Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[C:6]([O:12]C)[C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:12])[C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(F)c(C=O)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)cc(O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 2-fluoro-4,6-dimethoxybenzaldehyde (3.68 g, 20.0 mmol) in dichloromethane (50 mL) was added dropwise boron tribromide (12.50 g, 50.0 mmol) at −78° C. The reaction was stirred at room temperature overnight and poured into ice. The resulting mixture was extracted with ethyl acetate (3×60 mL) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/6) on silica gel to give the title compound as a white solid. (2.31 g, Yield: 76.4%). 1H NMR (400 MHz, DMSO-d) δ 11.53 (s, 1H), 11.22 (s, 1H), 9.99 (s, 1H), 6.16-6.24 (m, 2H). MS (ESI) m/z=157 [M+H]+.
Reaction SMILES: OO.[N:3]1([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]4[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[C:33]([CH3:37])([CH3:36])[C:34]#[N:35])=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[C:14]([F:38])=[CH:13][N:12]=2)[CH:7]=[CH:6][N:5]=[N:4]1.[O:39]1CCOCCOCCOCCOCCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[N:3]1([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]4[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[C:33]([CH3:36])([CH3:37])[C:34]([NH2:35])=[O:39])=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[C:14]([F:38])=[CH:13][N:12]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: CC(C)(C#N)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C(N)=O)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 399.7 %

Procedure:
Add hydrogen peroxide to a stirred solution of 2-(2-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)-4-fluorophenyl)-2-methylpropanenitrile (140 mg, 279 μmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (14 mg, 1% wt), and sodium carbonate (1 M, 5 mL, 5 mmol) in 10 mL ethanol drop wise. Stir the mixture at RT for 48 h. Dilute the reaction mixture with water and extract with DCM. Dry the organic phase over sodium sulfate and concentrate in vacuo. Purify the crude product by FCC (10% methanol in DCM as elute) to give the title compound as a yellow solid (110 mg, 76%). MS (ES) m/z 520 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:10]C(=O)CN2C(=O)C3=CC=CC=C3C2=O)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:10][CH:8]([CH3:9])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CC1CCCCC1)NC(=O)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)CC1CCCCC1
Reaction time: 24 h

Procedure:
To a suspension of (±)-N-(2-cyclohexyl-1-methylethyl)-2-phthalimidoacetamide (12.0 g, 36.7mmol) in ethanol (180 ml) was added hydrazine hydrate (2.05 g, 40.3 mmol) and the mixture heated under reflux for 1.5 hours. After cooling and standing at 0° for 24 hours, the slurry was filtered and the residue washed with petrol (40°-60°). The combined filtrateswere evaporated to dryness and the oily residue triturated with petrol (3×100 ml). The combined extracts were evaporated to dryness to givea colourless oil. The oil was dissolved in ether (50 ml) and the solution added to a warm solution of fumaric acid (2.7 g) in ethanol (50 ml). On standing, a colourless solid was deposited, m.p. 132°-134° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:31]=[N:30][C:12]3[N:13]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=4[C:11]=3[CH:10]=2)O1.C[N+]1([O-])CC[O:37]CC1>C1COCC1>[OH:37][C:9]1[CH:31]=[N:30][C:12]2[N:13]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:14]3[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=3[C:11]=2[CH:10]=1
Reactant: CC1(C)OB(c2cnc3c(c2)c2cc(C#N)ncc2n3COCC[Si](C)(C)C)OC1(C)C
Reactant: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(O)cnc21
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (245 mg, 0.54 mmol) in THF (2.0 mL), under an inert atmosphere, was added N-methylmorpholine-N-oxide (191 mg, 1.63 mmol) and the reaction mixture was heated under reflux for 90 minutes. The reaction mixture was allowed to cool to ambient temperature and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, 12 g column, ISCO 0-50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (180 mg, 97%). 1H NMR (CD3OD, 300 MHz): 9.10 (d, J=1.0 Hz, 1H), 8.64 (d, J=1.3 Hz, 1H), 8.35 (d, J=2.7 Hz, 1H), 8.04 (d, J=2.7 Hz, 1H), 5.99 (s, 2H), 3.59 (t, J=8.0 Hz, 2H), 0.86 (t, J=8.0 Hz, 2H), −0.14 (s, 9H). LCMS (Method B): RT=3.75 min, M+H+=341.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C@@H:25]1[C@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:33]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:32]([CH3:51])[O:31][C@H:26]1[O:27]CC=C)(=[O:3])[CH3:2]>C1COCC1>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C@@H:25]1[C@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:33]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:32]([CH3:51])[O:31][C@H:26]1[OH:27])(=[O:3])[CH3:2]
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1[C@H](O[C@@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](C)O[C@H]2O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
1,5-Cyclooctadiene-bis(methyldiphenylphosphine)iridium hexafluorophosphate (10 mg, 12 μmol) was dissolved THF (10 mL), and the resulting red solution was degassed in an argon stream. Hydrogen was then bubbled through the solution, causing the colour to change to yellow. The solution was then degassed again in an argon stream. A solution of 319 (830 mg, 1.16 mmol) in THF (40 mL) was degassed and added. The mixture was stirred at rt overnight. The mixture was concentrated. The residue was taken up in acetone (90 mL), and water (10 mL) was added. Mercuric chloride (475 mg, 1.75 mmol) and mercuric oxide (504 mg, 2.32 mmol) were added to the mixture, protected from light. The mixture was stirred for 2 h at rt, then concentrated. The residue was taken up in CH2Cl2 and washed three times with sat. aq. KI, then with brine. The organic phase was dried and concentrated. The residue was purified by column chromatography (cyclohexane-EtOAc 3:7) to give 320 (541 mg, 69%) as a white foam; [α]D+16° (c 1.0, CHCl3); 1H NMR: δ 7.35-7.05 (m, 10H, Ph), 5.50 (d, 1H, J2,NH=8.2 Hz, NHD), 5.22 (d, 1H, J1,2=1.1 Hz, H-1A), 5.06 (pt, 1H, J3,4=J4,5=9.5 Hz, H-4D), 5.00 (pt, 1H, J2,3=9.5 Hz, H-3D), 4.85-4.60 (m, 4H, CH2Ph), 4.56 (d, 1H, J1,2=7.0 Hz, H-1D), 4.22-4.13 (m, 2H, J5,6=4-5, J6a,6b=12.3 Hz, H-6aD, 6bD), 4.03 (m, 1H, H-2D), 4.00 (dq, 1H, J4,5=9.5, J5,6=6.2 Hz, H-5A), 3.96 (dd, 1H, J2,3=3.3 Hz, H-2A), 3.90 (dd, 1H, J3,4=9.5 Hz, H-3A), 3.60 (m, 1H, H-5D), 3.48 (d, 1H, J1,OH=3.5 Hz, OH), 3.40 (pt, 1H, H-4A), 2.08, 2.03, 2.01 (3s, 9H, OAc), 1.65 (s, 3H, NHAc), 1.30 (d, 3H, H-6A); 13C NMR: δ 171.2, 171.0, 170.4, 169.6 (C═O), 138.2-128.0 (Ph), 103.3 (C-1D), 94.1 (C-1A), 81.4 (C-4A), 79.9 (C-2A), 78.7 (C-3A), 75.8, 73.9 (2C, CH2Ph), 73.6 (C-3D), 72.4 (C-5D), 68.7 (C-4D), 68.2 (C-5A), 62.4 (C-6D), 54.5 (C-2D), 23.3 (NHAc), 21.1, 21.0, 21.0 (3C, OAc), 18.3 (C-6A). FAB-MS for C34H43NO13 (M, 673.2), m/z 696.3 [M+Na]+. Anal Calcd for C34H43NO13: C, 60.61; H, 6.43; N, 2.08. Found: C, 60.46; H, 6.61; N, 1.95.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37].N1C=CC=CC=1>C(Cl)Cl>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[S:36]([NH:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:37])=[O:38]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(N)cc2ccoc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(CN2C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]2C)c2occc2c1
Yield: 47.8 %

Procedure:
tert-Butyl trans-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-1-carboxylate (0.037 g, 0.1 mmol; obtained in Step 3) was dissolved in DCM and reacted with 2-methoxy-5-methylbenzenesulfonyl chloride (0.045 g, 0.2 mmol) and pyridine (0.024 g, 0.3 mmol) overnight. The mixture was washed with 1 M HCl and the organic layer was dried (MgSO4) and evaporated. The crude was purified using flashtube (10% MeOH in DCM) and afforded the title product (0.026 g, 48%). HPLC 93% RT=2.01 min (System A; 10-97% MeCN over 3 min), 93% RT=1.85 min (System B; 10-97% MeCN over 3 min). MS (ESI+) m/z 544.2 (M+H)+.
Reaction SMILES: FC(F)(F)C1C=C([C:12]([OH:14])=[O:13])C=C2C=1NN=C2.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27]([F:30])([F:29])[F:28])=[N:23][NH:24]2)=[CH:20][CH:19]=1>>[F:28][C:27]([F:30])([F:29])[C:22]1[C:21]2[C:25](=[CH:26][C:18]([C:12]([OH:14])=[O:13])=[CH:19][CH:20]=2)[NH:24][N:23]=1
Reactant: FC(F)(F)c1n[nH]c2cc(Br)ccc12
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Product: O=C(O)c1ccc2c(C(F)(F)F)n[nH]c2c1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 21, using 6-bromo-3-(trifluoromethyl)-1H-indazole. −ESI (M−H) 229.1.
Reaction SMILES: CS(O[C:6]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)=O.[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(#N)C>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:6]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1cnc2c(OC)nccc2c1OS(C)(=O)=O
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(OC)nccc2c1Nc1ccccc1C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Ethyl 4-methanesulfonyloxy-8-methoxy-1,7-naphthyridin-3-carboxylate (261 mg and o-toluidine (0.17 nl) were dissolved into 7 ml of acetonitrile and the solution was heated to reflex for 30 minutes. After cooling the mixture, the solvent was evaporated under reduced pressure and the beside was dissolved into chloroform. The solution was washed with water and then saturated sodium bicarbonate, dried, and concentrate under reduced pressure. The residue was subjected to silica gel column chromatography using a mixture of hexane:ethyl acetate (2:1) as an eluant to give yellow titled compound (180 mg, 67%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([N+:31]([O-:33])=[O:32])[CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[C:24]([N+:31]([O-:33])=[O:32])[CH:23]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(CNC(=O)c1ccc(Cl)cc1[N+](=O)[O-])NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-chloro-2-nitrobenzoic acid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:25]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:37]([NH:39][NH2:40])=[S:38])[CH2:29][CH2:28][CH2:27][CH2:26]1>CO>[CH:25]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:37]([NH:39]/[N:40]=[CH:19]/[C:18]2[CH:21]=[CH:22][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=4)[N:11]=3)=[CH:16][CH:17]=2)=[S:38])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: NNC(=S)Nc1ccccc1C1CCCC1
Solvent: CO
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(/C=N/NC(=S)Nc4ccccc4C4CCCC4)cc3)n2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a mixture of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (0.58 g, 1.7 mmol) and N-(2-cyclopentylphenyl)hydrazinecarbothioamide (0.41 g, 1.7 mmol) in a 100 mL roundbottom flask equipped with a magnetic stir bar and reflux condenser was added methanol (17 mL), and the reaction was heated to 50° C. and stirred overnight. The reaction was cooled to room temperature and the resulting solid was filtered, washed with methanol and dried under vacuum (25 in Hg) at 55° C. to give the title compound (795 mg, 1.44 mmol, 83% yield) as a yellow solid: mp 213-216° C.; 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 9.11 (s, 1H), 8.60 (s, 1H), 8.26 (d, J=8.4 Hz, 2H), 7.91 (s, 1H), 7.86-7.71 (m, 5H), 7.40 (dd, J=8.8, 6.4 Hz, 3H), 7.35-7.27 (m, 2H), 3.22 (t, J=8.0 Hz, 1H), 2.13 (d, J=2.5 Hz, 2H), 1.90-1.59 (m, 6H); ESIMS m/z 551 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:27][CH2:28][CH3:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CC(NC1CCN(Cc3ccccc3)CC1)CC2
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(C1CCN(Cc2ccccc2)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine from Step 1 and propionaldehyde (4.5 mL, 62.4 mmol) in dichloroethane (200 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (24 g, 0.113 mol, 2 eq.) in a single portion. The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica (10 g). This was placed on top of a flash column and eluted with 20% hexanes in acetone. The fractions containing product were pooled and concentrated to afford (1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine as a clear oil (6.86 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH3:8][CH:4]1[NH:3][CH:2]([CH3:1])[CH2:7][N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1
Reactant: CC1CNCC(C)N1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CC(C)NC(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a solution of 2,6-dimethylpiperazine (500 mg, 4.378 mmol, 1.0 eq) in THF were added K2CO3 (1.2 g, 8.75 mmol, 2.2 eq.) and ethyl 2-bromoacetate (731 mg, 4.378 mmol, 1 eq). The mixture was stirred at RT for 4 h and then quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 34% yield (0.3 g). LC-MS (ESI): Calculated mass: 200.0; Observed mass: 201.0 [M+H]+ (rt: 0.102 min).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=S)[CH3:2].[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[NH2:23])[C:16]([O:18][CH3:19])=[O:17]>>[CH3:19][O:18][C:16]([C:15]1[CH:20]=[CH:21][C:22]2[N:23]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:1][CH3:2])[NH:12][C:13]=2[CH:14]=1)=[O:17]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCc1ccccc1N=C=S
Product: CCc1ccccc1Nc1nc2ccc(C(=O)OC)cc2[nH]1

Procedure:
2-Ethyl-1-isothiocyanatobenzene (3 mmol) and methyl 3,4-diaminobenzoate (3 mmol) were reacted, following general procedure B, to yield 2-(2-ethylphenylamino)-3H-benzimidazole-5-carboxylic acid methyl ester, which was purified by silica gel chromatography using DCM/ethyl acetate as eluent.
Reaction SMILES: C([NH:8][CH:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[CH:16]1[C:13]2[CH2:14][CH2:15][CH:9]([NH2:8])[CH2:10][CH2:11][C:12]=2[CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CNC2CCc3ccccc3CC2)cc1
Agent: [Pd]
Solvent: CO
Product: NC1CCc2ccccc2CC1
Reaction time: 24 h

Procedure:
Benzyl-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amine (2.80 g) is dissolved in methanol (100 mL) and the composed is deprotected by adding a catalytic amount of 10% palladium on charcoal and placing the solution under an atmosphere of hydrogen. The reaction is shown to be complete by TLC after 24 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, dichloromethane/methanol 25:1 Rf=0.15).
Reaction SMILES: Cl[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=2[N:13]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:5]3[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=3[N:13]=2)=[CH:24][CH:23]=1)=[O:21]
Reactant: N#Cc1ncc2cc(-c3ccccc3)c(Cl)nc2n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Temperature: 95 °C

Procedure:
A mixture of 7-chloro-6-phenylpyrido[2,3-d]pyrimidine-2-carbonitrile (2-4) (0.350 g, 1.31 mmol), 4-formylphenyl boronic acid (0.492 g, 3.28 mmol), cesium carbonate (1.28 g, 3.94 mmol), and Pd(PtBu3)2 (0.067 g, 0.131 mmol) in anhydrous dioxane (8 mL) was degassed (3× vacuum pump/refilled with N2) and heated to 95° C. for 18 hr. The mixture was cooled, diluted with water, and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. Purified by silica gel chromatography (10-30% EtOAc in Hexanes). 1H-NMR (500 MHz, CDCl3) δ 10.05 (s, 1H), 9.61 (s, 1H), 8.44 (s, 1H), 7.84 (d, 2H, J=8.3 Hz), 7.72 (d, 2H, J=8.3 Hz), 7.46-7.36 (m, 3H), 7.29-7.25 (m, 2H); LRMS, calc'd: 337.0, found: 337.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:54])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16]C(=O)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36]([NH:38][C:39]5[CH:40]=[C:41]([NH:45][C:46]([C:48]6[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=6)=[O:47])[CH:42]=[CH:43][CH:44]=5)=[O:37])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.C[Si](C)(C)[O-].[K+].P([O-])([O-])([O-])=O>C1COCC1>[CH3:1][C:2]1([CH3:54])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[CH2:13][NH:14][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:30]=[C:31]([NH:35][C:36]([NH:38][C:39]4[CH:40]=[C:41]([NH:45][C:46]([C:48]5[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=5)=[O:47])[CH:42]=[CH:43][CH:44]=4)=[O:37])[CH:32]=[CH:33][CH:34]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(NC(=O)c6cccnc6)c5)c4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)Nc4cccc(NC(=O)c5cccnc5)c4)c3)ccc2O1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A solution of N-{3-[({[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]amino}carbonyl)-amino]phenyl}pyridine-3-carboxamide (0.209 g) in anhydrous THF (10 ml) was treated under nitrogen at 20° with potassium trimethylsilanolate (0.217 g). The mixture was heated to 65° for 2.5 h before cooling to room temperature. Phosphate buffer (pH 6.5, 25 ml) was added and the product extracted with EtOAc (3×20 ml). Solvent evaporation in vacuo gave a residue that was purified by SPE. Elution with dichloromethane-EtOH-ammonia (100:8:1 then 50:8:1) followed by solvent evaporation in vacuo gave the title compound (0.109 g). LCMS RT=2.86 min, ES+ve 712 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:14])=O>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Product: CCc1cccc(C(=O)Cl)c1

Procedure:
3-ethylbenzoic acid (9.40 g, 62.6 mmol) was added slowly to thionyl chloride (45 mL), and N,N-dimethylformamide (3 drops) was added dropwise. The resulting reaction mixture was heated under reflux for 2 hours under the same condition. The reaction mixture was concentrated, and used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=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.[NH2:64][C:65]1[S:66][CH:67]=[CH:68][N:69]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]([CH3:22])([CH3:23])[C:19]([NH:64][C:65]4[S:66][CH:67]=[CH:68][N:69]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: Nc1nccs1
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: CC(C)(C(=O)Nc1nccs1)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoic acid (10 mg, 0.025 mmol) and diisopropylethylamine (0.05 mL) in anhydrous DMF (0.2 mL) was added HATU (25 mg, 0.066 mmol) at rt under argon. After stirring at rt for 10 min, 2-aminothiazole (15 mg, 0.15 mmol) was added. The reaction mixture was stirred at rt for 2.5 hr, 40° C. for 1 hr, and 80° C. for 30 min. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenyl-N-(thiazol-2-yl)butanamide (Example 138, 7 mg, 0.01 mmol, 40% yield) as a white solid. MS found: (M+H)+=485. 1H-NMR (400 MHz, CDCl3) δ ppm 8.00 (1H, s) 7.53-7.58 (3H, m) 7.44 (1H, d, J=8.65 Hz) 7.35 (1H, d, J=3.56 Hz) 7.23 (1H, d, J=7.63 Hz) 7.11-7.15 (2H, m) 6.89-6.99 (7H, m) 3.63 (1H, dd, J=10.43, 4.32 Hz) 2.97-3.08 (2H, m) 1.37 (3H, s) 1.18 (3H, s).