Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[OH:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[I-].[Na+].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C.CO.ClCCl.ClCCl>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][OH:35])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: OCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Agent: O=C([O-])O
Agent: [I-]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3CCO)CC2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.40 g, 0.85 mmol), 4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.44 g, 0.85 mmol) (1.51 g, 3.2 mmol), sodium iodide (0.127 g, 0.84 mmol), and triethylamine (0.59 mL, 4.23 mmol) in acetonitrile (20 mL). Heat to reflux. After 30 hours, cool to ambient temperature and evaporate in vacuo, and partition the evaporated reaction mixture between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract three times with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with dichloromethane, 5% methanol/dichloromethane, 10% methanol/dichloromethane, and then 25% methanol/dichloromethane to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([C@@H]1COC(=O)N1[C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][C:24]2([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23]1)=[O:21])C1C=CC=CC=1.O.[OH-].[Na+]>O1CCCC1>[CH2:23]1[C:24]2([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:25][CH2:26][CH2:27][CH:22]1[CH2:20][OH:21]
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)C1CCCC2(CCCCC2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCCC2(CCCCC2)C1
Temperature: 25 °C

Procedure:
To a suspension of lithium aluminum hydride (55 mg) in tetrahydrofuran (5 mL) was added dropwise a solution of (4R)-4-benzyl-3-(spiro[5.5]undecane-2-carbonyl)-oxazolidin-2-one (chiral: A) (425 mg) obtained in Step 3 in tetrahydrofuran (5 mL) under ice-cooling and nitrogen atmosphere, followed by stirring the reaction mixture in the range of ice-cooling to room temperature for 1.5 hours. Then, to the reaction mixture were added successively water (0.06 mL), 4N aqueous sodium hydroxide solution (0.06 mL) and water (0.18 mL), followed by stirring the reaction mixture at room temperature for 30 minutes. The precipitated insolubles in the reaction mixture were filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:20 to 1:10) to give spiro[5.5]undec-2-yl-methanol (chiral: A)(185 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([CH3:24])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C>[CH3:24][C:10]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])=[C:4]2[N:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=1
Reactant: C1COCCN1
Reactant: Cc1nn2c(N)cc(Cl)nc2c1Cc1cccc(C(F)(F)F)c1C
Solvent: CCO
Product: Cc1nn2c(N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 140 °C

Procedure:
To a solution of 5-chloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-7-amine (331 mg, 0.93 mmol) in ethanol (2 mL) was added morpholine (406 mg, 4.7 mmol). Reaction mixture was heated in microwave reactor at 140° C. for 7 hours. Reaction mixture was concentrated to dryness. It was diluted with ethyl acetate (30 mL) and 5% HCl solution (5 mL). Two layers were separated. Organic layer was dried and concentrated to dryness. Product was obtained and used in next step. (270 mg, 71%); LC/MS: MS (ES+) m/e 406 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])=[CH:12][CH:11]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C@@H:18]([CH3:19])[NH2:20])=[CH:12][CH:11]=1
Reactant: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
1,1-dimethylethyl [(1R)-2-({6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 39, 29 mg) was dissolved in 3 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (168 μl, 2.179 mmol). The reaction was stirred during 1 hour at 0° C. and 2 hours at room temperature. The reaction mixture was evaporated. The residue obtained was purified by SCX (3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N)). Evaporation of the volatiles, afforded the title compound (21 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH3:7])[NH:5][C:4](=O)[CH2:3]1.[Cl:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[Cl:9][C:10]1[CH:17]=[C:16]([N:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[C@@H:6]2[CH3:7])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: C[C@@H]1NC(=O)C[C@@H]1O
Product: C[C@H]1[C@@H](O)CCN1c1ccc(C#N)c(Cl)c1

Procedure:
Using (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one and 2-chloro-4-fluorobenzonitrile as starting materials, the title compound was obtained by the same manner as shown in Example 2 (reaction time 1 hr).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C:33]([CH3:46])([CH3:45])[C:34]([NH:36][C@H:37]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:38](O)=[O:39])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[CH3:46][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:45])[C:34]([NH:36][C@H:37]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:38](=[O:39])[NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24])=[O:35]
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (200 mg) and (R)-2-(2-(tert-butoxycarbonylamino)-2-methylpropanamido)-4-methylpentanoic acid (200 mg) were dissolved in dichloromethane (2 mL), and to the solution was added dropwise a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (107 mg), and triethylamine (42 μL) in dichloromethane (2 mL) over 10 minutes under cooling on ice, followed by stirring at room temperature for 18 hours. The solvent was evaporated, and the thus-recovered residue was dissolved in ethyl acetate. The solution was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (hexane:ethyl acetate (1:1), chloroform:methanol (10:1)), whereby the title compound (342 mg) was yielded.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>CN(C=O)C.O>[C:2]([CH:3]([CH:18]([CH2:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[CH2:9][CH3:10]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CCCC(Br)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)C(C(=O)CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of ethyl 3-oxopentanoate (7.21 mL; 50 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added potassium carbonate (7.6 g; 55 mmol), which has been dried at 120° C. for 12 h before using. After stirring for 15 min at room temperature, ethyl 2-bromovalerate (8.53 mL; 50 mmol) was slowly added under nitrogen and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was poured in water (240 mL) and neutralized by adding a solution of hydrochloric acid 6N. The product was extracted with diethyl ether (2×240 mL) and the combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by distillation under reduced pressure furnished 7.9 g (58%) of the title compound as a colorless liquid (bp. 130-135° C., 4 mbar, temperature of the oil bath 150° C.).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].NCCCN.C(C1CCC(O)CC1)(C)(C)C>C(O)(C)C>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: CC(C)(C)C1CCC(O)CC1
Agent: NCCCN
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a stainless autoclave (100 ml) were fed, under a nitrogen atmosphere, 4.0 g (0.026 mol) of 4-t-butylcyclohexanone, 12.5 mg (0.013 mmol) of RuCl2 (PPh3)3, 1.04 ml (0.104 mmol) of a 0.1M solution of KOH in isopropanol, 2.89 ml (0.052 mmol) of a 0.018M solution of trimethylenediamine in isopropanol and 10 ml of isopropanol. The mixture was stirred under a hydrogen gas pressure of 50 atm at room temperature for 16 hours. When the reaction mixture was analyzed by gas chromatography, it was found out that 4-t-butylcyclohexanol (weight ratio of cis-isomer:trans-isomer=95: 5) was thus formed at a conversion ratio of 100%. The reaction mixture was filtered under reduced pressure and the oily substance thus obtained was distilled at 113°-115° C./15 mmHg. Thus 3.44 g of the target cis-4-t-butylcyclohexanol with a high purity was obtained (yield: 85%). The physical data of this product are as follows. MS(EI)(m/z): 57 (100), 67 (43), 82 (39), 99 (20), 123 (12). IR (KBr) (cm-1): 3300, 2950, 1480, 1440, 1360, 1340, 1030, 1010.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])=[O:9].[C:20](=O)([O:23]C)[O:21][CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OC)(C)(C)C>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:8](=[O:9])[CH2:7][C:20]([O:21][CH3:22])=[O:23]
Reactant: COc1ccc(C(C)=O)c(OC)c1
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: COC(C)(C)C
Product: COC(=O)CC(=O)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a three-necked round-bottomed flask equipped with a mechanical stirrer under N2 was added potassium tert-butoxide (1M in THF, 108.77 mL, 108.77 mmol), followed by a solution of 2,4-dimethoxyacetophenone (10.00 g, 54.38 mmol) and dimethyl carbonate (13.93 mL, 163.15 mmol) in methyl tert-butyl ether (50 mL) dropwise via an addition funnel over 1.5 hours. During addition, reaction turned from a initial cloudy yellow mixture to a thick red-orange slurry. Reaction mixture was stirred at room temperature overnight. Aqueous citric acid solution (0.5 N, 110.95 mL, 54.39 mmol) was added via addition funnel to quench the reaction. Exotherm was observed during quenching and solids dissolved to give an orange mixture. The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (2×25 mL). The combined organic extracts were concentrated to low volume. Heptane (50 mL) was added and brown solids precipitated. The resulting slurry was stirred under N2 overnight at room temperature. Solids were filtered and dried under N2 to give the title compound (11.05 g, 85% yield) as a beige colored powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[O:12]C(=O)[NH:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:8][C:7]1[CH:22]=[CH:23][CH:24]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:12]
Reactant: CC(C)(C)c1cccc(CC2NC(=O)OC2c2cccc(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Yield: 55.5 %

Procedure:
To a solution of (4RS,5SR)-4-[3-(tert-butyl)benzyl]-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (2.36 g, 6.86 mmol) in ethanol (60 ml) was added 8N aqueous sodium hydroxide (4.3 ml, 34.3 mmol), and the mixture was heated under reflux for 5 hrs. After the completion of the reaction, ethanol was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS,2SR)-2-amino-3-[3-(tert-butyl)phenyl]-1-(3-chlorophenyl)-1-propanol (1.21 g, 55%) as colorless crystals.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([F:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:29]=[N:30][CH:31]=1)=O)(C)(C)C.CO.[ClH:42]>O1CCOCC1>[ClH:23].[ClH:42].[ClH:23].[NH2:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:10]2[CH:11]=[C:12]([NH:15][C:16]3[C:21]([F:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=3)[CH:13]=[CH:14][C:9]=2[NH2:8])[CH:31]=[N:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3F)ccc2NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3F)ccc2N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into the reaction flask was added tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.050 g, 0.089 mmol), methanol (0.6 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (1 mL). The mixture was stirred at rt overnight and concentrated under vacuum to give the desired product (10 mg, 95%). LCMS for C17H17ClFN6 (M+H)+: m/z=359.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1F)C(=O)OC
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1F
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.37 g), 2-(4-chloro-2-fluorobenzyl)-3-oxopentanoic acid methyl ester (0.60 g), polyphosphoric acid (3 g) and dioxane (10 mL) was heated at 120° C. for 23 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:4 to 1:1 by volume) to afford title compound, 0.082 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[C:17]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)C(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(CC(C)C(F)(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
129 mg of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpentanoic acid (mixture of racemic diastereomers) and 59 mg (0.31 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 51 mg (30% of theory)
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9](Cl)=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:12][NH2:13]>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:8]=1[C:9]([NH:13][CH3:12])=[O:10]
Reactant: CN
Reactant: O=C(Cl)c1cnccc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a suspension of crude 4-chloronicotinoyl chloride hydrochloride in 25 mL of THF was added methylamine solution (2M in THF, 20 mL, 40 mmol, 4.0 eq) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude material was dissolved in ethylacetate (75 mL) and water/brine/saturated sodium bicarbonate solution (1/1/1, 75 mL). The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with water/brine/saturated sodium bicarbonate solution (1/1/1, 25 mL) and brine (25 mL) and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded the title compound as orange solid (400 mg, 24%), which was used without further purification. MH+=171.0, Rt=0.55 min.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:36]([O:39][CH3:40])[O:37][CH3:38])[CH2:10][NH:11][C:12]([C:14]1[N:15]([CH2:33][O:34][CH3:35])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([S:8][CH:9]([CH:36]([O:39][CH3:40])[O:37][CH3:38])[CH2:10][NH:11][C:12]([C:14]1[N:15]([CH2:33][O:34][CH3:35])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:41])[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCn1c(C(=O)NCC(SCc2ccccc2)C(OC)OC)cc2cccc(NS(=O)(=O)c3ccccn3)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COCn1c(C(=O)NCC(SCc2ccccc2)C(OC)OC)cc2cccc(N(C)S(=O)(=O)c3ccccn3)c21
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a solution of N-[2-(benzylthio)-3,3-dimethoxypropyl]-1-(methoxymethyl)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (1.52 g) and potassium carbonate (0.54 g) in N,N-dimethylformamide (14 mL) was added methyl iodide (0.16 mL) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was ice-cooled, potassium carbonate (0.30 g) and methyl iodide (0.16 mL) were added again, and the mixture was further stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=4:6-6:4) to give the title compound (1.6 g, yield: 100%) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1([OH:26])[CH2:21][C:20]2[C:19]([OH:22])=[C:18]3[C:9]([C:10](=[O:24])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:23])=[C:8]([OH:25])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1CNC(=O)C1.[Br:33][Br-]Br>O1CCCC1>[Br:33][CH2:2][C:1]([C:4]1([OH:26])[CH2:21][C:20]2[C:19]([OH:22])=[C:18]3[C:9]([C:10](=[O:24])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:23])=[C:8]([OH:25])[C:7]=2[CH2:6][CH2:5]1)=[O:3]
Reactant: CC(=O)C1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)c2c(O)c3c(c(O)c21)CCC(O)(C(=O)CBr)C3

Procedure:
Reaction of 9-acetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (352 mg) with pyrrolidone hydrotribromide (562 mg) was effected in tetrahydrofuran (50 ml) at room temperature for 40 hours. After removing insoluble materials by filtration, the filtrate was concentrated under reduced pressure to give 9-bromoacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione, which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][NH:7][CH2:6]1)=[O:4].C1(N[S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])CC1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])[CH2:6]1)=[O:4]
Reactant: CCCS(=O)(=O)NC1CC1
Reactant: COC(=O)C1CNC1
Product: CCCS(=O)(=O)N1CC(C(=O)OC)C1

Procedure:
Prepared by standard procedure from azetidine-3-carboxylic acid methyl ester and propane-1-sulfonyl chloride (e.g. example 279).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[CH2:11][CH:12]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1>[Pd].[Zn].CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[CH2:11][CH2:12][N:18]2[CH2:19][CH2:20][O:21][CH:16]([CH3:15])[CH2:17]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC1CNCCO1
Reactant: CC(C)c1ccc(C(C)CC=O)cc1
Agent: [Pd]
Agent: [Zn]
Solvent: CO
Product: CC1CN(CCC(C)c2ccc(C(C)C)cc2)CCO1
Yield: 82 %

Procedure:
A mixture of 190 parts of 3-p-isopropylphenyl-3-methylpropanal, 111 parts of 2-methylmorpholine, 300 parts of methanol and 20 parts of catalyst, comprising 0.5% by weight of Pd, 0.11% by weight of Zn and 0.1% by weight of Cd on Al2O3, is hydrogenated in a stirred autoclave of 1,000 parts by volume capacity, at 120° C. under a hydrogen pressure of 50 bar, until the pressure remains constant. The autoclave is then allowed to cool, the catalyst is filtered off and the filtrate is purified by distillation. 266 parts of N-(3'-(p-isopropylphenyl)-3'-methylpropyl)-2-methylmorpholine, boiling point 122° C./0.05 mm Hg are obtained. The yield is 82% of theory.