Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][C@@H:25]3[CH3:34])=[CH:20][N:19]=2)[C:3]1=[O:35].Br[C:37]1[C:42]([CH:43]=[O:44])=[C:41]([Cl:45])[N:40]=[CH:39][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[Cl:45][C:41]1[N:40]=[CH:39][CH:38]=[C:37]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH:30]5[CH2:33][O:32][CH2:31]5)[CH2:26][C@@H:25]4[CH3:34])=[CH:20][N:19]=3)[C:3](=[O:35])[N:2]([CH3:1])[CH:7]=2)[C:42]=1[CH:43]=[O:44]
Reactant: O=Cc1c(Br)ccnc1Cl
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(Cl)c3C=O)cn(C)c2=O)nc1
Temperature: 90 °C
Yield: 71.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (1.5 g, 1.0 eq., 3.11 mmol), 4-bromo-2-chloronicotinaldehyde 104a (1.02 g, 1.5 eq., 4.67 mmol), PdCl2(dppf) (130 mg, 0.05 eq., 0.16 mmol), K3PO4 (1.32 g, 2 eq., 6.22 mmol), sodium acetate (510 mg, 2.0 eq., 6.22 mmol), acetonitrile (35 mL), and water (1.0 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/ethanol to afford the 220a (1.1 g, 71%) as yellow solid. MS-ESI: [M+H]+ 495.3.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:32])[CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[CH:11]([CH2:33][NH:34]C(OCC2C=CC=CC=2)=O)[CH2:10][C:9]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:46].C(O)(=O)C>C(Cl)(Cl)Cl>[BrH:46].[NH2:34][CH2:33][CH:11]1[CH2:10][C:9](=[O:45])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]1[C:19](=[O:32])[CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]
Reactant: O=C(NCC1CC(=O)N(Cc2ccccc2)c2ccccc2N1C(=O)CN1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: NCC1CC(=O)N(Cc2ccccc2)c2ccccc2N1C(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82 %

Procedure:
To a solution of 1-benzyl-4-(benzyloxy-carbonylamino methyl)-5-(phthalimidoacetyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.51 g, 2.5 mol) in chloroform (20 mL) was added 25% hydrogen bromide-acetic acid solution (5 mL). The mixture was stirred for 25 minutes at room temperature, which was concentrated under reduced pressure. The concentrate was crystallized from ethanol-diethyl ether, followed by recrystallization from dichloromethane-ethanol-diethyl ether to afford the object compound (1.13 g, 82%), m.p.232°-234° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH:21]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][C:22]=1[OH:31].C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:22]2[CH:23]=[CH:24][C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:21]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc2c(c1)CCCC2
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)CCCC3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 5,6,7,8-tetrahydro-naphthalen-2-ol via the same procedure used for the: preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3), to produce a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:23])=O)=[CH:15][CH:14]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]#[N:23])=[CH:15][CH:14]=1
Reactant: NC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: N#Cc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
3-(4-(2-Quinolinylmethyloxy)benzyl)benzamide (0.03 mol) in pyridine (150 ml) with methane sulfonyl chloride (0.06 mol) is heated at 70° C. for several hours. The reaction mixture is poured into ice wter and extracted with ethyl acetate. The ethyl acetate extract is dried (magnesium sulfate) then applied to a silica gel column. The product is isolated be elution with the appropriate mixture of ethyl acetate and petroleum ether to obtain 3-(4-(2-quinolinylmethyloxy)benzyl)benzonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH3:10][C:11]1[S:12][C:13]2[CH:20]=[CH:19][C:18]3[CH:21]=[C:22]([CH2:25][CH2:26][CH3:27])[CH:23]=[CH:24][C:17]=3[CH:16](O)[C:14]=2[N:15]=1>C(O)(=O)C>[CH3:1][N:2]1[CH:9]=[C:8]([CH:16]2[C:14]3[N:15]=[C:11]([CH3:10])[S:12][C:13]=3[CH:20]=[CH:19][C:18]3[CH:21]=[C:22]([CH2:25][CH2:26][CH3:27])[CH:23]=[CH:24][C:17]2=3)[C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: CCCc1ccc2c(c1)C=Cc1sc(C)nc1C2O
Solvent: CC(=O)O
Product: CCCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
A mixture of the 1-methyluracil (0.5 g) and the product from step (xi) in acetic acid (50 ml) was heated at reflux 2 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate/water. The organic layer collected and dried over MgSO4. The solvent evaporated and the crude product purified by flash chromatography eluting with ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[CH:2]=1.[ClH:17]>O1CCOCC1>[ClH:17].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: COC(=O)c1ccc(-c2cccnc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cccnc2)cc1
Yield: 93 %

Procedure:
At room temperature, methyl 4-(3-pyridyl)benzoate (1.76 g) was dissolved in a mixed solvent of 1N hydrochloric acid (50 ml) and dioxane (50 ml), followed by heating under reflux for 4 hours. The solvent was then distilled off under reduced pressure. Tetrahydrofuran was added to the residue, followed by washing, whereby the title compound (1.55 g, 93%) was obtained as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:16][C:17]1([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:20]3[CH2:19][CH2:18][C:17]([CH3:16])([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])[CH2:22][CH2:21]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: CC1(Oc2ccccc2C(F)(F)F)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1COCCO1
Product: CC1(Oc2ccccc2C(F)(F)F)CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1
Yield: 20 %

Procedure:
To a stirred solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.020 g, 0.090 mmol) in dioxane (5 mL) was added 4-methyl-4-(2-trifluoromethylphenoxy)piperidine (0.015 g, 0.060 mmol), potassium carbonate (0.033 g, 0.240 mmol) and tetrabutyl ammonium bromide (0.002 g, 0.001 mmol). The resulting mixture was stirred at reflux for 48 hours, filtered and then concentrated in vacuo. The crude product was purified by column chromatography to yield the title compound in 20% yield (0.005 g). 1H NMR (300 MHz, CDCl3) δ 8.02-7.96 (m, 2H), 7.60-7.57 (m, 1H), 7.48-7.40 (m, 1H), 7.14-7.12 (d, J=8.0 Hz, 1H), 7.06-6.99 (m, 2H), 4.25-4.21 (m, 2H), 3.65-3.51 (m, 4H), 2.35-2.31 (m, 2H), 1.85-1.74 (m, 2H), 1.53-1.46 (dd, J=6.6 and 7.0 Hz, 2H), 1.20 (s, 3H), 0.77-0.69 (m, 1H), 0.48-0.42 (m, 2H), 0.11-0.05 (m, 2H). MS (ES+) m/z 449.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].IC.[CH:12](Cl)(Cl)Cl>C(=O)([O-])[O-].[Ag+2].C(N(CC)CC)C>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c(=O)ccc1Br
Reactant: ClC(Cl)Cl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CI
Product: COc1ccc(Br)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 5-bromo-6-methyl-1H-pyridin-2-one (5.5 g, 29 mmol), silver carbonate (10.89 g, 39 mmol), iodomethane (13.6 mL, 217 mmol) and chloroform (115 mL) is stirred overnight in the dark at room temperature. Triethylamine (10 mL) is added and stirring continued for 1.5 hr. The reaction mixture is filtered through a pad of Hi-Flo and the filtrate is washed with water (100 mL), dried, filtered and concentrated. The residue is purified by filtration through a pad of silica gel washing with cyclohexane-20% ethyl acetate. The solvent is concentrated to afford 3-bromo-6-methoxy-2-methylpyridine (3.7 g, 63% yield) as an oil. LC/MS RT 3.76 min; MS m/e=202/204 (M); NMR (CDCl3) 7.6 (1H, d), 6.43 (1H, d), 3.89 (3H, s), 2.57 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](Br)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[C:20]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(Br)c1
Reactant: OB(O)C1=CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(C2=CCCCC2)c1
Temperature: 60 °C
Reaction time: 9 h
Yield: 70 %

Procedure:
To a mixture of 2-(3-bromo-4-nitro-phenyl)-malonic acid dimethyl ester (as prepared in the previous step, 300 mg, 0.903 mmol), cyclohexane-1-enyl boronic acid (125 mg, 0.994 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (Pd(dppf)Cl2-CH2Cl2) (66.0 mg, 0.0903 mmol) in 5 mL of DMF was added K3PO4 (765 mg, 3.61 mmol). The resulting mixture was stirred at 60° C. for 9 h under Ar. After cooling to RT, the mixture was treated with 50 mL of EtOAc, washed with H2O (3×10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with 10% EtOAc-hexane to afford 210 mg (70%) of the title compound as a yellow oil: Mass spectrum (ESI, m/z): Calcd. for C17H19NO6, 334.1 (M+H). found 334.0.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]3[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=3[C:9]3[N:10](COCC[Si](C)(C)C)[C:11]([CH2:14][O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[N:12][C:13]=3[C:4]=2[CH:3]=1.C(=O)([O-])O.[Na+]>CO.Cl.O>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]3[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=3[C:9]3[NH:10][C:11]([CH2:14][O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[N:12][C:13]=3[C:4]=2[CH:3]=1
Reactant: CN(C)CCOCc1nc2c(n1COCC[Si](C)(C)C)-c1ccccc1Sc1ccc(Cl)cc1-2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)CCOCc1nc2c([nH]1)-c1ccccc1Sc1ccc(Cl)cc1-2
Temperature: 25 °C

Procedure:
To a solution of {2-[5-chloro-1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-dimethyl-amine (0.21 mmole) in methanol (6.0 ml), 0.5 M hydrochloric acid in methanol (2.0 ml) was slowly added. The reaction mixture was heated under reflux for 3 hours, then it was cooled to room temperature, neutralized with a saturated aqueous solution of sodium hydrogencarbonate, diluted with water and extracted with dichloromethane. The organic extract was washed with an aqueous sodium chloride solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure. After purification by chromatography on a silica gel column, [2-(5-chloro-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-dimethyl-amine in the form of an oily product was obtained;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1N2CN3CN(C2)CN1C3.[C:20](O)(=[O:22])C>O>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:20]=[O:22])=[CH:2]1
Reactant: c1cnc2cc[nH]c2c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2cccnc12
Temperature: 25 °C
Yield: 56 %

Procedure:
A mixture of 1H-pyrrolo[3,2-b]pyridine (947 mg, 8.02 mmol), hexamethylenetetramine (1.7 g, 12 mmol) and acetic acid (7.5 mL) in water (14 mL) was refluxed under N2 for 4 hours. The reaction mixture was cooled to RT, concentrated, and the residue was purified via flash chromatography (DCM/MeOH/NH4OH) affording 1H-Pyrrolo[3,2-b]pyridin-3-carbaldehyde as a white solid (660 mg, 56% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)[N:26]=[CH:25][C:24]=1[C:38](Cl)=[O:39].C(N(CC)CC)C.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]=[CH:16][C:17]([NH:21][C:38]([C:24]3[CH:25]=[N:26][N:27]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][N:29]=4)[C:23]=3[CH3:22])=[O:39])=[CH:18][C:19]=2[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: Cc1cc(N)cnc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of 4-(5-amino-3-methylpyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (4.4 g) in pyridine (50 ml) was added 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (5.16 g) described in Reference Example 180 at 0° C., and stirred at room temperature for 1 hour. To the reaction solution was added triethylamine (6.33 ml), then water was added thereto, and the precipitated solid was washed with water and ethyl acetate to give N-[6-(1-tert-butyloxycarbonylpiperidin-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (7.0 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.[CH2:26]([CH2:28][NH2:29])[OH:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:27][CH2:26][CH2:28][NH:29][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[C:3]([F:25])[C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:23]
Reactant: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)NCCO)ccc21
Yield: 70.5 %

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (71 mg) was prepared by following General Procedure F starting from 2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (90 mg), ethanolamine (17 mg), HBTU (114 mg), and DIEA (65 uL). LC/MS: m/z 404.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.34 (bs, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 7.95 (t, 1H), 7.76 (s, 1H), 7.56 (s, 1H), 7.46 (d, 1H), 4.72 (t, 1H), 3.62 (bs, 3H), 3.52 (q, 2H), 3.34 (q, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:13][CH2:12]2)[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:27]OC(OC)N(C)C.CC(C)([O-])C.[K+].Cl>CC1CCCO1.C1COCC1>[N+:24]([C:8]1[CH:7]=[C:3]2[C:2]([CH:1]=[CH:27][NH:6][C:4]2=[O:5])=[CH:10][C:9]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:15][CH2:16]1)([O-:26])=[O:25]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(c2cc3cc[nH]c(=O)c3cc2[N+](=O)[O-])CC1
Temperature: 105 °C

Procedure:
A mixture of 2-methyl-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzamide (3.0 g, 8.46 mmol) and dimethylformamide dimethyl acetal (1.32 g, 11.08 mmol) in 2-methyl tetrahydrofuran (60 mL) were heated in a Dean stark apparatus at 105° C. for 30 min. The progress of the reaction was monitored by LCMS. The volume of the reaction was reduced to half and the reaction mass was cooled to 55° C. A solution of potassium tert-butoxide (1.44 g, 12.8 mL, 12.86 mmol) in THF (1 M) was added dropwise over a period of 30 min. The reaction mixture was allowed to heat at 65° C. overnight. After completion of the reaction, solvent was removed in vacuo, residue obtained was acidified with 1.5 N HCl. The aqueous layer was extracted in dichloromethane (5×75 mL). The combined extract was washed with water, brine solution and dried over anhydrous Na2SO4. The crude product obtained was purified by the flash column chromatography (230-400 size mesh) using 1.0-1.25% methanol in dichloromethane to afford the compound 7-nitro-6-(4-o-tolyl-piperazin-1-yl)-2H-isoquinolin-1-one. Yield (0.25 g, 8.3%; and reddish brown solid).
Reaction SMILES: C(C1C(C)=NC(C)=C(C=1)C#N)(=[O:3])C.S1C=CN=C1C(=O)C.[CH3:22][C:23]1[N:30]=[C:29]([CH3:31])[C:28]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][C@H:45]4[CH3:49])[CH:38]=3)[N:33]=2)=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:22][C:23]1[N:30]=[C:29]([CH3:31])[C:28]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][C@H:45]4[CH3:49])[CH:38]=3)[N:33]=2)=[CH:27][C:24]=1[C:25]([NH2:26])=[O:3]
Reactant: CC(=O)c1cc(C#N)c(C)nc1C
Reactant: Cc1nc(C)c(-c2ccc3cc(CCN4CCC[C@H]4C)ccc3n2)cc1C#N
Agent: CC(=O)c1nccs1
Product: Cc1nc(C)c(-c2ccc3cc(CCN4CCC[C@H]4C)ccc3n2)cc1C(N)=O

Procedure:
The title compound was prepared using the procedure described in Example 57 using 5-acetyl-2,6-dimethylnicotinonitrile for 1-(1,3-thiazol-2-yl)ethanone providing the product from Example 67 which eluted first and the title compound which eluted second. 1H NMR (CDCl3) δ ppm 1.18 (d, J=5.43 Hz, 3 H), 1.53 (m, 1 H), 1.80 (m, 2 H), 1.98 (m, 1 H), 2.2-2.6 (m, 3 H), 2.65 (s, 3 H), 2.78 (s, 3 H), 3.09 (m, 2 H), 3.19 (m, 1 H), 3.33 (m, 1 H), 5.75 (s, 1 H), 5.90 (s, 1 H), 7.52 (d, J=8.48 Hz, 1 H), 7.66 (dd, J=8.65, 1.87 Hz, 1 H), 7.71 (s, 1 H), 7.94 (s, 1 H), 8.06 (d, J=8.82 Hz, 1 H), 8.19 (d, J=8.14 Hz, 1 H). MS (DCl-NH3) [M+H]+ at 389.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]CC)=[O:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:26]=3)[C:11]3[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 87.4 %

Procedure:
Following general procedure D, ethyl 2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (0.82 g, 1.74 mmol) was reacted with lithium hydroxide (0.365 g, 8.7 mmol) to afford the desired product (0.675 g, 87%) as a light yellow solid. MW=443.90. 1H NMR (DMSO-d6, 500 MHz) δ 12.33 (s, 1H), 8.81 (s, 1H), 8.23-8.16 (m, 2H), 7.66-7.53 (m, 4H), 7.33 (d, J=8.5 Hz, 2H), 3.77-3.71 (m, 2H), 3.61 (s, 2H), 3.09 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 444 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C@@H:13]2[CH2:15][C@H:14]2[C:16]2[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH2:23][C@@H:24]3[CH2:27][CH2:26][N:25]3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]=2)(=O)=O)=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-:53]>C1COCC1>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][C@H:24]1[CH2:23][O:22][C:20]1[CH:19]=[N:18][CH:17]=[C:16]([C@@H:14]2[CH2:15][C@H:13]2[CH2:12][CH2:11][F:53])[CH:21]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@H]2c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CCF)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97 %

Procedure:
A mixture of the p-toluenesulfonate (237 mg, 0.47 mmol) and 5 mL of 1.0 M solution of n-Bu4NF in THF was stirred at room temperature for 10 h. The reaction mixture was concentrated in vacuo. The residue was purified by CC (SiO2, 50-60% EtOAc in hexane eluent) to give 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1R,2S)-2-(2-fluoroethyl)cyclopropyl]pyridine as a viscous oil (160 mg, 97%). 1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 8.06 (s, 1H), 6.84 (s, 1H), 4.78-4.51 (m, 3H), 4.37-4.22 (m, 1H), 4.11 (dd, J=10.1, 2.7 Hz), 3.87 (t, 2H, J=7.6 Hz), 2.36-2.21 (m, 2H), 1.75-1.66 (m, 3H), 1.42 (s, 9H), 1.12-0.96 (m, 1H), 0.95-0.82 (m, 2H). MS (ESI) m/z 351 (M+H+).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([O:17][CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([O:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C(=O)C2CC2)CC3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CC1)N1CCc2ccc(OC3CCNCC3)cc2CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70 mg tert-butyl 4-(3-cyclopropanecarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylate are placed in 1.4 ml dichloromethane and combined with 224 l trifluoroacetic acid. The reaction mixture is stirred for 3 hours at ambient temperature, then evaporated to dryness. The residue is combined with toluene and evaporated to dryness. 77 mg (V-18) are obtained as an oil. Analytical HPLC-MS (method B): RT=1.18 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.Br[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: BrCCCc1ccccc1
Product: COc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O

Procedure:
6-Methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (example 1) is condensed with 1-bromo-3-phenylpropane under N-alkylation conditions described in example 1 to yield 6-methoxy-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline.