Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[O:7])([CH3:4])[CH3:3].B.C1COCC1>C1COCC1>[OH:22][CH2:21][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:3])([CH3:1])[CH3:4])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1C(F)(F)F
Reaction time: 12 h

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine (5 g, 15 mmol) in THF (75 mL) at 0° C. stirred was added BH3-THF (45 mL, 45 mmol-1M in THF). After 12 h, the reaction was quenched with AcOH:MeOH (1:5, 24 mL) and partitioned between saturated aqueous NaHCO3 and DCM. The aqueous phase was then extracted several times with DCM. The combined organic fractions were dried over Na2SO4 and used directly (4.2 g, 88%): LCMS (ES) m/e 320 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of 1,4-dibromobenzene (3.89 g, 16.49 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (10.3 mL, 16.5 mmol, 1.6 M in hexane) dropwise. After 15 minutes, a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.05 g, 16.49, mmol) in tetrahydrofuran (10 mL) was added over 5 minutes. The reaction continued to stir at −78 °C. for 15 minutes and was then quenched by the addition of saturated NH4Cl (150 mL) and diethyl ether (150 mL). After warming to room temperature, the layers were separated, and the aqueous was extracted with additional diethyl ether (2×100 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (10% ethyl acetate in hexane to 50% ethyl acetate in hexane) to give the title product. MS (ESI) m/z 342 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CC(C)=O>[Cl:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 2-chloro-4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (144 mg, 0.40 mmol, 1.0 eq) in acetone (3 mL) was added Cs2CO3 (193.5 mg, 0.59 mmol, 1.5 eq). The reaction mixture was stirred for 30 min, then ethyl 2-bromoacetate (79.3 mg, 0.48 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 1 h and the resulting mixture poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 1:20 to 1:10) to give the title compound as an oil (155 mg, 87%).
Reaction SMILES: C(Cl)Cl.C[O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=1.C[Si](C)(C)[O-].[K+]>C(OCC)(=O)C>[CH3:26][Si:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][O:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:30])=[O:5])=[O:29])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(OCOCC[Si](C)(C)C)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Dry DCM (25 mL) was added to 2-[4-(2-trimethylsilanylethoxymethoxy)benzoyl]-benzoic acid methyl ester (3.8 g, 9.8 mmol) followed by potassium trimethylsilanolate (1.53 g, 10.8 mmol). The system was stirred at room temperature under nitrogen for 16 h and monitored by TLC. Removal of the solvent gave a light yellow oil that was taken up into ethyl acetate (100 mL), washed with 5% HCl solution (3×30 mL), brine (30 mL) and dried with MgSO4. The solvent was removed to give 2-[4-(2-trimethylsilanylethoxymethoxy)benzoyl]benzoic acid as a yellow oil (3.66 g, 9.8 mmol, 99%); Rf 0.1 (40:60 EtOAc:petrol). λmax (CH3OH)/nm 276, 217, Abs 1.799, 2.108 respectively. IR: 3215, 3177, 1666, 1593 cm−1. 1H NMR: (300 MHz, CDCl3) δ 0.00 (s, 9H, Si—(CH3)3), 0.96 (m, 2H, R—O—CH2—CH2—Si), 3.76 (m, 2H, O—CH2—CH2—Si), 5.27 (s, 2H, O—CH2—O), 7.04 (m, 2H, Ar—H), 7.34 (m, 1H, Ar—H), 7.52-7.68 (dtd, 2H, J=30.2, 7.6, 1.3 Hz, Ar—H), 7.69 (m, 2H, Ar—H), 8.07 (m, 1H, Ar—H), 10.31 (bs, 1H, COOH). 13C NMR: (75 MHz, CDCl3) δ −3.2, 16.1, 64.8, 90.7, 113.8, 125.7, 126, 127.4, 128.8, 129.1, 129.9, 131.2, 140.9, 159.6, 168.8, 194. LC/MS-ES+ m/z 297.1, 373.1 [MH+]. HRMS (EI) m/z Calcd. for C20H24O5Si: 372.1393. Found 372.1387
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[CH2:11][C:12]1[N:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([NH:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:11][O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])[N:17]=1)=[O:24]
Reactant: CC(C)(C)C(=O)Nc1cccc(CCl)n1
Reactant: OCCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cccc(COCCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3,3-Trifluoro-propan-1-ol (0.214 g) in THF (8 mL) was treated under an argon atmosphere with sodium hydride (0.1 g, 60% suspension in oil) and stirred for 1 h at RT. N-(6-chloromethyl-pyridin-2-yl)-2,2-dimethyl-propionamide, 0.142 g, product of example 120 step A], was added and the mixture was heated at 85° C. for 2.5 h. The reaction mixture was cooled, partitioned between ice water and AcOEt, the layers were separated, the organic layer dried over Na2SO4, filtered and evaporated to give 2,2-dimethyl-N-[6-(3,3,3-trifluoro-propoxymethyl)-pyridin-2-yl]-propionamide (0.21 g) as a light brown oil. MS (ESI): 305.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:23][CH:24]([CH3:30])[C:25]([O:27]CC)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:23][CH:24]([CH3:30])[C:25]([OH:27])=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1
Reactant: CCOC(=O)C(C)Cc1ccc(OCc2cccc(Oc3ccccc3)c2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Cc1ccc(OCc2cccc(Oc3ccccc3)c2)c(F)c1)C(=O)O
Yield: 78.9 %

Procedure:
A mixture of ethyl 3-{3-fluoro-4-[(3-phenoxybenzyl)oxy]phenyl}-2-methylpropanoate (127 mg, 0.31 mmol), a 2 N aqueous sodium hydroxide solution (1 mL) and ethanol (2 mL) was stirred at 60° C. for 1.5 hours. The reaction solution was ice-cooled and acidified with 1 N hydrochloric acid, and then the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (5 mL), and the mixture was washed with water and saturated brine and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure to give the title compound (93 mg, 78%) as an oily matter.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12.C(N(CC)CC)C>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12)=[O:8]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 2 h

Procedure:
To a solution of 100 milligrams (0.6 millimole) of 2-thiopheneacetyl chloride in 5 milliliters of absolute methylene chloride was added slowly a slurry of 137 milligrams (0.5 millimole) of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and 86 milligrams (0.9 millimole) of triethylamine in 10 milliliters of absolute methylene chloride. The addition was carried out at -15° C., with stirring. After the addition, stirring was continued for two hours at -15° C. and for one and one-half hours at room temperature. The reaction mixture was then cooled and filtered to separate the precipitated solid. The solid, 80 milligrams, was analyzed on bioautogram. Bioautogram showed that approximately 50 percent of the sample was 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and another 50 percent was the desired 7-(2-(2-thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[O:14][CH2:13][C:12]3[C:11]([C:15](=[O:19])[CH2:16][C:17]#[N:18])=[N:10][N:9]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:8]=3[C:6]=2[CH:7]=1.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:17]([CH:16]([C:15]([C:11]1[C:12]2[CH2:13][O:14][C:5]3[C:4]([CH2:26][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:8]=2[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1)=[O:19])[C:40]([NH:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:41])#[N:18]
Reactant: N#CCC(=O)c1nn(-c2ccccc2)c2c1COc1c(CN3CCOCC3)cc(F)cc1-2
Reactant: O=C=Nc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1COc1c(CN3CCOCC3)cc(F)cc1-2
Temperature: 0 °C
Yield: 53.2 %

Procedure:
3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanenitrile (2.8 g) is reacted with phenylisocyanate (0.8 g) in dimethylformamide (20 ml) in the presence of triethylamine (0.7 g) at 25°-30° C. for 30 min. The reaction mixture is diluted with ice water and acidified with citric acid to pH 3. The precipitate is filtered and dissolved in chloroform. The organic solution is washed with 2% citric acid solution and then with water until neutral. Evaporation to dryness in vacuo gives a residue which is crystallized from chloroform/ethanol to yield 1.9 g of 2-cyano-3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 249°-253° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][CH2:15][C:16]([N:18]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>ClCCl>[C:19]1([N:18]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:16](=[O:17])[CH2:15][NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:13])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(C(=O)CNC(=O)c1ccc2ccccc2n1)c1ccccc1
Reaction time: 3 h
Yield: 38 %

Procedure:
A solution of 0.85 g of N,N'-carbonyldiimidazole in 10 cm3 of anhydrous dichloromethane is added dropwise, at a temperature close to 20° C., to a solution of 0.87 g of 2-quinolinecarboxylic acid in 15 cm3 of anhydrous dichloromethane. The suspension obtained is stirred for 3 hours at a temperature close to 20° C. and a solution of 2.6 g of tert-butyl 2-(2-amino-N-phenylacetamido)acetate in 25 cm3 of anhydrous dichloromethane is then added. The reaction mixture is stirred for 16 hours at a temperature close to 20° C. and 50 cm3 of water are then added. The aqueous phase is separated off by decanting and then reextracted with twice 15 cm3 of 1,2-dichloroethane. The organic phases are combined, washed with twice 25 cm3 of a saturated aqueous sodium bicarbonate solution and then with twice 25 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization of the residual solid from a mixture of cyclohexane and ethyl acetate (90/10 by volume), 0.8 g of tert-butyl 2-(N-phenyl-2-quinolinecarboxamidoacetamido)acetate melting at 114° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](O)=[CH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[NH2:17][NH2:18]>CCO>[C:7]1([C:6]2[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[NH:18][N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NN
Reactant: COC(=O)C(O)=CC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To a solution of 2-hydroxy-4-oxo-4-phenyl-but-2-enoic acid methyl ester (12.0 g, 58.2 mmol) in EtOH (30 ml) was added hydrazine monohydrate (2.84 mL, 58.2 mmol) and the mixture was heated at reflux for 5 h. The reaction mixture was cooled to room temperature and filtered in vacuo. The precipitate was washed with EtOH to give the desired product (6.02 g, 51.5% yield): MS (EI) for C11H10N2O2: 203.08 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:20]([O:19][C:17]([NH:16][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate, (3.12 g, 8.08 mmol), and 5-fluoro-2-methoxyphenylboronic acid (2.2 g, 12.93 mmol) in toluene (52 mL) and is added PdCl2(dppf)CH2Cl2 adduct (0.66 g, 0.81 mmol) and 2M aq. Na2CO3 (8.1 mL, 16.16 mmol). After stirring at 95° C. under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with ice water. The crude is diluted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 50:50) to give (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate (2.86 g). HPLC retention time=1.80 minutes (condition A); MS (m+1)=432.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.1 Hz, 3 H) 1.45 (s, 9 H) 2.45-2.65 (m, 2 H) 2.83-2.94 (m, 1 H) 2.94-3.09 (m, 1 H) 3.80 (s, 3 H) 4.20 (q, J=7.2 Hz, 2 H) 4.24-4.33 (m, 1 H) 5.11 (br. s., 1 H) 6.90-6.96 (m, 1 H) 7.00 (dd, J=7.8, 3.3 Hz, 1 H) 7.06 (dd, J=9.2, 3.2 Hz, 1 H) 7.27 (d, J=7.8 Hz, 2 H) 7.49 (d, J=7.8 Hz, 2 H)
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>CO>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: C[C@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Solvent: CO
Product: C[C@H](c1ccccc1)n1c(O)nc2c(N)nc3ccccc3c21
Temperature: 135 °C

Procedure:
4-Chloro-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol (3.87 g, 11.9 mmol) and ammonia (65 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 135° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.2:4.8:95). The chromatographed product was triturated sequentially with hot acetonitrile, hot isopropanol, and hot ethanol and washed with diethyl ether after each trituration and filtration. The filtrates were combined, concentrated under reduced pressure, washed with diethyl ether, and dried in a vacuum oven overnight to provide 214 mg of 4-amino-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol as tan needles, mp greater than 250° C.
Reaction SMILES: COC([O:7][CH3:8])N(C)C.C[C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13].P([O-])([O-])([O-])=O>CN(C=O)C.C1COCC1>[CH:8]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13])=[O:7]
Reactant: Cc1cccc([N+](=O)[O-])c1C#N
Reactant: COC(OC)N(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1c(C=O)cccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (13.56 mL, 102 mmol) was added to a solution of 2-methyl-6-nitrobenzonitrile (15.0 g, 92.5 mmol) in anhydrous DMF (60 mL) under nitrogen and was heated at 130° C. for 15 h. Ice water (300 mL) was added, and the resultant dark precipitate was collected by filtration and dried under vacuum. Phosphate buffer (pH 7, 350 mL) and then NaIO4 (40 g, 187 mmol) were added to a solution of the dark precipitate in THF (350 mL) and stirred at rt for 3 h. The mixture was extracted with EtOAc, the combined extract was washed with brine and dried with MgSO4. The filtrate was concentrated and the residue was purified by chromatography on silica using the solvent gradient hexanes→EtOAc, to give 3.07 g (19%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J=8.4 Hz, 1H), 8.41 (dd, J=1.2, 7.6 Hz, 1H), 8.62 (dd, J=1.2, 8.4 Hz, 1H), 10.25 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[N:3]1([CH:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:7]=[N:6][CH:5]=[N:4]1>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]([OH:10])[CH:8]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:12][CH:13]=1
Reactant: O=C(c1ccc(Cl)cc1)C(Cc1ccc(Cl)cc1Cl)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(Cl)cc1)C(Cc1ccc(Cl)cc1Cl)n1cncn1
Temperature: 25 °C
Yield: 80 %

Procedure:
Sodium borohydride (0.42 g) was added in small portions to 2-(1,2,4-triazol-1-yl)-2-(2',4'-dichlorobenzyl)-4'chloroacetophenone (4.2 g) in methanol (40 ml). When the effervescence ceased, the mixture was refluxed for 1 hour, cooled to room temperature and the methanol removed at the water pump. The residue was acidified with 1N-hydrochloric acid to give a solid which was filtered and washed. Recrystallisation from ethanol/water gave white crystals of the title compound (yield 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([CH3:17])=[N:14][CH:13]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([CH3:17])=[N:14][CH:13]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cnc(C)s1
Solvent: CCO
Product: COc1cc(N)ccc1-c1cnc(C)s1
Yield: 91.5 %

Procedure:
A suspension of 5-(2-methoxy-4-nitro-phenyl)-2-methyl-thiazole (330 mg, 1.32 mmol) and anhydrous stannous chloride (1.28 g, 6.59 mmol) in ethanol (21 mL) was stirred at reflux for 1 hour. The yellow solution is evaporated and the residue dissolved in ethyl acetate. This solution is washed twice with 2N aqueous sodium hydroxide solution, with brine, dried with magnesium sulfate and evaporated to dryness to afford the title compound (266 mg, 91%) as an orange solid. MS ISP (m/e): 221.2 (100) [(M+H)]. 1H NMR (CDCl3, 300 MHz): δ(ppm)=7.81 (s, 1H), 7.33 (d, 1H), 6.31 (m, 2H), 3.87 (s, 3H), 3.83 (m, 2H), 2.69 (s, 3H). mp 125-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=2)[N:20]=[C:19]([CH3:28])[C:18]=1[CH3:29]>>[Br:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=4)[N:20]=[C:19]([CH3:28])[C:18]=3[CH3:29])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCC21CCOCC1
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Product: Cc1nc2ccc(Cl)cc2c(N2CC3(CCOCC3)c3ccc(Br)cc32)c1C

Procedure:
Prepared according to procedure M using 6-bromo-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (0.3 g, 1.12 mmol) and 4,6-dichloro-2,3-dimethylquinoline (0.2783 g, 1.23 mmol) to give 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.03 (1H, d, J=9.0 Hz), 7.71 (1H, dd, J=8.9, 2.3 Hz), 7.65 (1H, d, J=2.2 Hz), 7.22 (1H, d, J=7.8 Hz), 6.83 (1H, dd, J=7.8, 1.5 Hz), 5.94 (1H, d, J=1.5 Hz), 4.04 (1H, d, J=9.8 Hz), 3.80-3.93 (3H, m), 3.39-3.54 (2H, m), 2.68 (3H, s), 2.22 (3H, s), 1.94-2.06 (2H, m), 1.85 (1H, d, J=13.4 Hz), 1.73 (1H, dd, J=13.4, 1.5 Hz); Mass Spectrum (ESI) m/e=457.1 [M+1 (79Br)] and 459.1 [M+1 (81Br)].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH2:34]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:33][CH2:32][CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][O:26]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCCC1CCCCO1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCC3CCCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 1H) 1.38-1.50 (m, 3H) 1.60 (d, J=12.9 Hz, 1H) 1.62-1.70 (m, 2H) 1.71-1.82 (m, 1H) 2.44 (s, 3H) 3.26-3.33 (m, 2H) 3.35-3.45 (m, 2H) 3.87 (dd, J=11.0, 1.9 Hz, 1H) 7.66 (dd, J=8.0, 1.4 Hz, 1H) 7.72 (s, 1H) 7.80 (d, J=8.1 Hz, 1H) 8.16 (s, 1H) 8.40 (br. s., 2H) 8.67 (t, J=5.6 Hz, 1H) 8.90 (t, J=1.5 Hz, 1H) 13.18 (br. s., 1H). MS m/z 432 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)#[N:2].[H][H]>N.C(O)C.[Ru]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1
Reactant: N#CCCCC1OCCO1
Reactant: [H][H]
Agent: [Ru]
Agent: N
Solvent: CCO
Product: NCCCCC1OCCO1
Yield: 802.4 %

Procedure:
To a solution of 14.5 gm (10.3 mmol) 2-(3-Cyanopropyl)-1,3-dioxolane in anhydrous ammonia and ethanol was added 5% ruthenium on aluminum oxide. The reaction mixture was hydrogenated with an initial hydrogen pressure of 100 psi at ambient temperature for 32 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 12.0 gm (80.5%) of the product.