Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11](C)[CH:10]=2)[N:5]=[C:4]([C:17]([NH:19][OH:20])=[NH:18])[N:3]=1.[F:21][C:22]([F:35])([F:34])[CH2:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][N:26]=1>N1C=CC=CC=1>[CH3:16][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:17]2[N:18]=[C:29]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH2:23][C:22]([F:35])([F:21])[F:34])=[CH:33][CH:32]=3)[O:20][N:19]=2)[N:5]=1
Reactant: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Reactant: O=C(Cl)c1ccc(OCC(F)(F)F)nc1
Solvent: c1ccncc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(OCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
In a sealed tube under nitrogen was placed 4-amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5]triazine-2-carboxamidine (Intermediate 1, 100 mg, 380 μmol). Then 5 mL anhydrous pyridine was added followed by 6-(2,2,2-trifluoroethoxy)-nicotinoyl chloride (prepared in an analogous manner to Intermediate 57, 91 mg, 380 μmol). The mixture was stirred at room temperature for 48 hrs. After this time the mixture was heated at 115 C for 18 h, allowed to cool and concentrated in vacuo. The crude residue was loaded onto a 2 g isolute silica column in a minimal amount of DCM and eluted with ethyl acetate-heptane 20-50% to give the title compound (54 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]1[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.CO[CH:36]1[CH2:40][CH2:39][CH:38](OC)O1>C(O)(=O)C>[CH3:1][C:2]1([CH3:33])[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:36]=[CH:40][CH:39]=[CH:38]3)=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]1[CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: CC1(C)c2ccc(N)cc2S(=O)(=O)N1CCCN1CCN(c2cccc3ccccc23)CC1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CC1(C)c2ccc(-n3cccc3)cc2S(=O)(=O)N1CCCN1CCN(c2cccc3ccccc23)CC1
Yield: 86 %

Procedure:
The pyrrole ring was assembled by reacting 3,3-dimethyl-2-[3-(4-(1-naphthyl)-1-piperazinyl)prop-1-yl]-6-amino-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide with 2,5-dimethoxytetrahydrofuran in glacial acetic acid at 100° C. (1 h) in 86% yield.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([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.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(C)c(-n2ncc3c(Cl)ncnc32)c1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(C)ccc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
60% sodium hydride (0.187 g, 4.67 mmol) was added to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1.568 g, 3.90 mmol) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AJ3)(1.008 g, 3.90 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The residue was diluted with water (20 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated to give the crude product. This was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane to afford the product (1.400 g, 57.5%). m/z (ES+) (M+H)+=625; HPLC tR=3.53 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15].[Cl-].[NH4+]>CCCCCC.O.O1CCCC1.CCOCC>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1cncnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C[Sn](C)(C)c1cncnc1
Temperature: -110 °C
Reaction time: 3.5 h

Procedure:
To a reaction vessel equipped with a mechanically driven agitator, water cooled condenser, addition funnel, thermometer, and nitrogen inlet was added a solution containing 47.7 g. (0.3 mole) of 5-bromopyrimidine in 300 cc. of anhydrous ether and 300 cc. of anhydrous tetrahydrofuran. The solution was cooled to -110° C. using an ethyl alcohol-liquid nitrogen bath. By a dropwise addition, 120 cc. (0.3 mole) of n-butyllithium in n-hexane was added over 50 minutes. The solution was stirred for an additional 3.5 hours. A solution containing 49.8 g. (0.25 mole) of trimethyltin chloride in 150 cc. of anhydrous tetrahydrofuran was added over 60 minutes. After 10 minutes of stirring at -110° C. the orange mixture solidified and stirring was discontinued. The mixture was allowed to warm to -32° C. over 16 hours during which time it liquified and stirring was resumed for 4 hours. The mixture was hydrolyzed with 300 cc. of a saturated aqueous solution of ammonium chloride plus an additional 100 cc. of water. The aqueous phase was separated from the organic phase and washed with 250 cc. of ether. The organic portions were combined, washed twice with 500 cc. of water, separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The dark orange residue was distilled under reduced pressure (19 mm.). A clear colorless liquid fraction (35.2 g.) boiling at 118°-122° C. was collected and found to be 90% pure by gas chromatography. The liquid was redistilled under reduced pressure (19 mm.) and the clear fraction boiling between 119°-120° C. was collected and analyzed. The tin content was found to be 48.14% while the nitrogen content was 11.82%. The calculated tin and nitrogen contents for trimethyl-5-pyrimidyltin are 48.87% and 11.53%, respectively. Gas chromatographic analysis indicated a purity of 97% and the refractive index was recorded as 1.5349 at 25° C. The nuclear magnetic resonance spectrum contained a singlet at 0.38 pp. (CH3 -Sn, 9H's), a triplet at 8.7 ppm. (α-pyrimidyl H's, 2H's), and a singlet at 9.12 ppm. (γ-pyrimidyl H, 1H), all consistent with the expected structure.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[NH:29][C:30]2[C:31]3[C:38]([CH3:39])=[C:37]([C:40]([OH:42])=O)[S:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O[N:44]1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=2[NH:29][C:30]2[C:31]3[C:38]([CH3:39])=[C:37]([C:40]([NH2:44])=[O:42])[S:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (74 mg) added to a mixture of the 4-[2-((S)-1-tert-butoxycarbonyl-piperidin-3-yloxy)-4-trifluoromethyl-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (177 mg) and N-hydroxysuccinimide (55 mg) in DMF (4 ml). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with water and brine. The organics were passed through a hydrophobic frit and the solvent was evaporated. The residue was dissolved in DMF (2 ml) and ammonia in methanol (2 ml) was added. The reaction was stirred for 1 h. Further ammonia in methanol (2 ml) was added and the reaction was stirred again. After 30 min the reaction was diluted with EtOAc and washed with water and brine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.[CH2:23]([O:30][CH2:31][C:32]1([C:36]2[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=2)[CH2:35][O:34][CH2:33]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C(O)C>[CH2:23]([O:30][CH2:31][C:32]1([C:36]2[CH:41]=[CH:40][C:39]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[Cl:1])[NH:8][CH:7]=[C:6]4[C:11]([O:13][CH3:14])=[O:12])=[CH:38][CH:37]=2)[CH2:33][O:34][CH2:35]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: Brc1ccc(C2(COCc3ccccc3)COC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(COCc5ccccc5)COC4)cc3)cc12
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A mixture of methyl 6-Chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1H-indole-3-carboxylate (241 mg, 0.75 mmol), 3-Benzyloxymethyl-3-(4-bromo-phenyl)-oxetane (250 mg, 0.75 mmol), 2M aqueous potassium carbonate (1.51 mL, 3 mmol), toluene (9 mL), and ethanol (3 mL) was sparged with N2 for 10 minutes, then treated with [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (29 mg, 0.035 mmol). The reaction mixture was heated to 100 degrees and stirred. After 2 hours the reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown oil, which was purified by flash chromatography (40 g silica, 10-60% ethyl acetate/heptane, 17 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless solid (215 mg, 62% yield). MS (ES+) 462 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 8.04 (s, 1 H), 8.02 (s, 1 H), 7.99 (s, 1 H), 7.43-7.57 (m, 4 H), 7.23-7.34 (m, 5 H), 4.90-5.01 (m, 4 H), 4.58 (s, 2 H), 3.90 (s, 3 H), 3.88 (s, 2 H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)(O)[O-].[Na+]>>[CH3:1][N:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CCCCCN(C)c1ccccc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 72.5 %

Procedure:
A mixture of N-methylaniline (25 g) and ethyl 6-bromohexanoate (50 g) was stirred at 120° C. for 24 hours. After cooling, an aqueous sodium bicarbonate was added to make the mixture alkaline. Then the resulting mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and distilled to obtain ethyl 6-(N-methylanilino)hexanoate (40.5 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]=[N+]=[N-])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[NH4+]>N1C=CC=CC=1>[NH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN=[N+]=[N-]
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NCCOCCOCCOCCN
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a chilled, stirred solution of 24.4 g of Compound XIX in 250 ml pyridine was added 89 g of triphenyl phosphine. Nitrogen bubbles evolved. The solution was stirred with ice cooling for 45 minutes and then allowed to warm to room temperature. After 45 minutes at room temperature 100 ml of concentrated ammonium hydroxide was added and the mixture stirred overnight. The mixture was partitioned between 500 ml of 0.5N citric acid and 250 ml of ether. The aqueous phase was washed with ether (2×250 ml) to remove triphenyl phosphine oxide. The aqueous phase was saturated with sodium chloride and extracted with 1-butanol (4×250 ml) and dichloromethane (4×250 ml). The combined alcohol and dichloromethane extracts were concentrated under reduced pressure and the residue was taken up in 100 ml of ethanol. Concentrated hydrochloric acid (15 ml) was added and the solvent removed under reduced pressure. The residue was crystallized from ethanol/ether. The hygroscopic crystals were dried under vacuum.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[N:21]([CH3:29])[CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd]>[NH:14]1[CH2:17][CH:16]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[N:21]([CH3:29])[CH:20]=2)[CH2:15]1
Reactant: Cn1cc(CC2CN(C(c3ccccc3)c3ccccc3)C2)c2cc(F)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: Cn1cc(CC2CNC2)c2cc(F)ccc21
Yield: 87.7 %

Procedure:
This compound was prepared as described for Intermediate 31, using 3-(1-benzhydryl-azetidin-3-ylmethyl)-5-fluoro-1-methyl-1H-indole (0.37 g, 0.94 mmol), palladium on carbon (10%, ˜0.1 g) and ammonium formate (0.24 g, 2.8 mmol), to afford 0.18 g of the title compound as a clear oil. The oxalate was prepared in ethanol and collected as a white solid, m.p. 155-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][CH:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 81.5 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 3-(5-aminopyridin-2-ylamino)pyrrolidine-1-carboxylate (417 mg, 1.5 mmol) to afford the desired product (450 mg, 98%) as a yellow solid: ESI MS m/z 552 [C27H30BrN5O3+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2].S[CH2:22][C:23]([OH:25])=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1]([C:4]1[C:5]([CH:13]([CH2:22][C:23]([OH:25])=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(cc1C(O)c1ccccc1)OCO2
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)c1cc2c(cc1C(CC(=O)O)c1ccccc1)OCO2
Yield: 102.4 %

Procedure:
1.2 g of α-(6-isopropyl-1,3-benzodioxol-5-yl)-benzyl alcohol was dissolved in 10 ml of benzene, followed by the addition of 490 mg of mercaptoacetic acid and a catalytic amount of p-toluenesulfonic acid monohydrate. The obtained mixture was heated under reflux for one hour and cooled, followed by the addition of benzene. The mixture was washed with water, followed by the addition of a 1N aqueous solution of sodium hydroxide. The alkaline layer was separated, acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane/chloroform=3:7) to obtain 1.42 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:5].[C:22](Cl)(Cl)=[O:23]>Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:1][C:22]2=[O:23])=[O:17])=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(C(=O)NNC(=O)c2ccccc2N)cc1
Agent: Cl
Product: COc1ccc(C(=O)Nn2c(=O)[nH]c3ccccc3c2=O)cc1

Procedure:
28.5 g N-(2-amino-benzoyl)-N'-p-methoxy-benzoylhydrazine are dissolved in 800 cc 2N hydrochloric acid. A phosgene stream is passed through the solution, for a period of time of 1 hour. After purging the apparatus, the reaction product is suction filtered and washed with water. It is purified by recrystallization from isopropanol. M.P.=289° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[C:16]([O:26][CH3:27])[CH:15]=1>N1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:22](/[CH:21]=[CH:20]/[C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[O:26][CH3:27])(=[O:23])=[O:24])=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1ccc(Cl)cc1S(N)(=O)=O
Yield: 99.5 %

Procedure:
A solution of 2-amino-5-chlorobenzenesulfonamide (0.041 g, 0.20 mmol) and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride (0.053 g, 0.20 mmol) in pyridine (2 mL) was stirred at room temperature over night. The reaction mixture was concentrated, 1 M hydrochloric acid was added and the mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulfate and the solvent was evaporated to give 0.087 g (99% yield) of the title compound.
Reaction SMILES: [Cl-].[K+].[OH:3][CH2:4][C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6].[OH2:15]>>[CH2:13]([OH:14])[C@H:11]1[O:12][C@H:4]([O:3][C@:11]2([CH2:13][OH:14])[O:15][C@H:5]([CH2:4][OH:3])[C@@H:7]([OH:8])[C@@H:9]2[OH:10])[C@H:5]([OH:6])[C@@H:7]([OH:8])[C@@H:9]1[OH:10]
Reactant: O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [Cl-]
Agent: [K+]
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
Pichia strains GTS115 (NRRL Y-15851) and NRRL Y-11430 were transformed according to the procedure of Example I. The transformed spheroplasts were allowed to regenerate on either 0.6M KCl or 1M Sorbitol containing regeneration media. For screening Suc+ colonies, the regenerated cells embedded in agar were carefully dislodged into a sterile 50 mL disposable centrifuge tube, mixed with 10 ml water, and vortexed to disperse the cells from agar. The agar-cells suspension was passed through several folds of sterilized cheesecloth. The agar chunks retained on the cheesecloth were rinsed two times with 10 mL water to recover cells trapped in agar and cloth. The filtrate containing cells and fine agar particles was centrifuged at 5000 rpm in HS-4 rotor for five minutes at room temperature. Under these conditions, cells formed a tight pellet, while agar particles formed a loose pellet on the top of cells. The agar layer was removed by disturbing the tubes gently and pouring off the milky supernatant solution. The tight cell pellet remaining in the tube was suspended in 5 mL water and aliquots were plated on MSu to screen for Suc+ transformants.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[S:25][C:26]4[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=4[CH:28]=3)[C:9]([CH2:18][O:19][CH2:20][C:21]([NH2:23])=[O:22])=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1.ClCCl>[C:42]([N:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:24]3[S:25][C:26]4[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=4[CH:28]=3)[C:9]=2[CH2:18][O:19][CH2:20][C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]1)(=[O:44])[CH3:43]
Reactant: COc1cc(C)cc2cc(-c3c(COCC(N)=O)c(CN4CCNCC4)n4ncnc(N)c34)sc12
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C)cc2cc(-c3c(COCC(N)=O)c(CN4CCN(C(C)=O)CC4)n4ncnc(N)c34)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 33 (105 mg, 68% purity, 144 μmol) in THF/dichloromethane (1:2.5, 3.9 ml) was treated with sodium carbonate (179 mg, 1.6 mmol) and stirred at rt for 30 min. Acetyl chloride (30 μl, 424 μmol) was added, and the resulting mixture was stirred at rt for 30 min, then quenched with methanol (2 ml) and evaporated. Purification by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) afforded 30 mg (85% purity, 34% of th.) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:12]1=[O:29].[OH-].[Na+]>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:13]2[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:12]2=[O:29])=[CH:23][CH:24]=1
Reactant: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product is produced as described in example 18 from 20 g of 8-[3-(4-chlorophenyl)-2-oxo-4-phenyl-4-imidazolin-1-yl] caprylic acid methyl ester and 1.88 g of NaOH in 100 cc. of methanol. Further purification by chromatography on silicic acid gel using a mixture of hexane annd ethyl acetate as eluant.
Reaction SMILES: [Mg].[CH:2](=O)[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][C:13]1[S:17][S:16][C:15](=[S:18])[CH:14]=1>CO>[C:5]1([CH:4]=[CH:3][CH:2]=[CH:12][C:13]2[S:17][S:16][C:15](=[S:18])[CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cc(=S)ss1
Reactant: O=CC=Cc1ccccc1
Agent: [Mg]
Solvent: CO
Product: S=c1cc(C=CC=Cc2ccccc2)ss1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 40 ml of methanol, 600 mg (24 milligrams atom) of magnesium metal was added, and the mixture was heated to reflux for 1 hour to dissolve the magnesium metal. While cooling the mixture in ice water, 1.4 g (10 milli moles) of cinnamaldehyde, and then 1.56 g (10 milli moles) of 5-methyl-1,2-dithiol-3-thione were added to the mixture and the mixture was stirred for 1 hour at the same temperature. Separated crystals were recovered by filtration, and were added to 300 ml of ethyl acetate. Insolubles were removed by filtration, and the mother liquor was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude crystals were recrystallized from benzene-ethanol to obtain dark red crystals of