Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:30][CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:41]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:38]([CH3:40])[CH3:39])[O:33][CH2:32][CH2:31][CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:43])[CH3:42]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 33.1 %

Procedure:
To a suspension of NaH (60% in mineral oil, 121 mg, 3.02 mmol) in DMF (2.00 mL) was added Intermediate A (122 mg, 0.75 mmol) and the reaction stirred for 20 min. Intermediate 84f (317 mg, 0.75 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for 1 h. The cooled reaction was quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave the title compound (140 mg, 33%). LCMS (Method 4): Rt 2.37, m/z 564.2 [MH+].
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]1[CH:32]=[CH:33][C:34]2[N:35]([C:37]([C:40](O)=[O:41])=[CH:38][N:39]=2)[CH:36]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]1[CH:32]=[CH:33][C:34]2[N:35]([C:37]([C:40]([NH:16][S:13]([C:10]3[CH:9]=[CH:8][C:7]([N:4]4[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]4)=[CH:12][CH:11]=3)(=[O:15])=[O:14])=[O:41])=[CH:38][N:39]=2)[CH:36]=1
Reactant: NS(=O)(=O)c1ccc(N2CCC(O)C2)cc1
Reactant: O=C(O)c1cnc2ccc(N3CCCCC3c3cc(F)ccc3F)cn12
Product: O=C(NS(=O)(=O)c1ccc(N2CC[C@H](O)C2)cc1)c1cnc2ccc(N3CCCCC3c3cc(F)ccc3F)cn12

Procedure:
The title compound was prepared by the method similar to that of Example 31 employing 4-(3-hydroxypyrrolidin-1-yl)benzene sulfonamide (Int-51) and 6-(2-(2,5-difluorophenyl)piperidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int 23) to afford an enantiomeric mixture which was purified by column chromatography using CHIRALPAK AD-H column and n-HEXANE:ETHANOL, 80:20 isocratic solution as eluent to afford 6-(2-(2,5-difluorophenyl)piperidin-1-yl)-N-((4-((S)-3-hydroxypyrrolidin-1-yl)phenyl)sulfonyl)imidazo[1,2-a]pyridine-3-carboxamide (0.012 g) (Isomer-II) MS (ESI): m/z 582.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 12.00 (1H, S), 8.83 (1H, s), 8.4 (1H, s), 7.76-7.74 (2H, m), 7.58-7.56 (1H, m), 7.46-7.43 (1H, m), 7.07-6.99 (2H, m), 6.91-6.90 (1H, m), 6.65-6.62 (1H, m), 5.04-5.03 (1H, d), 4.42 (2H, bs), 3.50-3.38 (4H, m), 3.28-3.20 (1H, m), 2.90-2.85 (1H, m), 2.06-2.03 (1H, m), 1.91-1.88 (3H, m), 1.76-1.67 (1H, m), 1.64-1.53 (1H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[CH:16]=[N+:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[CH:16]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][CH:5]=1
Reactant: Cc1cccc2[nH]ccc12
Reactant: COc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1c[nH]c2cccc(C)c12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-methyl-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 24.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:22]=1[CH3:38].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:22]=3[CH3:38])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (157 mg, 0.594 mmol; described herein), 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (162 mg, 0.59 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (150 μL, 0.59 mmol), and NMP (590 μL, 7.1 mmol), and heating in a microwave at 160° for 3 h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.70 (1H, d, J=4.7 Hz), 7.98 (1H, d, J=8.2 Hz), 7.87-7.93 (2H, m), 7.83 (1H, d, J=11.7 Hz), 7.55-7.65 (2H, m), 7.38 (1H, m), 7.13-7.24 (1H, m), 6.46 (1H, d, J=2.7 Hz), 3.88-4.03 (4H, m), 3.77-3.88 (4H, m), 3.01-3.28 (4H, br. s.), 3.04-3.14 (4H, m), 2.23 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=2[OH:20])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27](C=O)=[CH:26][CH:25]=1.CN1CCCC1=[O:38]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=2[O:20][C:24]2[CH:31]=[CH:30][C:27]([OH:38])=[CH:26][CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(O)c(-c3cccc(F)c3)ccc2c1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(Oc3ccc(O)cc3)c(-c3cccc(F)c3)ccc2c1
Temperature: 185 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Dissolve 2-(3-fluoro-phenyl)-6-methoxy-naphthalen-1-ol (3.36 g, 12.5 mmol) in N-methyl-2-pyrrolidinone (NMP) (10 mL) and add sodium hydride (500 mg, 60% oil dispersion, 12.5 mmol) at room temperature. After stirring for 1 hour this solution is added to a solution of 4-fluorobenzaldehyde (2.4 mL, 22.5 mmol) in NMP (10 mL) that has been heated to 185° C. Continue stirring for 2.5 hours. Cool the reaction to room temperature and add pH 7 buffer (50 mL) and extract with ethyl acetate (2×100 mL). Wash the organic extracts with water and filter through a plug of silica gel. Purify the crude product using radial chromatography giving 2.50 g (54%) of the title compound and use without further purification: mass spectrum (ion spray) m/z=371 (M−H).
Reaction SMILES: [Na].[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:27][OH:28])[CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:15][CH:14]=2)=[N:8][CH:9]=1)[CH3:3].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O>[C:35]([O:28][CH2:27][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:2][CH3:3])=[CH:9][N:8]=1)[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:24])=[CH:25][CH:26]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(C(CO)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Product: CCc1ccc(C(COC(C)=O)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-{4-[2-(5-ethyl-2-pyridyl)-3-hydroxypropoxy]benzyl}-2,4-thiazolidinedione sodium salt (408 mg), pyridine (10 ml) and acetic anhydride (0.15 ml) was stirred at room temperature for 8 hours, and poured in water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and freed of the solvent. The residue was chromatographed on a silica-gel (20 g) column and elution was effected with benzene-acetone (10:1, V/V) to give 5-{4-[3-acetoxy-2-(5-ethyl-2-pyridyl)propoxy]benzyl}-2,4-thiazolidinedione in the form of an oily substance. Yield of 350 mg (81.8%). IR(Neat): 1740, 1690, 1230 cm-1. NMR (CDCl3)δ: 1.24(3H,t,J=7 Hz), 2.00(3H,s), 2.64(2H,q,J=7 Hz), 3.03(1H,dd,J=14 and 9 Hz), 3.45(1H,dd,J=14 and 9 Hz), 3.60 (1H,m), 4.31(2H,d,J=5 Hz), 4.47(1H,dd,J=9 and 4 Hz), 4.55 (2H,d,J=5 Hz), 6.80(2H,d,J=9 Hz), 7.10(2H,d,J=9 Hz), 7.20(1H,d, J=8 Hz), 7.48(1H,dd,J=8 and 2 Hz), 8.42(1H,d,J=2 Hz).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1
Temperature: 90 °C
Yield: 74.4 %

Procedure:
To a stirring solution of p-fluorobenzaldehyde (6.15 mmol, 0.763 g) in dimethylformamide (20.5 mL) was added cesium carbonate (4.1 mmol, 1.33 g) and 38 (4.1 mmol, 0.819 g). This solution was heated to 90° C. and monitored with TLC. When complete, the reaction mixture was cooled to room temperature and filtered through a fritted funnel. The filtrate was then diluted with ethyl acetate (200 mL) and extracted with eight 15 mL portions of water and one 10 mL portion of brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and purified with flash chromatography to yield 0.930 g (3.05 mmol) of the title product. 1H NMR (500 MHz, CDCl3) δ 9.93 (s, 1H), 7.85 (d, J=8.6, 2H), 7.55-7.22 (m, 6H), 7.07 (d, J=8.7, 2H), 6.86 (d, J=8.3, 1H), 6.71 (dd, J=5.2, 10.7, 2H), 5.06 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 190.79, 162.93, 160.50, 156.39, 131.94, 130.61, 128.66, 128.15, 127.52, 117.78, 112.66, 111.44, 107.25, 70.18.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:15])[C:13]#[N:14])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:47](O)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>C1COCC1>[CH2:47]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:15])[C:13]#[N:14])[CH:6]=[CH:5]2)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CC(C#N)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc2cc(C(C)C#N)ccc2c1
Temperature: 5 °C

Procedure:
Into 20 ml of dry THF, were dissolved 1.5 g of oa (6-hydroxy-2-naphthyl)-propanonitrile and 3.0 g of triphenylphosphine, and cooled to 5° C. To this solution, were added dropwise 2.0 g of diethyl azodicarboxylate and then 1.2 g of n-decyl alcohol, and stirred at room temperature for 12 hours. The resulting reaction mixture was extracted with ether, followed by washing three times the ether phase with water and then distilling off the ether. The resulting oily product was extracted with hexane, and the hexanesoluble matter was recrystallized with methanol to obtain 0.7 g of oa (6-n-decyloxy-2-naphthyl)propanonitrile (Compound No. 1-10) of this invention.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.O=[C:13]([CH3:25])[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][N:10]=[C:13]([CH3:25])[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(C)=NCC(O)c2cccc(Cl)c2)cc1

Procedure:
2-(3-Chlorophenyl)-2-hydroxyethylamine (24.4 g, 0.142 mol) and methyl 4-(2-oxopropyl)benzoate (26 g, 0.135 mol) were combined and refluxed in 500 ml toluene for 3 hours, collecting formed H2O with a Dean-Stark trap. The reaction mixture was cooled and stripped of solvent to yield intermediate methyl 4-[2-(2-(3-chlorophenyl)-2-hydroxyethylimino)propyl]benzoate.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[N:4][C:3]=1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=1
Reactant: CC(C)(C=O)Nc1nc(-c2ccc(C#N)cc2)c(Cl)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)c(Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
4-{5-Chloro-2-[(1,1-dimethyl-2-oxoethyl)amino]-1,3-thiazol-4-yl}benzonitrile (1.15 g, 3.76 mmol), prepared in the previous step, was dissolved in tetrahydrofuran (20 mL) and cooled to 0° C. Lithium borohydride (2M in tetrahydrofuran; 2.25 mL, 2.5 mmol) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with saturated NH4Cl, diluted with ethyl acetate and washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (20% acetone/hexane) afforded 4-{5-chloro-2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (1.01 g, 88%) as a white solid. HRMS: calcd for C14H14ClN3OS+H+, 308.06188; found (ESI, [M+H]+), 308.0612; Analytical HPLC: purity 100% at 210-370 nm, 10.0 min; 100% at 252 nm, 10.0 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([Cl:19])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2)([O-:3])=[O:2].P(Cl)(Cl)(OCl)=O.CN([CH:29]=[O:30])C>ClCCl>[Cl:19][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:9]2[CH:29]=[O:30]
Reactant: O=[N+]([O-])c1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Reactant: CN(C)C=O
Agent: O=P(Cl)(Cl)OCl
Solvent: ClCCl
Product: O=Cc1c(-c2ccccc2)[nH]c2c([N+](=O)[O-])cc(Cl)cc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
7-Nitro-5-chloro-2-phenyl-1H-indole (1.0 g, 3.67 mmol) prepared in Preparation 26 was dissolved in dichloromethane (20 mL). Phosphoryloxychloride (0.84 g, 5.50 mmol) and DMF (0.80 g, 11.01 mmol) were added in drops thereto at 0° C., and the mixture was stirred for 6 h at room temperature. After completion of the reaction, the reaction was quenched by saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (0.5 g, Yield 45%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3=[C:16]4[C:21](=[N:22][C:14]3=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH2:12]3)[NH:7]2)[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C[Si]([N:33]=[C:34]=[O:35])(C)C>C1COCC1>[NH2:33][C:34]([N:1]1[CH2:2][CH2:3][C:4]2([C:15]3=[C:16]4[C:21](=[N:22][C:14]3=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH2:12]3)[NH:7]2)[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH2:5][CH2:6]1)=[O:35]
Reactant: C[Si](C)(C)N=C=O
Reactant: C1=CCC2=C3N=c4ccccc4=C3C3(CCNCC3)NC2=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: NC(=O)N1CCC2(CC1)NC1=CC=CCC1=C1N=c3ccccc3=C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4 g of 5,6-dihydrospiro[1H-indolo[3,2-c]quinoline-6,4'-piperidine] in 100 ml of THF were added 9.7 g of K2CO3 and 13.9 ml of trimethylsilyl isocyanate (32% xylene by weight). The mixture was stirred overnight at room temperature and filtered. Subsequently, an additional 5.6 ml of trimethylsilyl isocyanate was added and the resultant solution was stirred for 30 minutes at room temperature. Concentration gave a solid/gum mixture which was triturated with H2O to give 3.07 g of solid, m.p. 265°-267° dec.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[C:7]([OH:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[H][H]>[Pd]>[OH:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH2:4][NH:3][CH2:2]2
Reactant: Cc1ccc2c(Cl)nccc2c1O
Reactant: [H][H]
Agent: [Pd]
Product: Cc1ccc2c(c1O)CCNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethanol (20 mL). To the above hydrogen chloride (enough, gas) was introduced in. This was followed by the addition of 1-chloro-6-methylisoquinolin-5-ol (70 mg, 0.36 mmol, 1.00 equiv), Pd/C (30 mg). To the above hydrogen (enough, gas) was introduced in. The resulting solution was stirred overnight at room temperature with an inert atmosphere of H2 (gas). The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 1×10 mL of ether. This resulted in 50 mg (69%) of 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride as an off-white solid. 1H NMR (300 MHz, D2O) δ 2.72 and 2.16 (s, 3H), 2.93 (t, 2H), 3.45 (t, 2H), 4.25 (s, 2H), 6.69 (d, 1H), 7.06 (d, 1H); MS (ESI) m/z 164 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](=O)[CH2:21][C:22](=O)[C:23]([O:25][CH3:26])=[O:24]>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[N:13]=[C:20]([C:16]4[O:15][CH:19]=[CH:18][CH:17]=4)[CH:21]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:11]=3[C:10]([CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N)n(-c2cccc(Cl)c2)n1
Reactant: COC(=O)C(=O)CC(=O)c1ccco1
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccco2)nc2c1c(C)nn2-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
(see, e.g., Volochnyuk, D. M., et al., J Comb Chem 2010, 12, 510-7). A solution of 22 (306 mg, 1.47 mmol) and 20 (295 mg, 1.50 mmol) in glacial AcOH (10 mL) was heated to reflux for 3 h. When the reaction mixture was cooled down to room temperature, yellow precipitates formed which were filtered and washed with H2O. Filtercake was placed in a vacuum oven to give the title compound (470 mg, 87%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.48 (s, 1H), 8.29 (d, J=9.1 Hz, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 7.43 (t, J=8.1 Hz, 1H), 7.28-7.23 (m, 2H), 6.63-6.59 (m, 1H), 4.06 (s, 3H), 2.75 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.53, 152.95, 151.82, 148.42, 144.43, 143.32, 140.31, 134.59, 133.91, 129.93, 125.41, 120.77, 118.52, 113.87, 112.57, 112.24, 110.94, 52.73, 16.21.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=2[N:11]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[CH3:24].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:16]1[CH:17]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=3[N:11]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH3:13]
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
Reactant: COc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc[nH]c(=O)c3n2)cc1C
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of 6-chloro-pyrido[3,2-d]pyrimidin-4(3H)one (1.94 mmole) in 1,4-dioxane (40 ml) and water (20 ml) was added 4-methoxy-3-methylphenyl boronic acid (2.33 mmole), potassium carbonate (4.85 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.097 mmole). The reaction mixture was refluxed for two hours, cooled to room temperature and the solvents were evaporated in vacuo. The residue was adsorbed on silica and purified by silica gel column chromatography (the mobile phase being a methanol/dichloromethane mixture in a ratio of 3:97), affording the title compound as a pure white powder (398 mg, yield 77%) which was characterized by its mass spectrum as follows: MS (m/z): 268 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[NH2:12][NH2:13]>C1(C)C=CC=CC=1.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:12][NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C=Nc1cccc(F)c1
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: NNC(=O)Nc1cccc(F)c1
Reaction time: 2 h

Procedure:
A solution of 3-fluorophenyl isocyanate (5.0 g, 36.0 mmol) in 20 ml of toluene is added to hydrazine hydrate (2.1 g, 42.0 mmol) in 70 ml of dioxane, maintaining the temperature of the reaction at less than 12°. After 2 hours, the reaction is filtered and the solvent is removed from the filtrate by rotoevaporation to give the white solid, 4-(3-fluorophenyl)-semicarbazide.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>>[CH3:25][N:26]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[C:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1)=[CH:8]2)=[O:17]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CNCC1CCCCO1
Product: Cc1cc(Nc2cc3cc(C(=O)N(C)CC4CCCCO4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Methyl-(tetrahydro-pyran-2-ylmethyl)-amine to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid methyl-(tetrahydro-pyran-2-ylmethyl)-amide. LC-MS: m/e 438 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:22]([O:24]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[CH:9][CH:8]=1.[C:30]1([C:36]2[N:37]=[C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[S:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:22]([N:44]2[CH2:45][CH2:46][N:41]([C:38]3[S:39][CH:40]=[C:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:37]=3)[CH2:42][CH2:43]2)=[O:24])=[CH:11][CH:12]=1
Reactant: O=C1CCCN1c1ccc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc(N2CCCC2=O)cc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 68.4 %

Procedure:
A solution of bis(2,2,2-trichloroethyl) [4-(2-oxopyrrolidin-1-yl)phenyl]imidodicarbonate (200 mg, 0.379 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (196 mg, 0.758 mmol), diisopropylethylamine (0.132 ml, 0.758 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 116 mg (68.2%) of the desired product as a solid.