Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br[CH2:30][C:31]1[CH:32]=[C:33]([F:39])[C:34]([F:38])=[C:35]([F:37])[CH:36]=1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([CH2:30][C:31]3[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([F:39])[CH:32]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Fc1cc(CBr)cc(F)c1F
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3cc(F)c(F)c(F)c3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 5-(bromomethyl)-1,2,3-trifluorobenzene in the same manner as in Example 32.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[N:19][OH:20])[C:16]=2[C:17]=1[OH:18])=[O:7])C.Cl>O>[OH:18][C:17]1[C:16]2[C:15](=[N:19][OH:20])[CH2:14][CH2:13][CH2:12][C:11]=2[N:10]=[CH:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1cnc2c(c1O)C(=NO)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2c(c1O)C(=NO)CCC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Sodium hydroxide (1 g) was dissolved in 30 ml of water, and 1.5 g of the 4-hydroxy-5-hydroxyimino-5,6,7,8-tetrahydroquinoline-3-carboxylic acid ethyl ester obtained in Example 3 was added thereto. The resulting reaction mixture was stirred on an oil bath at 90° C. for 2 hours. After being cooled, the reaction mixture was adjusted to pH 2.2 with dilute hydrochloric acid. The crystals so precipitated were separated by filtration to obtain a yield of 1.2 g of the desired compound. This compound melted (and decomposed) at 285°-286° C. (uncorrected values). Its infrared absorption spectrum (KBr tablet) had absorption peaks at 3440, 3180, 2880, 1650, 1520, 1400, 1230, 970, and 820 cm-1.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH3:21]>CN(C=O)C.C(OCC)C.[I-].[K+]>[CH2:19]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH2:20][CH3:21]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCOc1ccc(C=O)cc1OC
Temperature: 65 °C
Reaction time: 5 h
Yield: 99.5 %

Procedure:
To a suspension of vanillin (2.00 g, 13.2 mmol), potassium carbonate (2.74 g, 19.8 mmol) and potassium iodide (60.0 mg, 0.361 mmol) in DMF (15 mL) was slowly added 1-bromopropane (1.56 mL, 17.2 mmol) via syringe. The reaction mixture was stirred at 65° C. for 5 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 mL), and the organic phase was washed with water (2×50 mL). After drying over anhydrous MgSO4, filtration and evaporation of the filtrate in vacuo gave crude 4-(propyloxy)-3-methoxybenzaldehyde (2.55 g) which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH2:15][OH:16])[CH:6]=1)C.[ClH:18]>>[ClH:18].[OH:16][CH2:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:8]=1)[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)c1cc(CO)nc(CC(C)C)c1
Agent: Cl
Product: CC(C)Cc1cc(C(=O)O)cc(CO)n1

Procedure:
A solution of 2-hydroxymethyl-6-isobutyl-isonicotinic acid ethyl ester (100 mg, 0.421 mmol) in 25% aq. HCl (5 mL) is stirred at 75° C. for 16 h. The solvent is removed in vacuo and the remaining residue is dried under HV to give 2-hydroxymethyl-6-isobutyl-isonicotinic acid hydrochloride (100 mg) as an oil; LC-MS: tR=0.52 min, [M+1]+=210.47.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:17][O:18][CH2:19][CH3:20])[CH2:12][C:13]([O:15]C)=[O:14])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[OH-].[Li+]>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:17][O:18][CH2:19][CH3:20])[CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(CC(=O)OC)=NOCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCOc1ccc(C(CC(=O)O)=NOCC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of crude methyl 3-(4-(allyloxy)phenyl)-3-(ethoxyimino)propanoate obtained from Step B in THF (7 mL) was added 1 N lithium hydroxide (10.2 mL), and the resulting solution was stirred at room temperature for 12 h. Most of the solvents were removed in vacuo, and 1N hydrochloric acid (10.2 mL) was added. The aqueous layer was extracted with ethyl acetate (×4), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as a white solid (850 mg). 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, d, J=7.6 Hz), 6.89 (2H, d, J=7.6 Hz), 6.02 (1H, m), 5.42 (1H, m), 5.29 (1H, m), 4.54 (1H, m), 4.26 (2H, q, J=5.6 Hz), 3.78 (2H, s), 1.30 (3H, t, J=5.6 Hz).
Reaction SMILES: [CH:1]([N:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12]C)=[O:11])=[CH:6][C:5]1=[O:14])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O>[CH:1]([N:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][C:5]1=[O:14])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccn(C(C)C)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1ccc(C(=O)O)cc1=O
Temperature: 50 °C

Procedure:
To methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (225 mg) was added NaOH (550 μL of 25% w/w, 4.3 mmol) and water (0.6 mL). The mixture was rapidly stirred and heated at 50° C. for 1 h. The mixture was cooled, acidified to pH 2 with 6N aq. HCl and the solids collected, rinsing with water and ACN (2×). The solid was dried in vacuo to give 1-isopropyl-2-oxo-pyridine-4-carboxylic acid as a white solid. ESI-MS m/z calc 181.2. found 182.3 (M−1)−. Retention time: 0.86 minutes (3 min run).
Reaction SMILES: CS(O[CH2:6][C:7]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)(=O)=O.FC(F)(F)C1C=CC(C2(C[C:34]#[N:35])CCCC2)=CC=1>>[Cl:19][C:14]1[CH:13]=[C:12]([C:7]2([CH2:6][C:34]#[N:35])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2ccc(Cl)c(Cl)c2)CCCC1
Product: N#CCC1(c2ccc(Cl)c(Cl)c2)CCCC1

Procedure:
2-(1-(3,4-Dichlorophenyl)cyclopentyl)acetonitrile (485) was synthesized from (1-(3,4-dichlorophenyl)cyclopentyl)methyl methanesulfonate (484) following the procedure described for [1-(4-trifluoromethyl-phenyl)cyclopentyl]-acetonitrile (241).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:27][CH:28]=[C:29]([CH:31]=O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:29]2[N:30]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:27][CH:28]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Reactant: O=Cc1csc(-c2ccccc2)n1
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 409.95 g/mol.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[OH-].[Na+]>>[CH3:2][C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]([C:14]2[NH:13][CH:17]=[CH:16][CH:15]=2)[C:17]2[NH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: c1cc[nH]c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(C(c2ccc[nH]2)c2ccc[nH]2)cc1
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Following a general procedure,8 a solution of 4-tert-butylbenzaldehyde (16.2 g, 100 mmol) in pyrrole (694 mL, 10.0 mol) at room temperature under argon was treated with InCl3 (2.21 g, 10.0 mmol) for 1.5 h. Powdered NaOH (12.0 g, 300 mmol) was added. After stirring for 1 h, the mixture was suction filtered and excess pyrrole was removed under high vacuum. The residue was treated with hexanes (3×100 mL) to facilitate removal of traces of pyrrole. The resulting solid was recrystallized [EtOH/H2O (6:1)], affording a grayish white solid (21.6 g, 79%): mp 155-157° C.; 1H NMR δ 1.31 (s, 9H), 5.45 (s, 1H), 5.94-5.96 (m, 2H), 6.15-6.17 (m, 2H), 6.68-6.70 (m, 2H), 7.13-7.16 (m, 2H), 7.32-7.35 (m, 2H), 7.89-7.95 (br, 2H); 13C NMR δ 31.5, 34.6, 43.6, 107.2, 108.5, 117.2, 125.7, 128.2, 132.9, 139.1, 149.9; FAB-MS obsd 278.1788, calcd 278.1783 (C19H22N2). Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C, 81.82; H, 7.96; N, 10.05. The data (1H NMR, mp, elemental analysis) are consistent with those obtained from samples prepared via earlier routes.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:32]1([C:38]2[CH:39]=[C:40]([NH2:43])[NH:41][N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)(=O)C.C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][N:41]4[N:42]=[C:38]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:39]=[C:40]4[N:43]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
A mixture of 1 (250 mg, 0.59 mmol) and 5-Phenyl-2H-pyrazol-3-ylamine (96 mg, 0.59 mmol) in acetic acid (0.4 mL) and ethanol (1.6 mL) was heated under reflux for 6 hours. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with NaHCO3 aq. and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 9-1.
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[C:22]([CH3:24])[CH3:23])[C:14]=1[C:15]#[N:16]>O1CCOCC1>[C:15]([C:14]1[C:17]([CH:21]=[C:22]([CH3:23])[CH3:24])=[CH:18][CH:19]=[CH:20][C:13]=1[NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])#[N:16]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(C)=Cc1cccc(N)c1C#N
Solvent: C1COCCO1
Product: CC(C)=Cc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
Benzoyl isocyanate (88.1 mg, 0.60 mmol) was added to a solution of 2-amino-6-(2-methylprop-1-enyl)benzonitrile (Example 129b) (75.2 mg, 0.44 mmol) in anhydrous 1,4-dioxane under nitrogen, and was stirred at room temperature for 12 h. The mixture was concentrated under vacuum, and purified by chromatography on silica gel eluting with solvent gradient 0% to 15% MeOH in CH2Cl2, to give 125.0 mg (86%) of N-(2-cyano-3-(2-methylprop-1-enyl)phenylcarbamoyl)benzamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.80 (d, J=1.2 Hz, 3H), 1.95 (d, J=1.2 Hz, 3H), 6.40 (s, 1H), 7.19 (m, 1H), 7.55 (m, 2H), 7.67 (m, 2H), 8.03 (m, 2H), 8.13 (m, 1H), 11.33 (s, 1H), 11.48 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:35])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][CH2:19][C:18]([OH:35])=[O:17])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCc1ccccc1OCCCCCBr
Product: CCCc1c(OCCCCCOc2ccccc2CCCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 4, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-[(5-bromopentyl)oxy]benzenebutanoic acid methyl ester from the preceding example, followed by saponification, in 46.5% overall yield. The product was an off-white solid, mp 116°-118° C., recrystallized from acetonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:15]>CO>[NH:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:15])[C:11]=2[N:12]=[CH:13]1
Reactant: N
Reactant: Clc1nc2ccccc2c2[nH]cnc12
Solvent: CO
Product: Nc1nc2ccccc2c2[nH]cnc12

Procedure:
Using the method of Example 18, the product of Example 30, 0.2g (0.0010 mole) of 4-chloro-1H-imidazo[4,5-c]quinoline was aminated at 175 ° C. in 12% ammonia in methanol to provide 1H-imidazo[4,5-c]quinolin-4-amine. The structure was verified by comparison of infrared and nuclear magnetic resonance spectra of the product with spectra of the product from Example 32 below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][CH2:30][OH:31].CCN(CC)CC.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:29][CH2:30][O:31][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40]
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CC(CCO)c1cccc(Br)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC2CC3(CCN(C(=O)NC4C5CC6CC(C5)CC4C6)CC3)c3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (±)-7-bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (40 mg, 0.082 mmol) and Et3N (9.9 mg, 0.098 mmol) in dry CH2Cl2(5 mL) was added TsCl (15.6 mg, 0.082 mmol) at 0° C. The mixture was stirred overnight at rt. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (±)-7-bromo-N-(2-adamantyl)-3-(2-(p-toluenesulfonyloxy)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (50 mg, crude).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([CH3:16])([N+:13]([O-])=O)[CH3:12])=[CH:4][C:3]=2[O:2]1.C(O)(=O)C.COCCOC>[H][H].[Pt](=O)=O>[CH3:16][C:11]([NH2:13])([CH3:12])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: CC(C)(Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: COCCOC
Product: CC(C)(N)Cc1ccc2c(c1)OCO2
Yield: 72.2 %

Procedure:
A mixture of 0.8 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropane, 100 mg of platinum dioxide, one ml of acetic acid and 20 ml of 1,2-dimethoxyethane is shaken at 60°-70° C. for 18 hours in hydrogen gas atmosphere under elevated pressure (initial pressure: 80 atmospheric pressures). After the reaction, the insoluble materials are removed by filtration, and the filtrate is evaporated to remove solvent. The residue is dissolved in ethyl acetate, and the solution is extracted with 5% hydrochloric acid. The extract is alkalized with potassium carbonate, and then extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then evaporated to remove solvent. The residue (oil) is distilled at 100°-120° C. (bath temperature) under reduced pressure (0.04 mm Hg). 0.5 g of α,α-dimethyl-3,4-methylenedioxyphenethylamine are thereby obtained as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].Cl.N(CC)(CC)CC>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:27]
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCCCc1ccccc1

Procedure:
5-Phenylvaleric acid (2.67 g, 15 mmol) in distilled THF was reacted with CDI (15 mmol) followed by glycine ethyl ester.HCl (15 mmol) and (C2H5)3N (15 mmol) as described in Example 56 Part A. The crude material (3.25 g, 82%) was used without purification.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:26]>CO.[OH-].[Pd+2].[OH-]>[ClH:26].[NH:14]1[CH2:17][CH:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]2)[CH2:15]1
Reactant: C[C@@H]1CN(C2CN(C(c3ccccc3)c3ccccc3)C2)C[C@H](C)O1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CN(C2CNC2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Cis-4-(1-benzhydryl-3-azetidinyl)-2,6-dimethylmorpholine (2.63 g, 7.82 mmol) was dissolved in methanol (40 mL), and 10% palladium hydroxide (wet) (500 mg) and a 1N-hydrochloric acid (5 mL) were added thereto. The mixture was stirred for 24 hours at room temperature under a hydrogen stream at normal pressure. The catalyst was removed by filtration, and the solvent was concentrated under reduced pressure. A 1N-hydrochloric acid (10 mL) was added to the obtained residue, and the mixture was washed with diethylether. The aqueous layer was concentrated to obtain the title compound (1.9 g, 100%) as an amorphous matter.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:14]([NH:24]C(=O)OC(C)(C)C)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[N:4][C:5]([N:8]2[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]2)=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:24][C@H:14]([C:3]1[N:4]=[C:5]([N:8]2[CH2:11][C:10]([CH3:12])([OH:13])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[Br:1])[CH2:15][C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: CC1(O)CN(c2ccc(Br)c([C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CN(c2ccc(Br)c([C@@H](N)Cc3cc(F)cc(F)c3)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 42G (64 mg, 0.13 mmol) was dissolved in 2 mL of 20% TFA/methylene chloride. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between EtOAc and saturated aq. NaHCO3. The organic layer was separated and concentrated to afford the title product. MS (m/z) 398.03[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[C:16]3[C:23]2[CH2:24][CH2:25][O:26][CH2:27][CH:28]=2)=[CH:4][N:3]=1>[Pt](=O)=O>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[C:16]3[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Nc1cc(-c2ccc3nccc(C4=CCOCC4)c3c2)cnc1Cl
Agent: O=[Pt]=O
Product: CS(=O)(=O)Nc1cc(-c2ccc3nccc(C4CCOCC4)c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
To a solution of N-(2-chloro-5-(4-(3,6-dihydro-2H-pyran-4-yl)quinolin-6-yl)pyridin-3-yl)methanesulfonamide (0.055 g, 0.13 mmol) in (10 mL) under N2 was added platinum (IV) oxide (0.015 g, 0.066 mmol). The reaction mixture was purged with N2 followed by evacuating. This procedure was done 3 times. After last evacuation, a hydrogen balloon was inserted. The reaction was stirred at rt under H2 for 4 h. The reaction mixture was passed through a pad of Celite® (diatomaceous earth). The reaction mixture was then concentrated. The crude product was purified by column chromatography (12 g, 20% to 30% acetone in hexanes) to afford the desired product as an off-white solid (30.0 mg). MS (ESI pos. ion) m/z: calcd for C20H26ClN3O3S: 417.1; found: 417.9 [M+1]. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.85-2.14 (m, 4 H) 3.14 (s, 3 H) 3.55-3.85 (m, 3 H) 4.10-4.29 (m, 2 H) 6.93 (br. s., 1 H) 7.39 (d, J=4.53 Hz, 1 H) 7.92 (dd, J=8.70, 1.97 Hz, 1 H) 8.17-8.37 (m, 3 H) 8.57 (d, J=2.34 Hz, 1 H) 8.94 (d, J=4.53 Hz, 1 H).
Reaction SMILES: Cl[CH:2]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.[O-]CC.[Na+].C(O)C>CCCCCC>[CH2:9]([C@@H:8]1[O:12][C@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH3:11]
Reactant: CCCC(O)C(Cl)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: CCC[C@@H]1O[C@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Ethyl 2-chloro-3-hydroxyhexanoate synthesized in Example 9 (0.8 g, 4 mmol), ethanol (3 ml) and 20% sodium ethoxide/ethanol solution (1.52 g, 1.1 equivalents) were mixed, and the mixture was stirred at room temperature for 30 minutes. Hexane (10 ml) was added, and the mixture was washed with water (10 ml×twice). After the mixture was dried with anhydrous magnesium sulfate, the inorganic salt was separated by filtration. The filtrate was concentrated under reduced pressure. The title compound was obtained as a colorless oil (0.9 g, yield: 87%, (2R,3S) was the main ingredient).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][CH3:13])=[CH:9][N:10]=2)[N:7]=1.[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:16][CH2:15]1.Cl>CCOCC>[ClH:1].[CH3:13][O:12][CH2:11][C:8]1[N:6]2[N:7]=[C:2]([NH:23][CH2:22][CH2:21][CH2:20][N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: COCc1cnc2ccc(Cl)nn12
Reactant: NCCCN1CCOCC1
Agent: Cl
Solvent: CCOCC
Product: COCc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 31 %

Procedure:
Prepared from 6-chloro-3-(methoxymethyl)imidazo[1,2-b]pyridazine (8a) and 3-morpholinopropylamine according to general procedure 4 (step B). The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (35 mg, 31%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 7.67 (d, J=9.8 Hz, 1H), 7.54 (s, 1H), 6.80 (d, J=9.8 Hz, 1H), 4.76 (s, 2H), 3.90-3.89 (m, 4H), 3.51 (t, J=6.5 Hz, 2H), 3.38 (s, 3H), 3.26-3.23 (m, 6H), 2.18-2.13 (m, 2H); 13C NMR (125 MHz, CD3OD) δ 154.7, 136.5, 128.7, 125.7, 124.2, 115.0, 64.3, 62.2, 57.3, 55.9, 52.5, 38.7, 23.6; HPLC tR=8.1 min (Synergi), 95.2%; ES-MS: (M+H)=306 m/z.