Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:19])=[C:13]([CH:18]=1)[C:14]([O:16]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]1COCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:20])[C:12]([Br:19])=[C:13]([CH2:14][OH:16])[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1Br
Reactant: C1CCOC1
Product: Cc1cc(OCc2ccccc2)cc(CO)c1Br
Temperature: -78 °C
Reaction time: 21 h

Procedure:
A solution of methyl 5-(benzyloxy)-2-bromobenzoate (1.08 g, 3.36 mmol) in anhydrous THF (7 mL) was made before cooling the reaction mixture in a −78° C. bath. Reaction mixture was then treated, dropwise, with LiAlD4 (1 M solution in THF; 3.7 mL, 3.7 mmol) and allowed to stir for 21 h. before the reaction mixture was warmed to room temperature and quenched with 1N HCl to adjust pH 7 before addition of 10 mL of EtOAc. The organic layer was separated and the aqueous layer was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give (5-(benzyloxy)-2-bromo-3-methylphenyl)methanol −d2 (2.00 g, 86%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:26][CH2:27][O:28][CH3:29])[N:15]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[C:11]=2[C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[Cl:30]CCl.CO>O1CCOCC1>[ClH:30].[NH2:18][CH2:17][CH2:16][N:15]1[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=[C:14]1[CH2:26][CH2:27][O:28][CH3:29]
Reactant: ClCCl
Reactant: COCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCCc1nc2c(N)nc3cccnc3c2n1CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of hydrochloric acid in dioxane (58 mL of 4 M) was added to a solution of tert-butyl N-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin 1-yl]ethyl}carbamate (3 g) in a small amount of dichloromethane/methanol. The reaction; mixture was stirred overnight at ambient temperature and then concentrated under reduced pressure to provide 3.7 g of crude 1-(2-aminoethyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:15]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:9](=[O:11])[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[O:12][CH3:13])=[CH:18][CH:17]=1)#[N:14]
Reactant: COC(C(=O)O)c1cccc(O)c1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(O)c1

Procedure:
(RS)-(3-Hydroxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(3-hydroxy-phenyl)-2-methoxy-acetamide. Colorless oil.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH:4]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C(=N)N(C)C.[CH:42]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][CH:48]=[CH:47]2)=O>ClCCl>[CH2:7]([O:6][C:5](=[O:14])/[C:4](/[O:3][CH3:2])=[CH:42]/[C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][CH:48]=[CH:47]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(C(=O)OCc1ccccc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: CO/C(=C\c1ccc2[nH]ccc2c1)C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 3.70 g of (1-methoxy-2-benzyloxy-oxoethyl)triphenyl phosphonium chloride in 60 ml of dichloromethane was added at 0° C. 1.07 ml of tetramethyl guanidine and the mixture was warmed to 22° C. The mixture was treated with 2.25 g of 5-formyl-indole and stirring was continued at 40° C. for 16 h. The mixture was treated again with 3.70 g of the Wittig salt and 1.07 ml of tetramethyl guanidine and stirring was continued at 40° for 24 h after which time the conversion was complete. The mixture was evaporated and the residue partitioned between AcOEt and water. The organic layer was dried, evaporated and the residue chromatographed on silica (n-hexane/AcOEt, 4:1) to give 1.67 g of the title compound as a pale yellow oil. MS: (M+H)+ 308.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH2:13]O)[CH:10]=[N:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C1COCC1>[Br:35][CH2:13][C:11]1[CH:10]=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cnn(-c2ccccc2Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1-n1cc(CBr)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
61 mg (0.27 mmol) of the compound from Example 39A and 105 mg (0.40 mmol) of triphenylphosphine were dissolved in 1.6 ml of THF, and 132 mg (0.40 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr, the filter residue was rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 5:1). This gave 30 mg (42% of theory) of the target compound which was immediately reacted further.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][NH:24][C:25](=O)[CH3:26].P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[C:5]2[C:25]([CH3:26])=[N:24][CH2:23][CH2:22][O:21][C:4]=12
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCNC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c2c1OCCN=C2C
Yield: 1 %

Procedure:
To N-(2-{[6-methoxy-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)acetamide (Intermediate 33, 0.10 g, 2.7 mmol) dissolved in acetonitrile (150 mL), phosphoryl chloride (2 mL) was added and the reaction mixture was heated at reflux for 5 days. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (0.010 g). MS m/z 371 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].C([Li])CCC.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>O1CCCC1>[CH3:1][N:2]1[C:34]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:37][CH:36]=2)=[CH:10][C:9]2[O:8][N:7]=[C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[C:3]1=[O:4]
Reactant: CN1CCN(Cc2ccc(C#N)cc2)CC1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(-c3cc4onc(-c5ccccc5)c4c(=O)n3C)cc2)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
In a 500 ml flask, 10.0 g (46.3 mmol) of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid methylamide is suspended in 150 ml of tetrahydrofuran (THF) under argon. At −70° C. a solution of butyl lithium (63 ml, 1.6M in hexane, 101 mmol, 2.2 eq.) is slowly added. After 1 h at this temperature, the solution is warmed to −10° C. and a solution of 11.9 g (55.5 mmol, 1.2 eq.) of 4-(4-methyl-piperazin-1-ylmethyl)-benzonitrile in 80 ml of THF is slowly added. Under warming to room temperature, the red solution is stirred for another hour, then quenched with 2 ml of water and concentrated. The yellow residue is then taken up in 75 ml of dioxane and kept at 5° C. Then, 230 ml of a 4M solution of HCl in dioxane is carefully added and the suspension stirred for 20 h at room temperature. Then, the solvent is removed and the residue dissolved in ethyl acetate and carefully neutralised with sat. NaHCO3-solution. The phases are separated and the organic phases washed with brine, dried over Na2SO4 and concentrated. Chromatographic purification (CH2Cl2/MeOH 95:5 to 90:10) yields 7.9 g (41%) of 5-methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one as a white solid. Mass spectrum: m/z (M+H)+: 415.0
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH:10]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]3[CH3:34])=[CH:24][CH:23]=2)[CH2:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:47][CH:46]=2)O1.C([O-])([O-])=O.[K+].[K+].ClCCl>O1CCOCC1.O.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]>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[C:7]([C:45]3[CH:46]=[CH:47][C:48]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[CH:49][CH:50]=3)=[CH:8][CH2:9][CH:10]2[C:22]2[CH:23]=[CH:24][C:25]([N:28]3[C:29]([CH3:34])=[CH:30][CH:31]=[C:32]3[CH3:33])=[CH:26][CH:27]=2)=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(C)n1-c1ccc(C2CC=C(OS(=O)(=O)C(F)(F)F)C2c2ccc(C(C)(C)C)cc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1ccc(C2CC=C(c3ccc(NC(=O)OC(C)(C)C)cc3)C2c2ccc(C(C)(C)C)cc2)cc1
Yield: 95.4 %

Procedure:
A mixture of Example 7J (373 mg, 0.721 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (253 mg, 0.793 mmol), K2CO3 (299 mg, 2.162 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (58.8 mg, 0.072 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 100° C. for 16 hours. The mixture was concentrated in vacuo, the residue was purified by column chromatography (on silica gel, eluted with dichloromethane/petroleum ether=2:1, v/v) to afford the title compound (386 mg, 0.688 mmol, 95% yield) as a solid. LC/MS (ESI) m/z 561 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[CH2:41]([N:49]1[CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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]>[CH2:41]([N:49]1[CH:53]=[C:52]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:5]=[CH:4][C:3]([CH:28]5[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:32][CH2:33]5)=[CH:2][CH:7]=4)[CH:9]=3)[N:14]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[CH:15]=2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(2-fluoro-4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67B) (125 mg, 0.190 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (85 mg, 0.285 mmol) using Pd(dppf)Cl2 (7 mg, 0.009 mol) and sodium carbonate (181 mg, 0.578 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 129 mg (crude) of the titled compound. MS: m/z=702.3 (M+1).
Reaction SMILES: I.[CH3:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=O)[CH2:5][C:4]1([CH3:13])[CH3:12].Cl.[NH2:15][OH:16].[OH-].[Na+]>O>[CH3:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[N:15][OH:16])[CH2:5][C:4]1([CH3:13])[CH3:12]
Reactant: NO
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Agent: Cl
Agent: I
Agent: [Na+]
Solvent: O
Product: CN1C(C)(C)CC(=NO)CC1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
A suspension of 1,2,2,6,6-pentamethyl-4-piperidone hydroiodide (3 g, 10.1 mmol) and hydroxylamine hydrochloride (980 mg, 14 mmol) in water (6 ml) was stirred at RT for 15 minutes. Solid NaOH was added until basic pH and thickening of the suspension. Water (3 ml) was added and stirring at RT was continued overnight. The suspension was filtered and the solid washed with water (few ml) and dried. The solid was then dissolved in Et2O, the solution was dried (MgSO4) and concentrated to give after drying pure title compound (1.55 g, 8.41 mmol, yield 83.3%) as white crystals.
Reaction SMILES: [C:1]1([P:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH:9]2[CH2:14][CH:13]3[CH2:15][C@H:11]([C:12]3([CH3:17])[CH3:16])[C:10]2=[CH2:18])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C[O:28]CC1>B1C2CCCC1CCC2>[C:1]1([P:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C@@H:9]2[CH2:14][CH:13]3[CH2:15][CH:11]([C:12]3([CH3:16])[CH3:17])[C@@H:10]2[CH2:18][OH:28])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: C=C1C(P(=O)(c2ccccc2)c2ccccc2)CC2C[C@@H]1C2(C)C
Agent: B1C2CCCC1CCC2
Product: CC1(C)C2CC1[C@H](CO)[C@H](P(=O)(c1ccccc1)c1ccccc1)C2
Temperature: 70 °C

Procedure:
8.0 g (20 mmol) of phosphine oxide (9) were dissolved under an argon atmosphere in 50 ml of 0.5 M THF solution of 9-BBN (Aldrich) and the reaction mixture was heated to 70° C. in a closed reaction vessel for 12 h.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:14][C:13]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([OH:26])=[C:24]([CH3:25])[C:12]2=3)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:29]=O.[OH-].[Na+]>C(O)=O>[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:15]3([CH2:16][CH2:17][N:18]([CH3:29])[CH2:19][CH2:20]3)[O:14][C:13]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([OH:26])=[C:24]([CH3:25])[C:12]2=3)=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCNCC1)O2
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Temperature: 100 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
A mixture of 3-(4-isopropylphenyl)-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol hydrochloride (2.80 g, 6.97 mmol), formic acid (30 mL) and 37% formalin (30 mL) was stirred for 15 hours at 100° C. The reaction mixture was cooled to room temperature, made basic with 8N sodium hydroxide solution, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Chromatorex NH DM1020, Fuji Silysia Chemical LTD) (hexane/ethyl acetate=1/1) to obtain the title compound (2.05 g, yield 77%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:22].[K+].[K+].OO.O>CS(C)=O>[CH:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:22])=[CH:15][N:14]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)c3ccsc23)nc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)c3ccsc23)nc1

Procedure:
6-(4-Formylbenzo[b]thiophen-7-yloxy)nicotinonitrile (Preparation 70) (111 mg, 0.42 mmol) was added to K2CO3 (29 mg, 0.21 mmol) in DMSO (3 mL) followed by H2O2 solution (0.42 mL, 0.42 mmol). After 3 h water was added and the resulting solid filtered and air-dried to give the title compound: RT=2.93 min; m/z (ES+)=283.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O.[O-]S([O-])(=O)=O.[Mg+2].[Al]>CC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:26]=2)=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1cc2c(NC(N)=S)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: COc1cc2c(Nc3nc(-c4ccccc4)cs3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reaction time: 3 h

Procedure:
A solution of (6,7-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (50 mg, 0.127 mmol) and 2-bromoacetophenone (27.9 mg, 0.140 mmol) in acetone (1.4 mL) in a conical vial was added MgSO4 (7.7 mg, 0.0637 mmol). The resulting suspension was placed in an aluminum block preheated to 60° C. and was allowed to stir for 3.0 h. The reaction was cooled and concentrated. The residue was purified using a 5.0 g silica cartridge (MeOH/CH2Cl2, 1:99) to give [6,7-dimethoxy-4-(4-phenyl-thiazol-2-ylamino)isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester as a yellow solid (44.6 mg; 71%). 1H-NMR (CDCl3): δ, 8.64 (s, 1H), 7.52-7.41 (m, 6H), 6.76 (s, 1H), 6.17 (s, 1H), 4.92 (d, 2H, J=4.7 Hz), 4.06 (s, 3H), 4.02 (s, 3H), 1.51 (s, 9H); MS: calculated for C26H28N4O4S+H 493.5; found: 493.5.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[N:24]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][N:21]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:24]3[C:20]([CH3:19])=[N:21][CH:22]=[N:23]3)=[CH:33][CH:32]=2)[CH2:2][CH2:3]1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4ncnc4C)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.77 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]([NH2:18])=[NH:17])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[F:36])[C:29](=O)[CH2:30]Br>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[NH:18][C:29]([C:28]3[CH:33]=[CH:34][C:35]([F:36])=[C:26]([Cl:25])[CH:27]=3)=[CH:30][N:17]=2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N=C(N)C1CCN(Cc2ccccc2)CC1
Reactant: O=C(CBr)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cnc(C3CCN(Cc4ccccc4)CC3)[nH]2)cc1Cl
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
Dissolve 1-benzyl-piperidine-4-carboxamidine dihydrochloride (2 g; 1.00 equiv; 6.89 mmoles) in dimethylformamide (90 mL). Add powdered potassium carbonate (4 equiv; 27.56 mmoles; 3.8095 g) and warm to ˜45° C. Add 3-chloro-4-fluoro-phenacyl bromide (2.00 equiv; 13.782 mmoles; 3.5366 g) in 8 mL with DMF dropwise over 40 minutes. Dilute with 50 mL ethyl acetate, stir 5 min and filter. Evaporate and partition with ethyl acetate/sat. sodium bicarbonate, wash organic layer with water, then saturated aqueous sodium chloride. Dry with MgSO4, filter and evaporate to red foam. Purify over flash silica gel with 0-10% MeOH/ACN. Pool fractions to give 1.9772 g (5.346 mmol, 78%) 1-Benzyl-4-[5-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:21][C:20]3[CH:22]=[C:23]([N:27]4[CH2:33][CH2:32][C:29]5([CH2:31][CH2:30]5)[CH2:28]4)[C:24]([Cl:26])=[CH:25][C:19]=3[N:18]=2)[CH:10]=1)(C)(C)C.Cl>C1COCC1>[CH2:30]1[C:29]2([CH2:32][CH2:33][N:27]([C:23]3[C:24]([Cl:26])=[CH:25][C:19]4[N:18]=[C:17]([NH:16][C:11]5[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=5[Cl:15])[CH2:8][NH2:7])[NH:21][C:20]=4[CH:22]=3)[CH2:28]2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC5(CC5)C4)cc3[nH]2)c1
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC5(CC5)C4)cc3[nH]2)c1

Procedure:
The sub-title compound was prepared in analogy to example 3, step (d) from {3-[6-(5-aza-spiro[2.4]hept-5-yl)-5-chloro-1H-benzimidazol-2-ylamino]-4-chloro-benzyl}-carbamic acid tert-butyl ester (50 mg, 0.1 mmol) and 6 M aq. HCl (0.40 mL) in THF (2 mL).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[CH:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C#CCCCCCC.[C:27]12([C:37]3[CH:42]=[C:41](I)[CH:40]=[CH:39][C:38]=3[O:44][CH:45]([CH3:47])[CH3:46])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[C:17][C:41]2[CH:40]=[CH:39][C:38]([O:44][CH:45]([CH3:47])[CH3:46])=[C:37]([C:27]34[CH2:36][CH:31]5[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]5)[CH2:28]3)[CH2:34]4)[CH:42]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(I)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)Oc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 58 %

Procedure:
When tert-butyl-5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step A was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 58% yield, as pale paste. 1H-NMR (CDCl3) 1.35 (d, 6H, J=6.01 Hz); 1.43 (s, 3H); 1.47 (s, 9H); 1.48 (s, 3H); 1.74 (s, 6H); 2.06 (s, 9H); 3.99 (d, 2H, J=11.45 Hz); 4.08 (d, 2H, J=11.51 Hz); 4.59-4.64 (m, 1H); 5.17 (broad s, 1H); 6.72 (d, 1H, J=8.61 Hz); 7.21 (dd, 1H, J=2.08, 8., Hz); 7.25 (d, 1H, J=2.09 Hz).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][N:18]=1.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>O.C(#N)C>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])=[O:23])=[CH:19][N:18]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCC(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C(NCC(F)(F)F)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
Triethylamine (1.03 ml, 7.4 mmol) and isobutyl chloroformate (0.76 ml, 5.5 mmol) were added to an acetonitrile solution (12 ml) of 6-chloronicotinic acid (0.58 g, 3.6 mmol) under ice cooling and the mixture was stirred at 0° C. for 30 minutes. To the solution mixture, 2,2,2-trifluoroethyl amine (0.88 ml, 11.2 mmol) was added and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1). The purified product was concentrated under reduced pressure and diisopropyl ether and n-hexane were added. The insoluble matter precipitated was obtained by filtration and dried to obtain 6-chloro-N-(2,2,2-trifluoroethyl)nicotine amide (0.58 g) as light yellow powder.