Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](OS(C)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C=O)CC1
Temperature: 100 °C
Yield: 78 %

Procedure:
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (3.15 g, 20 mmol), KI (0.1 g) and K2CO3 (8.28 g, 60 mmol) in DMF (100 mL) was added 4-methanesulfonyloxy-piperidine-1-caboxylic acid tert-butyl ester (7.26 g, 26 mmol). The mixture was heated at 100° C. for 2 h, then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N NaOH (30 mL), water, and dried over anhydrous Na2SO4, concentrated to give the title compound as white solid (Yield: 5.3 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[Br:21]Br>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:9]1[CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: BrBr
Reactant: O=C1CC=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=CC1Br
Yield: 65.3 %

Procedure:
A suspension of 0.78 g (2.56 mmole) of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one in 100 mL of carbon tetrachloride was heated to reflux, yielding a clear solution. Bromine (0.19 mL, 3.69 mmole) was added in one portion and the solution was, heated at reflux, under a sunlamp, for 15 minutes. Without cooling, the reaction solution was washed with 5% aqueous sodium thiosulfate and water, dried (sodium sulfate), and concentrated. The residue was triturated with ether. The solid was collected on a filter, washed with ether and dried yielding 0.64 g (65%) of the title compound. This crude material (shown by NMR to have a ratio of product to starting material of 85:15) was used as is in the next step.
Reaction SMILES: C(OC([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=1)CN>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([NH:8][CH2:39][C:54]3[CH:53]=[CH:50][CH:49]=[C:48]([O:47][CH3:46])[CH:55]=3)=[O:38])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: COc1cccc(CN)c1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: COc1cccc(CNC(=O)c2cc(N3CCCC3=O)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (187 mg) described in Example 769 and 3-methoxybenzylamine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (120 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Na+].Br[C:15]1[CH:23]=[CH:22][C:21]2[N:20]([CH3:24])[C:19]3[CH2:25][CH:26]4[NH:30][CH:29]([C:18]=3[C:17]=2[C:16]=1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27]4>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([C:15]2[CH:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19]4[CH2:25][CH:26]5[NH:30][CH:29]([C:18]=4[C:17]=3[C:16]=2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=[N+]([O-])c1cccc(S(=O)[O-])c1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc([N+](=O)[O-])c4)ccc31)C1CCC(C2)N1
Yield: 13 %

Procedure:
Intermediate 8 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) to give tert-butyl 2-(3-nitrophenylsulfonyl)-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (50 mg, 13%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.76 (s, 1H), 8.25-8.38 (m, 1H), 8.21 (s, 1H), 7.67-7.72 (m, 2H), 7.65 (s, 1H), 7.35 d, J=8.7 Hz, 1H), 5.27 (br s, 1H) 4.70-4.73 (m, 1H), 3.62 (s, 3H), 3.38-3.42 (m, 1H), 2.51 (d, J=15 Hz, 1H), 2.15-2.42 (m, 2H), 1.97-1.90 (m, 1H), 1.54-1.67 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O[C:13]1([C:23]#[C:24][CH:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]1([OH:22])[CH3:21].[OH-].[Na+]>O>[OH:22][C:14]1([CH3:21])[CH2:15][CH2:16][CH2:17][C:18]([CH3:19])([CH3:20])[C:13]1=[C:23]=[CH:24][CH:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC(O)C#CC1(O)C(C)(C)CCCC1(C)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(O)C=C=C1C(C)(C)CCCC1(C)O
Reaction time: 10 h
Yield: 60.2 %

Procedure:
To 5 ml of an anhydrous THF suspension containing 274 mg of lithium aluminum hydride was slowly added 10 ml of an anhydrous THF solution containing 1.0 g of 1-(1,2-dihydroxy-2,6,6-trimethylcyclohexyl)oct-1-yn-3-ol under ice-cooling in a nitrogen atmosphere. After the addition, the mixture was placed under refluxing conditions and stirred for 10 hours. After completion of the reaction, the reaction mixture was cooled, and 0.3 ml of water, 0.3 ml of a 15% sodium hydroxide aqueous solution, and 1.0 ml of water were carefully added thereto in this order, followed by vigorously stirring for 20 minutes. Any insoluble matter was removed by filtration with suction, and the filtrate was concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to obtain 568 mg (yield: 60%) of 1-(2-hydroxy-2,6,6-trimethylcyclohexylidene)oct-1-en-3-ol.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[F:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[C:6]=1[OH:12].C(N(CC)CC)C.[CH2:20]=[O:21].Cl>C(#N)C.CC(OC)(C)C>[F:4][C:5]1[CH:11]=[CH:10][C:9]([CH:20]=[O:21])=[C:7]([OH:8])[C:6]=1[OH:12]
Reactant: C=O
Reactant: Oc1cccc(F)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: COC(C)(C)C
Product: O=Cc1ccc(F)c(O)c1O
Temperature: 25 °C
Yield: 19.6 %

Procedure:
Magnesium chloride (3.71 g, 33 mmol) was added portionwise at room temperature to a solution of 3-fluorocatechol (2 g, 15.6 mmol) in acetonitrile (20 mL), followed by triethylamine (13.4 mL, 97.5 mmol). Paraformaldehyde (3.16 g, 105.3 mmol) was then added to the stirred suspension and the mixture was heated at reflux for 5 hours. The mixture was cooled to room temperature then poured into a mixture of 5% HCl and TBME. The organic phase was separated, and the aqueous layer re-extracted with TBME. The combined organic extracts were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure. The crude mixture (˜1:1 starting material:product) was purified on normal silica in neat DCM followed by DCM/MeOH 96:4 and 90:10 to yield 478 mg of 28 still contaminated with 11.4% w/w of 3-fluorocatechol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][CH2:17][CH:18]([NH2:20])[CH3:19]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:20][CH:18]([CH3:19])[CH2:17][O:16][CH3:15])[N:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Reactant: COCC(C)N
Product: COCC(C)Nc1nccc(-c2ccnc(Cl)c2)n1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Step A) (1.6 g, 7.0 mmol) in 1-methoxy-2-propylamine (5 mL) was stirred at reflux for 45 minutes. After cooling to room temperature, the mixture was purified using column chromatography on silica gel eluted with 40% ethyl acetate in hexanes to give 1.4 g of the title compound as a white solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCCOc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCOc2ccccc2)cc1

Procedure:
A mixture of 15 g of ethyl p-[(3-phenoxypropyl)-amino]benzoate, 15 g of potassium hydroxide and 150 ml of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, chilled and filtered to give yellow crystals, mp 159°-162° C. Recrystallization from ethanol gives pale yellow crystals, mp 161°-163° C.
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:53](I)[CH3:54].O>CN(C)C=O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:53][CH3:54])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CCI
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 50 mg (0.077 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, in 1.0 ml of N,N-dimethylformamide, 75 mg (0.23 mmol) of cesium carbonate and 12 μl (0.15 mmol) of ethyl iodide were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=70/30 (V/V)] to provide 45 mg of the title compound as a white solid (yield: 85%).
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)([OH:18])[C@:5]([CH3:26])([OH:25])[CH2:4]2)[CH3:2].I[CH2:28][C:29]([NH2:31])=[O:30]>>[CH2:1]([C@@:3]12[CH2:4][C@:5]([OH:25])([CH3:26])[C@:6]([OH:18])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:7][C@H:8]1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([O:17][CH2:28][C:29]([NH2:31])=[O:30])[CH:14]=[CH:15][C:16]2=1)[CH3:2]
Reactant: NC(=O)CI
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CCc1cc(O)ccc12
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CCc1cc(OCC(N)=O)ccc12

Procedure:
The title compound was prepared from the compound of Example 102 according to the procedure of Example 57, running the reaction at room temperature overnight and using iodoacetamide as the alkylating agent. Mass spectrum (m/e) 411 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[I-].[CH3:23][N:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:34][N+](C)(C)C)=[CH:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:34][CH:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:24]([CH3:23])[CH2:25]3)[C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: COC(=O)CC1(n2c(=O)[nH]c3ccccc32)CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CC1(n2c(=O)n(CC3CN(C)c4cccc(C)c43)c3ccccc32)CCCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
To a mixture of [1-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-cyclohexyl]-acetic acid methyl ester (115 mg, 0.40 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (200 mg, 0.58 mmol) in DMF (2.5 mL) was added K2CO3 (110 mg, 0.80 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 30% EtOAc in Hexane as the eluent to afford the desired {1-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclohexyl}-acetic acid methyl ester (131 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][N:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([O:27][CH3:28])[CH:21]=1)[CH3:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][N:17]([CH3:16])[CH3:18])=[CH:21][C:22]=2[O:27][CH3:28])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: COc1cc(CN(C)C)ccc1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(CN(C)C)cc2OC)c1C(=O)OC
Yield: 78 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 4-dimethylaminomethyl-2-methoxyphenylamine (0.56 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.9 g of the product at 92:8 methylene chloride-methanol, in 78% yield: 1H NMR (CDCl3) δ 2.31 (s, 6H), 3.47 (s, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H), 6.80 (dd, J=8.0 Hz, J=1.4 Hz, 1H), 6.99 (s, 1H), 7.14 (dd, J=7.3 Hz, J=0.9 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.45 (dd, J=8.5 Hz, J=0.9 Hz, 1H), 7.99 (br, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:20]([OH:22])[CH3:21])[C@H:12]([CH3:23])[N:11]1[C:24](=[O:34])[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:20]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[CH2:19][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[N:11]([C:24](=[O:34])[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])[C@H:12]2[CH3:23])(=[O:22])[CH3:21]
Reactant: CC(O)c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Reaction time: 0.67 h
Yield: 73.9 %

Procedure:
Dissolve 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (92 mg, 176 μmol, mixture of two diastereomers) in CH2Cl2 (1.8 mL). Add NaHCO3 (92 mg, 1.1 mmol) and 3,3,3-Triacetoxy-3-iodophthalide (90 mg, 211 μmol) at room temperature. Stir 40 min. Add saturated NaHCO3 solution and saturated Na2S2O3 solution, extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-60%) to give the title compound as a white foam (0.068 g, 130 μmol). MS (m/z): 522 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1OCC1CC1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2OCC2CC2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(cyclopropylmethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C20H17ClN4O2, 381; Found, 381.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28]O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cn3)cc2)CC1
Yield: 60.4 %

Procedure:
1,1-Dimethylethyl 4-({[4-(5-bromo-2-pyridinyl)phenyl]oxy}methyl)-1-piperidinecarboxylate (0.27 g, 60%) was prepared as a white solid from 4-(5-bromo-2-pyridinyl)phenol (0.25 g, 1.0 mmol), N-Boc-4-piperidinemethanol (0.23 g, 1.0 mmol) and Ph3P (0.27 g, 1.0 mmol) in THF (7 mL) followed by diisopropyl azodicarboxylate (0.22 g, 94%, 1.0 mmol) in THF (3 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 7.92 (d, 2H, J=8.8 Hz), 7.85 (d, 1H, J=8.5 Hz), 7.57 (d, 1H, J=8.5 Hz), 6.97 (d, 2H, J=8.8 Hz), 4.25-4.10 (m, 2H), 3.86 (d, 2H, J=6.4 Hz), 2.85-2.70 (m, 2H), 2.05-1.90 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 446/448 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]=O)[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([Mg]Br)[CH3:17].C(OCC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16]1)[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14]
Reactant: CC[Mg]Br
Reactant: CC1(C)CCN(C=O)c2ccc(Br)cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CCN(C2CC2)c2ccc(Br)cc21
Temperature: 50 °C
Yield: 64 %

Procedure:
A stirred, cooled (0° C.) solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-1-carbaldehyde (Intermediate 50, 21.8, 6.7 mmol) in anhydrous tetrahydrofuran (20 mL) under argon was treated with titanium tetra-iso-propoxide (2.15 mL, 7.39 mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (5.6 mL, 16.8 mmol) and the reaction mixture was then heated at 50° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered over celite and evaporated in vacuo to residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as an oil (1.2 g, 64%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: C1CCNC1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(N2CCCC2)n1
Temperature: 160 °C
Yield: 16 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.26 mmol, prepared as described in Example 18) in DMSO (14 ml). Pyrrolidine (0.022 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 3 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method B). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (17.6 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)=[O:7].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Ag-]=O>[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=[Ag-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCCC(C)C)cc23)c(OC)c1
Reaction time: 4 h
Yield: 12.9 %

Procedure:
Silver(I) oxide (4.92 g) was added to a solution of indole (F) (2.05 g) in toluene (15 ml). The mixture was protected from light, stirred, and heated to reflux under an atmosphere of nitrogen for 24 hours. A solution of methyl 4-bromomethyl-3-methoxybenzoate (B) (2.31 g) in toluene (5 ml) was added, and stirring was continued at 95° C. for 4 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was evaporated to give an amber gum which was purified by flash chromatography on silica gel (862 ml), eluting with 1:99 v/v methanol:chloroform to give (E) (0.47 g, 13%) as a white foam; partial NMR (80 MHz, CDCl3): 0.92[d, 6H, CH(CH3)2], 3.40(q, 2H, NCH2), 3.87(s, 3H, OCH3), 4.09(s, 2H, ArCH2), 6.18(br t, 1H, CONH), 7.98(br s, 1H, H4 -indole), 8.84(br s, 1; H, NH).