Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>N1C=CC=CC=1>[F:35][C:23]([F:22])([F:34])[C:24]1[CH:25]=[C:26]([S:30]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:16]=[C:15]4[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]4)=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)(=[O:31])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1n[nH]c2cc(-c3cccc(N)c3)ccc12
Solvent: c1ccncc1
Product: CCOC(=O)c1n[nH]c2cc(-c3cccc(NS(=O)(=O)c4cccc(C(F)(F)F)c4)c3)ccc12
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl 6-(3-aminophenyl)-1H-indazole-3-carboxylate (10 mg) in pyridine (1 Ml), was added 3-trifluoromethylbenzenesulfonyl chloride (6.3 μl) at room temperature. After 3 h, pyridine was removed by evaporation. Ethyl acetate and water were added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated in ethyl acetate/hexane to give ethyl 6-(3-(3-(trifluoromethyl)phenylsulfonamido)phenyl)-1H-indazole-3-carboxylate (8.6 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([N:18]2[C:22]3[N:23]=[C:24]([Cl:28])[N:25]=[C:26]([Cl:27])[C:21]=3[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:29][C:30]([CH3:32])=[O:31]>C1COCC1>[C:9]1([S:15]([N:18]2[C:22]3[N:23]=[C:24]([Cl:28])[N:25]=[C:26]([Cl:27])[C:21]=3[CH:20]=[C:19]2[C:30]([OH:31])([CH3:32])[CH3:29])(=[O:16])=[O:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)nc(Cl)nc21
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cc2c(Cl)nc(Cl)nc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Lithium diisopropylamide (2 mL, 4.0 mmol, 2 M in THF) was added dropwise to a solution of 7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (656 mg, 2.0 mmol) in anhydrous THF (15 mL) at −78° C. The resulting solution was stirred at −78° C. for 90 min, then acetone (0.4 mL, 5.5 mmol) was added and the reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo affording 2-(7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol. To a solution of 2-(7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (2 mmol) in a mixture of isopropyl alcohol (11 mL) and water (3 mL) was added sodium hydroxide (6 mL, 36 mmol, 6M aqueous solution). The resulting mixture was stirred at RT for 2 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 40% ethyl acetate in cyclohexane) affording 2-(2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (304 mg, 64%). LCMS (method A): RT=2.70 min, [M]−=244/246.
Reaction SMILES: BrC1C=C2C(=CC=1)C(=O)N([C@H](C(C)C)C(OC)=O)C2.[Br:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=O)=[C:23]([CH2:31]Br)[CH:22]=1.Cl.[NH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[Br:20][C:21]1[CH:22]=[C:23]2[C:24](=[CH:29][CH:30]=1)[C:25](=[O:27])[N:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31]2
Reactant: CCOC(=O)CCN
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: Cl
Product: CCOC(=O)CCN1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 377 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and ethyl 3-aminopropanoate hydrochloride.
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][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[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][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 72.8 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 5-aminopyridin-2-ylcarbamate (313 mg, 1.5 mmol) to afford the desired product (352 mg, 72%) as a yellow solid: ESI MS m/z 483 [C23H23BrN4O3+H]+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31](O)=[CH:30][C:29]=2[CH3:35])=[CH:26][CH:27]=1)=[O:22].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:18][CH2:17][C:5]3[C:6]([C:9]4[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=4[Cl:15])=[N:7][O:8][C:4]=3[CH:1]3[CH2:3][CH2:2]3)=[CH:30][C:29]=2[CH3:35])=[CH:26][CH:27]=1)=[O:22]
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2C)s1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)cc2C)s1
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of (5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl)-methanol (0.188 g, 0.66 mmol), 5-(4-hydroxy-2-methyl-phenyl)-thiophene-2-carboxylic acid methyl ester (0.15 g, 0.60 mmol), and tri-N-butyl-phosphine (0.16 g, 0.79 mmol) in toluene (2 mL) is added a solution of ADDP (0.2 g, 0.79 mmol) in 1 mL of toluene. The reaction is stirred overnight. The reaction mixture is partitioned between ethyl acetate and water and the layers are separated. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude oil. The oil is chromatographed using a gradient of 10% ethyl acetate in hexanes to 40% ethyl acetate in hexanes to yield the title compound (0.14 g, 41%). ES/MS m/e 514.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[N:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[C:6]=3[N:19]=2)=[C:25]([O:30][CH3:31])[CH:24]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CCC(=O)N3C)c(OC)c1
Yield: 38.3 %

Procedure:
2-Chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (Intermediate 1; 500 mg, 1.78 mmol), methyl4-amino-3-methoxybenzoate (324 mg, 1.78 mmol) and p-toluenesulfonic acid (847 mg, 4.45 mmol) were suspended in (2R/S)-4-methyl-2-pentanol (10 mL) and heated at reflux for 5 h. The reaction mixture was cooled and loaded onto an SCX-2 column and washed with MeOH (20 mL). The crude product was then eluted from the SCX-2 column with NH3 (40 mL, 7M in MeOH) and the volatiles removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient 0-10% MeOH in DCM) afforded the title compound (290 mg, 38%) as a solid.
Reaction SMILES: [F:1][C:2]([F:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][N:4]=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[F:13][C:2]([F:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:3][NH2:4]
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC(F)(F)c1ccccn1

Procedure:
A stirred solution of 100 mg of 2,2-difluoro-2-(2-pyridyl)ethylazide was hydrogenated in 10 mL of ethyl acetate over 100 mg of 10% palladium on carbon using a balloon for 1 h. The catalyst was removed by filtration and the solvents removed at reduced pressure to give the title compound as a yellow oil:
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8])#[N:2]>N.CCO.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(OCC)P(=O)(CCC#N)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CCCN)OCC
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a solution of 2.47 g (9.91 mmol) of ethyl 2-cyanoethyl (diethoxymethyl)phosphinate (from Step A) in 20 mL 2.0 M ammonia in EtOH was added 250 mg Raney Nickel. The mixture was subjected to hydrogenation conditions (H2, 40 psi, rt) for 16 hr. The reaction mixture was filtered over Celite and partitioned between CH2Cl2 and H2O. The aqueous phase was extracted twice with CH2Cl2. The organic layer and extractions were combined, dried, and concentrated to provide 2.13 g (85% yield) of the title compound: 1H NMR (500 MHz) δ 1.23 (dt, J1=7.1, J2=1.6 6H), 1.29 (t, J=7.1, 3H), 1.42 (s, br, 2H), 1.71-1.82 (m, 4H), 2.72-2.75 (m, 2H), 3.63-3.70 (m, 2H), 3.78-3.86 (m, 2H), 4.08-4.21 (m, 2H), 4.64 (d, J=6.7, 1H); ESI-MS 254 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCO
Product: Cc1cc(N[C@H]2CCc3ccccc32)nc(Cl)n1
Yield: 4.8 %

Procedure:
2,4-Dichloro-6-methylpyrimidine (2.54 g, 0.156 mol) was dissolved in ethanol (100 mL) and N,N-Diisporopylethylamine (4.07 mL, 0.23 mol) was added followed by (S)-1-Aminoindan (2.00 mL, 0.156 mol). The solution was heated to reflux for 2 hours, TLC indicated complete conversion. The solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 0 to 50% ethyl acetate in hexane to afford the title compound (1.95 g, 46%). LC/MS: Rt=1.90 min, ES+ 260 (AA standard).
Reaction SMILES: O.[OH-].[Na+].[Cl:4][CH2:5][C:6]([NH:8][CH:9]([C:15]1[N:16]=[CH:17][S:18][CH:19]=1)[C:10]([O:12]CC)=[O:11])=[O:7]>CO>[Cl:4][CH2:5][C:6]([NH:8][CH:9]([C:15]1[N:16]=[CH:17][S:18][CH:19]=1)[C:10]([OH:12])=[O:11])=[O:7]
Reactant: CCOC(=O)C(NC(=O)CCl)c1cscn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(CCl)NC(C(=O)O)c1cscn1

Procedure:
In 15 ml of dimethylacetamide is dissolved 4 g of ethyl 2-aminothiazol-4-ylacetate and, under ice-cooling, 3.62 g of chloroacetyl chloride is added dropwise. The mixture is stirred under ice-cooling for 30 minutes and, then, at room temperature for another 30 minutes. Then, following the addition of 50 ml of water, the mixture is extracted twice with 100 ml portions of ethyl acetate-tetrahydrofuran. The extract is washed with 100 ml of a 5% aqueous solution of sodium hydrogen carbonate and, then, with 100 ml of a saturated aqueous solution of sodium chloride, followed by drying. The solvent is then distilled off. By the above procedure is obtained 2.95 g of ethyl 2-chloroacetamidothiazol-4-ylacetate as an oily product. The entire amount of this oil is suspended in 100 ml of methanol and, under ice-cooling, 12 ml of water containing 761 mg of sodium hydroxide is added. The mixture is stirred at room temperature for 30 minutes, at the end of which time a major portion of the methanol as distilled off under reduced pressure. To the residue is added 10 ml of water. The water layer is washed with 50 ml of ethyl acetate and after the addition of 20 ml of ethyl acetate, it is adjusted to pH 2 with 10% hydrochloric acid. The mixture is shaken well and the organic layer is taken, washed with a saturated aqueous solution of sodium chloride and dried. The solvent is then distilled off. By the above procedure is obtained 1.51 g of 2-chloroacetamidothiazol-4-ylacetic acid as colorless crystals, melting point: 202°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.O[CH:12]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[CH3:21][C:18]([O:17][C:16](=[O:22])[N:15]([CH2:14][CH2:13][CH:12]([O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH2:24][CH:25]([CH3:26])[CH3:27])[CH3:23])([CH3:19])[CH3:20]
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: CC(C)CC(O)CCN(C)C(=O)OC(C)(C)C
Product: CC(C)CC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N

Procedure:
The title compound was prepared according to the method of Example 2 step (b) but using 4-chloro-2-hydroxybenzonitrile and (3-hydroxy-5-methylhexyl)methylcarbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:9][S:10](=[S:13])([O-:12])=[O:11].[Na+].CN(C=O)C>O>[CH3:9][S:10](=[S:13])([O:12][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:11]
Reactant: BrCC1CCCCC1
Reactant: CS(=O)([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=S)OCC1CCCCC1
Temperature: 50 °C
Yield: 81.9 %

Procedure:
The reaction mixture of bromomethylcyclohexane (1.560 g, 0.00881 mol), sodium methanethiosulfonate (1.180 g, 0.00881 mol) and dry DMF (6 mL) was heated at 50° C. for 24 hr. At room temperature, water (15 mL) was added and the mixture was extracted with ether (3×30 mL). The extracts were washed with brine, dried, concentrated and the residue was subjected to flash column chromatography on silica gel with EtOAc-hexanes (1:4) to afford a colorless oil (1.5033 g, 82%). IR (CDCl3 cast): 3030 (w), 3012 (w), 2926 (st), 2853 (st), 1446 (m), 1410 (m), 1320 (st), 1134 (st), 955 (st), 746 cm−1 (st); 1H NMR (200 MHz, CDCl3): δ 3.32 (s, 3H, CH3SO2S), 3.07 (d, J=6.9 Hz, 2H, SCH2CH), 1.95-1.55 (m, 6H), 1.40-0.90 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 50.42, 43.30, 37.83, 32.43, 26.02, 25.82.
Reaction SMILES: [CH3:1][C:2]([S:10][CH2:11]Cl)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[P:13]([S-:19])(=[S:18])([O:16][CH3:17])[O:14][CH3:15].[Na+]>CC(C)=O>[P:13]([S:19][CH2:11][S:10][C:2]([CH3:9])([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[S:18])([O:16][CH3:17])[O:14][CH3:15]
Reactant: COP(=S)([S-])OC
Reactant: CC(C)(SCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COP(=S)(OC)SCSC(C)(C)c1ccccc1
Reaction time: 8 h

Procedure:
To 0.078 mole of chloromethyl α,α-dimethylbenzyl sulfide in 100 ml. of acetone is added 15.3 grams (0.078 mole) of sodium O,O-dimethyl phosphorodithioate followed by stirring overnight. The reaction mixture is maintained at a temperature of 25° C. to 30° C.
Reaction SMILES: OC1C=C2C(=CC=1)[C:8](=[O:12])[N:7]([CH3:13])[CH2:6]C2.COC1C(CCN2CCC(N3C4C(=CC=C(C(N)=O)C=4)C=C3)CC2)=C2C(C(=O)C(C)(C)CO2)=CC=1.C(C1C(OC)=CC2COC(=O)NC=2C=1)C=C.[CH3:65][O:66][C:67]1[C:78]([CH2:79][CH2:80][N:81]2[CH2:86][CH2:85][CH:84]([N:87]3[C:95]4[C:90](=[CH:91][CH:92]=[C:93]([C:96]([NH:98][CH3:99])=[O:97])[CH:94]=4)[CH:89]=[CH:88]3)[CH2:83][CH2:82]2)=[CH:77][C:70]2N(C)C(=O)O[CH2:74][C:69]=2[CH:68]=1>>[CH3:65][O:66][C:67]1[CH:68]=[C:69]2[C:70](=[CH:77][C:78]=1[CH2:79][CH2:80][N:81]1[CH2:86][CH2:85][CH:84]([N:87]3[C:95]4[C:90](=[CH:91][CH:92]=[C:93]([C:96]([NH:98][CH3:99])=[O:97])[CH:94]=4)[CH:89]=[CH:88]3)[CH2:83][CH2:82]1)[C:8](=[O:12])[N:7]([CH3:13])[CH2:6][CH2:74]2
Reactant: CN1CCc2cc(O)ccc2C1=O
Reactant: CNC(=O)c1ccc2ccn(C3CCN(CCc4cc5c(cc4OC)COC(=O)N5C)CC3)c2c1
Agent: C=CCc1cc2c(cc1OC)COC(=O)N2
Agent: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)OCC(C)(C)C2=O
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4cc5c(cc4OC)CCN(C)C5=O)CC3)c2c1

Procedure:
The subject compound was synthesized from 6-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one (CAS#: 308110-07-8) according to the methods described in Example 22, (1), (2) and (3), and Example 23, (5).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][CH:18]([CH:22]([CH3:26])[C:23]([OH:25])=O)[C:19]([OH:21])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:19](=[O:21])[CH:18]([CH3:17])[CH:22]([CH3:26])[C:23]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:10]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16])=[O:25])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: CC(C(=O)O)C(C)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Yield: 67.9 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 600 mg (4.1 mmol) 2,3-dimethylsuccinic acid afforded, after flash chromatography (EtOAc), 1.45 g (69%) of the title compound as a colorless oil.
Reaction SMILES: O=C[C@@H]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)O)O)O.[C:13]([OH:18])(=[O:17])[C@H:14]([CH3:16])[OH:15].C(O)(=O)CC>C(O)(=O)C>[C:11]([OH:12])(=[O:15])[CH2:9][CH2:7][CH3:5].[C:13]([OH:18])(=[O:17])[CH2:14][CH3:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C[C@H](O)C(=O)O
Solvent: CC(=O)O
Solvent: CCC(=O)O
Product: CCCC(=O)O

Procedure:
When glucose is used as the sole substrate, as in the first experiment, the difference between total carbon yield and butyric carbon yield is greater than when a combination of glucose and L-lactic acid is used, because higher amounts of acetic acid and propionic acid are generated during the fermentation. See FIG. 7. In addition, the butyric carbon yield (61%) is much higher than that of free cell fermentation (see Table 1, 36%), because the immobilized cell beads can be used repeatedly for a long period of time, which may cause cell adaptation to endure higher butyrate concentration, thereby resulting in a higher butyric carbon yield. The second experiment using a feedstock containing both glucose and L-lactic acid affords 69% butyric carbon yield (higher than the theoretical yield), while suppressing the generation of acetic acid and propionic acid (the difference between total carbon yield and butyric carbon yield is only 5%). See FIG. 8. Third, when L-lactic acid is used as the sole substrate, butyric acid is produced in an significant amount, although acetic acid and propionic acid are also generated (the difference between total carbon yield and butyric carbon yield is 23%). See FIG. 9. The total carbon yield, 96%, is very close to the theoretical value (100%). In view of the above, the combination of lactic acid and carbohydrate as substrates in fermentation exceeds those results anticipated under conventional fermentation using glucose as the only substrate, and in some instances may be deemed synergistic with the improvement of the butyric carbon yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccc2)cn1

Procedure:
To a solution of 2-methyl-5-phenylpyridine (step 1) (169 mg) and N-bromosuccinimide (177 mg) in CCl4 (3 cc) was added benzoyl peroxide (25 mg) and the mixture irradiated with visible light for 5 hours under reflux. After removal of the solvent the residue was purified by chromatography to afford the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].O>ClCCl>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:20])[CH3:19])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(C)C)cc1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of 4-isopropylaniline (1.0 eq) in dichloromethane at 0° C., triethylamine (2.2 eq) was added and stirred for 15 min. Then, acetic anhydride (1.0 eq) in dichloromethane was added at 0° C., after addition the reaction was continued at room temperature for 5 hrs. Water was added and the organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired N-(4-isopropylphenyl)acetamide. (Yield=95%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13])([O-:3])=[O:2]>C(OCC)(=O)C>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:13]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1O
Solvent: CCOC(C)=O
Product: Nc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 144 h
Yield: 47.6 %

Procedure:
8.6 g of 2,6-dinitrophenol (46.71 mmol) were dissolved in 95 ml of ethyl acetate. The solution was degassed and then 0.86 g (10% by weight) of palladium on carbon at 10% was added. The reaction medium was stirred under a hydrogen atmosphere for 6 days at ambient temperature. The reaction medium was filtered through celite and concentrated to dryness. The residue obtained was chromatographed on a cartridge of silica gel eluted with 100% dichloromethane to 80/20 dichloromethane/ethyl acetate. 3.43 g of product were obtained in the form of a dark copper solid. Yield=48%.
Reaction SMILES: [C:1]([C:6]1[CH:26]=[CH:25][C:9]2[NH:10][C:11]([S:13][CH2:14][C:15]3[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][N:16]=3)=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].C([O-])(O)=[O:28].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:6]1[CH:26]=[CH:25][C:9]2[NH:10][C:11]([S:13]([CH2:14][C:15]3[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][N:16]=3)=[O:28])=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc2[nH]c(SCc3nccc(OC)c3OC)nc2c1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc2[nH]c(S(=O)Cc3nccc(OC)c3OC)nc2c1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
5--Carbethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (95.2% pure) (1.4 g, 0.0036 mol) was dissolved in CH2Cl2 (30 ml). NaHCO3 (0.6 g, 0.0072 mol in H2O (10 ml) was added and the mixture was cooled to +2° C. m-Chloroperbenzoic acid 69.5% (0.87 g, 0.0035 mol) dissolved in CH2Cl2 (5 ml) was added dropwise under stirring. Stirring was continued at +2° C. for 10 min. The phases were separated and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN (15 ml ) giving the title compound (0.76 g, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:33])[NH:25][C:26]4[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=4)=[CH:20][C:19]=3[N+:34]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O.C(O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:33])[NH:25][C:26]4[CH:27]=[CH:28][C:29]([Br:32])=[CH:30][CH:31]=4)=[CH:20][C:19]=3[NH2:34])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Oc3ccc(C(=O)Nc4ccc(Br)cc4)cc3[N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2cc(Oc3ccc(C(=O)Nc4ccc(Br)cc4)cc3N)ccc21
Yield: 66.5 %

Procedure:
The product of Example 93C (517 mg, 0.936 mmol), iron powder (322 mg, 5.76 mmol), and ammonium chloride (328 mg, 6.13 mmol) in water (3 mL) and ethanol (6 mL) were heated at 90° for 30 minutes. The hot reaction mixture was vacuum filtered and the residue washed with methanol and ethyl acetate. The filtrate was concentrated by rotary evaporation under vacuum, the residue partitioned with water (50 mL) and ethyl acetate (100 mL), and the organic phase washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum to provide the title compound as an off-white foam (325 mg, 66%).