Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[N:17]=[C:5]2[N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N+:10]([O-:33])=[CH:9][C:8]=3[N:17]=[C:5]2[N:4]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:3]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2nc3cnc4ccccc4c3n21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)c2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 18 h
Yield: 100.1 %

Procedure:
tert-Butyl (10S)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline-8-carboxylate (1.16 g, 3.58 mmol) was dissolved in 50 mL of CHCl3 and treated with MCPBA (1.05 g, 77% max). After 18 hours, the reaction was treated with 20 mL of 1% Na2CO3 solution and the layers were separated. The aqueous layer was extracted with CHCl3 (6×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give tert-butyl (10S)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline-8-carboxylate 5-oxide (1.22 g) as a brown foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][C:21]1([CH3:45])[CH2:30][CH2:29][C:28]2[N:27]=[CH:26][N:25]=[C:24]([N:31]3[CH2:37][C:36]4[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:35]=4[O:34][CH2:33][CH2:32]3)[C:23]=2[CH2:22]1>>[NH2:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:39]2[CH:40]=[CH:41][C:35]3[O:34][CH2:33][CH2:32][N:31]([C:24]4[C:23]5[CH2:22][C:21]([CH3:20])([CH3:45])[CH2:30][CH2:29][C:28]=5[N:27]=[CH:26][N:25]=4)[CH2:37][C:36]=3[CH:38]=2)=[CH:4][N:3]=1
Reactant: CN1CC[C@H](CNS(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CN1CC[C@H](CNS(=O)(=O)c2cc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cnc2N)C1

Procedure:
Prepared according to the method of example 5 by using 2-amino-5-bromo-N-{[(3S)-1-methylpyrrolidin-3-yl]methyl}pyridine-3-sulfonamide (reagent preparation 25) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.44 (br, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 7.05 (d, 1H), 4.70 (s, 2H), 4.31 (m, 2H), 3.97 (m, 2H), 3.16 (m, 1H), 3.04 (t, 2H), 2.94 (d, 2H), 2.67 (t, 2H), 2.67 (s, 3H), 2.47 (s, 2H), 2.52 (m, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.65 (m, 3H), 0.92 (s, 6H); MS (EI) for C29H37N7O3S: 564 (MH+).
Reaction SMILES: Cl.[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([OH:26])=[O:25])=[C:16]([CH2:19]OC(=O)C)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.[CH3:31][N:32]1[CH:36]=[N:35][N:34]=[C:33]1[SH:37].C(=O)([O-])O.[Na+:42].O>P([O-])([O-])([O-])=O>[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([O-:26])=[O:25])=[C:16]([CH2:19][S:37][C:33]4[N:32]([CH3:31])[CH:36]=[N:35][N:34]=4)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.[Na+:42]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1
Reactant: Cn1cnnc1S
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: Cn1cnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
In 20 ml of phosphate buffer (0.2M, pH 6.4) there was dissolved 0.883 g of 7-[2-(2-imino-4-thiazolin-4-yl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn-isomer) together with 0.23 g of 4-methyl-1,2,4-triazole-3-thiol and 0.336 g of sodium hydrogen carbonate and the mixed solution was stirred at a temperature of 70° C. for 3.5 hours. The reaction mixture was subjected to column chromatography on polystyrene resin (Amberlite XAD-2, Rohm and Haas Co.), development being carried out with water. The fractions containing the desired product were pooled and lyophilized. By the above procedure there was obtained 0.371 g of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][NH:35][CH3:36]>C1COCC1.CCOC(C)=O>[CH3:34][N:35]([CH3:36])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: CNC
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N(C)C)c3)n2)n1
Yield: 54.1 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available dimethylamine (40% in water, 0.52 ml, 4.1 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 54%) as a white foam. MS (ISP) 498.3 [(M+H)+]; mp 155° C.
Reaction SMILES: C(CC(Cl)(Cl)Cl)(Cl)(Cl)[Cl:2].[OH-].[K+].[C:12]([CH2:16][C:17]([F:20])(F)[F:18])([F:15])([F:14])[F:13]>Cl[Ti](Cl)(Cl)Cl>[C:12]([CH2:16][C:17]([Cl:2])([F:20])[F:18])([F:15])([F:14])[F:13]
Reactant: ClC(Cl)(Cl)CC(Cl)(Cl)Cl
Reactant: FC(F)(F)CC(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Product: FC(F)(F)CC(F)(F)Cl
Temperature: -10 °C

Procedure:
A 600 mL, magnetically stirred, model autoclave fitted with a condenser (maintained at -10° C.), was evacuated, cooled to about -40° C., and charged with 0.6.9 g (0.036 mol) TiCl4 followed by 64 g (0.255 mol) CCl3CH2CCl3, and 102.5 g (5 mol) HF. The temperature was increased to 120° C. and maintained at that temperature for a total of 22 h. During the heating period, pressure in excess of 400 psig was periodically vented to an aqueous KOH scrubber which was attached to two -78° C. cold traps. At the end of the heating period, the remainder of the autoclave contents were slowly vented. The cold traps contained 36.1 g material which by GC analysis, contained 14.5% CF3CH2CF3 and 84.0% CF3CH2 CF2Cl, corresponding to a yield for CF3CH2CF2Cl of 69%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:27][C:24]6([CH2:26][O:25]6)[CH2:23][CH2:22][C:21]5([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:27][C:24]([CH3:26])([OH:25])[CH2:23][CH2:22][C:21]5([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-n2ncc3cc4c(nc32)CCCC2CC3(CCC42Cc2ccccn2)CO3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(O)CCC2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4nc3CCCC2C1
Temperature: 65 °C

Procedure:
rac-(2′R,4aS,12bS)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine-3,2′-oxirane] (119, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (1.865 g, 4.10 mmol) was suspended in EtOH (41.0 mL). NaBH4 (0.776 g, 20.52 mmol) was added to the then the mixture was warmed to about 65° C. for about 2 h. The mixture was cooled then concentrated under reduced pressure. Water (50 mL) was added to the material then the solids were collected by filtration and dried the material was purified on silica gel (120 g) using a gradient from 0-10% MeOH in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(3R,4aS,12bS)-9-(4-fluorophenyl)-3-methyl-12b-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3-ol (120, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl, R3=Methyl) (1.87 g, 99%); LC/MS, method 2, Rt=2.65 min, MS m/z 457 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.42-8.35 (m, 2H), 8.28-8.26 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 7.46-7.37 (m, 3H), 7.05-7.02 (m, 1H), 6.58 (d, J=7.8 Hz, 1H), 4.10 (s, 1H), 3.70 (d, J=12.6 Hz, 1H), 3.56-3.49 (m, 1H), 3.44-3.32 (m, 1H), 2.91 (d, J=12.8 Hz, 1H), 2.66-2.53 (m, 2H), 2.15-1.80 (m, 3H), 1.70-1.59 (m, 2H), 1.53-1.30 (m, 2H), 1.16-1.14 (m, 2H), 0.92 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[CH:5]([OH:20])[C:4]=2[C:3]=1[CH3:21].S(=O)(=O)(O)O>CC(C)=O.O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: CCCC1Cc2c3c(c(C)c(C)c2C1O)OC(C(=O)O)C3
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CCCC1Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3

Procedure:
A stirred suspension of 4,5-dimethyl-6-hydroxy-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (5.0 g., 0.017 mole) in acetone (250 ml.) is treated over a ten minute period with an oxidizing reagent prepared from chromium trioxide (2.5 g. and concentrated sulfuric acid (2.2 ml.) in water (18 ml.). The acetone solution is decanted from the precipitated chromium salts and poured into water (700 ml.) affording 4,5-dimethyl-6-oxo-7-propyl-1,2,7,8-tetrahydro-6H-indeno-[5,4-b]furan-2-carboxylic acid which melts at 161°C. after recrystallization from butyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(/C=C/CN2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Yield: 99.7 %

Procedure:
8-[trans-3-(4-Chlorophenyl)allyl]-1,4-dioxa-8-azaspiro[4.5]decane (1.38 g) was dissolved in methanol (40 ml) and 6 N hydrochloric acid (120 ml) was added. The mixture was heated to reflux for 4 h. The mixture cooled and was basified to pH 14 with solid sodium hydroxide pellets (CARE! Exotherm), the solution becoming opaque. The aqueous was extracted three times with ether. The organics were washed with brine, dried over anhydrous MgSO4 and evaporated to give 1.17 g (100%) of the desired ketone 1H NMR (400 MHz, CDCl3) 2.38 (m, 4H), 2.70 (m, 4H), 3.15 (d, J=5 Hz, 2H), 3.96 (s, 4H), 6.17 (dt, J=12 & 5 Hz, 1H), 6.40 (d, J=12 Hz, 1H), 7.20 (m, 4H). MS (ES+) 250/252 M+H+.
Reaction SMILES: [CH:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.O>C(#N)C>[Br:21][C:13]1[C:14]([CH3:15])=[C:9]([CH2:8][C:7]2[CH:19]=[CH:20][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[C:10]([O:17][CH3:18])=[CH:11][C:12]=1[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Solvent: CC#N
Solvent: O
Product: COc1cc(C)c(Br)c(C)c1Cc1ccc(C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-isopropylbenzyl)-1-methoxy-3,5-dimethylbenzene obtained in Reference Example 213 (3.45 g, 12.9 mmol) in acetonitrile (40 mL) was added N-bromosuccinimide (2.29 g, 12.9 mmol) with ice-cooling, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate, was filtered, and then was concentrated under reduced pressure. Ethyl acetate-hexane (1:9) was added to the residue, and the precipitated crystals were filtered, and the filtrate was concentrated to obtain 4.50 g (yield is quantitative) of the title compound. Oily matter.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12](O)[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH2:23]([N:25](CC)[CH2:26][CH3:27])[CH3:24].C(=O)=O.S(Cl)(C)(=O)=O.C(NCC)C>CC(C)=O.C(Cl)(Cl)Cl.C(OCC)C>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: CCN(CC)CC
Reactant: Cc1oc2c(C(O)CO[Si](C)(C)C(C)(C)C)cccc2c1C
Agent: CS(=O)(=O)Cl
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCNCC
Product: CCN(CC)C(CO[Si](C)(C)C(C)(C)C)c1cccc2c(C)c(C)oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
3 g (9.82 mmol) of 2,3-dimethyl-7-(2-[tert-butyldimethylsilyloxy]-1-hydroxyethyl)benzofuran, 50 ml of ethyl ether and 2.2 ml (15.7 mmol) of triethylamine are introduced into a 100 ml round-bottomed flask. The mixture is cooled to -30° C. by a bath of dry ice in acetone and 1.24 ml (15.7 mmol) of mesyl chloride are added. The cooling bath is removed and the reaction mixture is allowed to return to room temperature over 30 minutes. 200 ml of water are added and extraction is carried out with ethyl ether (3×150 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. The residue is transferred, without additional purification, to a 100 ml three-necked flask equipped with a reflux condenser. 20 ml (190 mmol) of diethylamine and 3 ml of chloroform are added and the reaction mixture is heated at reflux for 16 hours. The reaction mixture is cooled to room temperature and concentrated under vacuum, 150 ml of water are added and extraction is carried out with ethyl ether (3×200 ml). The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent: 10% methanol in dichloromethane). 2.77 g (Yield 78%) of 2,3-dimethyl-7-(1-diethylamino-2-[tert-butyldimethylsilyloxy] ethyl)-benzofuran are obtained in the form of an oil. (0.5 g of unreacted 2,3-dimethyl-7-(2-[tert-butyldimethylsilyloxy]-1-hydroxyethyl)benzofuran is recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:18][CH2:17]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure D, 1-(6-bromo-4-((trans-4-((dimethylamino)methyl)cyclohexyl)amino)quinolin-3-yl)ethanone (32 mg, 0.079 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (32 mg, 0.118 mmol) to afford the desired product (24.0 mg, 65%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 8.91 (s, 1H), 8.33 (d, J=1.9 Hz, 1H), 7.97 (dd, J=8.7, 1.9 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.47 (s, 1H), 7.37 (d, J=11.8 Hz, 1H), 4.27-4.18 (m, H), 2.69 (s, 3H), 2.59-2.55 (m, 2H), 2.52 (s, 6H), 2.34 (d, J=12.7 Hz, 2H), 1.99 (d, J=13.2 Hz, 2H), 1.84-1.74 (m, 1H), 1.67-1.55 (m, 2H), 1.28-1.17 (m, 2H). ESI MS m/z 470 [C26H29ClFN3O2+H]+; HPLC>99% (AUC), tR=10.56 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]1[C:13](C)=[C:12]([CH3:15])[CH2:11][CH:10]=[C:5]1[C:6]([O:8][CH3:9])=[O:7].[Se](=O)=O.[C:20](OC(=O)C)(=O)C>C(Cl)Cl>[CH3:9][O:8][C:6](=[O:7])[C:5]1[C:4](=[CH:13][C:12]([CH3:15])=[C:11]([CH3:20])[CH:10]=1)[C:3]([O:2][CH3:1])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1=CCC(C)=C(C)C1C(=O)OC
Agent: O=[Se]=O
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(C)cc1C(=O)OC
Temperature: 100 °C

Procedure:
232 parts of the 5,6-dimethyl-1,4-dihydro-phthalic acid dimethyl ester (I) obtained in A) are first freed from readily volatile constituents in vacuo and then diluted with 400 parts by volume of acetic anhydride. Then 133 parts of selenium dioxide are slowly added by small amounts to the reaction mixture, which is heated to 100° C, and the temperature rises to 130° C without external application of heat. The reaction mixture is subsequently refluxed for 3 hours and freed from acetic anhydride in vacuo. The residue is taken up in methylene chloride, the solution is freed from precipitated selenium by filtration, then freed from acid constituents with a saturated aqueous sodium bicarbonate solution, washed neutral with water, dried over sodium sulphate and concentrated to dryness in vacuo. Yield: 230 parts of a yellowish brown oil which a gas chromatogram shows to have a 94% content of 4,5-dimethyl-phthalic acid dimethyl ester (II). The product is distilled under a high vacuum. The fraction with a boiling range of 116°-120° C (0.04 Torr) contains 174 parts (78% of theory) of 4,5-dimethyl-phthalic acid dimethyl ester (II) with a melting point of 54°-55° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH2:27]([O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)=[O:26])=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Cc1ccc(O)c([N+](=O)[O-])c1)Nc1cccc(C2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)Nc1cccc(C2CCCCC2)c1

Procedure:
A mixture of N-(3-cyclohexylphenyl)-4-hydroxy-3-nitrophenylacetamide (the compound of Example 29) (300 mg), benzyl bromide (287 mg), potassium carbonate (500 mg) and acetone (10 ml) is heated under reflux for 18 hours. After cooling, water is added to the mixture, and the mixture is extracted with ethyl acetate. The organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-benzyloxy-N-(3-cyclohexylphenyl)-3-nitrophenylacetamide (320 mg). This product is dissolved in ethanol (5 ml), and thereto are added reduced iron (200 mg), ammonium chloride (80 mg) and water (5 ml), and the mixture is heated under reflux for one hour. The reaction solution is filtered through Celite, and the filtrate is concentrated, and the residue is dissolved in chloroform. The organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (240 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N+:17]([O-])=[C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]2=[N:14]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O.C(O)CCC>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]2=[N:14]1
Reactant: Cc1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 86.1 %

Procedure:
33.2 g (0.1 mol) of 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole-N-oxide, 0.125 g of palladium carbon, 300 ml of a solvent mixture comprising toluene, butanol and water (ratio by volume of 1:1:1) and 5 g 50% dimethylamine were charged into a 500-ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature of the resultant mixture was increased to 50° C. under agitation, and agitation was continued until no more hydrogen gas was absorbed by the mixture. The pressure of hydrogen was always kept at 8 to 10 kg/cm2 during the reaction. After the reaction had been completed, the autoclave was cooled, and the catalyst was filtered off. The most part of solvent was distilled off, and the residual solid was washed with isopropyl alcohol and then dried to obtain 27.2 g of 2-(2'-hydroxy-3'-t-butyl- 5'-methylphenyl)-5-chlorobenzotriazole as a target substance (yield, 86.2%; melting point, 138° to 140° C.).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)=[O:7])(C)(C)C.Cl.[C:24]([C:26]1[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=1)#[N:25].CN1CCOCC1.ClC(OCC)=O>O1CCOCC1.CN(C)C=O.C(OCC)(=O)C>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)=[O:7])=[CH:28][CH:27]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(C#N)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N2CCC[C@@H]2COc2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70 mg (0.23 mmol) of 1-t-butoxycarbonyl-(2R)-2-[(3-cyanophenoxy)methyl]pyrrolidine was dissolved in a dioxane solution containing 4 N hydrogen chloride and then stirred at room temperature for 3 hours. The solvent was distilled off to obtain the crude de-t-butoxycarbonyl product. 38 mg (0.25 mmol) of 4-cyano-benzoic acid was dissolved in 3 ml of dimethylformamide, and 100 mg (1 mmol) of N-methyl morpholine and 25 mg (0.23 mmol) of ethyl chloroformate were added thereto and stirred at 0° C. for 5 minutes, and the crude de-t-butoxycarbonyl product was added thereto and stirred at room temperature for 2 hours. The reaction solution was treated in an ordinary manner with ethyl acetate as the extractant to obtain the title compound.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 86.5 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.03 g, 0.11 mmol) was reacted with benzaldehyde (0.012 g, 0.11 mmol) in the presence of glacial acetic acid (0.007 g, 0.11 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.009 g, 0.14 mmol) in methanol (5 ml) (Procedure D) to give compound 16k (0.034 g, 85%).