Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][NH:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[C:21]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][C:35]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[C:21]3[C:11]4[CH:10]=[N:9][NH:8][C:12]=4[N:13]=[CH:14][C:15]=3[CH2:16][CH2:17]2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCNc2ccccc2-4)cc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N1CCc2cnc3[nH]ncc3c2-c2ccccc21
Yield: 31 %

Procedure:
The compound N-phenyl-6,7-dihydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine-8(3H)-carboxamide was prepared using 3-(4-methoxybenzyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine and phenyl isocyanate as described in the two step general procedure L to give the desired compound as an off-white solid (0.048 g, 31%). M.p.>140° C.; 1H NMR (CDCl3, 400 MHz) δ 11.35 (brs, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.99 (m, 1H), 7.68-7.60 (m, 2H), 7.46 (dd, J1=1.6 Hz, J2=7.2 Hz, 1H), 7.15-7.06 (m, 4H), 6.90 (m, 1H), 5.97 (s, 1H), 4.75 (m, 1H), 3.77 (m, 1H), 2.90 (m, 2H); LCMS [M+H]: 356.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([N:11]2[C:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([C:31]#[N:32])=[CH:3][CH:4]=3)=[CH:8][C:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)=[N:10]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(C)C=O
Reactant: FC(F)(F)Oc1ccc(-c2cc(Cc3ccc(Br)cc3)n(C3CCCCC3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C2CCCCC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 651 mg 5-(4-bromobenzyl)-1-cyclohexyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazole from Step C Example 11, 95.7 mg zinc cyanide, 62.9 mg tetrakis(triphenylphosphine)palladium(0) in 2.5 mL DMF was heated under nitrogen in 80° C. oil bath for 24 hours. Evaporate most of DMF. The residue was purified on silica gel using 1 and 3% MeCN in methylene chloride to give the title compound as a yellow foam. 1H NMR (CDCl3, 600 MHz) δ 7.78˜7.81 (m, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 7.215 (d, J=8.3 Hz, 2H), 6.25 (s, 1H), 4.09 (s, 2H), 3.83 (tt, J=3.9 & 11.7 Hz, 1H), 1.96˜2.03 (m, 2H), 1.85˜1.89 (m, 2H), 1.73˜1.77 (m, 2H), 1.68˜1.71 (m, 1H), 1.23˜1.33 (m, 3H). LC-MS: 2.63 min. (M+H=426).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH:35]=O)[CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([O:21]CC1C=C(C=O)C=C(Cl)C=1)=[O:20].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH2:35][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([OH:21])=[O:20]
Reactant: Cc1nnc2ccc3c(cc(C(=O)OCc4cc(Cl)cc(C=O)c4)n3Cc3cc(Cl)cc(C=O)c3)n12
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cc(Cl)cc(CN4CCCC4)c3)n12
Reaction time: 8 h

Procedure:
3-Chloro-5-formylbenzyl 6-(3-chloro-5-formylbenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (0.035 g, 0.067 mmol, from Example 131, Step 7) was suspended in DCM (4 mL) and pyrrolidine (0.03 g, 0.4 mmol, Aldrich) and sodium triacetoxyborohydride (0.2 g, 0.8 mmol, Aldrich) were added. After stirring overnight, the reaction mixture was made basic by the addition of 1N solution of NaOH, and the product was extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered and concentrated. The crude product was stirred with 1.0 M solution of NaOH (2 mL, 2 mmol) and THF (2 mL) for 1.5 hours. The product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (5 mg, 18%). LCMS (M+H)+: 424.2.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=1.CC(O)=O>C1COCC1>[CH3:38][C:37](=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([OH:28])=[CH:34][CH:33]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=Cc1ccccc1)CCc1ccc(O)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a suspension of benzyltriphenylphosphonium bromide (10.9 g, 25.1 mmol, 1.2 equiv.) in THF (35 mL), was added potassium-t-amylat (1.7 M in toluene, 20 mL, 34.0 mmol, 1.7 equiv.) at 25° C. 4-(4-Hydroxyphenyl)butan-2-one (3.3 g, 20.1 mmol, 1.0 equiv.) in THF (5 mL) was added to the red suspension, and the mixture was stirred at 70° C. for 30 min. After addition of 20% aq. AcOH-solution (10 mL) at 25° C., the aqueous layer was diluted with hexanes (50 mL). The organic phase was washed with H2O (2×30 mL) and MeOH/H2O (8:2, 2×20 mL) and concentrated. The residue was purified by flash chromatography on SiO2 to yield 2.10 g (44%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH:28]([CH3:30])[CH3:29])[C:5](=[O:27])[O:6][C:7]1[C:15]2[C:14]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=3[CH2:12][CH2:11][C:10]=2[N:9]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:8]=1)([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.Cl.C(O)(C)C>[ClH:20].[CH:28]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:27])[O:6][C:7]1[C:15]2[C:14]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=3[CH:12]=[CH:11][C:10]=2[N:9]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:8]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N(C(=O)Oc1nn(-c2ccncc2)c2c1-c1ccc(Cl)cc1CC2)C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Solvent: CC(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)N(C(=O)Oc1nn(-c2ccncc2)c2ccc3cc(Cl)ccc3c12)C(C)C
Yield: 153.8 %

Procedure:
1.65 g (3.38 mmol) of 7-chloro-4,5-dihydro-3-(pyrid-4-yl)-3H-benzo[e]indazol-1-yl N,N-diisopropylcarbamate, prepared according to the method described in Example 5, 1.105 g (6.21 mmol) of N-bromosuccinimide and 0.127 g (0.78 mmol) of 2,2′-azobis(2-methylpropionitrile) are added to a 100 ml reactor. The mixture, dissolved in 40 ml of carbon tetrachloride, is stirred at reflux for 24 h and is then concentrated under reduced pressure. The resulting product is taken up in 300 ml of dichloromethane and 2 ml of a concentrated aqueous ammonia solution. The organic phase is separated and washed with 200 ml of water and then with 200 ml of a saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulphate and then concentrated under reduced pressure. The resulting product is purified by chromatography on an alumina column (eluents: mixture of dichloromethane and of methanol) and then on a silica column (eluents: mixture of dichloromethane and of ethyl acetate). The product thus isolated is converted to the hydrochloride by dissolution in a 0.1N solution of hydrochloric acid in isopropanol. The solution is concentrated to dryness under reduced pressure. After triturating from ethyl ether, filtering off and drying under reduced pressure, 1.2 g (2.6 mmol) of the final product are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH:9]([CH3:12])[CH2:10][OH:11])[CH:5]=[C:4]([Cl:14])[N:3]=1.[Li+].[OH-:16].OO>O>[Cl:14][C:4]1[CH:5]=[C:6]([N:8]([CH:9]([CH3:12])[CH2:10][OH:11])[CH3:13])[NH:7][C:2](=[O:16])[N:3]=1
Reactant: [OH-]
Reactant: CC(CO)N(C)c1cc(Cl)nc(Cl)n1
Agent: OO
Agent: [Li+]
Solvent: O
Product: CC(CO)N(C)c1cc(Cl)nc(=O)[nH]1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)propan-1-ol (3.0 g, 13 mmol) and LiOH one hydrate (1.60 g, 38 mmol) in water (2 mL) was added H2O2 (0.78 mL, 25 mmol). The reaction mixture was stirred at 45° C. for 3 h, then quenched with Na2S3O3 solution (2 mL) and concentrated. Purification via Biotage Spla HPFC system (C18, mobile phase: 0.01% NH4HCO3 in H2O/CH3CN, 10˜95%, 9.5 min, 30 mL/min) afforded the title product as a white solid.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[OH-].[Na+].[CH3:9][N:10]1[C:18]([S:19]([O-:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N:11]1.[Li+]>O>[CH3:9][N:10]1[C:18]([S:19]([NH2:1])(=[O:21])=[O:20])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]2)=[N:11]1
Reactant: NOS(=O)(=O)O
Reactant: Cn1nc2ccccc2c1S(=O)[O-]
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc2ccccc2c1S(N)(=O)=O
Temperature: 10 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
A solution containing 9.5 g (72 mmol) of 2-methyl-2H-indazole in 200 ml of ethyl ether, was cooled to -30° C., and 61.4 g (144 mmol) of n-butyl lithium (a 15% hexane solution) was dropwise added thereto. The mixture was stirred for one hour at the same temperature, and then an excess amount of sulfurous acid gas was blown thereinto for 3 hours at a temperature of not higher than -20° C. After completion of the reaction, the mixture was returned to room temperature, stirred for 12 hours and then diluted with ethyl ether. The product was subjected to filtration. The crystals were dried to obtain crude lithium 2-methyl-2H-indazole-3-sulfinate. This product was used for the subsequent reaction without purification. 48.8 g (430 mmol) of hydroxylamine-O-sulfonic acid was gradually added to a solution containing 17.2 g (430 mmol) of sodium hydroxide in water (300 ml) under cooling with ice (not higher than 10° C.). This solution was added all at once to a solution containing the crude lithium 2-methyl-2H-indazole-3-sulfinate previously prepared in water (100 ml), and then the mixture was stirred for 12 hours at room temperature. Formed crystals were collected by filtration to obtain 8.8 g (yield: 58%) of 2-methyl-2H-indazole-3-sulfonamide (slightly yellow granular crystals). Melting point: 181°-183° C.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.P(Br)(Br)[Br:28]>N1C=CC=CC=1>[Br:28][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][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][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccccc1CO
Reactant: BrP(Br)Br
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccccc1CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound is prepared by the procedure of Example 20 using 2.5 g of product from Example 21, 10 ml acetonitrile, 2.11 g of phosphorus tribromide and 0.339 g of pyridine. The reaction is cooled for 10 minutes at 0° C., followed by stirring at room temperature for 1 hour. The product, 2.58 g, is obtained as cream crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=1.O=[C:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:27]([O:26][C:24]([N:22]1[CH2:23][CH:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[F:16])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:18])[C:7](=[O:17])[NH:8][N:9]=2)[CH2:21]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1C(=O)NN=C2COc3cc(F)c(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
A solution of 6-amino-7-fluoro-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.100 g, 0.400 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.171 g, 0.999 mmol) in MeOH (10 mL) and HOAc (1 mL) was stirred at rt for 1 h. Sodium cyanoborohydride (0.176 g, 2.80 mmol) was added and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by column on silica gel (eluting with 0-10% MeOH in DCM to give 3-(7-fluoro-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.115 g, 71%) as a crude gum, which was used directly in the next step. LC/MS (Table 1, Method 3) Rt=1.374 min.; MS m/z: 428 [M+23]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[S:19](Cl)(=[O:21])=[O:20]>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[S:19]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:20])=[O:21]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: Cc1noc(N)c1Br
Product: COc1ccc(OC)c(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 58 %

Procedure:
2,5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5-dimethoxybenzenesulfonyl chloride according to the procedures described in Example 200. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 118-120°, yield 58%.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([CH:9]=[O:10])=[C:7](Cl)[N:6]=[CH:5][N:4]=1>C1(C)C=CC=CC=1.O>[NH2:1][C:7]1[C:8]([CH:9]=[O:10])=[C:3]([Cl:2])[N:4]=[CH:5][N:6]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: N
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ncnc(Cl)c1C=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
NH3 (g) was blown through a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde Compound 1a (50 g, 282.5 mmol) in toluene (565 mL, 0.5M) for 3 mins using a 12C glass frit, then the mixture was warmed at 60° C. with stirring for 30 min. NH3 (g) was blown through the reaction mixture a second time for 3 min and the reaction was heated for 30 mins. NH3 (g) was blown through the reaction mixture a third time for 3 min and the reaction was heated for a final 20 mins. The reaction mixture was diluted with H2O (1 L), and extracted with EtOAc (1×750 mL, 3×500 mL). The organic extracts were washed with brine (4×) and dried (Na2SO4), then concentrated to afford 4-amino-6-chloro-pyrimidine-5-carbaldehyde Compound 1b (38.5 g, 87%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.74 (br s, 1H), 8.58 (br s, 1H), 8.42 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:50]1[CH2:55][CH2:54][CH:53]([C:56]#[N:57])[CH2:52][CH2:51]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:56]([CH:53]1[CH2:54][CH2:55][N:50]([CH2:46][C:42]2[CH:41]=[C:40]([C:35]3[C:36]([F:39])=[CH:37][CH:38]=[C:33]([CH2:32][NH:31][C:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([NH:20][CH2:19][C:10]5[C:11]([NH:12][CH:13]6[CH2:14][CH2:15][O:16][CH2:17][CH2:18]6)=[C:6]6[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]6=[N:8][C:9]=5[CH2:48][CH3:49])=[O:22])[CH:24]=4)=[O:30])[CH:34]=3)[CH:45]=[CH:44][CH:43]=2)[CH2:51][CH2:52]1)#[N:57]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Reactant: N#CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCC(C#N)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 28.1 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (82 mg, 0.129 mmol) in DCM (2.58 mL) was added 4-piperidinecarbonitrile (14.21 mg, 0.129 mmol), NaBH(OAc)3 (41.0 mg, 0.193 mmol). This mixture was stirred at room temperature for 19 h. The reaction mixture was washed with H2O (1 mL), concentrated, purified using a Gilson HPLC (with 0.1% TFA), and basified with an amine cartridge to afford 0.0274 g (28%) of the title compound. LC-MS m/z 757 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.41 (t, J=7.53 Hz, 3 H) 1.49 (t, J=7.15 Hz, 3 H) 1.82-1.93 (m, J=13.05 Hz, 2 H) 1.96-2.38 (m, 6 H) 2.92-3.20 (m, 4 H) 3.22-3.29 (m, 1 H) 3.49-3.73 (m, 4 H) 4.00-4.09 (m, 2 H) 4.31-4.52 (m, 5 H) 4.62 (s, 2 H) 4.72 (s, 2 H) 7.20 (dd, J=10.54, 8.53 Hz, 1 H) 7.39-7.46 (m, 1 H) 7.50-7.65 (m, 4 H) 7.67-7.77 (m, 2 H) 8.05 (d, J=8.03 Hz, 2 H) 8.30 (s, 1 H) 8.39 (t, J=1.51 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24]([O:32][CH2:33]Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[K+].[Br-]>>[C:24]([O:32][CH2:33][O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OCCl)c1ccccc1
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Agent: [Br-]
Agent: [K+]
Product: CN1C(C(=O)Nc2ccccn2)=C(OCOC(=O)c2ccccc2)c2ccccc2S1(=O)=O

Procedure:
By the procedure of Example 6, piroxicam (3.33 g, 10.1 mmol) and chloromethyl benzoate (4.29 g, 25.0 mmol) were converted to chromatographed title product, 2.3 g (4.9 mmol), 48.9%) white foam which gave white crystals from isopropyl alcohol: mp 149°-150° C.; IR (KBr) 1745, 1687 cm-1 ; 1H NMR (CDCl3) delta 3.07 (s, 3H), 5.89 (s, 2H), 6.97-7.08 (m, 1H), 7.19-7.35 (m, 2H), 7.35-7.63 (m, 2H), 7.63-7.99 (m, 6H), 8.22-8.35 (m, 2H), 9.22 (br s, 1H); precise mass calcd for C23H19N3O6S m/e 465.1001, found 465.1051
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:19])[CH3:18].C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:17](=[O:19])[CH3:18])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CS[C@H](COC(=O)c2ccccc2)O1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 29.76 g (0.132 mol) of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (as prepared in Example 1) in dichloromethane (65 mL) and pyridine (32 mL) was added dropwise 28.1 mL (0.395 mol) of acetyl chloride at 0-5° C. over 1.5 to 2 hours. The reaction mixture was stirred at 0-5° C. for 30 minutes then it was poured carefully onto a cold (0° C.) solution of saturated sodium bicarbonate. The organic layer was separated and the water layer was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated sodium bicarbonate (3×20 mL) and brine (20 mL), and was dried over sodium sulfate. Following filtration, the solvents were removed in vacuo to give 32.1 g of crude product which was purified by Kugelrohr distillation or filtration through a short silica gel column (eluent hexanes: EtOAc 3:1). The purified product consisted of a 3:1 mixture of trans:cis isomers.
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.[F:18][C@@H:19]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH2:20]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:30][CH:27]1[CH2:26][CH2:25][CH:24]([N:21]2[CH2:22][CH2:23][C@@H:19]([F:18])[CH2:20]2)[CH2:29][CH2:28]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: NC1CCC(N2CC[C@@H](F)C2)CC1
Product: O=C(c1cnc2ccc(Br)cc2c1NC1CCC(N2CC[C@@H](F)C2)CC1)C1CC1
Yield: 74.9 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (278 mg, 0.89 mmol) was reacted with (R)-4-(3-fluoropyrrolidin-1-yl)cyclohexanamine (200 mg, 1.1 mmol) to afford the desired product (307 mg, 75%) as a yellow solid: ESI MS m/z 460 [C23H27BrFN3O+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[C:25]1([C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N+]=[N-])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 19.2 %

Procedure:
3-Methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylic acid (17.75 g., 51 mmoles) was dissolved in 100 ml. methylene chloride. Diphenyldiazomethane (ca. 75 mmoles) was added dropwise with stirring until purple color persisted in the reaction mixture. After an additional 30 minutes of stirring at room temperature, the methylene chloride was evaporated in vacuo. The residue was taken up in a mixture of 100 ml. of water and further processed according to Preparation 4 to yield benzhydryl 3-methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylate [5.03 g.; pnmr (CDCl3 /TMS/delta): includes 2.0 (s, 3H), 3.2 (m, 2H), 4.5 (s, 2H), 6.9-7.6 (m, 11H)].
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1.[SH2:17]>N1C=CC=CC=1>[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:16])=[S:17])[CH2:10][CH2:9]1
Reactant: N#CCN1CCOCC1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)CN1CCOCC1
Reaction time: 8 h

Procedure:
A reaction mixture was prepared from 203 ml. each of triethylamine and pyridine plus 63 g. of morpholinoacetonitrile. Hydrogen sulfide was bubbled through the heated, stirred reaction mixture for about 2.5 hours. Stirring was continued overnight at ambient temperature. The next day, H2S was passed through the heated, stirred reaction mixture for an additional 1.5 hours. At this point, the solvents were evaporated in vacuo and the residue triturated with ether. The ether was discarded and the residue dissolved in ethanol. Crystalline morpholinothioacetamide formed in the above reaction precipitated and was separated by filtration. Treatment of the filtrate with alcoholic hydrogen chloride yielded morpholinothioacetamide hydrochloride melting in the range 64°-80° C. See also J.A.C.S., 72, 2804 (1950).