Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[F:6][C:7]1[C:15]([F:16])=[CH:14][C:13]([OH:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:2]1([O:17][C:13]2[CH:14]=[C:15]([F:16])[C:7]([F:6])=[C:8]([CH:12]=2)[C:9]([O:11][CH:2]2[CH2:5][CH2:4][CH2:3]2)=[O:10])[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1cc(O)cc(F)c1F
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OC1CCC1)c1cc(OC2CCC2)cc(F)c1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Bromocyclobutane (150 g, 1.12 mol) was added to a mixture of 2,3-difluoro-5-hydroxybenzoic acid (50 g, 287 mmol), and potassium carbonate (230 g, 1.67 mol) in acetonitrile (1500 mL), and the resulting mixture stirred overnight at 90° C. The reaction mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with petroleum ether) to afford cyclobutyl 5-cyclobutoxy-2,3-difluorobenzoate (49 g, 60%) as a yellow green solid. MS (ESI, pos. ion) m/z 283 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([CH3:14])[CH3:13].C(O)C.[H][H]>[Pd].O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)=C1C(=O)Nc2ccc(O)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C1C(=O)Nc2ccc(O)cc21
Yield: 81 %

Procedure:
23 g. 5-Hydroxy-3-isopropylideneindolinone are dissolved in 100 ml. ethanol and 150 ml. tetrahydrofuran and hydrogenated in the presence of 1 g. 10% palladium-charcoal at ambient temperature and 1 bar hydrogen pressure. After filtering off the catalyst with suction, the filtrate is distilled off in a vacuum and the residue is triturated with diethyl ether and filtered off with suction. There are obtained 19 g. of the title compound; yield 81% of theory; m.p. 175° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1>CC(O)C>[N+:27]([C:22]1[CH:21]=[C:20]([NH:19][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:25]=[CH:24][C:23]=1[OH:26])([O-:29])=[O:28]
Reactant: Clc1ccnc2ccccc12
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(Nc2ccnc3ccccc23)ccc1O
Temperature: 130 °C

Procedure:
TFA (0.57 mL) was added to a suspension of 4-chloroquinoline (0.48 mg, 2.9 mmol) and 4-amino-2-nitrophenol (0.45 g, 2.9 mmol) in i-PrOH (4 mL) was added at RT. The reaction was heated to 130° C. in a sealed tube for 2 h. A solid precipitated upon cooling. The solid was filtered out and washed with i-PrOH to give 2-nitro-4-(quinolin-4-ylamino)-phenol.
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)(=[O:4])=[O:3].[NH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[Br:29]>>[Br:29][C:24]1[C:25]([CH3:28])=[N:26][O:27][C:23]=1[NH:22][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccsc1C/C=C/c1ccc2c(c1)OCO2
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccsc2C/C=C/c2ccc3c(c2)OCO3)c1Br
Yield: 33 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene with 5-amino-4-bromo-3-methylisoxazole. The crude product was purified by HPLC resulting in a 33% yield, m.p. 147-149° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]1=O.[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28]C(O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][C:2]([O:1][CH2:5][CH2:4][OH:3])=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
1,3-Dioxolan-2-one (1093 mg, 12.41 mmol) was added to 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (907 mg, 2.48 mmol) and potassium carbonate (686 mg, 4.97 mmol) in DMF (10 mL). The resulting mixture was stirred at 80° C. for 16 hours. The reaction mixture was evaporated to dryness, the residue redissolved in DCM (100 mL) and the solution washed with water (100 mL). The aqueous washings were re-extracted with DCM (100 mL), then the combined organic phases were washed with saturated brine (50 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (695 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C>C(O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:19]3[CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21][C:20]=3[NH:8][C:4]=2[CH:3]=1
Reactant: NNc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Reaction time: 18 h
Yield: 41.7 %

Procedure:
3-Bromophenylhydrazine (40.0 g, 0.179 mol) and N-Boc-4-oxo-piperidine (35.4 g, 0.179 mol) were dissolved in ethanol (368 mL), and conc. HCl (72 mL) was added. The reaction mixture was then heated to reflux for 18 h, concentrated and basified using 10% NH4OH in methanol (10%, 100 mL). The solvent was removed, and the residue was suspended in CH2Cl2 (1.2 L). Boc2O (39.2 g, 0.179 mol) followed by DMAP (195 mg, 1.6 mmol) and triethylamine (46.4 mL, 0.358 mol) were then added, and the reaction progressed at room temperature for 18 h. The mixture was washed with 0.5 N HCl, and the organic phase was removed, dried over Na2SO4, filtered and concentrated to dryness. The resulting mixture of regioisomers was purified by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) to give the more polar title compound (26.2 g, 42%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.16 (br s, 1H), 7.42 (s, 1H), 7.28 (d, J=8.1 Hz, 1H, partially masked by solvent), 7.18 (d, J=8.1 Hz, 1H), 4.60 (s, 2H), 3.80 (t, J=5.5 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[C:2]=S.NC1C=CC=CN=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:27]2[NH:28][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)=[N:17][C:18]=2[CH:19]=1)=[O:22]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1ccccn1
Agent: Nc1ccccn1
Product: COC(=O)c1ccc2[nH]c(Nc3ccccn3)nc2c1

Procedure:
2-Isothiocyanatopyridine (4 mmol), prepared from 2-aminopyridine employing general procedure A, was reacted with methyl 3,4-diaminobenzoate as described in general procedure B to afford 2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid methyl ester. This ester was hydrolyzed, following general procedure C, to obtain 2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)([F:28])[F:27])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[Cl:35][C:31]1[CH:30]=[C:29]([C:26]([F:27])([F:28])[CH2:25][O:24][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[C:15]([NH:14][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:36])[CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCC(F)(F)c3cccc(Cl)c3)c2)Cc2ccccc2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCC(F)(F)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.1 %

Procedure:
20 mg of the compound of step 3 were dissolved in 5 ml of a mixture of THF and water (9:1), and 1.9 mg (77.5 μmol) of lithium hydroxide were added. After stirring at room temperature for 3 d, the mixture was acidified with 1 M hydrochloric acid and evaporated. The residue was purified by silica gel chromatography (DCM/methanol 95:5) and RP HPLC (water/ACN gradient) to give 8 mg of the title compound.
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH3:23])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH:9]([CH:20]=O)[C:8]2=[O:22].O=S(Cl)[Cl:26]>ClCCl>[Cl:26][CH:20]=[C:9]1[C:10]2([CH2:13][CH2:12][CH2:11]2)[O:14][C:15]2[C:7](=[C:6]([CH3:23])[C:5]([OH:4])=[C:17]([CH3:18])[C:16]=2[CH3:19])[C:8]1=[O:22]
Reactant: O=S(Cl)Cl
Reactant: COCOc1c(C)c(C)c2c(c1C)C(=O)C(C=O)C1(CCC1)O2
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)C(=O)C(=CCl)C1(CCC1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-(methoxymethoxy)-5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-3-carbaldehyde (2.0 g) in 20 mL of dichloromethane was added dropwise 5 mL of SOCl2. The reaction was allowed to stir at room temperature for 2 hr. After the reaction was complete, the mixture was concentrated and the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 1.46 g of 3-(chloromethylene)-6-hydroxy-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one, as a yellow solid. It is a mixture of two isomers with a ratio of about 3:1, as indicated by TLC analysis.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH2:6][CH:5]2[CH3:12].N1C=CC=CC=1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>C(Cl)Cl>[C:20]([N:7]1[C:8]2[C:4](=[C:3]([CH3:13])[C:2]([OH:1])=[C:10]([CH3:11])[CH:9]=2)[CH:5]([CH3:12])[CH2:6]1)(=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc2c(c(C)c1O)C(C)CN2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2c(c(C)c1O)C(C)CN2C(=O)C(C)C
Temperature: 0 °C
Reaction time: 17 h
Yield: 73.2 %

Procedure:
To an ice-cold solution of indoline 10 (160 mg, 0.9 mmol) dissolved in methylene chloride (4 mL) and kept under an argon atmosphere were added sequentially pyridine (1 mL) and isobutyryl chloride (0.I mL, 9 mmol); the mixture was stirred over the range of 0° C. to room temperature for some 17 h. The mixture was diluted with methylene chloride, washed with brine and dried (MgSO4). Removal of solvents followed by purification of the residue using 1:9 ethyl acetate:hexanes as eluent afforded the desired N-isobutyryl-5-hydroxy-3,4,6-trimethylindoline (11b, 163 mg, 73% yield) as a colorless solid, mp 123°-125° C. Spectral data: 1H NMR: δ1.1-1.25 (m, 9H), 2.17 (s, 3H), 2.20 (s, 3H), 2.72 (quintet, 1H, J=6.5 Hz), 3.35 (t, 1H, J=6.5 Hz), 3.78 (dd, 1H, J=10.1, 1.0 Hz), 4.13 (t, 1H, J=9.1 Hz), 7.95 (s, 1H); 13C NMR: δ 11.9, 16.5, 18.8, 19.3, 20.7, 33.1, 34.0, 56.3, 116.8, 119.5, 122.1, 134.1, 135.0, 148.8, 175.0; HRMS: calcd. for C15H21NO2 247.1523, fnd. 247.1573. Anal: calcd. for C15H21NO2C, 72.85, H, 8.55, N, 5.66, fnd. C, 72.63, H, 8.59, N, 5.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([CH2:8][N:14]([CH2:13][CH2:12][O:11][CH3:10])[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CNCCOC
Reactant: Clc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN(C)Cc1cccc(Cl)n1
Temperature: 80 °C
Yield: 93.9 %

Procedure:
To a solution of 2-chloro-6-(bromomethyl)pyridine (490 mg, 2.37 mmole) in 5 mL of dry acetonitrile is added 0.51 mL (4.74 mmol) of 2-methoxy-N-methylethylamine and 328 mg (2.37 mmol) of potassium carbonate. The reaction is heated at 80° C. for 2 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 478 mg (94% yield) of (6-Chloro-pyridin-2-ylmethyl)-(2-methoxy-ethyl)-methyl-amine. Diagnostic 1H NMR (400 MHz, CDCl3) 2.34 (s, 3h), 2.67 (t, 2H, J=5.9 Hz), 3.34 (s, 3H), 3.52 (t, 2H, J=5.8 Hz), 3.71 (s, 3H), 7.19 (d, 1H, J=7.9 Hz), 7.54 (d, 1H, J=7.9 Hz), 7.60–7.64 (m, 1H); MS 215.2 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:49])[CH2:19][C:20]3[NH:21][C:22]([CH2:42][CH2:43][C:44]4[S:45][CH:46]=[CH:47][N:48]=4)=[C:23]([C:38]([O:40][CH3:41])=[O:39])[CH:24]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[C:25]=3[C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:50][S:51](Cl)(=[O:53])=[O:52].C(N(CC)CC)C>ClCCl>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[CH:24]1[C:23]([C:38]([O:40][CH3:41])=[O:39])=[C:22]([CH2:42][CH2:43][C:44]2[S:45][CH:46]=[CH:47][N:48]=2)[NH:21][C:20]([CH2:19][C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:5]3([CH2:4][NH:3][S:51]([CH3:50])(=[O:53])=[O:52])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[CH2:13][CH2:14]2)=[O:49])=[C:25]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CN)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CNS(C)(=O)=O)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 2-[2-[4-[[1-(aminomethyl)cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate dihydrochloride (230 mg/0.28 mmol) methansulfonylchloride (0.2 ml/2.5 mmol) and triethylamine (0.5 ml/3.5 mmol) in dichloromethane (5.0 ml) was stirred for 5 hours at ambient temperature. The mixture was diluted with dichloromethane (50 ml), and then washed with water (10 ml) and brine (10 ml) successively. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/200-350 mesh/20 g/dichloromethane) to give a yellow film (122 mg/55%).
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[S:4]([C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][C:8]=1[CH3:22])(=[O:6])=[O:5])[CH3:2].[NH2:24][C:25]1[C:26]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:42])[NH:37][CH2:36][CH2:35]3)=[N:27][C:28](Br)=[CH:29][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CCC>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:23])(=[O:5])=[O:6])=[C:8]([CH3:22])[CH:9]=2)=[N:27][C:26]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[NH:37][CH2:36][CH2:35]2
Reactant: Nc1ncc(Br)nc1-c1ccc2c(c1)CCNC2=O
Reactant: CCN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1C
Yield: 28.6 %

Procedure:
A solution of N-ethyl-2,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (140 mg, 0.42 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (150 mg, 0.38 mmol) Pd(PPh3)4 (13.2 mg, 0.011 mmol) and 2.0 M aq. Na2CO3 (0.38 mL) in n-butanol (2 mL) was microwave heated at 150° C. for 10 min to provide 4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)-N-ethyl-N,2-dimethylbenzenesulfonamide (49 mg, 29% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (s, 1H), 8.04 (s, 1H), 7.93-8.02 (m, 3H), 7.82 (d, J=8.28 Hz, 1H), 7.67-7.77 (m, 2H), 6.62 (s, 2H), 3.43 (td, J=6.40, 2.51 Hz, 2H), 3.18 (q, J=6.94 Hz, 3H), 3.00 (t, J=6.53 Hz, 2H), 2.76 (s, 3H), 2.59 (s, 3H), 1.08 (t, J=7.15 Hz, 3H). MS (EI) m/z: 452 [M+H]+. HPLC (Sunfire C18 4.6 mm×50 mm, 10-90% MeCN:10 mM aq NH4OAc, 4 min gradient) tR=2.14 min, 100% integrated area.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=1)(=[O:12])=[O:11].[C:27]1([CH:37]=O)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=1)[CH2:37][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1)(=[O:12])=[O:11]
Reactant: Cc1cnc(CNCCCCS(=O)(=O)c2nc3ccccc3[nH]2)c(C)c1
Reactant: O=Cc1nccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCS(=O)(=O)c2nc3ccccc3[nH]2)Cc2nccc3ccccc23)c(C)c1
Yield: 50 %

Procedure:
Using General Procedure B: Reaction of [4-(1H-benzoimidazole-2-sulfonyl)-butyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine and isoquinoline-1-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave COMPOUND 177 as a white foam (50% yield). 1H NMR (CDCl3) δ 1.51-1.63 (m, 4H), 2.10 (s, 3H), 2.27 (s, 3H), 2.42-2.45 (m, 2H), 3.26-3.30 (m, 2H), 3.81 (s, 2H), 4.17 (s, 2H), 7.12 (t, 1H, J=8 Hz), 7.27 (s, 1H), 7.37-7.42 (m, 2H), 7.50-7.55 (m, 2H), 7.69-7.74 (m, 3H), 8.05 (d, 1H, J=8 Hz), 8.28 (br s, 1H), 8.40 (d, 1H, J=6 Hz); 13C NMR (CDCl3) δ 17.9, 18.3, 21.4, 23.7, 53.1, 54.4, 57.7, 58.7, 117.2, 120.8, 124.8, 125.9, 126.9, 127.6, 130.2, 132.4, 133.1, 136.3, 139.5, 140.9, 146.2, 148.0, 153.1, 158.2; ES-MS m/z 514 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][CH:34]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27])=[O:9])=[O:4].[C@@H:43]1([NH2:53])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][N:2]([CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1)[C:3](=[O:4])[C:5]1[CH:34]=[CH:33][CH:32]=[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:13][C:12]=2[C:23]2[CH:24]=[C:25]([C:26](=[O:27])[NH:53][C@@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:46][CH2:45][CH2:44]3)[CH:29]=[CH:30][N:31]=2)=[O:9])[CH:6]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A solution of 550 mg of 2-(2-(3-(methyl(2-morpholinoethyl)carbamoyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid, 142 mg of (S)-1,2,3,4-tetrahydronaphthalen-1-amine, and 497 mg of diisopropylethylamine in 6 mL of DMF was treated with 366 mg of HATU. After stirring for 2 h the product was isolated by reverse phase HPLC, eluting with 0.05% TFA in a water/acetonitrile gradient. The procedure gave 220 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25](O)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: C1CCNC1
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2n1C
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CCCC3)cc2n1C
Yield: 39 %

Procedure:
The title compound was prepared as a colorless amorphous in 39% yield (45 mg) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (100 mg, 0.27 mmol, STEP 2 of Example 19) and pyrrolidine (38 mg, 0.53 mmol) by the same manner in STEP 3 of Example 11.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:7]2=[O:12].[CH:20]1([CH2:27][C:28](O)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[CH:20]1([CH2:27][C:28]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:7]3=[O:12])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1cccc2c(=O)n(CC3CCOCC3)ccc12
Reactant: O=C(O)CC1CCCCCC1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CCCCCC1)Nc1cccc2c(=O)n(CC3CCOCC3)ccc12

Procedure:
5-Amino-2-(tetrahydro-pyran-4-ylmethyl)-2H-isoquinolin-1-one (40 mg, 0.0002 mot), 2-cycloheptylacetic acid (63 mg, 0.00041 mol), fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (110 mg, 0.00041 mol), N,N-diisopropylethylamine (100 mg, 0.0008 mol) were stirred in methylene chloride (3 mL, 0.05 mol) at room temperature over 72 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) to give a light yellow solid.
Reaction SMILES: C(C1N=C(N2CCOCC2)[C:8]2N=N[N:11]([CH2:14][C:15]3[CH:20]=CC=C[C:16]=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].CC1(C)CCNC1>>[C:28]([C:32]1[N:33]=[C:34]([N:11]2[CH2:9][CH2:8][C:15]([CH3:16])([CH3:20])[CH2:14]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1(C)CCNC1
Product: CC1(C)CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-dimethylpyrrolidine. MS (m/e): 399.4 (MH+).