Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][CH2:8][C:9]2[NH:10][C:11](=[O:19])[C:12]3[CH2:18][O:17][CH2:16][CH2:15][C:13]=3[N:14]=2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([CH:29]2[CH2:30][CH2:31][N:32]([CH2:35][C:36]([N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)[CH2:8][C:9]3[NH:10][C:11](=[O:19])[C:12]4[CH2:18][O:17][CH2:16][CH2:15][C:13]=4[N:14]=3)=[O:37])[CH2:33][CH2:34]2)=[O:28])=[CH:39][CH:40]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCc2ccc(F)cc2)nc2c1COCC2
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2ccc(F)cc2)Cc2nc3c(c(=O)[nH]2)COCC3)CC1
Yield: 13.3 %

Procedure:
The title compound (20 mg) was prepared following the general procedure of Example 1 from 2-((4-fluorobenzylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (80 mg, 0.28 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (86 mg, 0.28 mmol, 85% purity). 1H NMR (400 MHz, CDC3) δ 7.98 (dd, J=8.0, 5.5 Hz, 2H), 7.10-7.35 (m, 4H), 6.90-7.10 (m, 2H), 4.46-4.67 (m, 3.5H), 4.29 (s, 1.5H), 3.78-4.03 (m, 1H), 3.42 (br. s., 3H), 3.05 (t, J=11.5 Hz, 2H), 2.68 (t, J=5.3 Hz, 3H), 2.59 (t, J=5.5 Hz, 1H), 2.38 (br. s., 1H), 2.09-2.31 (m, 3H), 1.88 (br. s., 1H), 1.74-1.86 (m, 1H). HRMS calculated for C29H30F2N4O4 537.2331. found (ESI, [M+H]+), 537.2313. MS m/z 537.2 (M+1), retention time=3.25 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([SH:22])=S)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:4][CH2:5][CH2:6][CH3:7].[F:23][C:24]1[C:29]([F:30])=[C:28]([O:31][CH2:32][CH3:33])[CH:27]=[CH:26][C:25]=1[OH:34].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[CH2:3]([C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:34][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH3:33])=[C:29]([F:30])[C:24]=3[F:23])=[S:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOc1ccc(O)c(F)c1F
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(C(=S)S)cc2)CC1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C(=S)Oc3ccc(OCC)c(F)c3F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension prepared by suspending 1.52 g (38.0 mmol) of 60% sodium hydride in 15 ml of THF was added dropwise solution of 5.29 g (17.3 mmol) of the 4-(trans-4-n-pentylcyclohexyl)-phenyldithiocarboxylic acid obtained by the first step, in 20 ml of THF under a condition cooled with ice in 15 min, and stirred as it was for 30 min. To this reaction solution was added dropwise solution of 2.50 g (14.4 mmol) of 2,3-difluoro-4-ethoxyphenol in 20 ml of THF in 15 min and stirred as it was for 30 min. To this reaction solution was added dropwise solution of 9.64 g (38.0 mmol) of iodine in 20 ml of THF in 15 min, stirred as it was for 1 hour, warmed up to room temperature, and then stirred at the same temperature overnight. This reaction solution was poured into 10% aqueous sodium thiosulfate solution and extracted with 100 ml of diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under a reduced pressure, and the residue was purified by silica gel column chromatography (eluent: heptane) and further recrystallized from heptane to obtain 2.0 g of 2,3-difluoro-4-ethoxyphenyl 4-(trans-4-n-pentylcyclohexyl)thiobenzoate (yield 31.2%).
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:9](=[O:26])[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[OH-].[Na+].CO>[OH:26][CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:13][CH2:12]1
Reactant: O=C(CN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC1CCN(CC(O)c2ccccc2)CC1)c1ccccc1

Procedure:
Sodium borohydride (6.00 g.) in 0.2N NaOH solution (60 ml.) was added dropwise to a stirred solution of 1-(2-phenyl-2-oxoethyl)-4-benzamidopiperidine (4.83 g.) in methanol (300 ml.). After refluxing the solution for 2 hours it was filtered and the filtrate concentrated to ca. 100 ml., whereupon the product crystallised out to give the title compound, m.p. 178°-180° C. (Found: C,74.1; H, 7.5; N, 8.6. C20H24N2O2 requires C, 74.0; H, 7.5; N, 8.6%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].I[CH3:34].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][CH3:34])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: CI
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.435 mmol) in dry DMF (2.0 mL) is added iodomethane (0.136 mL, 2.18 mmol), the mixture is cooled to 0° C., and NaH (60% suspension in oil, 35 mg, 0.87 mmol) is added in portions over 5 min. The mixture is stirred at 0° C. for 1 h 40 min, and it is quenched by addition of water and acidified with 2N HCl. The mixture is diluted with ethyl acetate and washed with brine. The organic layer is separated, dried over Na2SO4, concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with 0→50% ethyl acetate in hexane to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (65 mg, 32%).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1([CH3:35])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=3[CH2:32][CH2:33][CH3:34])=[CH:16][C:9]=2[O:8]1)C.O1CCCC1.O.O.[OH-].[Li+]>O>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:10]3[CH2:11][CH2:12][C:7]([CH3:35])([CH2:6][CH2:5][C:4]([OH:36])=[O:3])[O:8][C:9]=3[CH:16]=2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: CCCc1c(OCCCOc2ccc3c(c2)OC(C)(CCC(=O)OCC)CC3)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCOc2ccc3c(c2)OC(C)(CCC(=O)O)CC3)ccc(C(C)=O)c1O
Yield: 95.7 %

Procedure:
To a mixture of 1.55 g of the ester from Example 3 and 35 ml of 1:1 tetrahydrofuran-water was added 2.3 g of lithium hydroxide monohydrate, with stirring. The mixture was stirred at room temperature for 22 hours then diluted with water and extracted 3 times with ether (ether extracts discarded). The aqueous solution was acidified to pH 1 by the addition of saturated aqueous oxalic acid and worked-up with ether in the usual manner. There was obtained 1.4 g (95.8%) of racemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-propanoic acid as a viscous yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][C@H:18]([C:26]([NH:28][C@H:29]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:15])[CH3:14]
Reactant: CCO[PH](=O)CCCCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Product: CCOP(=O)(CCCCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
(4-Phenylbutyl)phosphinic acid, ethyl ester is reacted with L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride according to the procedure of Example 1(c) to yield N-[N-[ethoxy(4-phenylbutyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[C:6]=2[CH:7]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][N:60]1[CH:64]=[CH:63][C:62]([NH2:65])=[N:61]1>CN(C=O)C.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([NH:65][C:62]3[CH:63]=[CH:64][N:60]([CH3:59])[N:61]=3)=[O:13])[CH:9]=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[C:6]=2[CH:7]=1)[CH3:2]
Reactant: Cn1ccc(N)n1
Reactant: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
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
Solvent: O
Product: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccn(C)n3)cc2o1
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A solution of 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylic acid (400 mg, 1.1 mmol), HATU (635 mg, 1.6 mmol) and DIPEA (214 mg, 1.6 mmol) in DMF (20 mL) was stirred for 1 h. Then, 1-methyl-1H-pyrazol-3-amine (129 mg, 1.3 mmol) was added. The resulting solution was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 1:1). The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4, concentrated and purified by preparative HPLC to afford the desired product (109.5 mg, 22%) as a yellow solid. 1H NMR (400 MHz, DMSO): δ 10.89 (s, 1H), 8.15 (s, 1H), 7.94 (d, 2H), 7.65 (s, 1H), 7.00 (s, 1H), 7.24 (d, 2H), 6.61 (s, 1H), 6.55 (d, 2H), 3.77 (s, 3H), 3.20 (s, 3H), 2.82 (q, 2H), 1.25 (t, 3H); MS (APCI, pos): 440.3.
Reaction SMILES: Cl.[N+:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C@@H:12]2[CH:19]3[CH2:20][N:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[CH:7][CH:6]=1)([O-])=O>C1COCC1.CO.[Ni]>[NH2:2][C:5]1[N:10]=[CH:9][C:8]([O:11][C@@H:12]2[CH:19]3[CH2:20][N:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OC2C3CC4CC2CN(C4)C3)cn1
Agent: [Ni]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(OC2C3CC4CC2CN(C4)C3)cn1
Temperature: 50 °C

Procedure:
A solution of the product of Example 16B (380 mg, 1.2 mmol) in THF-MeOH (10 mL, 1:1) was treated with Raney nickel (401 mg, 6.83 mmol) under an atmosphere of hydrogen (60 psi), and the mixture was warmed to 50° C. for 1 hour. After removing the catalyst by filtration, the product was purified by preparative HPLC [Waters® XTerra RP18 column, 5μ, 30×100 mm, flow rate 40 mL/minutes, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide), with UV detection at 254 nm]. Fractions containing the desired compound were pooled, concentrated under vacuum, diluted with methanol, and filtered to afford the title compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.66 (s, 1H), 1.80 (d, J=12.5 Hz, 2H), 1.99 (s, 2H), 2.28-2.39 (m, 2H), 3.01-3.12 (m, 4H), 3.24 (ddd, J=14.1, 2.4, 2.2 Hz, 2H), 4.45 (t, J=3.2 Hz, 1H), 6.57 (dd, J=9.2, 0.7 Hz, 1H), 7.27 (dd, J=9.0, 2.9 Hz, 1H), 7.67 (dd, J=3.1, 0.7 Hz, 1H). MS (+ESI) m/z=246 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:15][C:9]2=[C:10]([CH3:14])[S:11][C:12]([CH3:13])=[C:8]2[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:26]([O:25][C:19]1[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([NH:16][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2=[C:12]([CH3:13])[S:11][C:10]([CH3:14])=[C:9]2[CH2:15]1)=[O:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2c(C)sc(C)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3c(C)sc(C)c3C2)c1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
The mixture of 5-(2-isopropoxy-3-methyl-benzoylamino)-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (88) (448 mg, 1.08 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (89) as a brown solid (360 mg, 86%).
Reaction SMILES: C(OC([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])=O)(C)(C)C.[CH2:14]([O:16][C:17](=[O:25])[CH2:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1)[CH3:15]>>[CH3:9][NH:8][CH2:10][C:11]([NH:24][C:21]1[S:22][CH:23]=[C:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:25])[N:20]=1)=[O:13]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)CNC)n1

Procedure:
The subtitle compound was prepared from N-tert-butoxycarbonyl sarcosine (6.0 g) and 2-amino-4-thiazoleacetic acid ethyl ester (6.6 g) by the method of example 10 step (i). Yield 5.24 g
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([C:25]5[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:38])[O:4][N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]5[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][CH2:26]5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:38])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
(tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.2 mmol) was dissolved in methanol (6 mL), and the mixture was degassed with nitrogen for 15 min, followed by addition of palladium on carbon (30 mg, 0.02 mmol) [Aldrich, cat. #130108]. After three vacuum/nitrogen gas refilling cycles, 1 atm hydrogen gas was charged to the mixture with a balloon. After stirring for 2 h at room temperature, the reaction mixture was filtered through Celite and the filter was subsequently washed with methanol (30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography eluting ethyl acetate in hexanes (75-100%) to afford the desired product (48 mg, 60%). LCMS for C29H34O4N5 (M+H)+: calculated m/z=516.3. found 516.2; 1H NMR (400 MHz, CD3OD) δ 8.59-8.49 (m, 1H), 7.73 (m, 1H), 7.36-7.28 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.00 (m, 1H), 4.89 (dd, J=11.7, 3.1 Hz, 1H), 4.60 (dd, J=11.6, 3.1 Hz, 1H), 4.16 (d, J=13.4 Hz, 1H), 4.04 (d, J=13.5 Hz, 1H), 2.95 (ddd, J=11.8, 8.3, 3.6 Hz, 1H), 2.88-2.51 (m, 2H), 2.25 (s, 3H), 2.11 (s, 3H), 2.06-1.94 (m, 1H), 1.92-1.66 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]1[S:12][C:11]([CH2:13][CH2:14][O:15][CH2:16][C:17]([NH2:19])=O)=[CH:10][CH:9]=1.CO>O1CCCC1>[CH3:7][C:8]1[S:12][C:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH2:19])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CCOCC(N)=O)s1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CCOCCN)s1

Procedure:
Borane-tetrahydrofuran solution (1.0 M in THF, 21.7 ml) was added dropwise to a stirred solution of the product from step b) (1.25 g) in dry tetrahydrofuran (100 ml). The reaction was heated at reflux under an inert atmosphere for 5 hours. The reaction was cooled and methanol (10 ml) added cautiously. The solvents were removed in vacuo and the residue dissolved in methanol (100 ml) to which was added concentrated hydrochloric acid (sg. 1.18, 0.45 ml). This solution was heated at reflux for 15 min then the solvent removed in vacuo. The residue was purified by flash chromatography (dichloromethane: 5% methanol as eluant) to give the subtitle compound as a white solid (0.916 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](Br)[C:11]#[CH:12].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:12]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:11]#[CH:10]
Reactant: N#Cc1ccc(N)cc1
Reactant: C#CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C#CCNc1ccc(C#N)cc1

Procedure:
A solution of 23.6 g (0.20 mol) of 4-amino-benzonitrile, 16.6 ml (0.22 mol) of propargyl bromide and 38.3 ml (0.22 mol) of diisopropylethylamine is heated to 90° C. in 500 ml of toluene for 27 hours. It is then diluted with ethyl acetate, washed 3× with H2O and dried over MgSO4. After removal of the solvent by distillation the crude product is purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=20:80 to 75:25).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].CO.[H][H]>[Rh].C(O)(=O)C>[C:1]([CH:9]1[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)CC(C)(C)C1CCC(O)CC1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
4-t-octylphenol (250 g, used as received from Rohm and Haas), methanol (250 ml), acetic acid (2.5 ml) and rhodium on carbon catalyst (5.0 g, 5% rhodium, MCB Chemicals) were added to a 3 L glass lined autoclave. The autoclave was charged to 60 psig H2 and heated at 60° C. until hydrogen uptake was complete (about 10 hrs.). The mixture was cooled to room temperature and the catalyst was removed by filtration in a glove bag under a nitrogen atmosphere (CAUTION: pyrophoric catalyst). The solvent was removed on a rotary evaporator and the residue was dissoved in dichloromethane and extracted with 10% sodium carbonate solution (3×250 ml) to remove phenolic contamination, thus avoiding the formation of a yellow impurity in the subsequent oxidation step. The dichloromethane solution was washed with 25% sulfuric acid (2×100 ml) distilled water (1×250 ml), and dried over anhydrous magnesium sulfate, after which the solvent was evaporated to isolate 4-t-octylcyclohexanol as a low melting off-white solid (182 g, 81%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>C1COCC1>[O:29]=[C:22]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCOC(=O)Cc1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1cccnc1)c1ccsc1
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a solution of ethyl 2-(thiophen-3-yl)acetate (2.3 g, 16.2 mmol) in anhydrous THF (20 mL) was added LiHMDS (19.4 mL, 19.44 mmol) at −78° C. After stirring at that temperature for 0.5 h, a solution of nicotinoyl chloride (2.8 g, 16.2 mmol) in anhydrous THF (10 mL) was added into the reaction mixture and stirred at −78° C. for 4 hours. The mixture was quenched with NH4Cl solution, extracted with EtOAc. The organic layer was concentrated in vacuo and purified by column on silca gel (1.7 g, yield 38%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[CH3:32][N:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:32][N:33]1[CH2:34][CH:35]=[C:36]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][N:27]=4)(=[O:24])=[O:23])=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH2:37][CH2:38]1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Br)nccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2-c2nccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)CC1
Temperature: 100 °C
Yield: 95.2 %

Procedure:
A vial was charged with 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (42.16 mg, 0.083 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (27.7 mg, 0.124 mmol) Pd(AmPhos)2Cl2 (2.93 mg, 4.14 μmol), potassium phosphate (52.7 mg, 0.248 mmol), dioxane (414 μl), and water (138 μl). The vial was sealed and heated in a microwave reactor for 30 min at 100° C. The mixture was extracted with EtOAc (three times). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel, eluting with 5 to 10% MeOH/DCM, then with 15% MeOH/EtOAc, and finally with a solution of 20% of 2N ammonia in methanol in DCM. The fractions containing product were collected and concentrated. The residue was dissolved in DCM and filtered through cotton. The filtrate was concentrated to give 1-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (41.4 mg, 0.079 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.63 (d, J=5.7 Hz, 1H), 8.55 (d, J=1.5 Hz, 1H), 8.35 (s, 1H), 8.08 (d, J=5.8 Hz, 1H), 8.01 (d, J=6.2 Hz, 1H), 7.91 (dd, J=1.8, 8.9 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.76 (s, 1H), 7.63 (dd, J=8.4, 19.4 Hz, 2H), 6.72 (d, J=6.2 Hz, 1H), 5.37 (br. s., 1H), 2.98 (br. s., 2H), 2.52 (br. s., 2H), 2.20 (s, 3H), 2.16-1.96 (m, 2H). m/z (ESI) 526.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[C:8]([CH2:13][C:14]1[N:18]3[N:19]=[C:20]([CH2:23][CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=1)=[C:7]([F:25])[CH:6]=2.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([CH2:13][C:8]3[C:9]([F:12])=[C:10]4[C:5](=[CH:6][C:7]=3[F:25])[N:4]=[CH:3][C:2]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)=[CH:11]4)=[N:15][N:16]=2)[N:19]=1)[CH3:24]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCc1ccc2nnc(Cc3c(F)cc4ncc(Br)cc4c3F)n2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCc1ccc2nnc(Cc3c(F)cc4ncc(-c5cnn(C)c5)cc4c3F)n2n1
Yield: 64.1 %

Procedure:
To a mixture of 3-bromo-6-(6-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline (86 mg, 0.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.21 mmol, 44 mg) and cesium carbonate (0.6 mmol<195 mg) in 1,4-dioxane (2 mL) at reflux was added [2-[(D-N)methyl]phenyl-c](tricyclohexylphosphine)trifluoroacetato-O-(SP-4-3)-palladium (Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.; Light, M. E. Organometallics 2003, 22, 987) (0.5 mol %, 0.1 μmol, 0.1 mg). After 30 min the reaction mixture was filtered through a pad of silica gel (2 g) eluting with dichloromethane/methanol (17/3, 12 mL). The filtrate was concentrated onto silica gel and purified via flash column chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound as an off white solid (52 mg, 60% yield). Analytical data presented in Table 2.