Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([C:28]2[C:36]([OH:37])=[CH:35][C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=2)[C:20]1=[O:38])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C1COCC1>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][C:21]1([C:28]2[C:36]([OH:37])=[CH:35][C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:38])[CH3:45]
Reactant: CCOC(=O)CBr
Reactant: CCCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCN1C(=O)C(CC(=O)OCC)(c2cc3c(cc2O)OCO3)c2ccccc21
Temperature: -75 °C
Yield: 8 %

Procedure:
To a solution of diisopropylamine (1.14 g, 11.0 mmol) in THF (10.0 mL) was added n-butyl lithium (7.00 mL, 11.0 mmol, 1.6 M solution in hexane) at −75° C. The resulting mixture was stirred at −75° C. for half an hour and added slowly to a solution of 1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one in THF (20.0 mL) at −75° C. After stirring at −75° C. for another half an hour, ethyl bromoacetate was added. The mixture was stirred at ambient temperature for 18 hrs and quenched with saturated ammonim chloride solution. The organic solvent was removed in vacuo and the aqueous residue was diluted with ethyl acetate (100 mL). The orgnic layer was washed with saturated ammonium chloride (25.0 mL), brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with 40% EtOAc/Hexanes to yield the title compound (0.19 g, 8%) as an oil: MS (ES+) m/z 440.5 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[CH:7]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Product: CC1CCN(c2cc(N3CCN(C)CC3)ccc2[N+](=O)[O-])CC1
Yield: 100.8 %

Procedure:
The procedure of Example 4, step (b) was followed using 150 mg (0.589 mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the Example 12, step (a)) and 327 μL (2.95 mmol) of 1-methylpiperazine at 142° C. for 21 h to afford 189 mg (100%) of the title compound as a yellow semisolid: Mass spectrum (ESI, m/z): Calcd. for C16H24N4O2, 319.2 (M+H), found 319.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[CH:7][CH:8]=[CH:9][C:10]1[S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]=1[CH3:15])[C:4]([O-:6])=[O:5].[CH2:20]1CCN2C(=NCCC2)CC1.C(OC(C)C)(C)C>C(Cl)Cl>[CH3:1][O:2]/[C:3](=[CH:7]/[CH:8]=[CH:9]/[C:10]1[S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]=1[CH3:15])/[C:4]([O:6][CH3:20])=[O:5]
Reactant: COC(=CC=Cc1sc2ccccc2c1C)C(=O)[O-]
Reactant: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: COC(=O)/C(=C\C=C\c1sc2ccccc2c1C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 1 %

Procedure:
Methyl (2Z,4E)-2-(methoxy-5-(3-methylbenzothiophen-2-yl)-2,4-pentadienoate and methyl (2Z,4E)-2-(methoxy-5-(3-methylbenzothiophen-2-yl)-2,4-pentadienoate. A solution of (E)-3-[2-(3-methylbenzothiophen-2yl)]-2-propenal (1 g, 5 mmol) in CH2Cl2 (30 ml) under nitrogen was treated with methoxycarbonylmethyl-2-methoxy triphenylphosphonium bromide (4.45 g, 10 mmol) and DBU (1.5 ml, 10 mmol). The reaction mixture was stirred at room temperature for 2 hours, washed with 10% aqueous HCl (5 ml), saturated solution of NaHCO3 (5 ml) and brine (5 ml), dried over Na2SO4 and evaporated under vacuum. The residue was purified by chromatography on silicagel (hexane/EtOAc 7/3) to afford, after trituration with isopropyl ether, methyl (2Z,4E)-2-methoxy-5-)3-methylbenzothiophen-2-yl)-2,4-pentiadienoate (380 mg, 1.32 mmol, yield 26.3%), m.p.=106-107° C., and methyl (2E,4E)-2-methoxy-5-(methylbenzothiophen-2-yl)-2,4-pentadienoate, (13 mg, 0.050 mmol, yield 1.0%), m.p.=91-92° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:43][O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
TEA (0.259 ml, 1.86 mmol) was added to solution of (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (481 mg, 1.24 mmol) in DCM (15 ml). The mixture was cooled down to 0° C., and EDC (356 mg, 1.86 mmol) and HOBt (251 mg, 1.86 mmol) were added. The mixture was stirred at 0° C. for 2 h, then NH2OTHP (174 mg, 1.49 mmol) was added and the mixture was stirred at RT overnight. The solution was washed with aqueous 5% NaHCO3 solution and brine. The organic layer was then dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (410 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=O>O1CCOCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[N:12]=[C:27]([C:23]3[O:22][CH:26]=[CH:25][CH:24]=3)[O:1][N:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccco1
Reactant: N=C(NO)Oc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(Oc2noc(-c3ccco3)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
To the mixture of 4-chlorophenyl hydroxycarbamimidate (0.5 mmol. 1 eq) and DIEA (1.25 mmol, 2.5 eq) in dioxane was added dropwise furan-2-carbonyl chloride (0.53 mmol, 1.05 eq) at 0-5° C. The mixture was allowed to warm to room temperature and then stirred for 0.5-1 h or until complete as determined by LC-MS analysis of the reaction mixture. The cyclodehydration reaction was run at reflux (115-120° C.) overnight. The mixture was cooled down and solvent was removed in vacuo. The resulting residue was purified by HPLC purification to provide desired 3-(4-Chloro-phenoxy)-5-furan-2-yl-[1,2,4]oxadiazole in a yield of 50% and purity of 99.9%. LC-MS [M+H] 263.3 (C12H7C1N2O3+H, requires 263.65). 1H NMR (DMSO-d6) δ 8.17 (d, 1H, J=1.75), 7.63 (d, 1H, J=3.5), 7.55 (d, 2H, J=8.8), 7.46 (d, 2H, J=8.8), 6.87 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[OH-].[Na+]>CO>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([C:5]2[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[CH:12]=[CH:13][C:4]=2[C:3]([OH:21])=[O:2])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(-c2ccc(C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)ccc2C(=O)O)cc1
Yield: 66.2 %

Procedure:
Dimethyl-2-(4-tolyl)terephthalate (11.88 g) was suspended in methanol (99 ml). 5M NaOH (50 ml) was added. The reaction mixture was heated at reflux for 1.5 hours. The methanol was removed under reduced pressure. The residue was treated with ethyl acetate and water and the layers separated. The aqueous layer was washed once with ethyl acetate. The aqueous layer was then acidified with 2N HCl and extracted three times with ethyl acetate. These combined organic extracts were then dried over MgSO4, filtered and evaporated under reduced pressure which gave the product (7.09 g).
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:39]=[CH:38][O:37][CH:36]=2)=[O:34])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[O:37]1[CH:38]=[CH:39][C:35]([C:33]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([CH3:25])=[C:31]([C:2]3[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH2:15][N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[O:7])=[CH:4][N:3]=3)[CH:30]=2)=[O:34])=[CH:36]1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.53 min, MH+ 510. NMR: δH [2H6]-DMSO 11.64,(1H, b), 10.02,(1H, s), 9.23,(1H, s), 8.38,(2H, m), 8.31,(1H, d), 7.86,(1H, s), 7.80,(1H, s), 7.76,(2H, m), 7.38-7.29,(3H, m), 7.11,(1H, t), 7.01,(1H, s), 3.77,(2H, s), 2.66-2.20,(11H, m), 2.16,(3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[N:13]=1)[C:5](N(OC)C)=[O:6].O1CCC[CH2:16]1.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:16])[CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cc(Cl)nc(Cl)c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)nc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
490 mg of 2,6-dichloro-N-methoxy-N-methyl isonicotinamide was dissolved in tetrahydrofuran, 2.1 ml of 3M methyl magnesium bromide tetrahydrofuran solution was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hour. To the reaction solution was added ammonium chloride aqueous solution, and the mixture was diluted with ethyl acetate. The mixture was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 325 mg of the objective compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([CH3:31])[C:23]=1[CH3:32]>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([CH3:31])[C:23]=2[CH3:32])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1C
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])cc(C)c1C)OCC

Procedure:
Analogously to Example 13A/Step 1, two batches of 100 mg (0.36 mmol) and of 1.50 g (5.43 mmol), respectively, of the compound of Example 4A and 92 mg (0.40 mmol) and 1.37 g (5.97 mmol), respectively, of 1-bromo-2,3-dimethyl-5-nitrobenzene gave a total of 1.31 g (23% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([NH2:25])=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:3][CH:4]=3)[N:9]=[C:10]([C:23]#[N:25])[CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)nn2-c2ccc(O)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(-n2nc(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
A mixture of 1-(4-hydroxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxamide (1.3 g) and methanesulfonyl chloride (2.5 g) in pyridine (20 ml) was stirred at 50° C. for 5 hours. The solvent was evaporated, and dilute hydrochloric acid and ethyl acetate was added to the residue. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of chloroform and methanol (20:1) to give crystals of 5-[4-(methylsulfonyl)phenyl]-1-[4-(methylsulfonyloxy)-phenyl]pyrazole-3-carbonitrile (0.79 g).
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][Se:9][N:10]=[C:6]2[C:5]([S:11](Cl)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH2:15]([N:17]([CH2:21]C)[CH2:18][CH2:19][NH2:20])C.C(N(CC)CC)C>C(#N)C>[F:1][C:2]1[C:7]2=[N:8][Se:9][N:10]=[C:6]2[C:5]([S:11]([NH:20][CH2:19][CH2:18][N:17]([CH3:21])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCN
Reactant: O=S(=O)(Cl)c1ccc(F)c2n[se]nc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)CCNS(=O)(=O)c1ccc(F)c2n[se]nc12
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
7-fluoro-2,1,3-benzoselenadiazole-4-sulfonyl chloride (75 mg) was dissolved in 3 ml of acetonitrile. After the addition of N,N-diethylethylenediamine (22 mg) and triethylamine (351), the mixture was stirred on ice for 30 min. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in CH2Cl2 and chromatographed on silica gel using CH2Cl2-CH3OH (93:7) to yield 7-fluoro-N-[2-(dimethylamino)ethyl]-2,1,3-benzoselenadiazole-4-sulfonamide (49 mg, 56%) as red powder. mp: 117-120° C. 1H-NMR δH8.09 (1H, d, J=7.5 Hz), 7.24 (1H, d, J=7.5 Hz), 2.93 (2H, t, J=6.7 Hz), 2.27 (2H, t, J=6.7 Hz), 1.98 (6H, s) in CD3OD; ESI-MSm/z 353 [(M+H)+]
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>ClCCl.N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCCCCCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 6-chlorohexan-1-ol (25.0 g, 0.183 mol) in dichloromethane (DCM) (166 ml) and pyridine (33 ml) was cooled to −5° C. Toluene-p-sulphonyl chloride (40.1 g, 0.210 mol) was slowly added to the stirred solution and left to react overnight. The reaction mixture was treated with ice (80 g) and left stirring for 1 h. The organic layer was washed with ice cold 2M-sulphuric acid and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by column chromatography [DCM] to give a white powder 40.20 g, 85%; mp 27-28° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.FC(F)(F)S(O[CH2:56][C:57]([F:60])([F:59])[F:58])(=O)=O>O>[CH3:38][O:37][C:4]1[CH:3]=[C:2]([O:1][CH2:56][C:57]([F:60])([F:59])[F:58])[CH:7]=[CH:6][C:5]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(O)cc4OC)nccc3c2)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCC(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A vial was charged with 1-(4-hydroxy-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (from EXAMPLE 361, STEP 1; 54 mg, 0.102 mmol), cesium carbonate (100 mg, 0.306 mmol), and DMF (511 μl). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (28.0 μl, 0.204 mmol) was added and the vial was heated to 50° C. for 1 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (1 mL), and the resulting solution was stirred overnight. The mixture was diluted with MeOH and concentrated. The residue was dissolved in EtOAc and washed with saturated aq. sodium bicarbonate solution. The aq. wash was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (3.5% MeOH/DCM) to give 1-(2-methoxy-4-(2,2,2-trifluoroethoxy)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (32.7 mg, 0.067 mmol, 65.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.06 (br. s., 1H), 8.70-8.61 (m, 2H), 8.57 (s, 1H), 8.25 (d, J=5.6 Hz, 1H), 8.06 (d, J=5.8 Hz, 1H), 7.94 (dd, J=1.9, 8.9 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.03 (d, J=5.1 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.82 (dd, J=2.3, 8.4 Hz, 1H), 4.89 (q, J=8.9 Hz, 2H), 3.65 (s, 3H). m/z (ESI) 491.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][NH:13][C:12](=[O:22])[CH:11]=2)[CH:3]=1.CC(C)([O-])C.CC(C)([O-])C.[Mg+2].CC(C)([O-])C.[K+].Br[CH:41]([CH3:45])[C:42]([OH:44])=[O:43]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]([CH:41]([CH3:45])[C:42]([OH:44])=[O:43])[C:12](=[O:22])[CH:11]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1OCC(F)(F)F
Reactant: CC(Br)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Mg+2]
Product: CC(C(=O)O)n1cc(OCC(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
140 mg (purity 87%, 0.37 mmol) of 4-chloro-2-[2-oxo-5-(2,2,2-trifluoroethoxy)-1,2-dihydropyridin-4-yl]benzonitrile, 2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassium tert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. and, after aqueous work-up, used without purification for the next step. Yield: 214 mg (purity 73%, quant.)
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>O1CCCC1>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCNC(=O)N1CCc2cc(C(=O)CCCCN(CCc3ccccc3OC)C(=O)OC(C)(C)C)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Ethyl isocyanate (85 mg) was added to a solution of tert-butyl 5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate (362 mg) obtained in Reference Example 50 in tetrahydrofuran (2 ml), and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was-purified by silica gel chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give the title compound as a pale yellow oil (254 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[C:11](=[C:12]4[CH:20]=[C:19]5[O:21][CH2:22][O:23][C:18]5=[CH:17][C:13]4=[N:14][CH:15]=3)[N:10]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:9](=[O:29])[C:8]=2[CH:30]=1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[C:11](=[C:12]4[CH:20]=[C:19]5[O:21][CH2:22][O:23][C:18]5=[CH:17][C:13]4=[N:14][CH:15]=3)[N:10]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:9](=[O:29])[C:8]=2[CH:30]=1
Reactant: CN(C)CCn1c(=O)c2cc([N+](=O)[O-])ccc2c2cnc3cc4c(cc3c21)OCO4
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCn1c(=O)c2cc(N)ccc2c2cnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
To a solution of compound 4a (40 mg, 0.1 mmol) in ethanol (10 mL), Ra—Ni (˜50 mg) then hydrazine hydrate (0.2 mL) were added and the reaction stirred at room temperature for 3 h. The catalyst was filtered through the Celite and filtrate was concentrated in vacuo to provide 26 mg of a solid (69.1% yield); mp 245–246° C.; 1H NMR (CDCl3) δ 2.36 (s, 6H), 3.01 (t, 2H, J=7.4), 4.11(s, 2H), 4.68 (t, 2H, J=7.4), 6.17(s, 2H,), 7.18 (dd, 1H, J=2.8, 11.4), 7.46 (s, 1H) 7.71 (d, 1H, J=3), 7.80 (s, 1H) 8.20 (d, 1H, J=8.8), 9.40 (s, 1H); HRMS m/z calcd for C21H20N4O3H: 377.1614. found 377.1604.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.O1CCCC1.C[CH2:24][O:25][C:26]([C@@H:28](O)[CH3:29])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C>[CH:15]1([C:13]([NH:12][C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([O:1][C@H:28]([CH3:29])[C:26]([O:25][CH3:24])=[O:27])[CH:11]=3)=[O:14])[CH2:16][CH2:17]1
Reactant: CCOC(=O)[C@H](C)O
Reactant: O=C(Nc1cc2ccc(O)cc2cn1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (68.7 mg, 0.301 mmol) in tetrahydrofuran (3.0 mL, 37 mmol) was added ethyl L-(-)-lactate (44 uL, 0.39 mmol) and triphenylphosphine (108.4 mg, 0.4133 mmol), followed by dropwise addition of diethyl azodicarboxylate (62 uL, 0.39 mmol). The resulting mixture was stirred at room temperature for 1 hour, and then ethyl L-(-)-lactate (13 uL, 0.11 mmol) and diethyl azodicarboxylate (19 uL, 0.12 mmol) were added. After an additional 2.5 hours, the reaction mixture was poured into ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-80% ethyl acetate in heptanes) to provide a quantitative yield of (R)-methyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)propanoate. LCMS (ESI): M+H=329.2.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[O:35]([CH2:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:43](=[O:44])[CH2:42][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)COc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
To a cooled (0° C.) mixture of 1.5 g (3.8 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.7 ml (19 mmol) of triethylamine in 15 ml of CH2Cl2 was added 1.58 g (11.4 mol) of phenoxyacetyl chloride. The mixture was stirred at room temperature overnight and filtered. The filtrate was washed with H2O, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed to give 2.4 g of crude methyl 2-{(4-methoxybenzenesulfonyl)-[2-(phenoxyacetylamino)benzyl]amino}acrylate as an oil. Anal. for C26H26N2O7S: Calc'd: C, 61.2; H, 5.1; N, 5.5; Found: C, 62.6; H, 5.1; N, 4.0.