Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:22])[N:10]2[CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].Cl>C(OCC)(=O)C.O.C(O)C>[NH2:29][CH:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:22])[CH2:16][CH2:17]1
Reactant: [BH3-]C#N
Reactant: COc1ccc2ncc(=O)n(CCC3CCC(=O)CC3)c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc2ncc(=O)n(CCC3CCC(N)CC3)c2c1
Temperature: 32.5 °C
Reaction time: 0.5 h

Procedure:
To 9 mL of an ethanol solution containing 0.16 g of 7-methoxy-1-(2-(4-oxocyclohexyl)ethyl)quinoxalin-2(1H)-one, 54 mg of ammonium acetate and 0.32 g of molecular sieves 3A were added at room temperature, and the mixture was stirred in an external bath at 30 to 35° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, 35 mg of sodium cyanoborohydride was added thereto, and the mixture was stirred for 15 minutes. The reaction mixture was added with water and ethyl acetate, and the resultant solution was adjusted to pH 5.2 with 2.0 mol/L hydrochloric acid, and the aqueous layer was separated. The aqueous layer was added with ethyl acetate, and the resultant solution was adjusted to pH 9.5 with an aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted sequentially with ethyl acetate and chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 60 mg of a yellow oily substance, 1-(2-(4-aminocyclohexyl)ethyl)-7-methoxyquinoxalin-2(1H)-one.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5](C(Cl)(Cl)Cl)[O:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][C@H:22]2[CH2:24][C@@H:19]1[CH2:20][NH:21]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:23][C@H:22]2[CH2:24][C@@H:19]1[CH2:20][N:21]2[C:5]1[O:4][N:3]=[C:2]([CH3:1])[N:6]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1noc(C(Cl)(Cl)Cl)n1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1CN2
Solvent: Cc1ccccc1
Product: Cc1noc(N2C[C@H]3C[C@@H]2CN3C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.2 %

Procedure:
A solution of 1.06 g of 3-methyl-5-trichloromethyl-1,2,4-oxadiazole prepared by the procedure of F. Eloy, Bull. Soc. Chim. Belg., 1964, 73, 793, in 2 ml of toluene is added slowly to a solution of 1.05 g of product from Example 1 and 0.82 g of diazabicyclo[3.6.0]unodecene-5 in 1 ml of toluene. The resulting mixture is stirred at room temperature for 3 days and then concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5; methylene chloride) to give 0.74 g of the desired product as an off-white solid:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11]/[CH:12]=[CH:13]\[CH2:14][OH:15])=[C:4](Cl)[N:3]=1.C(O)=[O:18].O>>[OH:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:18])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1nc(Cl)c2ncn(C/C=C\CO)c2n1
Reactant: O=CO
Solvent: O
Product: Nc1nc2c(ncn2C/C=C\CO)c(=O)[nH]1

Procedure:
cis-4-(2-Amino-6-chloropurin-9-yl)-2-buten-1-ol (50 mg) in formic acid-water 7+3 (5 ml) was heated at 45° C. under a nitrogen atmosphere for 20 hours. The solvent was evaporated in vacuum and the residue was dried. Water (0.5 ml) was added and the solution was neutralized with aqueous ammonia. The precipitate was filtered, washed with water, ethanol and ether, and dried to give the compound cis-9-(4-hydroxy-2-butenyl)guanine (40 mg).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].[SH:18][CH2:19][CH2:20][OH:21].C(N(CC)CC)C>CO>[OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][S:18][CH2:19][CH2:20][OH:21]
Reactant: OCCS
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=C/CO)CC/C=C(\C)CCC(=O)C(C)CSCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 300 mg (0.0013 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one in 10 ml of methanol is treated with 0.27 ml of 2-mercapto-ethanol and 0.53 ml of triethylamine. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent on a rotary evaporator the residue is treated with water and methylene chloride. After extraction the organic phase is dried and freed from solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-methanol 50:1. There is obtained (6E,10Z)-12-hydroxy-1-[(2-hydroxyethyl)thio]-2,6,10-trimethyl-6,10-dodecadien-3-one which has the following absorption bands in the IR spectrum: 3369 cm-1, 1708 cm-1, 1667 cm-1, 1450 cm-1, 1044 cm-1, 1055 cm-1.
Reaction SMILES: [CH2:1]([O:19][C:20]1[C:21]([O:23][C@H:24]([C@H:27]([CH2:29][OH:30])[OH:28])[C:25]=1[OH:26])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClC(Cl)(Cl)C(O)=O>C(Cl)(Cl)Cl>[C:31]1([NH:37][C:38]([O:30][CH2:29][C@H:27]([OH:28])[C@H:24]2[O:23][C:21](=[O:22])[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:25]2[OH:26])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O
Reactant: O=C=Nc1ccccc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1=C(O)[C@@H]([C@@H](O)COC(=O)Nc2ccccc2)OC1=O
Temperature: 60 °C
Yield: 68.5 %

Procedure:
To a solution of 2-O-octadecyl-L-ascorbic acid (0.8 g, 2 mmole) and phenylisocyanate (0.24 g, 2 mmole) in chloroform (20 ml) was added trichloracetic acid (0.1 ml). The mixture was heated at 60° C. for one hour, which was washed with water, dried and concentrated to give a product. The product was recrystallized from isopropyl ether - ethyl acetate to give 6-O-phenylcarbamoyl-2-O-octadecyl-L-ascorbic acid (0.75 g), m.p. 149°-150° C. C31H49NO7 (Found: C,68.14; H,9.08; N,2.74%. Anal. Calcd: C,67.98; H,9.02; N,2.56).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:22])[N:6]=1)[CH2:3][CH3:4].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[N:32][C:25]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:32]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][C:24]=2[NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13](=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:22])[N:6]=2)[CH2:3][CH3:4])[NH:30][CH:31]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Reactant: Clc1ccnc2[nH]cnc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ccnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (27 mg, 0.091 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 7-chloro-3H-imidazo[4,5-b]pyridine (21 mg, 0.14 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 4A).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH2:28][C:29]([N:31]([CH3:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30])[C:22](=[O:27])[CH2:23][N:24]=[C:25]=[O:26])=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH2:28][C:29]([N:31]([CH3:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:30])[C:22](=[O:27])[CH2:23][NH:24][C:25]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([CH2:2][OH:1])[CH:4]=1)=[O:26])=[O:14])[CH3:11]
Reactant: Nc1cccc(CO)c1
Reactant: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CN=C=O
Product: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CNC(=O)Nc1cccc(CO)c1
Yield: 55.2 %

Procedure:
Using a procedure similar to that described in Example 31, but starting with 3-(hydroxymethyl)aniline (0.86 g) and 2-[N-(2-ethoxycarbonylphenyl)isocyanatoacetamido]-N-methyl-N-phenylacetamide (2.9 g), and after recrystallisation in ethyl acetate, 2-[N-(2-ethoxycarbonylphenyl)-2-{3-[3-(hydroxymethyl)phenyl]ureido}acetamido]-N-methyl-N-phenylacetamide (2 g), m.p. 184° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccc(-c2ccc(Cl)cc2)nc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-chloro-phenyl)-pyridin-3-ol (Preparation 23) and 3-iodomethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (94 mg, 46%)
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[OH:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]([O:12][Si:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=[CH:8][CH:7]=1.C(N(CC)CC)C>C(OCC)C>[Cl:4][C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][Si:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=[CH:30][CH:31]=1)=[S:2]
Reactant: CC(C)(C)[Si](OC(=O)c1ccc(O)cc1)(c1ccccc1)c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](OC(=O)c1ccc(OC(=S)Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 40.7 ml of thiophosgene in 300 ml of dry diethyl ether at -78° C. was added dropwise a solution of 20 g of diphenyl-(2-methylprop-2-yl)silyl 4-hydroxybenzoate and 8.5 ml of triethylamine. After having been stirred for a further 30 minutes at -78° C. and 90 minutes at room temperature, the mixture was partitioned between diethyl ether and water. The organic layer was washed with water and brine, was dried over calcium chloride, and then evaporated in vacuo to afford 25.9 g of an orange oil. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded 16.8 g of the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([CH:11]=O)=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[C:18]([F:26])[C:17]=1[NH2:27].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH:1]1([NH:4][C:5]2[C:10]([CH:11]=[N:27][C:17]3[C:18]([F:26])=[C:19]([O:24][CH3:25])[CH:20]=[C:21]([O:22][CH3:23])[C:16]=3[F:15])=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(N)c1F
Reactant: CSc1ncc(C=O)c(NC2CC2)n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(F)c(N=Cc2cnc(SC)nc2NC2CC2)c1F
Reaction time: 48 h
Yield: 70 %

Procedure:
To a solution of the 7.00 g (33.4 mmol) of 4-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 500 mL of toluene was added 6.33 g 33.4 mmol, 1 equivalent) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 1.94 g (8.36 mmol, 0.25 equivalents) of camphorsulfonic acid. The reaction was warmed to reflux and the formed water was removed with the aid of a Dean-Stark trap. After reacting for 48 hours, the reaction was concentrated in vacuo. The residue was stirred with ether and filtered. The filter pad was dissolved in dichloromethane, stirred with silica gel, and concentrated in vacuo. The residue was placed in the sample injection module of a Biotage FLASH 75 chromatographic apparatus. Chromatography of the crude material down a Biotage 500 g silica gel column with 2:1 hexane/ethyl acetate, then 1:1 hexane/ethyl acetate and finally 9:1 ethyl acetate/ethanol gave 8.92 g (70%) of title compound as a solid: mp 172° C.–174° C. MS (APCI) (m+1)/z 381.0 Analysis calculated for C17H18aF2N4SO2: C, 53.67; H, 4.77; N, 14.73. Found: C, 53.54; H, 4.58; N, 14.61.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([I:10])[N:7]=[CH:6]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CS(C)=O.O>[I:10][C:8]1[N:7]=[CH:6][N:5]([CH2:4][CH2:3][CH2:2][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]=1
Reactant: C1CCNC1
Reactant: ClCCCn1cnc(I)c1
Solvent: O
Solvent: CS(C)=O
Product: Ic1cn(CCCN2CCCC2)cn1
Yield: 78.2 %

Procedure:
A solution of the chloride 292 (1.2 g, 4.44 mmol) and pyrrolidine (1.1 mL, 13.3 mmol) in dry DMSO (2 mL) was heated at 60° C. under nitrogen for 3 h. The reaction mixture was cooled, diluted with water and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane, 5:95 to 20:80) to afford 293 (1.06 g, 3.47 mmol, 78% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, J=1.2 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 2.45-2.33 (m, 4H), 2.29 (t, J=7.2 Hz, 2H), 1.84 (q, J=7.2 Hz, 2H), 1.72-1.62 (m, 4H). MS (m/z): 305.9 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)=[O:5])[CH3:2].[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22]1)=[C:10]([CH3:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2cc(O)c(C)cc2[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(C)cc2[nH]1
Temperature: 0 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
To a suspension of 0.125 g (0.57 mmol) 5-hydroxy-6-methyl-1H-indole-2-carboxylic acid ethyl ester in 3 mL tetrahydrofuran, 98 mg (0.68 mmol) 1-isopropyl-piperidin-4-ol and 0.18 g (0.68 mmol) triphenylphosphine were added. The reaction was cooled to 0° C., 0.16 g (0.68 mmol) di-tert-butyl azodicarboxylate were added and the cooling bath was removed. After stirring 18 h at room temperature the volatile components were evaporated and the residue was purified by flash chromatography on silica gel using a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) as eluant, to afford 74 mg (38%) of the title compound as a light-yellow foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:7]([CH:21]=O)=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=O.[NH2:23][NH2:24]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:5]4[C:3](=[O:2])[NH:24][N:23]=[CH:21][C:7]=2[C:6]=34)=[CH:15][CH:16]=1
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(F)cc3)c(C=O)c12
Reactant: NN
Product: O=C1NN=Cc2c(-c3ccc(F)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Example ZZZ, 2-(4-fluoro-phenyl)-3-formyl-1H-indole-4-carboxylic acid methyl ester (145 mg, 0.49 mmol) was condensed with hydrazine (45 mg, 1.41 mmol) to give 2-(4-fluoro-phenyl)-1,5-dihydro-[1,2]diazepino[4,5,6-cd]indol-6-one, 120 mg (88%) as a bright yellow solid: m.p. 340-341° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 7.22 (app t, J=7.8 Hz 1H), 7.43 (m, 3H), 7.54 (m, 2H), 7.73 (m, 2H), 10.33 (s, 1H), 12.23 (br s, 1H). MS (electrospray, MH+) 280. Anal. (C16H10FN3O) C, H, N.
Reaction SMILES: [CH:1]1[NH:5][CH:4]=[C:3]2[C:6](=[O:10])[O:7][CH2:8][CH2:9][C:2]=12.CN(C)[CH:13]=[O:14].P(Cl)(Cl)(Cl)=O>ClCCl>[O:10]=[C:6]1[C:3]2[CH2:2][CH2:1][N:5]([CH:13]=[O:14])[C:4]=2[CH2:9][CH2:8][O:7]1
Reactant: CN(C)C=O
Reactant: O=C1OCCc2c[nH]cc21
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=CN1CCC2=C1CCOC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
6,7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one (5 g, 36 mmol) was formulated under standard Vilsmeier reaction using N,N-dimethylformamide (DMF, 1.2 eq.) and phosphorus oxychloride (POCl3, 1.1 eq.) in dichloromethane. The above mixture was stirred at room temperature for 1 hour. The precipitate salt was filtered, washed with dichloromethane, suspended in water and made basic with 6 N sodium hydroxide to pH=12. The mixture was stirred for 5 minutes and filtered. The solid was washed with ethanol/water mixture (1:1) to give 3.5 g (58%) of 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4]pyrrole-1-carbaldehyde.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:12][C:13]([C:15]1[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29](=[O:35])[NH:30][CH:31]2[CH2:34][CH2:33][CH2:32]2)=[O:23])[N:17]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:16]=1)=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:31]1([NH:30][C:29]([C@@H:25]2[CH2:26][CH2:27][CH2:28][N:24]2[C:22](=[O:23])[CH2:21][O:20][C:18]2[N:17]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:16]=[C:15]([C:13]([NH:12][C@@H:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:42])=[O:5])=[O:14])[CH:19]=2)=[O:35])[CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reaction time: 16 h

Procedure:
To a solution of 422 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-methyl-pentanoic acid tert-butyl ester in 5 ml dichloromethane were added 1.5 ml TFA. After stirring for 16 h it was concentrated and codistilled twice with toluene to give the crude product which was used directly in the subsequent coupling step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH3:13])[CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14].[CH2:19]([Li])CCC.CCCCCC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]([CH3:17])[CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH3:19])[CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14]
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-bromo-6-isopropyl-4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-quinoline (Intermediate 5, 6.81 g, 24.9 mmol), and 150 ml of anhydrous THF under argon at −78° C. was slowly added 1.6 M solution of n-butyl lithium and hexane (33 ml, 52.4 mmol). The reaction mixture was stirred at −78° C. for 10 minutes and thereafter N,N-cirmethylformamide (8.0 ml, 100 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 15 minutes and then quenched with saturated NH4Cl. The product was extracted with diethyl ether. The organic layer was washed with water and brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (silica, using 5% ethyl acetate in hexane) to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:5]([OH:7])[CH3:6].COC(=O)[C@H](CNC(=O)C1C=CC=CC=1)[C@H](O)C>>[CH3:1][O:2][C:3](=[O:18])[CH:4]([CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5](=[O:7])[CH3:6]
Reactant: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Agent: COC(=O)[C@H](CNC(=O)c1ccccc1)[C@@H](C)O
Product: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O

Procedure:
The ADH-LK variant with SEQ ID No. 90 was used for further evolution of an efficient KRED for production of (2S,3R)-methyl-2-benzamidomethyl-3-hydroxybutyrate. Similarly, an ADH-LK variant with SEQ ID No.94 containing 10 mutations compared to ADH-LK which gave primarily the (2R,3R) stereoisomer, was used for further evolution of an efficient KRED for production of (2R,3R)-methyl-2-benzamidomethyl-3-hydroxybutyrate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[C:30]1([Sn](CCCC)(CCCC)CCCC)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2c(c1O)c(-c1ccccc1)c(-c1ccc(F)cc1)n2-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 3-bromo-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (180 mg, 0.395 mmol), phenyltributlytin (149 μL, 0.454 mmol), and Pd(PPh3)2Cl2 (14 mg, 0.020 mmol) in DMF (2 mL) was stirred at 130° C. overnight. Then the mixture was diluted with EtOAc, washed with water and saturated NaCl aqueous solution respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, the residue was purified by column and prep TLC to give a white solid, the desired title compound (59 mg). The title compound, ESI MS (m/z): 453 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([N:8]([CH3:24])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[C:21]=[CH:22][CH3:23])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6]C)=[O:5].[OH-].[Li+].O>O1CCCC1.CO>[CH3:24][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]=[C:21]=[CH:22][CH3:23])=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C@H:3]([C:4]([OH:6])=[O:5])[CH:2]([CH3:25])[CH3:1]
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC=C=CCOc1ccc(S(=O)(=O)N(C)[C@H](C(=O)O)C(C)C)cc1
Yield: 87.1 %

Procedure:
The procedure of Example 12 was followed using the product from Example 20 (240 mg, 0.65 mmol), and lithium hydroxide (31 mg, 1.31 mmol) in tetrahydrofuran (2 ml), methanol (2 ml), and water (1 ml) to give 200 mg (87%) of the product.