.61-7.55 (m, 1H), 7.30-7.17 (m, 2H), 7.11-7.04 (m, 1H), 6.90-6.85 (m, 1H), 6.52 (s, 1H), 6.18 (s, 1H), 5.03 (ABq, J=40.9, 15.6 Hz, 2H), 4.80 (ABq, J=79.6, 9.0 Hz, 2H), 4.23-4.09 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.7, 155.2, 154.2, 149.9, 144.8, 141.2, 138.4, 132.1, 129.8, 129.0, 127.0, 124.4, 124.0, 123.0, 120.5, 117.4, 111.4, 108.6, 99.5, 80.0, 64.5, 63.9, 58.0, 41.2; MS (ES+) m/z 426.9 (M+1).
Reaction SMILES: CS([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([F:15])([F:14])[CH3:13])[CH2:8][CH2:7]1)(=O)=O.O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([CH2:27][N:28]1[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]1)[CH:21]=[CH:20]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl>C(O)(C)(C)C.CC(=O)CC>[F:14][C:12]([C@H:9]1[CH2:10][CH2:11][C@H:6]([O:5][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([CH2:27][N:28]2[CH2:29][CH:30]([C:32]([OH:34])=[O:33])[CH2:31]2)[CH:21]=[CH:20]3)[CH2:7][CH2:8]1)([F:15])[CH3:13]
Reactant: CC(F)(F)[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reactant: COC(=O)C1CN(Cc2ccc3cc(O)ccc3c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc(CN4CC(C(=O)O)C4)ccc3c2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
(trans)-4-(1,1-difluoroethyl)cyclohexyl methanesulfonate (WO 2010051030) (0.98 mmol, 236 mg, 1.0 eq.), methyl 1-((6-hydroxynaphthalen-2-yl)methyl)azetidine-3-carboxylate (1.17 mmol, 317 mg, 1.2 mmol) and Cs2CO3 (4.41 mmol, 1.4 g, 4.5 eq.) were dissolved in t-butanol (4 mL) and 2-butanone (2 mL). The mixture was stirred at 110° C. for 16 h. 1 M aq. HCl solution was added to the mixture to adjust pH=6. Then the mixture was extracted with EtOAc. The organic layer was purified by silica gel column chromatography using DCM/CH3OH (10/1) as eluent to give product (7 mg, 1.8%) as a white solid. ESI-MS (M+1)+: 404.1. HPLC: 89.46%. 1H NMR (400 MHz, CD3OD) δ: 7.89 (s, 1H), 7.86-7.81 (m, 2H), 7.46 (dd, 1H), 7.31 (s, 1H), 7.19 (dd, 1H), 4.47 (s, 2H), 4.43-4.41 (m, 1H), 4.21 (d, 4H), 3.45-3.41 (m, 1H), 2.32-2.30 (m, 2H), 2.02-1.99 (m, 2H), 1.64-1.54 (m, 3H), 1.51-1.45 (m, 3H), 1.36-1.28 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:21][CH:22]([OH:24])[CH3:23]>>[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH:22]([OH:24])[CH3:23])[CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13]
Reactant: CC(O)CBr
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNCC3)cc12
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CC(C)O)CC3)cc12
Yield: 13.6 %

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (1 g) and 1-bromo-2-propanol (994 mg), 5-methyl-3-[1-(2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (147 mg) was obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C@@H:15]([CH2:35][CH2:36][C@@H:37]([C:47](=[O:65])[NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([C:60]([O:62][CH3:63])=[O:61])[N:51]2[C:50]1=[O:64])[CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:16]([NH:18][C@H:19]1[CH2:25][CH2:24][S:23][C@H:22]2[CH2:26][CH2:27][CH2:28][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[N:21]2[C:20]1=[O:34])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([C@H:15]([C:16]([NH:18][C@H:19]1[CH2:25][CH2:24][S:23][C@H:22]2[CH2:26][CH2:27][CH2:28][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[N:21]2[C:20]1=[O:34])=[O:17])[CH2:35][CH2:36][C@@H:37]([C:47](=[O:65])[NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([C:60]([O:62][CH3:63])=[O:61])[N:51]2[C:50]1=[O:64])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@@H](CCC(=O)OC(C)(C)C)CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@@H](CCC(=O)O)CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)C(=O)N21
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.8 %

Procedure:
TFA (0.1 mL) was added to a 0° C. solution of methyl (4S,7S,10aS)-4-(((2R,5R)-2-benzyl-8-tert-butoxy-5-(((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepin-4-yl)carbamoyl)-8-oxooctanoyl)amino)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (45 mg, 0.053 mmol) in DCM (0.2 mL). The reaction mixture was then stirred at rt for 4 hr. The reaction mixture was concentrated and dried under vacuum. The residue was purified by RP prep-HPLC to give (4R,7R)-7-benzyl-8-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)-4-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamoyl)-8-oxooctanoic acid (8.5 mg, 0.011 mmol, 20% yield) as a white solid. Anal. Calcd. for C38H52N4O10S2 m/z 788.5. found: 789.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (1H, d, J=5.5 Hz), 7.29-7.10 (6H, m), 5.44-5.29 (2H, m), 5.24-4.96 (6H, m), 3.72 (3H, s), 3.69 (3H, s), 3.30-3.19 (1H, m), 3.18-3.08 (1H, m), 2.97-2.68 (4H, m), 2.50-2.17 (6H, m), 2.10-1.91 (5H, m), 1.90-1.54 (11H, m), 1.53-1.39 (2H, m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][CH2:8]2)(=[O:4])[CH2:2][CH3:3].C([O-])(O)=O.[Na+].[Br:20]Br>CCOCC>[Br:20][CH:2]([CH3:3])[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][CH2:8]2)=[O:4]
Reactant: BrBr
Reactant: CCC(=O)c1ccc2c(c1)CCCS2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(Br)C(=O)c1ccc2c(c1)CCCS2
Temperature: 5 °C
Yield: 86 %

Procedure:
To a solution of 32 gr. of 6-propionyl-thiochromane in 400 ml of anhydrous ether, 8 ml of bromine are dropwise added, temperature being maintained at ±5° C. After addition, the mixture is still stirred for 2 to 3 hours at room temperature, than an aqueous saturated NaHCO3 solution is slowly added. The aqueous phase is twice extracted with 100 ml ether, combined organic phases are dried on MgSO4, filtered, and solvent is evaporated in vacuo. The residue so obtained is treated with 100 ml of petroleum ether; 38 gr. of α-bromo-6-propionyl-thiochromane are obtained.
Reaction SMILES: Br[C:2]1[C:3]([C:36](=[O:46])[N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:10][C:9]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:6]=1[CH3:7].[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[CH:48]=[CH2:49]>CN(C=O)C.CCN(CC)CC.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>[C:52]([O:51][C:47](=[O:50])/[CH:48]=[CH:49]/[C:2]1[C:3]([C:36](=[O:46])[N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:42][CH2:43][CH2:44][CH3:45])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:10][C:9]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:6]=1[CH3:7])([CH3:55])([CH3:54])[CH3:53]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1/C=C/C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 47.8 %

Procedure:
To a solution of benzyl 4-(4-bromo-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 164A, 80 mg, 0.12 mmol) in DMF (580 μL) and Et3N (580 μL) was added (PPh3)2PdCl2 (8 mg, 0.012 mmol) followed by tert-butyl acrylate (58 μL, 0.40 mmol). The reaction mixture was purged with N2 for 5 min and then heated at 140° C. overnight. The reaction mixture was poured into a separatory funnel containing 1N aq. HCl solution and EtOAc. The organic layer was washed 1N aq. HCl solution (2×) and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with sat. aq. NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (gradient from 0% to 35% EtOAc/hexanes) to provide the title compound (42 mg, 50%) as a colorless oil. MS(ESI+) m/z 733.5 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.O>O1CCCC1>[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[NH2:25]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Clc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nn1ncc2c(Cl)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.8 %

Procedure:
Sodium hydride (60 % wt suspension in mineral oil; 0.33 g, 8.3 mmol) is suspended in dry tetrahydrofuran (THF, 10 mL) and is cooled to 0° C. A mixture of 4-chloroindazole (1.05 g, 6.9 mmol) and THF (10 mL) is added to the slurry at 4° C. After the addition is completed, the mixture is stirred for 30 min. Then a mixture of O-mesitylenesulfonylhydroxylamine (1.25 g, 7 mmol) and THF (10 mL) is added slowly, at a temperature below 5° C. After the addition is completed, the reaction mixture is allowed to reach room temperature and is subsequently stirred for 3 h. Then the mixture is cooled again to 0° C., and a second aliquot of O-mesitylenesulfonylhydroxylamine (1.25 g, 7 mmol) in THF (10 mL) is added slowly. The mixture is allowed to reach ambient temperature and is subsequently stirred overnight. The reaction mixture is worked up by adding it to water, extracting into ethyl acetate, and drying over sodium sulfate. The crude product (1.2 g) is obtained after filtration of the drying agent and evaporation of the solvent. This material is used for the next reaction step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([S:26]([N:29]([CH3:34])[CH2:30][C:31]([OH:33])=[O:32])(=[O:28])=[O:27])=[CH:23][CH:24]=2)[C:19]([NH:35][C:36]([NH2:38])=[NH:37])=[N:18][CH:17]=1.[H-].[Na+].[C:41](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)C)([CH3:44])([CH3:43])[CH3:42]>COCCOC>[C:41]([O:32][C:31](=[O:33])[CH2:30][N:29]([S:26]([C:22]1[CH:21]=[C:20]2[C:25]([C:16]([Cl:15])=[CH:17][N:18]=[C:19]2[NH:35][C:36]([NH2:38])=[NH:37])=[CH:24][CH:23]=1)(=[O:27])=[O:28])[CH3:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 50 °C

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-methylglycine bis(trifluoroacetate) ##STR15## Guanidine hydrochloride (286 mg, 2.99 mmol was added in one portion to a stirred suspension of NaH (77.5 mg, 80% dispersion by wt in mineral oil, 2.58 mmol) in DME (2.0 mL) and the mixture was heated at 50° C. under N2 for 20 min. A solution of N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-methylglycine t-butyl ester (393 mg, 0.97 mmol) in DME (10 mL) was added and the mixture heated at 90° C. for 2 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-methylglycine t-butyl ester (260 mg, 0.607 mmol) as an off-white foam
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][C:3]=1[C:4]#[N:5].[F:19][CH:20]([C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])[O:28][CH2:29][C:25]=2[CH:24]=1)[CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:21][CH:20]([F:19])[C:23]3[CH:32]=[CH:31][C:26]4[C:27](=[O:30])[O:28][CH2:29][C:25]=4[CH:24]=3)[CH2:14][C:13]2=[O:18])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=CC(F)c1ccc2c(c1)COC2=O
Reactant: N#Cc1cc(CCN2CCNCC2=O)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc(CCN2CCN(CC(F)c3ccc4c(c3)COC4=O)CC2=O)ccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a flask charged with 2-Fluoro-5-[2-(2-oxopiperazin-1-yl)ethyl]benzonitrile (53 mg, 0.25 mmol) and Fluoro(1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (20 mg, 0.10 mmol) was added NaBH(OAc)3 (153 mg, 0.72 mmol). The mixture was stirred at RT for 12 hours. Then the reaction was diluted with DCM (120 mL), washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified with prep-TLC (MeOH/DCM=1:15) to obtain the title product. 1H-NMR (400 MHz, MeOD) δ ppm 7.88 (d, J=8.0 Hz, 1H), 7.55-7.65 (m, 4H), 7.25 (t, J=9.0 Hz, 1H), 5.90 (dd, J=7.6, 3.2 Hz, 1H), 5.78 (dd, J=7.6, 3.2 Hz, 1H), 5.39 (s, 2H), 3.59 (d, J=7.6, 7.0 Hz, 2H), 2.80-2.95 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: COC(=O)CCCBr
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCOC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (150 mg, 0.34 mmol) in 10 ml of anhydrous DMF were added methyl 4-bromobutanoate (123 mg, 0.68 mmol) and potassium carbonate (94 mg, 0.68 mmol). The mixture was heated at 60 C. for 2 hours, cooled to room temperature, and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2˜3% of methanol in chloroform to give 4-methoxy-4-oxobutyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as off-white solid. Yield: 130 mg, 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][CH2:10]O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cc(Cl)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(Cl)cc1CCCBr
Yield: 88.8 %

Procedure:
Compound 64-2 (2.28 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.50 g) and N-bromosuccinimide (2.37 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.70 g) as a colorless oil.