Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)(=[O:9])[CH3:8]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]1([C:13]2[CH2:14][CH2:15][N:10]([C:7](=[O:9])[CH3:8])[CH2:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CC=C(N2CCOCC2)CC1
Yield: 100.1 %

Procedure:
According to Scheme 1, step 1: A mixture of morpholine (67.85 g, 0.779 mol), 1-acetyl-4-piperidone (99.95 g, 0.708 mol) and para-toluenesulfonic acid monohydrate (0.366 g, 2.1 mmol) in toluene (300 ml) was heated in a Dean-Stark trap apparatus for 16 h at reflux. Solvents were evaporated in vacuo to give 149 g of 1-(4-morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1) which was used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[N:6]([C:13](=[O:23])[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[C@H:7]2[CH3:12].[CH2:33](OB(C=C)OCCCC)[CH2:34]CC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Si:26]([O:25][CH2:24][C@H:5]1[CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH:33]=[CH2:34])[C@H:7]([CH3:12])[N:6]1[C:13](=[O:23])[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: C=CB(OCCCC)OCCCC
Reactant: C[C@H]1c2cccc(Br)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Dissolve 1-[(1S,3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (300 mg, 0.54 mmol) and vinylboronic acid dibutyl ester (0.24 mL, 1.08 mmol) in 1,4-dioxane (5.4 mL). Add aqueous Na2CO3 solution (2.7 mL, 2M in water). Degas with nitrogen 10 min Add bis(triphenylphosphine)palladium(II) chloride (76 mg, 0.11 mmol). Heat to 80° C. Stir 2 hours. Add water and extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate:hexanes (gradient, 5-80%) to give the title compound as a white foam (220 mg, 0.44 mmol). MS (m/z): 504 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=1>CO.C1COCC1>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c2ccccc12
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)c2ccccc12

Procedure:
Method C1 was used with tert-butyl 4-(2-amino-3-nitropyridin-4-yloxy)naphthalen-1-ylcarbamate (3.0 g, 7.6 mmol) with solvent mixture MeOH:THF 1:1 to afford the title compound in quantitative yield (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:26][CH:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH:14]2[CH2:13]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][CH:12]2[CH2:26][CH:15]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18][CH:14]3[CH2:13]2)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3C#N)CC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
To a solution of 2,4-dichloropyrimidine-5-carbonitrile (600 mg, 3.4485 mmol) and tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (936.8 mg, 4.139 mmol) in ethanol (50 mL) was added N,N-diethylethanamine (698.5 mg, 6.903 mmol). The mixture was stirred at rt for 3 h. Then it was concentrated under vacuo, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title product as yellow oil (332.5 mg, 26.50%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (274 mg, 69%).
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11](N3C[C@H](CNC(=O)C)OC3=O)=[CH:10][C:9]=2[F:26])[CH2:4][CH2:3]1.[N+:28]([O-:31])(O)=[O:29].O>C(O)(=O)C>[F:14][C:13]1[CH:12]=[C:11]([N+:28]([O-:31])=[O:29])[CH:10]=[C:9]([F:26])[C:8]=1[N:5]1[CH2:4][CH2:3][S:2](=[O:27])(=[O:1])[CH2:7][CH2:6]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a suspension of the product of example 1 (300 g, 1.21 mol) in 3 L of acetic acid, nitric acid (255 mL, ca. 6 mol, fuming, 90%) is added over 30 min at room temperature. Yellow precipitate is formed within minutes and increases over time. The reaction is kept at room temperature for 18 hours, before it is poured into 6 L of water. After stirred for 2 hours, the yellow suspension is filtered. The precipitate is washed with water (1.5 L×3) and EtOH (0.5 L×2) and dried in oven at 50° C. overnight to give 333 g (94%) of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:35](OCC)[O:36]CC)=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:35]=[O:36])=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (6.0 g) in acetone (60 ml) was added 6 N hydrochloric acid (6 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate solution, and acetone was distilled off under reduced pressure. The resultant solution was diluted with water (150 ml) to separate out oily precipitates, which were extracted twice with ethyl acetate (100 ml and 50 ml, respectively). The organic layer was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give oily 2-benzyloxyethyl 2 -methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (5.02 g).
Reaction SMILES: C(O[Cl:6])(C)(C)C.[CH2:7]([O:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=2[O:22][CH3:23])[CH2:14][O:13]1)=[O:11])[CH3:8]>C(Cl)Cl>[CH2:7]([O:9][C:10]([CH:12]1[CH2:21][C:20]2[C:15](=[C:16]([O:24][CH3:25])[C:17]([Cl:6])=[CH:18][C:19]=2[O:22][CH3:23])[CH2:14][O:13]1)=[O:11])[CH3:8]
Reactant: CC(C)(C)OCl
Reactant: CCOC(=O)C1Cc2c(OC)ccc(OC)c2CO1
Solvent: ClCCl
Product: CCOC(=O)C1Cc2c(OC)cc(Cl)c(OC)c2CO1
Reaction time: 3 h
Yield: 46 %

Procedure:
Under argon and at room temperature, was added dropwise 0.820 g (7.6 mmol) of t-butylhypochlorite to a stirred solution containing 1.973 g (7.4 mmol) of the isochroman from step 5 in 75 ml of anhydrous CH2Cl2. The reaction mixture was stirred for 3 hours and then washed successively with 25 ml portions of saturated aqueous sodium thiosulfate, water and brine. After drying over Na2SO4, the organic layer was evaporated and the residue was flash chromatographed with 2.5% ethyl acetate in toluene as the eluting solvent mixture. The title compound was obtained in 46% yield (1.02 g). (MP: 95.0° C.) 1H NMR (200 MHz, CDCl3) δ: 1.35 (t, 3H, J=7.1 Hz, CH3), 2.93 (broad dd, J=16.8, 10.3 Hz, HCHaCHC=O), 3.16 (broad dd, J=16.9, 3.2 Hz, HCHeCHC=O), 3.78 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.27 (dd, J=10.2, 3.3 Hz, --CH), 4.31 (q, 2H, J=7.1Hz, OCH2), 4.63 (broad d, 1H, J=16.2 Hz, HCHa0), 5.01 (d, 1H, J=16.2 Hz, HCHe0), 6.73 (s, 1H, ArH).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C1C(=O)NC(=O)N([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]2[OH:27])C=1>P([O-])([O-])([O-])=O>[CH:2]1[N:3]=[C:4]2[N:5]([C@@H:19]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]3[OH:27])[CH:6]=[N:7][C:8]2=[C:9]([NH2:10])[N:1]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Yield: 70.1 %

Procedure:
5 kg of wet cell paste or the corresponding crude or purified extract obtained by fermenting the strain MG1655/pGM716 or the strain DH5α/pGM716 were resuspended in approximately 20 liters of 30 mM phosphate buffer at pH 7 and mixed with 980 liters of phosphate buffer in which had been dissolved at elevated temperature 10.1 kg of adenine (final concentration approximately 74.6 mM) and 18.3 kg of Ara-U (final concentration approximately 74.6 mM). The mixture was maintained at 60° C., with agitation, for 4 hours to obtain a bioconversion yield of approximately 70%. The cell paste was recovered in order to be used again in subsequent reactions by dilution at elevated temperature and diafiltration in accordance with the procedure described above. The ultrafiltrate was concentrated to a volume of approximately 1000 liters, cooled to collect the precipitate constituted by Ara-A which was subsequently crystallised from water to obtain approximately 14 kg of Ara-A with a degree of purity higher than 99.5%. According to an alternative procedure, in which the cells were not recovered and the diafiltration step was omitted, at the end of the reaction the mixture was heated to approximately 90° C. and filtered at elevated temperature to eliminate the cells, and the filtrate was cooled to precipitate Ara-A contaminated with non-reacted adenine (approximately 20 g of adenine per 100 g of Ara-A). 14 kg of Ara-A (total yield 65%) having a degree of purity higher than 99.5% were finally obtained after crystallisation from reaction of 1000 liters. Similar results were obtained starting from a mixture of the cell pastes or the corresponding crude or purified extracts obtained by fermenting the recombinant E. coli strains MG1655/p707 or MG1655/p708 and the strains DH5α/pGM707 or DH5α/pGM707 overexpressing UdP and PNP, respectively.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:10][C:11](=[N:13]O)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:12][C:11]1[N:13]=[C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[O:8][CH:10]=1
Reactant: CC(C)=NO
Reactant: O=C(Cl)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1coc(-c2cccnc2)n1
Temperature: 130 °C
Yield: 31.3 %

Procedure:
30 g of nicotinoyl chloride is added to 5.1 g of cooled acetoxime, then the mixture is heated to 130° C. The exothermic reaction mixture is maintained under agitation for 6 hours at 140° C. After cooling, iced water is added, followed by alkalizing with sodium carbonate and extracting with methylene chloride. The solvent is evaporated, the residue is taken up with ether and filtered; the solvent is evaporated and the residue is distilled at 150° C. under 0.08 mbar. 3.5 g of expected product is obtained which is purified by chromatography on silica (eluant: cyclohexane-ethyl acetate 7-3), with further distillation. After cooling, a solid product is obtained.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2].[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][C:27]([NH:26][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:28])[S:15][CH:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(=O)NCc1cccc(-c2csc(N)n2)c1
Solvent: CC(C)=O
Product: CC(=O)NCc1cccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)c1
Yield: 88.6 %

Procedure:
A suspension of 4-(3-acetylaminomethylphenyl)-2-aminothiazole (2.0 g) and benzoyl isothiocyanate (1.32 g) in acetone (40 ml) was refluxed for 5 hours. The resulting precipitate was collected by filtration to afford 4-(3-acetylaminomethylphenyl)-2-(3-benzoyl-2-thioureido)thiazole (2.94 g).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[C:20]([C:21](Cl)=[O:22])=[C:19]([CH3:24])[O:18][N:17]=1.[CH3:25][O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)=[O:28]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:25][O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:21]([C:20]2[C:16]([C:10]3[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])=[N:17][O:18][C:19]=2[CH3:24])=[O:22])[CH2:30]1)=[O:28]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: COC(=O)N1CCCC(N)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCCC(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)C1
Yield: 89.5 %

Procedure:
Add 4-dimethylamino-pyridine (0.19 g, 1.5 mmol), triethylamine (3.2 mL, 23.2 mmol), and 3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride (5.53 g, 20.1 mmol) to a solution of 3-amino-piperidine-1-carboxylic acid methyl ester (2.45 g, 15.5 mmol) in dichloromethane (100 mL). Stir the reaction at room temperature under nitrogen overnight. Wash the reaction with 1N HCl, saturated aqueous sodium bicarbonate solution, and brine; dry over magnesium sulfate; and concentrate. Purify by flash chromatography on silica gel (eluting with 0.75% methanol/chloroform) to give 5.49 g of the title compound as a yellow foam, 90% yield. 1H NMR: consistent with structure. MS (ion spray) 396 (M+).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=O)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH2:14][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN1CCOCC1)c1ccc(F)cc1
Reaction time: 48 h
Yield: 63.9 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde (Example 73, 0.12 g, 0.31 mmol) in DCE (5 ml) was added morpholine (0.1 g, 1.14 mmol) and NaBH(OAc)3 (0.30 g, 1.5 mmol). The reaction was then stirred for 2 days, quenched with aq. Na2CO3 (10 ml), and extracted with DCM (2×20 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse-phase column chromatography (5-35% ACN) to give the title compound (0.09 g, 67%). 1H NMR (400 MHz, CD3OD) δ 7.41 (br s, 2H), 7.06-7.02 (m, 3H), 6.13 & 5.44 (s, 1H), 5.12 & 4.97 (s, 1H), 3.63 (br s, 4H), 3.42 (br s, 2H), 2.41 (br s, 4H), 1.87-1.82 (m, 1H), 1.54 (d, J=6.5 Hz, 3H), 0.96-0.90 (m, 2H), 0.65-0.64 (m, 2H). MS: Calcd.: 454. Found: [M+H]+ 455.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:3]1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 10.0 mg (0.025 mmol) of ethyl 4- [2-(1,1-dimethyl-3-(4-methylphenyl)-5- indenyl)ethynyl]benzoate (Compound 47) in 0.5 ml THF/H2O (3:1 v/v) was added 5.2 mg (0.12 mmol) LiOH H2O. After stirring at room temperature for 48 hours the solution was extracted with hexanes and the aqueous layer was acidified with saturated aqueous NH4Cl. Solid NaCl was added and the resulting mixture extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a colorless solid. 1H NMR (300 MHz, d6-DMSO): δ 7.95 (2H, d, J=8.3 Hz), 7.65 (2H, d, J 8.3 Hz), 7.57 (2H, m), 7.49 (3H, m), 7.30 (2H, d, J=7.9 Hz), 6.61 (1H, s), 2.36 (3H, s). 1.36 (6H, s).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.Cl[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][CH:25]([CH3:36])[N:24]([C:37](=[O:39])[CH3:38])[N:23]=2)=[CH:18][CH:17]=1)=[O:14]>C(O)C>[CH3:4][NH:6][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][CH:25]([CH3:36])[N:24]([C:37](=[O:39])[CH3:38])[N:23]=2)=[CH:18][CH:17]=1)=[O:14]
Reactant: CCN(CC)CC
Reactant: CC(=O)N1N=C(c2ccc(NC(=O)CCl)cc2)c2cc3c(cc2CC1C)OCO3
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNCC(=O)Nc1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Yield: 38.4 %

Procedure:
1.31 g (19.5 mmol) of methylamine hydrochloride and 2.24 ml (23.3 mmol) of triethylamine were added to a suspension containing 1.61 g (3.89 mmol) of 1-(4-chloroacetylamino-phenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (see Example 106) in 100 ml of ethanol and the reaction mixture was refluxed for 10 hours, then evaporated under reduced pressure. The residue was purified by column chromatography (adsorbent: Kieselgel 60, eluent: chloroform--methanol 9:1). The crude product was triturated with 3 ml of 50% ethanol at 25° C. to give 0.61 g (38.6%) of the aimed product, m.p.: 220°-222° C. (weak decomp.).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[CH3:8][CH:9]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[CH2:10][O:11][CH3:12]>C1(C)C=CC=CC=1>[CH3:8][CH:9]([N:13]([C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[CH2:10][O:11][CH3:12]
Reactant: CCOCC(=O)Cl
Reactant: COCC(C)Nc1c(C)cccc1C
Solvent: Cc1ccccc1
Product: CCOCC(=O)N(c1c(C)cccc1C)C(C)COC

Procedure:
With stirring, 7.3 g of ethoxyacetyl chloride in 20 ml of abs. toluene were added at room temperature to 9.6 g of N-(1'-methyl-2'-methoxyethyl)-2,6-dimethylaniline. After stirring for 3 hours at room temperature, the reaction mixture was filtered. The filtrate was freed from solvent and the residual oil was distilled in a high vacuum. Boiling point: 122°-124° C./0.04 torr.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(SCCCCl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(SCCCCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a cooded (5° C.) solution of 1-chloro-3-(4-aminothiophenoxy)propane (4.9 g, 0.024 mol) and pyridine (2.1 g 0.027 mol) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (3.1 g, 0.027 mol). The mixture was stirred at room temperature for 16 hours, washed with 2 N HCl, brine, dried (MgSO4), and concentrated. Recrystallization from EtOH gave 4.0 g (59%) of product as a pink solid m.p. 61°-63° C.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][C:29]1[S:33][C:32]2=[CH:34][N:35]=[CH:36][N:31]2[CH:30]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:35]3[CH:34]=[C:32]4[S:33][C:29]([CH2:28][OH:27])=[CH:30][N+:31]4=[CH:36]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: OCc1cn2cncc2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4sc(CO)c[n+]4c3)[C@H](C)[C@H]12
Yield: 3.1 %

Procedure:
The same procedure as in Example 1 was repeated except that 103 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 87 mg of 2-hydroxymethylimidazo[5,1-b]thiazole were used, thereby obtaining 3.3 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]([C:30]([F:33])([F:32])[F:31])([CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:9][C:8]=1[N+:27]([O-])=O)[C:3](O)=[O:4].O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1([C:30]([F:33])([F:32])[F:31])[CH2:6][C:7]2[C:8](=[CH:9][C:10]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[N:16]([CH3:25])[C:15]3=[O:26])=[C:11]([F:13])[CH:12]=2)[NH:27][C:3]1=[O:4]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+](=O)[O-])c(CC(Cl)(C(=O)O)C(F)(F)F)cc2F)c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)CC(Cl)(C(F)(F)F)C(=O)N3)c1=O
Yield: 53.5 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 1, using 6.8 grams (0.013 mole) of 2-chloro-2-trifluoromethyl-3-[5-fluoro-2-nitro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoic acid, 7.0 grams (0.130 g-atom) of iron powder, and 20 mL of water in 100 mL of acetic acid, yielding 3.2 grams of 3-(3-chloro-6-fluoro-3,4-dihydro-3-trifluoromethylquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.