Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[CH:7]=[C:6]1[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:3]>CO.[Pd]>[CH3:3][N:2]([CH2:4][CH:5]1[CH:6]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:8]2[CH2:12][CH:11]1[CH2:10][CH2:9]2)[CH3:1]
Reactant: CN(C)CC1C(c2cccc(O)c2)=CC2CCC1C2
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1C2CCC(C2)CC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.2 %

Procedure:
Add Pd/C (80 mg) to a solution of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (250 mg, 0.97 mmol) in MeOH (40 mL). Then stir the mixture at 25° C. for 12 hours under 45 PSI of H2. After filtration, Concentrate the solution under vacuum to afford 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol as white solid (252 mg, Yield: 100%). MS (m/z): 260 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Product: Clc1cc(N2CCOCC2)ncn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
45.0 g (302.1 mmol) 4,6-dichloropyrimidine are initially introduced into 450 ml water. 26.3 g (302.1 mmol) morpholine are added and the mixture is stirred at 90° C. for 16 h. Thereafter, it is cooled to 0° C. and the precipitate formed is filtered off. The precipitate is washed once with 50 ml water and dried in air.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:12]2[CH:13]=[C:14]([NH:22][C:23]([CH2:25][CH2:26][CH2:27][NH:28][C:29](OC(C)(C)C)=[O:30])=[O:24])[CH:15]=[CH:16][C:17]=2[O:18][CH2:19][CH2:20][CH3:21])[NH:6][C:7](=[O:11])[C:8]=1[CH2:9][CH3:10])[CH3:2].F[C:37](F)(F)C(O)=O.C(Cl)(=O)C>ClCCl>[C:29]([NH:28][CH2:27][CH2:26][CH2:25][C:23]([NH:22][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH3:21])=[C:12]([C:5]2[NH:6][C:7](=[O:11])[C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[N:4]=2)[CH:13]=1)=[O:24])(=[O:30])[CH3:37]
Reactant: CCCOc1ccc(NC(=O)CCCNC(=O)OC(C)(C)C)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCCOc1ccc(NC(=O)CCCNC(C)=O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
The compound (200 mg, 0.412 mmol) of example 106 was dissolved in dichloromethane (30 ml) and added with trifluoroacetic acid (2 ml), followed by stirring at room temperature for 0.5 h. The reaction mixture was directly concentrated to dryness. The resultant oil was dissolved in dichloromethane (30 ml) and added with triethylamine (1 ml). Under ice-water both, acetyl chloride (33 mg, 0.42 mmol) was added dropwise thereinto. 0.5 h later, TLC showed that the reaction was complete. The reaction mixture was washed with water (50 ml) and saturated saline (50 ml). The organic layer was dried with anhydrous sodium sulfate, and concentrated, and the residue was passed through a silica gel column to give the white title compound (50 mg, yield: 28%). 1H NMR (CDCl3) δ: 8.79 (1H, br), 8.51 (1H, d), 7.93 (1H, dd), 6.99 (1H, d), 6.05 (1H, br), 4.15 (2H, t), 3.40 (2H, t), 2.68 (2H, q), 2.60 (2H, q), 2.44 (2H, t), 2.03 (3H, s), 1.97 (2H, m), 1.94 (2H, m), 1.32 (3H, t), 1.16 (3H, t), 1.14 (3H, t).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[Cl-].[Li+].CN(C=O)C>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1O)CCC2=O
Temperature: 160 °C
Reaction time: 60 h

Procedure:
A mixture of 5,6dimethoxyindan-1-one (25.0 g, 0.13 mole), lithium chloride (20.0 g, 0.47 mole) and DMF (200.0 mL) was stirred at 160° C. for 60 hrs. Water (400.0 mL) was added and the mixture washed with ethyl acetate. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (2×300.0 mL). The organic layer was washed with brine and the solvent removed in vacuo. The crude material was purified on a silica gel column using DCM/MeOH(97/3) as the eluent. The solvent was removed in vacuo to yield 5-hydroxy-6-methoxy-indan-1-one (Intermediate H) as a light yellow solid. MS m/z 179 (M+H)+. :179 m/z. The title compound (Intermediate H) is a known compound and may also be prepared by demethylation of 5,6 dimethyoxyindan-1-one using KCN/DMSO at 100° C. (J. M. Saa et al., J. Org. Chem. 1992, 57, 589).
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][C@H:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[CH:1]1([C@H:7]2[CH2:12][C@H:11]([C:13]3[O:20][NH:27][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](C2CCCCC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1C1CCCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
Trans-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (349 mg, 1.03 mmol) (from example 79, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (41.1 mg, 1.03 mmol) dissolved in water (0.500 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.063 mL, 1.03 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 2 h 20 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5 mL, 30.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase was dried over Na2SO4 and evaporated to yield a yellow oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (170 mg, 53%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.82-1.08 (m, 2H), 1.08-1.32 (m, 3H), 1.45-1.83 (m, 8H), 1.89-2.02 (m, 1H), 2.12-2.23 (m, 1H), 2.79-3.04 (m, 2H), 3.70 (s, 3H), 3.87-4.83 (m, 2H), 5.64 (s, 1H). MS m/z 309 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>>[C:26]([NH:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)(=[O:28])[CH3:27]
Reactant: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1

Procedure:
A suspension of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine (0.25 g, 0.7 mmol), acetic acid anhydride (0.11 mg, 1.1 mmol), triethylamine (0.11 mg, 1.1 mmol) and a catalytic amount of N,N-dimethylaminopyridine is heated at reflux for 18 hours. The volatiles are evaporated under reduced pressure and the product is crystallized by the addition of diethyl ether. Filtering and drying gives the N-[4-(2-acetylamino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine, m.p. >260° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:70][CH:71]([CH3:75])[C@@H:72]([NH2:74])[CH3:73]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:74][C@@H:72]([CH3:73])[CH:71]([CH3:75])[CH3:70])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)[C@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@@H](C)C(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and (2S)-3-methyl-2-butanamine (10.5 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 40%). LC-MS m/z 591 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:16])[C:6]([Cl:15])=[C:7]([OH:14])[C:8]=2[CH2:11][CH:12]=[CH2:13])[C:3]1=[O:17].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:15][C:6]1[C:7]2[O:14][CH:12]([CH2:13][OH:32])[CH2:11][C:8]=2[C:9]2[CH2:10][C:2]([CH3:1])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:3](=[O:17])[C:4]=2[C:5]=1[Cl:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)c(Cl)c(Cl)c2c1CC(C)(c1ccccc1)C2=O
Solvent: ClCCl
Product: CC1(c2ccccc2)Cc2c3c(c(Cl)c(Cl)c2C1=O)OC(CO)C3
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-2-phenyl-4-allyl-5-hydroxy-6,7-dichloro-1-indanone (1.73 g., 0.005 mole) in methylene chloride (30 ml.) is added m-chloroperbenzoic acid (1.03 g., 0.006 mole) and 4,4'-thiobis-6-tert-butyl-m-cresol (10 mg.). The reaction is heated at reflux for 5 hours then cooled to 25°C. The m-chlorobenzoic acid which separates is filtered and the solution is washed with water, aqueous sodium bicarbonate and brine. The solvent is distilled at reduced pressure and the residual oil is heated at 120°C. for twenty minutes affording 4,5-dichloro-2-hydroxymethyl-6-oxo-7-methyl-7-phenyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]-furan (β-isomer) which is used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=1.[Na].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CN(C=O)C>[N:28]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:26]=[CH:25][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCBr)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCn2cncn2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2.16 g ethyl 6-[p-(5-bromopentyloxy]-phenoxy)-2,2-dimethylhexanoate in 10 ml DMF, was added with stirring 0.55 g sodium salt of 1,2,4-triazole at room temperature, and stiring was continued overnight. DMF was distilled off under reduced pressure, the residue was extracted with chloroform, and the extract was washed with water, dried and concentrated. The crude product thus obtained was purified by silica gel column chromatography, affording 1.21 g of ethyl 6-[p-[5-(1,2,4-triazol-1-yl)pentyloxy]phenoxy]-2,2-dimethylhexanoate.
Reaction SMILES: [CH3:1][C:2]([NH:13][C:14]1[C:23]([CH3:24])=[N:22][C:21]2[C:16](=[C:17]([C:25]3[NH:33][C:32]4[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=4[CH:26]=3)[CH:18]=[CH:19][CH:20]=2)[N:15]=1)([CH3:12])[CH2:3][NH:4]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:4][CH2:3][C:2]([NH:13][C:14]1[C:23]([CH3:24])=[N:22][C:21]2[C:16]([N:15]=1)=[C:17]([C:25]1[NH:33][C:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=3[CH:26]=1)[CH:18]=[CH:19][CH:20]=2)([CH3:12])[CH3:1]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A solution of tert-butyl (2-methyl-2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)propyl)carbamate (339) (0.13 g, 0.28 mmol) in DCM (2.80 mL) and TFA (1.0 mL, 13.99 mmol) was stirred at 0° C. for 20 min before it was warmed to RT and stir for 1 h. The reaction mixture was concentrated and the residue was diluted with CHCl3/IPA(3:2) (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give 2-(3-((1-amino-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (65 mg, 0.17 mmol, 63% yield) which was impure by NMR. This material was dissolved in MeOH (˜20 mg/mL) and injected (2×1.0 mL) onto the Shimadzu preparatory LC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% MeCN/water with 0.1% TFA); the pure fractions were combined, basicified with NaHCO3 (saturated, aq.), extracted with CHCl3/IPA(3:2), separated, dried over Na2SO4, and concentrated via rotary evaporation to give 2-(3-((1-amino-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (341) (19 mg, 0.05 mmol, 18% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.60 (s, 6H) 2.59 (s, 3H) 2.95 (s, 2H) 2.99 (t, J=6.85 Hz, 2H) 3.65 (td, J=6.85, 2.54 Hz, 2H) 5.33 (br. s., 1H) 6.19 (s, 1H) 7.10 (d, J=2.15 Hz, 1H) 7.36 (t, J=7.82 Hz, 1H) 7.65 (dd, J=8.02, 1.37 Hz, 1H) 7.92 (dd, J=7.63, 1.37 Hz, 1H) 12.64 (br. s., 1H). MS (ESI, pos. ion) m/z: 365.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:21][OH:22])[CH:20]=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>O=[Mn]=O.C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH:21]=[O:22])[CH:20]=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCn2nc(CO)cc2C1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2n(n1)CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2

Procedure:
MnO2 (activated) (84.2 g) was added to the CHCl3-MeOH (95:5, 253 mL) solution of 2-hydroxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid 4-nitrobenzyl ester (8.42 g), and the mixture was refluxed for 1 h under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. Silica-gel (20 g) was added to the filtrate and the solvent was removed under reduced pressure to give the silica-gel coating with crude reactant. The above silica-gel was adsorbed to silica-gel column chromatography and the column was eluted with CHCl3-MeOH (49/1 to 19/1). The titled compound was obtained as yellow crystals (2.82 g, 34%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCOCC1
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (2.5 g, 24.5 mmol) in DCM (40 mL) was added DIEA (6.40 mL, 36.7 mmol) at 0° C. and allowed to stir under nitrogen for 10 minutes. Methane sulfonyl chloride (2.18 mL, 28.1 mmol) was added slowly. The reaction was allowed to proceed for 1 hour at 0° C. The reaction was partitioned between 100 mL of DCM and 50 mL of 0.5 M hydrochloric acid. The layers were separated and the organic layer was then washed sequentially with water, saturated sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure and dried on high vacuum to afford tetrahydro-2H-pyran-4-yl methanesulfonate (4.4 g, 24.4 mmol, 99.7% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[N+:27]([O-])([O-:29])=[O:28].[K+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:27]([O-:29])=[O:28])[C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1OC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc2c(c([N+](=O)[O-])c1OC)c(=O)c(C(=O)O)cn2C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
1-Cyclopropyl-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 50b) (20 g, 69.1 mmol) was dissolved in sulfuric acid (44.2 ml, 830 mmol) with stirring. The thick dark solution was cooled to 0° C. and potassium nitrate (10.48 g, 104 mmol) was added in small portions, while the temperature was maintained below 10° C. by use of an ice-water bath. After the addition, the mixture was kept under 10° C. for 1 h, and then was allowed to warm up to r.t. and stirred overnight. LCMS showed completion of reaction. The mixture was poured into ice-water (300 mL). A yellow solid precipitated out and was collected by filtration, washed with water and ethanol, and dried in vacuo to afford 1-cyclopropyl-6,7-dimethoxy-5-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (14 g, 41.9 mmol, 60.6% yield) as a pale yellow solid. LCMS: [M+H]+: 335.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc2c(-c3cccnc3)cnn12
Yield: 67 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (274 mg, 67%). MS (ISP) 409.1 [(M+H)+]; mp 224° C.
Reaction SMILES: [NH:1]1[C:5]([N:6]2[CH2:11][CH2:10][CH:9]([C@H:12]([OH:14])[CH3:13])[CH2:8][CH2:7]2)=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C.CC(C)=O>[CH3:23][CH:22]([N:3]1[N:2]=[N:1][C:5]([N:6]2[CH2:11][CH2:10][CH:9]([C@H:12]([OH:14])[CH3:13])[CH2:8][CH2:7]2)=[N:4]1)[CH3:24]
Reactant: C[C@@H](O)C1CCN(c2nnn[nH]2)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)n1nnc(N2CCC([C@@H](C)O)CC2)n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
A solution of (1R)-1-[1-(1H-tetrazol-5-yl)-4-piperidinyl]ethanol (256 mg, 1.3 mmol) in DMF (1 mL) and acetone (5 mL) was treated with potassium carbonate (359 mg, 2.59 mmol) at room temperature. After stirring for 15 min, 2-iodopropane (661 mg, 3.89 mmol) was added and the mixture was heated at 50° C. for 3 h. The salt was removed by filtration and washed by EtOAc. After concentration, the crude product was purified by chromatography on a silica gel column using MeOH/CH2Cl2 gradient (2.5% to 12.5%) to give 225 mg (69%) of (1R)-1-{1-[2-(1-methylethyl)-2H-tetrazol-5-yl]-4-piperidinyl}ethanol. 1H NMR (400 MHz, CDCl3): δ 4.85 (septet, 1H, J=6.8 Hz), 4.24-4.07 (m, 2H), 3.63 (quint, 1H, J=6.2 Hz), 2.94-2.81 (m, 2H), 2.00-1.89 (m, 1H), 1.76-1.68 (m, 1H), 1.59 (d, 6H, J=6.8 Hz) 1.53-1.31 (m, 4H), 1.22 (d, 3H, J=6.2 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.[ClH:33].C(OCC)(=O)C>C(O)C>[ClH:33].[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccncc32)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccncc32)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.50 g of 1-tert-butyl 4-ethyl 4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate in 3 mL of ethanol, 3.0 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 2.0 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solution, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off to obtain 0.29 g of ethyl 4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylate hydrochloride as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([C:31]3[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=3)[C:11]=12)[NH2:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(-c3nccn3C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 60 °C
Yield: 78.9 %

Procedure:
4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (200 mg, 0.408 mmol, prepared in Example 7, step B), 1-methyl-2-(tributylstannyl)-1H-imidazole (908.4 mg, 2.45 mmol), tetrakis (triphenylphosphine) palladium (94.28 mg, 0.0816 mmol) and toluene (4 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at 60° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (50 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (0.143 g, 79%). LRMS (APCI pos): >99% purity, 254 nm, m/e 445 (M+1). 1H NMR (400 MHz, CDCl3 δ 8.31 (m, 1H), 7.71 (m, 1H), 7.50 (m, 1H), 7.35 (m, 2H), 6.94 (m, 1H), 6.84 (m, 2H), 6.50 (m, 1H), 6.43 (m, 1H), 6.28 (d, 1H), 5.64 (s, 2H), 3.90 (s, 3H), 3.75 (s, 3H), 3.67 (s, 2H, NH2).