Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:15]=[CH:16][CH:17]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:16][CH:17]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
After tert-butyl 3-[3-(4-oxo-4H-1,3-benzothiazin-2-yl)phenyl]propionate (0.19 g, 0.52 mmol) was dissolved in trifluoroacetic acid (1.0 ml), the mixture was stirred at room temperature for 2 hours. Isopropyl ether was added to the reaction solution and the precipitated crystals were taken by filtration. The precipitates were recrystallized from ethanol-isopropyl ether to give the title compound (0.056 g, 35%) as crystals.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[NH3:14]>O>[NH2:14][C@@H:3]([CH2:2][C:10]([OH:12])=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N
Solvent: O
Product: N[C@@H](CC(=O)O)c1ccccc1

Procedure:
The reaction solution (250 g) containing 12 weight % (wt %) of L-phenylalanine, a bacterial cell (in an appropriate amount) of MT-11046 produced in Example 1 and water was reacted at 20 degrees centigrade for 24 hours or more. During the reaction, pH of the reaction solution was adjusted to 9.2 with 25% ammonia water. A solid of (S)-β-phenylalanine precipitated under examined condition was observed. The reaction yield of (S)-β-phenylalanine was 62%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:36]=[N:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=3)=[CH:3][CH:4]=2)[N:9]=[C:10]([C:20]([C:22]([F:23])([F:25])[F:24])([C:26]([F:29])([F:27])[F:28])[OH:21])[CH2:11]1
Reactant: CSc1ccc(B(O)O)cn1
Reactant: OC(C1=NN(c2ccc(Br)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Product: CSc1ccc(-c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)cn1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 421, except for using 1-(4-bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole prepared in Step 5 of Preparation 24; and using 6-methylthiopyridin-3-ylboronic acid instead of 3-methylthiophenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][CH:28]=[CH:29][C:30](=[O:32])[CH3:31]>>[C:30]([C:29]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:27]([CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH:28]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)C=CNCc1ccccc1F
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3F)C=C1C(C)=O)C2=O

Procedure:
The title compound 55 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 56 (115 mg, 0.59 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum/EtOAc=2:1) afford the title compound 55 as a yellow solid. (Yield 0.11 g, 65%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl>O>[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)Cl
Reactant: c1ccsc1
Agent: Cl
Solvent: O
Product: CCCCCC(=O)c1cccs1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
The 2-hexanoyl thiophene was prepared by dissolving thiophene (0.9 g, 10.7 mmol) and hexanoyl chloride (1.52 g, 11.3 mmol), both of which were obtained from Aldrich Chemical Supply and used without further purification, in benzene (20 mL). The solution was cooled to 0° C. under argon. Stannic chloride (10.7 mL, 10.7 mmol, 1M solution in dichloromethane) was added dropwise and the resulting solution was stirred overnight. The next day, 20 mL of a 50:50 mixture of concentrated hydrochloric acid and water was added. The resulting mixture was stirred for two hours whereupon the color became golden yellow. The organic layer was separated, washed with sodium bicarbonate solution, dried (Na2 SO4) and concentrated to yield 2-hexanoyl thiophene (94% yield). The compound was further purified by column chromatography using hexane/dichloromethane as the elutant.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][C:14]2[N:23]3[N:24]=[C:25]([NH2:27])[N:26]=[C:22]3[C:21]3[CH:20]=[CH:19][C:18](F)=[CH:17][C:16]=3[N:15]=2)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C2C=CC(CC3N4N=C(N)N=C4C4C=CC(F)=CC=4N=3)=CC=2OC1.[OH:58][CH2:59][CH2:60][CH2:61][NH2:62]>>[NH2:27][C:25]1[N:26]=[C:22]2[N:23]([C:14]([CH2:13][C:12]3[CH:29]=[CH:30][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:10]([O:31][CH3:32])[CH:11]=3)=[N:15][C:16]3[CH:17]=[C:18]([NH:62][CH2:61][CH2:60][CH2:59][OH:58])[CH:19]=[CH:20][C:21]=32)[N:24]=1
Reactant: NCCCO
Reactant: COc1cc(Cc2nc3cc(F)ccc3c3nc(N)nn23)ccc1OCc1ccccc1
Agent: Nc1nc2c3ccc(F)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Product: COc1cc(Cc2nc3cc(NCCCO)ccc3c3nc(N)nn23)ccc1OCc1ccccc1
Yield: 35 %

Procedure:
Operating as in Example 54, but employing 5-(4-benzyloxy-3-methoxy-benzyl)-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine prepared as described in Example 34 instead of 5-benzo[1,3]dioxol-5-ylmethyl-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine and 3-hydroxy-propylamine instead of morpholine, the title compound was obtained in 35% yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].C[O-].[Na+].[C:27](=O)=[O:28]>CO>[CH3:27][O:28][C:19]([C:4]1[C:3]([S:21]([CH3:23])=[O:22])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[NH:20]
Reactant: O=C=O
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Temperature: 0 °C

Procedure:
To a stirred suspension of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (5.0 g) in anhydrous methanol was added a 25% w/w solution of sodium methoxide (8.95 ml) in methanol, at 20 ° C. The mixture was stirred for 16-hours, cooled to 0° C. and diluted with ice-cold anhydrous methanol. Carbon dioxide was passed into the solution for 15-minutes until a pH of 8 was attained. The precipitate was filtered off, washed (ethyl acetate) and evaporated to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidic acid methyl ester (3.65 g), 1H NMR (CDCl3) in ppm: 8.34(s,1H), 7.79(s,2H), 5.11(brs,2H), 3.93(s,3H), 2.94(s,3H). By proceeding in a similar manner the following compound was prepared:5-Amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-trifluoromethylsulfinyl-1H-pyrazole-3-carboximidic acid methyl ester, m.p. 179-180 ° C.
Reaction SMILES: Cl.Cl.[OH:3][C:4]([CH3:21])([CH3:20])[CH2:5][NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[Cl:22][C:23]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[Cl:22][C:23]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:24]=1[CH2:25][N:16]1[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]2/[C:7]([NH:6][CH2:5][C:4]([OH:3])([CH3:21])[CH3:20])=[N:8][C:9](=[O:19])[S:10]/2)[CH2:14][CH2:15]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution of (5Z)-4-[(2-hydroxy-2-methylpropyl)amino]-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (2 mL) was added a solution of triethylamine (0.32 mL) and 2-chloro-4-(trifluoromethyl)benzaldehyde (117 mg) in DMF (1 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (501 mg) was added. The reaction mixture was stirred at room temperature overnight, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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) and recrystallized from ethyl acetate/heptane to give the title compound (73 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:27]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(CCc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(CCc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 27 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-4-phenylbutanoic acid (310.3 mg) and ethyl 4-aminophenylacetate hydrochloride (201.6 mg) were condensed in THF (5 ml) in the presence of triethylamine (421.2 μl) and pivaloyl chloride (153.6 μl), and then the resulting crude product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide (117.6 mg).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:11]1[Cl:24])(C)(C)C.Cl.C=O.[OH-].[Na+]>C(O)C>[Cl:24][C:11]1[N:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:14]2=[C:13]([C:15]#[N:16])[C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCn1cc(C#N)c(-c2cccc(F)c2)c1Cl
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Reaction time: 0.75 h
Yield: 58.6 %

Procedure:
To a solution of 47.3 g (130 mmol) of tert-butyl{2-[2-chloro-4-cyano-3-(3-fluorophenyl)-1H-pyrrol-1-yl]ethyl}-carbamate in 85 ml of ethanol are added slowly 488 ml (1465 mmol) of aqueous 3N hydrochloric acid solution. Setting to a solid is rapidly observed, and the medium then becomes clear. After 45 minutes, 5.56 g (48.1 mmol) of paraformaldehyde are added and heating is continued at 70° C. for 2 hours 30 minutes. After cooling, the reaction medium is poured slowly into ice-cold aqueous 4N sodium hydroxide solution. The product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown oil, which is chromatographed on a column of 300 g of silica gel, eluting with a mixture of 1 to 2% methanol in dichloromethane, to give 21.0 g of 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile in the form of a beige-coloured powder after triturating in 150 ml of diisopropyl ether, at reflux, chilling, filtering off and drying.
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:66]1([CH2:72][SH:73])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:72]([S:73][C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: SCc1ccccc1
Reactant: Cc1c(Br)cccc1-c1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(SCc2ccccc2)cccc1-c1cccnc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Intermediate 73 (3 g, 12.09 mmol) in dioxane (50 ml) was stirred under argon, then DIPEA (3.82 ml, 24.18 mmol), xantphos (0.42 g, 0.73 mmol) and Pd2(dba)3 (0.33 g, 0.36 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (1.56 ml, 13.3 mmol) was slowly added and the reaction stirred for 16 h. The reaction was quenched by addition of 150 ml of H2O. After extraction (three times) with ethyl acetate the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the compound was obtained and used without further purification in step 22.3.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([O-:3])=[O:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([C:10]2[NH:21][N:20]=[N:19][N:11]=2)[CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1cccc(-c2nnn[nH]2)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
In 40 ml of N,N-dimethylformamide was dissolved 4.0 g of 3-(2-nitrophenoxy)benzonitrile followed by addition of 2.28 g of sodium azide and 1.88 g of ammonium chloride, and the mixture was stirred at 110° C. for 4 hours. After cooling, the reaction mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water twice, dried and concentrated. The residue was crystallized from ethyl acetate-benzene to give 3.6 g of the title compound as light brown crystals.
Reaction SMILES: [CH3:1]I.[CH:3]([C@@H:16]1[N:21]2[CH2:22][C@H:23]([OH:25])[CH2:24][C@H:20]2[CH2:19][N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].O>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.ClCCl>[CH:3]([C@@H:16]1[N:21]2[CH2:22][C@H:23]([O:25][CH3:1])[CH2:24][C@H:20]2[CH2:19][N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H](O)CN2[C@@H](C(c2ccccc2)c2ccccc2)C1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1C[C@H]2CN(C(=O)OC(C)(C)C)C[C@H](C(c3ccccc3)c3ccccc3)N2C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Methyl iodide (23 μl) was added to an ice-cooled mixture of tert-butyl (4S,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (155 mg) and cetyltrimethylammonium bromide (15 mg) and finely powdered sodium hydroxide (76 mg) in dichloromethane (2 ml), and the whole was stirred for 5 hours. Additional methyl iodide (23 μl) was added to the mixture and the mixture was further stirred overnight. The resulting mixture was poured into water and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected to give tert-butyl (4S,7R,8aS)-4-benzhydryl-7-methoxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (56 mg) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][O:17]C(=O)C)[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][OH:17])[N:6]2[CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(=O)OCc1nc2c(Cl)ncnc2n1CC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Cn1c(CO)nc2c(Cl)ncnc21

Procedure:
A solution of 6-chloro-8-acetoxymethyl-N9-neopentylpurine (1 mmol) in THF-water was treated with aqueous sodium hydroxide (1.5 mmol) at 0° C. for 0.5 h. Extraction and chromatography afforded 6-chloro-8-hydroxymethyl-N9-neopentylpurine as a yellow gel. TLC: Rf=0.38, 33% EtOAc-hexane.
Reaction SMILES: [CH3:1][C:2]1[S:6][N:5]=[N:4][C:3]=1[S:7][CH2:8][C:9]1[CH2:16][S:15][C@H:14]2[N:11]([C:12](=[O:26])[C@H:13]2[NH:17][C:18](=[O:25])[CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:10]=1[C:27]([O:29]C(C)(C)C)=[O:28].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.ClCCl>[CH3:1][C:2]1[S:6][N:5]=[N:4][C:3]=1[S:7][CH2:8][C:9]1[CH2:16][S:15][C@H:14]2[N:11]([C:12](=[O:26])[C@H:13]2[NH:17][C:18](=[O:25])[CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:10]=1[C:27]([OH:29])=[O:28]
Reactant: Cc1snnc1SCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1snnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 40.6 %

Procedure:
A cold (0° C.) solution of 2.62 g of the product of Example 7 in 20 ml of dry anisole and 25 ml of dichloromethane was treated with 20 ml of trifluoroacetic acid. After evaporation the residue was chromatographed as described in Example 7, giving 950 mg of the desired product. 'H NMR (300 MHz, CDCl3): δ 2.57 (s, 3H); 3.70 (AB quartet, 2H, 4-CH2); 3.87 (s, 2H); 4.17 (AB quartet, 2H, CH2S--); 4.97 (d, 1H, J=4.8 Hz, 6-H); 5.76 (dd, 1H, J=9.24 Hz, 4.8 Hz, 7-H); [6.98 (m, 2H) and 7.24 (m, 1H)(thienyl)].
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[C:7]([NH2:11])[CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[C:7]([NH2:11])[CH:8]=2)[N:3]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Nc1cc2c(cc1Cl)NC(=O)C2
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)Cc2cc(N)c(Cl)cc21
Reaction time: 4 h
Yield: 19.1 %

Procedure:
To a mixture of 2-oxo-5-amino-6-chloroindoline (3.2 g), potassium carbonate (4.8 g) and acetone (60 ml) was added dropwise ethyl chloroacetate (3.2 g) at ambient temperature. The reaction mixture was refluxed with stirring for 4 hours and then filtered under warm condition. The filter cake was washed with acetone. The combined filtrate and washings were concentrated under reduced pressure to give a residue, which was purified by a column chromatography on silica gel to give crystalline ethyl 2-oxo-5-amino-6-chloro-1-indolineacetate (0.9 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:41]([O-])=O)[C:18]([NH:19][CH:20]4[CH2:28][CH:27]5[CH:23]([CH2:24][C:25](=[O:40])[N:26]5[CH2:29][C:30]5[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=5[O:38][CH3:39])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:41][C:17]1[C:18]([NH:19][CH:20]2[CH2:28][CH:27]3[CH:23]([CH2:24][C:25](=[O:40])[N:26]3[CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=3[O:38][CH3:39])[CH2:22][CH2:21]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]2=[N:15][CH:16]=1
Reactant: COc1ccc(CN2C(=O)CC3CCC(Nc4c([N+](=O)[O-])cnc5c4ccn5S(=O)(=O)c4ccccc4)CC32)c(OC)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN2C(=O)CC3CCC(Nc4c(N)cnc5c4ccn5S(=O)(=O)c4ccccc4)CC32)c(OC)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a solution of 6-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-1-(2,4-dimethoxy-benzyl)-octahydro-indol-2-one (prepared as in Example 111) (152.3 mg, 0.2515 mmol) in ethanol (3 mL) was added ammonium chloride (59.0 mg, 1.10 mmol), iron powder (70.4 mg, 1.26 mmol), and water (5 mL). The reaction mixture was stirred at 70° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered through celite to remove iron and inorganic solids, rinsing with ethanol. The filtrate was neutralized with saturated aqueous sodium bicarbonate, and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulphate, filtered, and evaporated in vacuo to yield 134.5 mg (93%) of 6-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-1-(2,4-dimethoxy-benzyl)-octahydro-indol-2-one, which was carried forward without purification. LCMS (Method E, ESI): RT=1.43 min, m+H=576.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[SH:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(O)C>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1
Reactant: Sc1cccc2nccn12
Reactant: ClCCCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: ClCCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a nitrogen atmosphere, 8.87 ml (77 mmol) of 1-bromo-4-chlorobutane was added to a solution of 10.51 g (70 mmol) of 5-mercaptoimidazo[1,2-a]pyridine and 10.73 ml (77 mmol) of triethylamine in 150 ml of ethanol was added, followed by stirring at room temperature for 16 hours. After the solvent was distilled off, the residue was dissolved in dichloromethane. This solution was washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to yield 12.93 g (76.7%, light brown oily substance) of the desired product.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])(O)(=O)=O.[Na+].[CH:15]([C:18]([CH3:20])=O)([CH3:17])[CH3:16]>O>[CH3:20][C:18]1[C:15]([CH3:17])([CH3:16])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[N:7]=1
Reactant: CC(=O)C(C)C
Reactant: NNc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CC1=Nc2ccccc2C1(C)C
Reaction time: 3 h
Yield: 94 %

Procedure:
226 g (2 mol) of phenylhy-drazine (95.7% pure) were initially introduced at 90° C. in a solution of 5 mol of sodium hydrogen sulphate in 1900 ml of water. 225 ml (2.1 mol) of methyl isopropyl ketone were added dropwise in the course of 30 min. The mixture was stirred for 3 h at 90° to 100° C. After cooling, the batch was neutralised and the organic phase was separated off and distilled. 299.3 g of 97.5% pure 2,3,3-trimethylindolenine were obtained Yield: 91.6% of the theoretical yield.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[N+:8]([C:11]1[C:12]([Cl:20])=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14][NH2:15])([O-:10])=[O:9]>C1COCC1>[N+:8]([C:11]1[C:12]([Cl:20])=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14][NH:15][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])([O-:10])=[O:9]
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 8 h

Procedure:
2,2-Dimethyl-propionic acid chloride (0.124 mL, 1.01 mmol) is added to a mixture of 3-nitro-2,4-dichloro-benzylamine (0.28 g, 1.01 mmol) and TEA (0.35 mL, 2.52 mmol) in THF (10 mL) and it is stirred overnight. The reaction mixture is concentrated, diluted with EtOAc, washed successively with 5% aq. NaHCO3 solution and brine, dried with Na2SO4 filtered and concentrated.