Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].CCCCCC>C(Cl)Cl>[C:21]([O:13][C:10]1[CH:11]=[CH:12][C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:4])=[O:5])=[CH:8][CH:9]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)Cl
Reactant: CN(c1ccc(O)cc1)S(C)(=O)=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(N(C)S(C)(=O)=O)cc1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of 20.13 g (0.10 mol) of N-methyl-N-(4-hydroxyphenyl)methanesulfonamide, 10.12 g (0.10 mol) of triethylamine and 300 ml of methylene chloride cooled to 0° C., was added a solution of 10.45 g (0.10 mol) of methacryloyl chloride in 50 ml of methylene chloride for a 15-minute period. The solution was stirred for another 2 hours at reduced temperature, washed three times with water, dried over magnesium sulfate and concentrated to a white solid. Recrystallization from 500 ml of 1:1 benzene:hexane gave 16.4 g (60.9 percent yield) of N-(4-methacryloyloxyphenyl)-N-methylmethanesulfonamide, m.p.=126° to 127° C.
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][NH2:17])(=[O:12])=[O:11].[CH3:18][C:19]1[C:20]([CH:26]=O)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.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][NH:17][CH2:26][C:20]1[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=1)(=[O:12])=[O:11]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: NCCCCS(=O)(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(CNCCCCS(=O)(=O)c2nc3ccccc3[nH]2)c(C)c1
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A solution of 4-(1H-benzoimidazole-2-sulfonyl)-butylamine (350 mg, 1.4 mmol) and 3,5-dimethylpyridine-2-carbaldehyde (187 mg, 1.4 mmol) in dry MeOH (10 mL) was stirred for 3 h. At this time, solid NaBH4 (116 mg, 4.2 mmol) was added in one portion. Stirring was continued for 1 h, then saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (20 mL) was added. The biphasic mixture was extracted with CH2Cl2 (3×20 mL), then the combined organic fractions were dried (MgSO4), and concentrated. Purification of the crude material by flash chromatography (silica gel, CH2Cl2/MeOH/NH4OH; 20:2:1) afforded 70 mg of [4-(1H-benzoimidazole-2-sulfonyl)-butyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine (14% yield). 1H NMR (CDCl3) δ 184-1.86 (m, 4H), 2.26 (s, 3H), 2.29 (s, 3H), 2.95-3.00 (m, 2H), 3.34-3.56 (m, 2H), 4.12 (s, 2H), 7.34-7.37 (m, 2H), 7.44 (s, 1H), 7.67-7.71 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:16]([C:4]1[CH:3]=[C:2]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O-:18])=[O:17]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Yield: 53.4 %

Procedure:
A solution of tert-butyl 4-bromo-2-nitrophenylcarbamate 175 (3.97 g, 12.5 mmol), 2-thiophene boronic acid 176 (1.68 g, 13.4 mmol), sodium carbonate (3.98 g, 37.56 mmol) and Pd(PPh3)4 (0.94 g, 0.814 mmol) were stirred at 110° C. in a mixture of DME and water (2:1, 70 mL overnight. The solution was evaporated to dryness, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to provide the crude product which was purified by flash chromatography (10% ethyl acetate in hexane) to provide the title compound 177 (2.14 g, 53% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.63 (s, 1H), 8.12 (d, J=2.3 Hz, 1H), 7.92 (dd, J=8.4, 2.2 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.61 (q, J=2.2 Hz, 2H), 7.15 (dd, J=5.1, 3.7 Hz, 1H), 1.46 (s, 9H). MS: (calc.) 320.08; (obt.) 343.1 (M+Na).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)S(O[C:15]1[C:24]2[C:19](=[C:20]([CH:25]3[CH2:27][CH2:26]3)[CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:28]([N:30]2[CH2:35][CH2:34][C:33]3([CH2:44][C:43](=[O:45])[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:46]5[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=5)[CH:41]=4)[O:36]3)[CH2:32][CH2:31]2)=[O:29])[CH:16]=1)(=O)=O.[CH3:54][O:55][C:56]([C:58]1[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=1)=[O:57]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:25]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[N:18]=[C:17]([C:28]([N:30]2[CH2:35][CH2:34][C:33]4([CH2:44][C:43](=[O:45])[C:42]5[C:37](=[CH:38][CH:39]=[C:40]([C:46]6[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=6)[CH:41]=5)[O:36]4)[CH2:32][CH2:31]2)=[O:29])[CH:16]=[C:15]3[C:61]2[CH:62]=[CH:63][C:58]([C:56]([O:55][CH3:54])=[O:57])=[CH:59][CH:60]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OS(=O)(=O)C(F)(F)F)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COC(=O)c1ccc(-c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)nc3c(C4CC4)cccc23)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
K3PO4 (109 mg, 0.515 mmol) was added to a stirred mixture of TBAB (8.30 mg, 0.0260 mmol), PdCl2(dppf) (18.9 mg, 0.0260 mmol), 8-cyclopropyl-2-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}quinolin-4-yl trifluoromethanesulfonate (165 mg, 0.258 mmol) and [4-(methoxycarbonyl)phenyl]boronic acid (55.6 mg, 0.309 mmol) in MeCN (2 ml) and the mixture was stirred at 90° C. overnight. The mixture was filtered, washing with CHCl3 and the solvent was evaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/EtOAc) to give intended compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([O:26][C:27]1[C:34]([Br:35])=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([Cl:36])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:19]([O:26][C:27]1[C:34]([Br:35])=[CH:33][C:30]([CH:31]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=2)[OH:32])=[C:29]([Cl:36])[CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cc(Br)c(OCc2ccccc2)cc1Cl
Reactant: COCOCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCCc1ccc(C(O)c2cc(Br)c(OCc3ccccc3)cc2Cl)cc1
Reaction time: 0.17 h
Yield: 24.6 %

Procedure:
To a tetrahydrofuran solution (6 mL) of 1-bromo-4-[2-(methoxymethoxy)ethyl]benzene (1.52 g, 6.20 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M hexane solution of n-butyllithium (2.38 mL, 6.20 mmol), and the mixture was stirred for 10 minutes at the same temperature. Then a tetrahydrofuran solution (6 mL) of 4-(benzyloxy)-5-bromo-2-chlorobenzaldehyde (2.02 g, 6.20 mmol) was added dropwise over 10 minutes, and the mixture was stirred for 30 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain the title compound (750 mg, 25%) as a colorless oily compound.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH3:2].C(P(CCCC)CCCC)CCC.[I-:34].[K+].CN(C=O)C>C1(C)C=CC=CC=1.[Ni](Br)Br>[CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([I:34])=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: [I-]
Agent: Br[Ni]Br
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC1(CC)c2cc(I)ccc2-c2ccc(C=O)cc21
Yield: 75 %

Procedure:
A mixture of 9,9-diethyl-7-bromofluorene-2-carboxaldehyde, (28.8 g., 0.0875 mol.), nickel (II) bromide (2.1 g., 9.6 mmol.), tri-n-butyl phosphine (4m1, 16 mmol.), potassium iodide (52.0 g., 0.3132 mole, 3.6 equivalents), and DMF (125 ml), was held at reflux under an atmosphere of nitrogen for 15 hours, cooled, diluted with toluene (450 ml), and filtered. The filtrate was washed with water in several portions, dried, and concentrated. The residual solids were recrystallized from toluene-heptane (1:2, 150 ml); 24.79 g., m.p. 138-140° C., (75% yield). When the reaction was run longer, 24 and 34 hours, the yields fell to 61 and 59% respectively. Mass Spec (m/z): 376 (M+), not contaminated with the bromo aldehyde. Anal.Calcd. for C18H17Ol: C, 57.46; H, 4.55; and l, 33.73%. Found: C, 58.04 and 58.02; H, 4.72 and 4.66; and l, 32.62 and 32.89.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:18][CH2:19][CH3:20])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CN(C)C1C=CN=CC=1>[C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:18][CH2:19][CH3:20])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCc1[nH]c2cc(C(=O)O)ccc2c1C(=O)C(C)C
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCc1[nH]c2cc(C(=O)OCc3ccccc3)ccc2c1C(=O)C(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-isobutyryl-2-propylindole-6-carboxylic acid (331 mg) in tetrahydrofuran (5 ml) were added benzylalcohol (1.25 ml), dicyclohexylcarbodiimide (303 mg) and 4-dimethylaminopyridine (20 mg) at 20° C. The reaction mixture was stirred at 20° C. for 8 hours. The precipitated urea was filtered off and the filtrate was evaporated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with water two times and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give the crystals which were recrystallized from a mixture of ethyl acetate and hexane to give benzyl 3-isobutyryl-2-propylindole-6-carboxylate (215 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1)[CH3:23]
Reactant: CCOc1ccccc1B(O)O
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccccc1-c1cccc(COc2ccc(CCC(=O)OC)cc2)c1
Yield: 62.5 %

Procedure:
A mixture of methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate (0.30 g, 0.86 mmol), 2-ethoxyphenylboronic acid (0.16 g, 0.95 mmol), tetrakistriphenylphosphine palladium (40 mg, 0.034 mmol), 2N potassium carbonate aqueous solution (0.3 mL), ethanol (0.3 mL) and toluene (3 mL) was heated under reflux overnight under an argon atmosphere. The reaction mixture was cooled, diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give methyl 3-(4-((2′-ethoxybiphenyl-3-yl)methoxy)phenyl)propanoate (0.21 g, 63%) as a colorless oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[C@@H:53]1[CH2:63][CH2:62][C@H:61](O)[C:56]2=[N:57][CH:58]=[CH:59][CH:60]=[C:55]2[C@H:54]1[NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69]>C(Cl)Cl>[F:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[C@@H:53]1[CH2:63][CH2:62][C@@H:61]([N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])[C:56]2=[N:57][CH:58]=[CH:59][CH:60]=[C:55]2[C@H:54]1[NH:65][C:66](=[O:72])[O:67][C:68]([CH3:70])([CH3:69])[CH3:71]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](O)CC[C@H]1c1cccc(F)c1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](N2C(=O)c3ccccc3C2=O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 113.7 %

Procedure:
DIAD (0.356 mL, 1.832 mmol) was added to a methylene chloride (5 mL) solution of phthalimide (0.270 g, 1.832 mmol), triphenylphosphine (0.481 g, 1.832 mmol) and tert-butyl (5S,6S,9S)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (0.358 g, 0.916 mmol) at 0° C. The reaction was gradually warmed up to room temperature and stirred at room temperature for 3 days. Volatile components were removed in vacuo and the crude residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed two more times with water before being dried (sodium sulfate), filtered and concentrated. Flash chromatography using ethyl acetate in hexane from 0 to 45% gave the desired product (0.541 g, ca 80% purity, 90% for 2 steps): MS(ESI)[M+H+]=520.16.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.C(N(CC)C(C)C)(C)C.[C:36](O)(=[O:38])[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH-].[Na+]>CN(C=O)C>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:38])[CH3:37])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) in DMF (3 ml) was added N,N-diisopropylethylamine (113 mg, 150 μl, 0.88 mmol), acetic acid (22.6 mg, 21.5 μl, 376 μmol) and TBTU (121 mg, 376 μmol). The mixture was allowed to stir at room temperature for 5 h, poured into ice/water (5 ml) and 1N NaOH (5 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4) and evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) and trituration from dichloromethane (1 ml) and heptane (5 ml) for 30 min. The precipitate was collected by filtration, washed with heptane and dried to yield the title compound as an off-white solid (74 mg, 80%), MS (ISP) m/z=369.3 [(M+H)+], mp 167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][NH:24][S:25]([C:28]5[CH:29]=N[N:31]([CH3:33])[CH:32]=5)(=[O:27])=[O:26])[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:36]O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][NH:24][S:25]([C:28]5[CH:32]=[N:31][CH:33]=[CH:36][CH:29]=5)(=[O:27])=[O:26])[CH:19]=4)[CH2:14][CH2:13][NH:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cn1cc(S(=O)(=O)NCCOc2ccc3c(c2)C(C2(c4ccc(Cl)cc4)CC2)=NCC3)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)NCC2)c1cccnc1

Procedure:
A solution of N-[2-({1-[1-(4-chlorophenyl)cyclopropyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]-1-methyl-1H-pyrazole-4-sulfonamide (46 mg, 0.09 mmol), sodium borohydrid (7.2 mg, 0.19 mmol) in water (0.25 ml) and methanol (2 ml) was stirred for 3 days at room temperature. The solvent was removed, the residue dissolved in methylenehloride and extracted with water. The methylenehloride was evaporated and the remaining solid purified by chromatography. Yield: 20 mg (0.04 mmol, 43%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20]([OH:22])=O)[N:17]([CH3:19])[N:18]=[C:11]12.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:46]([NH:49][CH2:50][CH:51]1[CH2:53][CH2:52]1)[CH2:47][CH3:48]>ClCCl.C(N(CC)CC)C>[CH:51]1([CH2:50][N:49]([CH2:46][CH2:47][CH3:48])[C:20]([C:16]2[N:17]([CH3:19])[N:18]=[C:11]3[C:12]=2[CH2:13][CH2:14][CH2:15][N:10]3[C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[Cl:1])=[O:22])[CH2:53][CH2:52]1
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3C(=O)O)c(Cl)c1
Reactant: CCCNCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CC1CC1)C(=O)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 25 °C

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (107.0 mg), 1-hydroxybenzotriazole hydrate (50.3 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.5 mg), triethylamine (93 μL), and N-propylcyclopropanemethylamine (49 μL) were combined in 4 mL of dichloromethane and stirred at room temperature over night. The reaction mixture was then partitioned between ethyl acetate and 1M hydrochloric acid. The ethyl acetate solution was washed with aqueous sodium bicarbonate, dried with magnesium sulfate, and concentrated. The crude product was chromatographed on silica gel eluting with an acetone/hexane gradient giving a solid. Recrystallization from hexane provided 75.6 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylic acid cyclopropylmethylpropylamide, mp 120.6-122.0° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[NH:12][CH:11]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.Cl.O.N>C(#N)C.O1CCOCC1.CCOC(C)=O>[Cl:23][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:11][N:12]=1
Reactant: Cc1ccc(CCc2c[nH]c(=O)c3ccccc23)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc(CCc2cnc(Cl)c3ccccc23)cn1
Temperature: 25 °C

Procedure:
3.12 g (11.8 mmol) of 4-[2-(6-methyl-pyridin-3-yl)-ethyl]-2H-isoquinolin-1-one in 48 ml of acetonitrile are mixed, whilst excluding air, with 3.7 ml (40 mmol) of phosphorus oxychloride and 6 ml of 4 N HCl in dioxane and stirred for 18 h at 55° C. After cooling to RT, water/NH3 conc. 10:1 (pH=9) and EtOAc are added, the water phase is separated and extraction effected twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 1-chloro-4-[2-(6-methyl-pyridin-3-yl)-ethyl]-isoquinoline; 1H NMR (DMSO-d6) δ8.3 (m, 3H), 8.09 (s, 1H), 7.94 (t, 1H), 7.83 (t, 1H), 7.56 (d, 1H), 7.15 (d, 1H), 3.30 (t, H2C), 2.94 (t, H2C), 2.40 (s, H3C).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].CCO.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 130 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
3-Iodo-5-nitro-benzoic acid (10.0 g, 34 mmol) was dissolved in 17.5 mL warm EtOH. Toluene (17.5 mL) was added, followed by 2-methoxy-phenyl-boronic acid (5.7 g), Palladium tetra(triphenylphosphine) (1.26 g) and aqueous Cs2CO3 solution (12.23 g in 12.5 mL H2O). The reaction mixture was stirred under Argon atmosphere at 130° C. for 18 hours, then cooled to room temperature. Solvent was removed under reduced pressure, and the residue was partitioned between aqueous 1N HCl and EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting solid residue was added to a mixture of methylene chloride (50 mL)and hexanes (10 mL) and stirred for two hours. The mixture was filtered, and the resulting white solid was washed with cold methylene chloride/hexanes (5:1) and dried to give 8.62 g of 2′-methoxy-5-nitro-biphenyl-3-carboxylic acid, MS (M+H)=274.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[C:11]([F:19])[CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[C:7]=1[F:20])[CH2:2][CH2:3][CH3:4].C([Li])CCC.CC(C)([O-])C.[K+].[CH:32](=[O:35])[CH2:33][CH3:34].Cl>O>[CH2:1]([O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[C:11]([F:19])[C:12]([CH:32]([OH:35])[CH2:33][CH3:34])=[CH:13][CH:14]=3)[CH2:9][C:8]=2[C:7]=1[F:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1F)Cc1c(F)cccc1-2
Reactant: CCC=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCOc1ccc2c(c1F)Cc1c-2ccc(C(O)CC)c1F

Procedure:
The metallation of 23 mmol of 2-butoxy-1,8-difluorofluorene with 25 mmol of n-butyllithium (1.6 M solution in hexane) and 25 mmol of potassium tert-butoxide is effected in a similar manner to the procedure described in Example 1. 28 mmol mmol of propionaldehyde are subsequently added dropwise at ≦−70° C. and the mixture is allowed to thaw gradually. The reaction mixture is admixed at −10° C. with 50 ml of water and acidified to pH I using concentrated hydrochloric acid. The mixture is extracted using tert-butyl methyl ether, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent is removed under reduced pressure. Chromatography on silica gel using dichloromethane as eluent provides 2-butoxy-1,8-difluoro-7-(1-hydroxypropyl)fluorene.