Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[O:12]1[CH:18]2[CH:13]1[C:14]([CH3:31])([CH3:30])[O:15][C:16]1[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][C:17]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[C@@H:18]1[C:17]2[CH:19]=[C:20]([S:23]([C:26]([F:27])([F:29])[F:28])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][C:14]([CH3:30])([CH3:31])[C@H:13]1[OH:12]
Reactant: C[Si](C)(C)Oc1ccccn1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2C2OC21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](n2ccccc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.4 %

Procedure:
1.63 g of 2-trimethylsilyloxypyridine was added to a solution of 1.00 g of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran (prepared as described in Preparation 8) in 1.2 ml of anhydrous tetrahydrofuran, and a solution of 2.54 g of tetrabutylammonium fluoride in anhydrous tetrahydrofuran was added to the resulting mixture through a syringe, whilst ice-cooling and under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 72 hours, after which it was poured into water and extracted with ethyl acetate. The extract was then washed with water, with a 5% w/v aqueous solution of hydrochloric acid, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and cyclohexane as the eluent, to afford 503 mg of the title compound as about a 1:1 mixture of rotational isomers, melting at 219°-220° C.
Reaction SMILES: [Br-].[CH2:2]([N+:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH:6]=1)[CH:3]=[CH2:4].C1(CCN2CCCC(C(C)=O)=C2)C=CC=CC=1>>[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][C:7]([C:11]([CH2:12][CH2:13][CH3:14])=[O:15])=[CH:6]1)[CH2:3][CH3:4]
Reactant: C=CC[n+]1cccc(C(=O)CCC)c1
Agent: CC(=O)C1=CN(CCc2ccccc2)CCC1
Agent: [Br-]
Product: CCCC(=O)C1=CN(CCC)CCC1

Procedure:
1-(2-Propenyl)-3-butyryl pyridinium bromide was hydrogenated according to the procedure described in Part (b) of Example 6 to give propyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone. The product was distilled as a pale yellow oil (b.pt 150-153°C./0.3 mm Hg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]2[C:15]([N:17]2[CH2:23][C:22]3[CH:24]=[C:25]([C:28]4[CH:29]=[C:30]5[N:36](C(OCC(C)C)=O)[CH:35]=[N:34][C:31]5=[N:32][CH:33]=4)[CH:26]=[CH:27][C:21]=3[O:20][CH2:19][CH2:18]2)=[O:16])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]2[C:15]([N:17]2[CH2:23][C:22]3[CH:24]=[C:25]([C:28]4[CH:29]=[C:30]5[N:36]=[CH:35][NH:34][C:31]5=[N:32][CH:33]=4)[CH:26]=[CH:27][C:21]=3[O:20][CH2:19][CH2:18]2)=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CN(C(=O)N3CCC(=O)CC3c3cccc(F)c3)CCO4)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCN(C(=O)N2CCOc3ccc(-c4cnc5[nH]cnc5c4)cc3C2)C(c2cccc(F)c2)C1
Yield: 289.6 %

Procedure:
2-methylpropyl 6-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (0.19 g, 0.32 mmol) and potassium carbonate (0.20 g, 1.4 mmol) in methanol (10 mL) was stirred for 45 minutes at 25° C. The mixture was diluted with ethyl acetate (80 mL) washed with water (50 mL) and brine (25 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (methanol/ethyl acetate 1:10). Residue obtained by the concentration of product containing fractions was stirred 18 hours at 25° C. in diethyl ether (20 mL) and the solid product thus formed was isolated by filtration to give 2-(3-fluorophenyl)-1-{[7-(3H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}piperidin-4-one (0.45 g, 27% yield). 1H NMR (400 MHz, d6-DMSO): 8.62 (s, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 7.69 (d, 1H), 7.57 (d, 1H), 7.24 (q, 1H), 7.10-7.01 (m, 4H), 5.19 (t, 1H), 4.61 (m, 2H), 4.24 (m, 2H), 3.72 (m, 3H), 3.41 (m, 2H), 2.84 (m, 2H), 2.61 (m, 1H), 2.34 (d, 1H); MS (EI) for C27H24FN5O3: 486 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(N(CC)CC)C.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=2[OH:40])[N:23]=1>C(Cl)Cl>[F:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:40])[C:33]=1[C:24]1[N:23]=[C:22]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]=1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3c(O)cccc3F)nc2c1
Reaction time: 1 h

Procedure:
A solution of tert-butyl(R)-pyrrolidin-3-ylcarbamate (368 mg, 1.97 mmol) and triethylamine (0.46 mL, 3.28 mmol) in CH2Cl2 was rapidly added to a stirring solution of 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (475 mg, 1.65 mmol) in 15 mL CH2Cl2 at 0° C. under an N2 atmosphere. The reaction was stirred for 1 h before it was quenched with water, and the aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 yielded tert-butyl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 439.5 (M+H)+ at 2.42 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C@@H:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:12]=[CH:11][C:5]([C@@H:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@H](O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)[C@H](O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
(R)-4-Hydroxymandelic acid (2.02 g) was dissolved in N,N-dimethylformamide (24 ml), and benzyl bromide (3.57 ml) and potassium carbonate (3.65 g) were added to the solution at room temperature with stirring. After reaction for 12 hours, ice-water was poured into the reaction mixture and the resulting precipitates were collected by filtration. The precipitates were suspended in methanol (24 ml) and 1N aqueous sodium hydroxide solution (12 ml) was added to the suspension under ice-cooling with stirring. After reaction at room temperature for 2 hours, 1N hydrochloric acid (12 ml) was added to the reaction mixture under ice-cooling with stirring. Collection by filtration of the resulting precipitates gave (R)-4-benzyloxymandelic acid (2.43 g) having a melting point of 161-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CCl)cc1
Yield: 81.5 %

Procedure:
To a solution of p-methoxycarbonylbenzyl alcohol (332.0 g, 2.0 mol) in methylene chloride (600 mL) is added thionyl chloride (380 g, 3.2 mol) dropwise over 3 hours and the reaction mixture heated at gentle reflux for 6 hours, allowing excess gases to escape. The excess thionyl chloride and methylene chloride are removed and the yellow oil triturated with hexane to yield a total of 300 g (81.5% yield) of white, solid methyl α-chloro-p-toluate, the identity of which is confirmed by elemental analysis and mass spectrum analysis as follows:
Reaction SMILES: [CH:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH:20](Br)Br)([CH3:3])[CH3:2].C(=O)([O-])[O-:24].[Ca+2].O>C(O)C>[CH:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH:20]=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(C(Br)Br)c(-c2ccc(F)cc2)c2cccnc21
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Product: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2cccnc21

Procedure:
1 g of the product of step 1, above, in 35 ml of 100% ethanol is mixed with 0.4g of calcium carbonate (powdered) and 15 ml of water. The mixture is refluxed for about 4 hours, then cooled, quenched with water and extracted with ethyl acetate. The extracts are dried and then evaporated to dryness to yield a dark amber gum, which is chromatographed on prep. plates, using petroleum ether/ether (85/15) and the largest (second of three) major band eluted with ethyl acetate to obtain the title product of this example as yellow solids, mp 95°-101°.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH2:14][O:13][CH:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Sn](C)(C)C)[N:18]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][O:13][CH:12]1[C:17]1[N:18]=[C:19]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: C[Sn](C)(C)c1cccc(C2OCCCO2)n1
Reactant: Ic1n[nH]c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: c1cc(-c2n[nH]c3ccccc23)nc(C2OCCCO2)c1
Reaction time: 0.25 h

Procedure:
60 mg of Pd(PPh3)4 are added to 0.82 g (3.35 mmol) of 3-iodoindazole in 10 ml of DMF at room temperature under argon, and the mixture is stirred for 15 minutes. 1.1 g (3.35 mmol) of 2-(1,3-dioxan-2-yl)-6-trimethylstannylpyridine are added and the mixture is stirred at 100° C. for 4 hours. It is then evaporated in vacuo and the residue is chromatographed over silica gel. 300 mg (32% of theory) of an oil are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:37]([O:39][CH2:40][CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]=[C:43]1[NH:51][CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH3:38].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C.CO>C(#N)C.ClCCl>[CH3:36][O:35][C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:32]=1[O:33][CH3:34])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:55]2[CH2:54][CH2:53][CH:52]([NH:51][C:43]3[N:42]([CH2:41][CH2:40][O:39][CH2:37][CH3:38])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:57][CH2:56]2)([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOCCn1c(NC2CCN(CCC3(c4ccc(OC)c(OC)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 54 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.51 g, 0.97 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.34 g, 1.2 mmol), and N,N-diisopropylethylamine (0.25 g, 1.9 mmol) in acetonitrile (5 mL). Heat to reflux. After 54 hours, partition the residue between ethyl acetate and 5% sodium bicarbonate solution. Separate the layers and extract the organic layer with 5% sodium bicarbonate and then water. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/methanol to give a residue. Combine the residue with dichloromethane and extract with water. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Dry the residue in vacuo at 60° C. to give the title compound: Rf=0.37 (silica gel, 1/1 ethyl acetate/methanol).
Reaction SMILES: C(OC(C([N:15]1[CH:18]([S:19][CH2:20][C:21]#[C:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]([NH:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]1=[O:50])=C(C)C)=O)C1C=CC=CC=1.[Mn]([O-])(=O)(=O)=O.[K+]>N1C=CC=CC=1.O.C(OCC)(=O)C.S(=O)=O.[O-2].[O-2].[Mn+4]>[C:24]1([CH2:23][C:22]#[C:21][CH2:20][S:19][CH:18]2[NH:15][C:16](=[O:50])[CH:17]2[NH:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Mn+4]
Agent: O=S=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: O=C1NC(SCC#CCc2ccccc2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
1-(1-Benzyloxycarbonyl-2-methyl-1-propenyl)-3-(triphenylmethylamino)-4-(4-phenylbut-2-ynylthio)azetidin-2-one (5.40g) was dissolved in a mixture of pyridine (60ml) and water (6ml). The stirred mixture was cooled in an ice-salt bath and finely powdered potassium permanganate (2.30g) was added. The cooled mixture was stirred for a further 1.5 hours. The mixture was diluted with ethyl acetate (100ml) and water (10ml) and sulphur dioxide was passed until the manganese dioxide had dissolved. The organic layer was separated and washed successively with sodium bicarbonate solution, brine, N.hydrochloric acid, and brine The dried (MgSO4) organic layer was evaporated to give a crude gum (4.8g). The crude gum was chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give 4-(4-phenylbut-2-ynylthio)-3-triphenylmethylamino-azetidin-2-one as a crystalline solid (0 852g, 22%). Recrystallisation of the product gave a colourless crystalline solid, MP=145°-6°C.
Reaction SMILES: [Br:1][C:2]([F:18])([F:17])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH:7]1[C:14]([OH:16])=O)([F:5])[F:4].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[Br:1][C:2]([F:18])([F:17])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:13])[CH2:8][CH:7]1[C:14]([NH:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])([F:4])[F:5]
Reactant: NC1CCCCC1
Reactant: O=C(O)C1CC(C(=O)O)C(C(F)(F)C(F)(F)Br)C1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)C1CC(C(=O)NC2CCCCC2)C(C(F)(F)C(F)(F)Br)C1
Yield: 76 %

Procedure:
Into a glass flask were charged 3.00 g (8.90 mmol) of 4-(2-bromo-1,1,2,2-tetrafluoroethyl)cyclopentane-1,3-dicarboxylic acid, 8.83 g (89.0 mmol) of cyclohexylamine and 50 g of toluene, and the mixture was refluxed using a Dean and Stark apparatus for 10 hrs. Thereafter, the solvent was distilled off, and 100 mL of dichloromethane was added thereto. The organic layer washed with 50 mL of 1 M aqueous hydrochloric acid four times, with 50 mL of an aqueous sodium bicarbonate solution three times, and then with 50 mL of saturated brine once. After washing, the solvent of the organic layer was distilled off, and purification was carried out on column chromatography to obtain 3.38 g of 4-(2-bromo-1,1,2,2-tetrafluoroethyl)-N1,N3-dicyclohexylcyclopentane-1,3-dicarboxamide (precursor compound (a-8)) represented by the following formula (a-8) (yield: 76%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: Fc1ccccc1CBr
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(Cc2ccccc2F)c2ccccc12

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and 2-fluorobenzyl bromide in place of the benzyl bromide used in Example 1 to give 1.46 g of 1-(2-fluorobenzyl)indole-3-carbaldehyde as yellowish brown crystals. The yield thereof was found to be 96%.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[CH3:16][CH:17]1[N:22]([CH3:23])[CH2:21][CH2:20][N:19]([C:24]([C@@H:26]2[CH2:30][C@H:29]([S:31]CC3C=CC(OC)=CC=3)[CH2:28][N:27]2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[O:42])=[O:25])[CH2:18]1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[CH3:16][CH:17]1[N:22]([CH3:23])[CH2:21][CH2:20][N:19]([C:24]([C@@H:26]2[CH2:30][C@H:29]([SH:31])[CH2:28][N:27]2[C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=2)=[O:42])=[O:25])[CH2:18]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)C(C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.4 ml of trifluoroacetic acid and 0.31 ml of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 940 mg of (2S,4S)-2-(3,4-dimethyl-1-piperazinylcarbonyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 13) in 1.88 ml of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was treated in a similar manner to that described in Example 13(1), to give 1.2 g of the title compound as a powder.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][OH:28])C>CS(C)=O>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][OH:28])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CCO
Solvent: CS(C)=O
Product: O=c1cc(CO)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-hydroxy-but-2-ynoic acid ethyl ester (G. Cai et al., Tetrahedron, 2006, 5697-5708) employing the procedure described in Example 99. [α]D25 +5.80 (c 0.5, DMSO)
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11](Cl)[CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:17])=[N:8]1)[CH3:2].Br.BrCCCN1CCCC1.NC1C2C(=CC=C([Cl:40])C=2)NN=1.Br.BrCCCN(CC)CC.NC1C2C(=CC=CC=2Cl)NN=1>>[N:3]1([CH2:4][CH2:5][CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:40])=[CH:13][CH:14]=3)[C:9]([NH2:17])=[N:8]2)[CH2:18][CH2:19][CH2:2][CH2:1]1
Reactant: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Reactant: Nc1n[nH]c2ccc(Cl)cc12
Agent: Br
Agent: BrCCCN1CCCC1
Agent: CCN(CC)CCCBr
Product: Nc1nn(CCCN2CCCC2)c2ccc(Cl)cc12

Procedure:
The same procedures for preparing 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole as described in Example 89 were repeated except that 4.78 g of 3-bromopropylpyrrolidine hydrobromide and 5.66 g of 3-amino-5-chloroindazole were employed instead of the 3-bromopropyldiethylamine hydrobromide and the 3-amino-4-chloroindazole, respectively. As a result, 4.98 g of 1-(3-pyrrolidinopropyl)-3-amino-5-chloroindazole was obtained.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([C:16]([OH:18])=O)[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=O>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]2[C:16](=[O:18])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)O
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 5 °C

Procedure:
To a suspension of 750 g of monosodium-4-chlorophthalate and 1200 ml water was added 120 ml conc. sulfuric acid. The resulting brown solution was extracted with three 400 ml portions of ether. The combined extracts were treated with carbon black, filtered and the ether distilled. The 4-chlorophthalic acid obtained was dehydrated by heating to 170°C for two hours to give 550 g of anhydride. To a solution of the anhydride in 600 ml of toluene was added 219 g of n-butylamine diluted with an equal weight of toluene. The solution was refluxed for 16 hours and the water formed was collected in a Dean-Stark trap. After treatment with carbon black the hot toluene solution was cooled to 5°C to give 280 g of crude 4-chloro-N-butyl phthalimide. Recrystallization from 1000 ml ethanol afforded 240 g of 99% pure imide.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[O:22]=[C:19]1[N:18]=[C:17]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:21][S:20]1
Reactant: CCOC(=O)CN
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
To a solution of ethyl glycinate hydrochloride (5.00 g) and triethylamine (4.99 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.98 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.84 g).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.Cl.[CH3:21][C:22]1[CH:26]=[C:25]([NH2:27])[S:24][N:23]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:27][C:25]2[S:24][N:23]=[C:22]([CH3:21])[CH:26]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: Cc1cc(N)sn1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)sn1
Reaction time: 5 h
Yield: 85.2 %

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 3-methylisothiazol-5-amine hydrochloride (50 mg, 0.332 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 5 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-methylisothiazol-5-ylamino)pyrazine-2-carbonitrile (80 mg, 0.219 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (44 mg). MS 384.2 (M+H); UV 209.0, 270.7, 321.3 nm; t 0.362 min.