Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)C(O)=O.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.C(O)(C)(C)C.Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CSc1ccc(C=C(C(=O)O)c2ccccc2Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1ccc(CC(=O)c2ccccc2Cl)cc1
Temperature: 0 °C
Yield: 90 %

Procedure:
A solution of the acid from Step 1 (17.88 g, 58.7 mmol) and triethylamine (9.53 g, 94.2 mmol) was dissolved in 50 mL of anhydrous toluene, cooled to 0° C. and treated with diphenylphosphoryl azide (16.46 g, 59.8 mmol). The solution was maintained at 0° C. for 36 minutes and warmed to room temperature for 4 hours. The reaction was poured into water, extracted with ether, dried over magnesium sulfate, and concentrated in vacuo to remove the ether. The remaining toluene solution was heated to 110° C. for 1 hour. Tert-Butyl alcohol (7 mL, 74 mmol) was added to the reaction mixture. After an additional twenty minutes, concentrated hydrochloric acid (5 mL) was cautiously added and the reaction maintained at 90° C. for 16 hours. The solution was concentrated in vacuo and the residue taken up in ethyl acetate, washed with water, sat. aq. NaHCO3, and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the ketone as an orange oil (14.62 g, 90%) that was used in the next step without further purification: 1H NMR (CDCl3) 300 MHz 7.40-7.10 (m,8H), 4.20 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:19])[C:16]([OH:18])=[O:17])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][CH2:23][CH2:24]O)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:19])[C:16]([O:18][CH2:21][CH2:20][O:22][CH2:23][CH3:24])=[O:17])[S:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2csc(NC(=O)C(=O)O)n2)cc1
Reactant: CCOCCO
Product: CCOCCOC(=O)C(=O)Nc1nc(-c2ccc(OC)cc2)cs1

Procedure:
Using a method similar to Example 12, 6.95 g of N-[4-(4-methoxyphenyl)-thiazol-2-yl]-oxamic acid and 5.6 g of ethylene glycol monoethyl ether give, after crystallization of the crude product from ethanol/active charcoal, 4 g of the compound of the formula I, with R1 =4--OCH3 --C6H4 and R2 =CH2CH2 --OC2H5, of melting point 130°-133° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13]C(=O)C)[CH2:8][CH:7](O)[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.Cl.[OH-].[Na+]>O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH2:13])[CH:8]=[CH:7][C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: COc1c([N+](=O)[O-])cc(Cl)c2c1C(O)C[C@@H](NC(C)=O)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c([N+](=O)[O-])cc(Cl)c2c1C=C[C@@H](N)CC2
Temperature: 95 °C
Yield: 50 %

Procedure:
A mixture of the crude N—((S)-4-Chloro-9-(R,S)-hydroxy-1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide and 6 M of Hydrogen Chloride in Water (15 mL) were warmed to 95° C. for 3 days. The reaction mixture was then cooled and treated slowly with 30% aqueous NaOH. When the pH proved >10, the reaction mixture was extracted with Et2O (3×). The organic phases were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2, dried over Na2SO4, filtered, and then chromatographed on a normal phase column eluting with a gradient of 100% CH2Cl2 to 5:1 CH2Cl2:MeOH to give 42 mg (50% over two steps) of (S)-4-Chloro-1-methoxy-2-nitro-6,7-dihydro-5H-benzocyclohepten-7-ylamine as an oil, which was used for subsequent steps without further manipulation. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 6.68 (d, J=12.37 Hz, 1H), 6.23-6.19 (dd, J=4.29 Hz, 11.98 Hz, 1H), 3.89 (s, 3H), 3.56 (m, 1H), 3.15 (m, 1H), 2.74-2.66 (m, 1H), 2.28 (m, 1H), 2.01 (m, 1H); MS (m/e) weak parent at 269 (M+H).
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+].[F:5][C:6]([F:24])([F:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>CCO.CCOC(C)=O.[Pd]>[F:24][C:6]([F:5])([F:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH:1]=[O:3])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=CNc1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Yield: 77.8 %

Procedure:
Ammonium formate (1.38 g, 22 mmol) and 10% Pd/C (230 mg, 0.2 mmol) are added to a solution of 1-(2,2,2-trifluoroethyl)-4-(4-nitrophenyl)piperidine (1.26 g, 4.4 mmol) in EtOH (10 mL) and EtOAc (10 mL). The suspension is heated at reflux for 24 hours, adding further portions of ammonium formate (2 g) after 4 h and 8 h. The mixture is filtered through celite and evaporated to afford an orange solid. This is partitioned between DCM (40 mL) and water (20 mL) and the layers separated. The aqueous phase is extracted with DCM (2×20 mL) and the combined organic layers are dried over MgSO4 and evaporated under reduced pressure to afford N-{4-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl} formamide as a pale orange solid (980 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:23][Sn](C)(C)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([CH3:23])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Reactant: C[Sn](C)(C)C
Product: CCOC(=O)c1nc(C)c2snc(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to Example 36 from 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and tetramethyltin; MS (m/z): 315.32 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4].[NH2:27][CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CCO>[CH2:33]([O:32][C:30](=[O:31])[C:29]([CH3:36])([CH3:35])[CH2:28][NH:27][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:9]=2)=[O:4])[CH3:34]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O

Procedure:
1-Cyano-4-hydroxy-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (23 mg, 0.07 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (38 mg, 0.26 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 20 mg. 1H NMR (CDCl3, 200 MHz): δ=8.36 (d, 1H, J=9.0 Hz), 8.29 (t, 1H, J=6.2 Hz), 7.55-7.47 (m, 1H), 7.42-7.39 (m, 1H), 7.33-7.22 (m, 1H), 7.20-6.98 (m, 3H), 4.23 (q, 2H, J=7.0 Hz), 3.80 (s, 3H), 3.60 (d, 2H, J=6.2 Hz), 1.36 (t, 3H, J=7.0 Hz), 1.29 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([C:32](=[O:33])[CH2:31][N:7]2[C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])[N:3]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)[C:2]2=[O:1])=[CH:35][CH:36]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(OCC(F)(F)F)cc(=O)[nH]c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cn2c(=O)cc(OCC(F)(F)F)n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethoxy)-3,4-dihydropyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.65 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.33 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.071 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.59 g, 91%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C@@H:25]1[C@@H:29]([NH:30][CH3:31])[CH2:28][NH:27][CH2:26]1.C(#N)C.[CH2:35]([O:37][C:38]([C:40]1[C:49](=[O:50])[C:48]2[C:43](=[N:44][C:45](Cl)=[CH:46][CH:47]=2)[N:42]([C:52]2[S:53][CH:54]=[CH:55][N:56]=2)[CH:41]=1)=[O:39])[CH3:36]>[Ag].C(N(CC)CC)C>[CH3:23][O:24][C@@H:25]1[C@@H:29]([NH:30][CH3:31])[CH2:28][N:27]([C:45]2[N:44]=[C:43]3[C:48]([C:49](=[O:50])[C:40]([C:38]([O:37][CH2:35][CH3:36])=[O:39])=[CH:41][N:42]3[C:52]3[S:53][CH:54]=[CH:55][N:56]=3)=[CH:47][CH:46]=2)[CH2:26]1
Reactant: CN[C@H]1CNC[C@@H]1OC
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Agent: [Ag]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@H](NC)[C@@H](OC)C3)ccc2c1=O
Yield: 97.6 %

Procedure:
To a glass reactor covered with silver foil and equipped with an overhead stirrer was added (3S,4S)-3-methoxy-4-methylaminopyrrolidine di-p-toluenesulfonic acid (1190 g) and acetonitrile (9.0 L), and the mixture stirred. The solution was cooled and triethylamine (TEA) (1560 mL) was added, maintaining the batch temperature below 5° C. Ethyl-7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylate (750 g) was added, the ice-bath was removed and the reaction temperature allowed to rise and then stirred an additional 48 hours. The reaction was filtered, the filter cake was washed with acetonitrile (3×800 mL), and dried in vacuo to afford 936 g of the title compound as a white solid (97.6%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:47]=[CH:46][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:20][C:19]=3[N:37]([CH3:45])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1>Cl.O1CCOCC1>[CH3:45][N:37]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:46]=[CH:47][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccccc3N3CCOCC3)cc21
Yield: 78.9 %

Procedure:
Using 1.45 g of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[2-(morpholin-4-yl)phenoxy]phenyl}-N-methylcarbamate and 20 ml of 4N hydrochloric acid/dioxane, reaction and purification were carried out in a similar manner to Example 2a, whereby 0.94 g of the title compound were obtained.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]2[CH2:13][O:14][B:15]([OH:16])[C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:18]=[CH:17][C:12]2[CH2:13][O:14][B:15]([OH:16])[C:11]=2[CH:10]=1
Reactant: OB1OCc2ccc(OCc3ccccc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OB1OCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
H178 (13 mmol) was dissolved in MeOH (300 mL). To this solution under nitrogen was added 10% Pd/C (200 mg). The reaction mixture was vacuumed and backfilled hydrogen for 3 times, then stirred overnight at room temperature. After filtration and rotary evaporation, the residue was purified by recrystallization to give H181 (1.98 mg, 98% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.29 (s, 1H), 9.04 (s, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.87 (dd, J=8.1 & 2.4 Hz, 1H) and 4.86 (s, 2H) ppm. Mp 133-135° C.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4]OC.Cl.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[CH3:1][O:2][CH2:3][CH2:4][NH:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:25])[F:26])=[CH:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COCC(OC)OC
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
A solution of methoxyacetaldehyde dimetylacetal (0.162 mL, 1.26 mmol) in 0.5 M HCl aq. (2.52 mL, 1.26 mmol) was heated to 50° C. and stirred under nitrogen for 1 h. The reaction mixture was allowed to cool to room temperature and extracted with CH2Cl2 (10 mL). The organic extract was separated by hydrophobic frit and dried by standing over molecular sieves for 2 h. To this solution was added 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.3 g, 1.26 mmol), then after 20 minutes sodium triacetoxyborohydride (0.375 g, 1.77 mmol) and acetic acid (0.072 mL, 1.26 mmol) were added. The resultant mixture was stirred at room temperature under nitrogen for 18 h. The reaction was quenched by cautious addition of sat. NaHCO3 aq. (30 mL) and extracted into CH2Cl2 (2×30 mL). The organic extract was passed through a hydrophobic frit and the solvents removed in vacuo. Purification by Biotage™ chromatography eluting with 19:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (0.1 g).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(OC(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])=O)C>C(#N)C.O>[CH:16]1([O:15][C:9]2[CH:8]=[C:7]([CH:2]([N:1]3[C:36](=[O:37])[C:35]4=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]4[C:33]3=[O:42])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC1CCCC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
A mixture of 3-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)propanoic acid (3.00 g, 10.8 mmol) and sodium carbonate (1.20 g, 11.3 mmol) in acetonitrile (30 mL) and water (30 mL) under nitrogen was stirred at room temperature for 15 minutes. To the resulting solution was added N-ethoxycarbonyl phthalimide (2.36 g, 10.8 mmol). The resulting mixture was stirred at room temperature for 18 hours. Most of solvent was removed in vacuo. To the solution was added hydrochloric acid (6N) until the pH of solution <1 to give a suspension and stirring was continued for 1 hour. The suspension was filtered, the solid was washed with water (2×10 mL), and then was dried in a vacuum oven overnight (60° C., <1 torr) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phthalimidopropanoic acid as a white solid (3.0 g, 68% yield): mp, 168.0-169.0° C.; 1H NMR (DMSO-d6) δ1.55-1.88 (m, 8H, C5H8), 3.27 (dd, J=6.9, 16.5 Hz, 1H, CHH), 3.51 (dd, J=8.9, 16.5 Hz, 1H, CHH), 3.71 (s, 3H, CH3), 4.71-4.75 (m, 1H, CH), 5.61 (dd, J=6.9, 8.8 Hz, 1H, NCH), 6.87-6.95 (m, 2H, Ar), 7.03 (br s, 1H, Ar), 7.81-7.91 (m, 4H, Ar), 12.4 (br s, 1H, OH); 13C NMR (DMSO-d6) δ23.51, 32.14, 32.17, 36.07, 50.08, 55.52, 79.57, 112.15, 113.97, 119.39, 123.17, 131.09, 131.19, 134.66, 146.77, 149.16, 167.67, 171.72; Anal Calcd for C23H23NO6: C, 67.47; H, 5.66; N, 3.42. Found: C, 67.21; H, 5.46; N, 3.45.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)OCCC[O:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH3:4].Cl>C(O)C.O>[C:14]([C:7]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:5]([CH:3]([CH3:4])[CH2:2][OH:1])[CH:6]=1)(=[O:15])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(CO)c1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(CO)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
To a solution of 2-(3-(2-hydroxy-1-methylethyl)-4-nitrophenyl)-2-phenyl-1,3-dioxane (18) (23.6 g; approx. 69 mmol) in ethanol (350 mL) was added water (70 mL) under vigorous stirring. Concentrated hydrochloric acid (about 12 N aqueous solution, 35 mL) was then added drop wise. The reaction mixture was stirred at ambient temperature for 4 hours, diluted with water and extracted with ethyl acetate. The organic phase was successively washed with an aqueous, saturated solution of NaHCO3 and with water. The organic phase was then concentrated in vacuo and seeded with crystals of the product 4f to provide a yellow solid. Finally, the powdered solid was washed with hexane and air dried to yield 17.83 g (62.5 mmol, 91%) of a yellow powder. 1H NMR (250 MHz, DMSO-d6) δ 7.91-7.52 (m, 8H, arom.), 4.75 (br. s., 1H, OH), 3.53 (d, 2H, α-CH2), 3.23 (sextet, 1H, β-CH), 1.24 (d, 3H, γ-CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([O:21][C:22](=[O:30])[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:30])[NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Product: COc1ccc2nccc(N3CCC(NC(=O)OCc4ccccc4)CC3)c2n1

Procedure:
According to procedure F and starting from 8-bromo-2-methoxy-[1,5]naphthyridine and piperidin-4-yl-carbamic acid benzyl ester the title compound was isolated as a pale yellow foam (806 mg, 60%).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:7][CH:8]([CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si](C(C)(C)C)(C)C)[C:3]([O:5][CH3:6])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]([CH3:30])([CH2:7][CH:8]([CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)CC(CCCCO[Si](C)(C)C(C)(C)C)CCCc1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CC(CCCCO)CCCc1cccnc1
Reaction time: 1 h

Procedure:
To a solution of 1.85 g (4.2 mmol) of methyl 2,2-dimethyl-4-[3-(3-pyridyl)propyl]-8-(t-butyldimethylsilyloxy)-octanoate in 2 ml dry tetrahydrofuran is added 4.8 ml (4.8 mmol) of 1M tetra-n-butylammonium fluoride in tetrahydrofuran and the mixture is stirred for 1 h. The reaction is quenched by addition of saturated ammonium chloride solution and the mixture is extracted with ethyl acetate. The organic phase is washed with water and brine, dried, filtered and concentrated. The residue is purified by silica gel chromatography using 4:1 ethylacetate/hexane as eluent to yield methyl 2,2-dimethyl-4-[3-(3-pyridyl)propyl]-8-hydroxyoctanoate as an oil; NMR (CDCl3): delta 3.59 (s,3H), 3.6 (m,2H), 2.58 (t,2H), 1.21 (s,6H).
Reaction SMILES: [C:1]([OH:4])(=S)[CH3:2].[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)=[CH2:6]>CN(C=O)C>[CH:10]([C:9]1[CH:8]=[CH:7][CH:5]=[CH:6][C:2]=1[CH:1]=[O:4])=[CH2:11].[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)=[CH2:6]
Reactant: CC(O)=S
Agent: C=Cc1ccc(C=O)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccccc1C=O

Procedure:
Aldehyde 11 was synthesized by radical addition (Lub et al. (1997) Liebigs Ann. Recueil, 2281-2288) of thioacetic acid to 4-vinylbenzaldehyde. Vinyl benzaldehyde was synthesized by the procedure of Ren et al. (1993) Bull. Chem. Soc. Jpn. 66: 1897-1902 with the following changes: The addition of DMF was performed at a 38 mmol scale at 0° C. Purification by column chromatography (silica, Et2O/hexanes, 1:3) afforded 4-vinylbenzaldehyde in 60% yield (FIG. 37)/
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#N)=[C:11]([NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC1.[H-].C([NH2+]CC(C)C)C(C)C.C1C[O:41]CC1>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:41])=[C:11]([NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Reactant: C1CCOC1
Agent: CC(C)C[NH2+]CC(C)C
Agent: [H-]
Solvent: C1CCCCC1
Product: C[C@H](O)CNc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product of Step B (19.3 g, 68.3 mmol) in a mixture of anhydrous cyclohexane and THF (200 mL, 40 mL) at 0° C. under nitrogen was added diisobutylammonium hydride (1 M solution in hexane, 239 mL, 239 mmol) over 30 min. This mixture was stirred 18 h at ambient temperature, additional diisobutylammonium hydride (40 mL, 40 mmol) was added, and the mixture was stirred an additional 24 h. The reaction mixture was cooled on an ice bath and the reaction was quenched by the addition of MeOH (exothermic) and 2 N HCl to maintain a pH of 1. The mixture was extracted with EtOAc (3×300 mL) and the extracts were dried and concentrated to a brown oil (18.5 g). The crude oil was triturated with EtOAc/hexane, and filtered to give an oil (16.1 g, 83% crude yield). A small portion of this material was purified by chromatography (silica, 20% to 50% EtOAc/hexane) to afford a solid; mp 68-69° C.
Reaction SMILES: C(OC(=O)[C:5]1[C:10]([OH:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=1[OH:16])C>Cl>[F:15][C:12]([F:13])([F:14])[C:8]1[N:7]=[C:6]([OH:16])[CH:5]=[C:10]([OH:11])[CH:9]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1O
Agent: Cl
Product: Oc1cc(O)nc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 99.5 %

Procedure:
2,4-Dihydroxy-6-trifluoromethyl-nicotinic acid ethyl ester (62 g/247 mmol) was added in several portions over 30 min to 6M HCl(aq) (620 mL) at reflux. Heated at 100° C. overnight with vigorous stirring to obtain complete solution. Allowed to cool and concentrated in vacuo to a white solid. Slurried in water (250 mL) and adjusted to pH 7 with concentrated ammonia to get heavy white suspension. Collected solid by filtration, rinsing through with fresh water, and dried to provide 6-trifluoromethyl-pyridine-2,4-diol (44.0 g) as a white solid.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4]C1C=CC(Cl)=C2C=1C=C([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)N=C2.[C:34]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[CH:44]=[N:43][C:42](OS(C(F)(F)F)(=O)=O)=[CH:41]2)#[N:35]>>[ClH:4].[ClH:1].[ClH:4].[NH2:33][C:17]1[C:16]([C:42]2[N:43]=[CH:44][C:45]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][C:36]=3[C:34]#[N:35])=[CH:21][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)=[CH:19][N:18]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Reactant: N#Cc1cccc2cc(OS(=O)(=O)C(F)(F)F)ncc12
Agent: Cl
Product: N#Cc1cccc2cc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)ncc12

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 8-cyanoisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.30-2.42 (m, 4H), 3.21-3.27 (m, 2H), 3.59 (d, J=13.4 Hz, 2H), 4.59-4.71 (m, 1H), 7.97-8.04 (m, 1H), 8.08 (s, 1H), 8.25-8.30 (m, 2H), 8.42-8.49 (m, 2H), 8.86 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 9.70 (s, 1H). MS (ES+): m/z=396.19 [MH+]. HPLC: tR=1.67 min (ZQ2, polar—5 min).