Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[CH:33][CH:34]=3)[CH2:18][CH2:17]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(=O)CC2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Nc3ccc(F)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.1 %

Procedure:
To a solution of the compound obtained in Example 208 (1000 mg, 2.2 mmol) and 4-fluoroaniline (269 mg, 2.4 mmol) in THF (3 mL) were added acetic acid (0.126 mL, 2.2 mmol) and sodium triacetoxyborohydride (699 mg, 3.3 mmol) under ice cooling, and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added saturated aqueous solution of sodium hydrogen carbonate (100 mL). The mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate (100 mL×2). The organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 20 g, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (695 mg, 1.3 mmol, Yield 58%) as a pale purple amorphous substance.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]4)[N:18]=3)=[CH:15][CH:16]=2)[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.C(O)CC>[NH:6]1[CH2:7][CH2:8][N:9]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:29][C:28]([CH3:31])([CH3:30])[NH:27][C:26]([CH3:33])([CH3:32])[CH2:25]4)[N:18]=3)=[CH:15][CH:16]=2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCN(c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)s2)CC1
Agent: C[Si](C)(C)I
Agent: Cl
Agent: [Na+]
Solvent: CCCO
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(Nc2nccc(-c3ccc(N4CCNCC4)s3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{5-[2-(2,2,6,6-Tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-thiophen-2-yl}-piperazine-1-carboxylic acid ethyl ester (120 mg, 0.25 mmol) in chloroform (5 ml) was treated with Me3SiI (0.34 ml, 2.5 mmol) at 60° C. for 4 hours. 6N-HCl in propanol (5 ml) was added and stirred for 30 minutes at room temperature. The reaction mixture was poured on 2N-NaOH and extracted 5 times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and purified via chromatography on silicagel (TBME/MeOH/ammonia:95/4.5/0/5 to 80/18/2) to give the title compound as yellow crystals. Yield: 20 mg (20%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]([C@@H:39]([CH3:47])[CH:40]([O:44][CH2:45][CH3:46])[O:41][CH2:42][CH3:43])[C:8](=[O:38])[C@@H:9]([NH:33]C(=O)OC)[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]2[CH:48]=[CH:49][CH:50]=[CH:51][C:2]1=2.N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:33][C@@H:9]([CH2:10][C:11]([NH:12][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:32])[C:8]([N:7]([CH2:6][C:4]1[C:3]2[CH:48]=[CH:49][CH:50]=[CH:51][C:2]=2[S:1][CH:5]=1)[C@@H:39]([CH3:47])[CH:40]([O:41][CH2:42][CH3:43])[O:44][CH2:45][CH3:46])=[O:38]
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC
Solvent: CO
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
9H-Fluoren-9-yl)methyl (S)-1-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-1,4-dioxo-4-(tritylamino)butan-2-ylcarbamate (Compound III-21) 23.5 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 15.1 g, (yield 86%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C>C(#N)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1

Procedure:
A solution of 2,4-dichloro-6-methyl-pyrimidine (1.25 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.15 g (46%) of the title compound. 1H NMR (400 MHz, DMSO): δ1.24-1.31 (m, 2H), 1.40 (s, 9H), 1.80-1.83 (br d, 2H), 2.18 (s, 3H), 2.90 (br s, 2H), 3.87 (br s, 2H), 3.96 (br s, 1H), 6.23 (br s, 1H), 7.68 (d, J=8.0 Hz, 1H). MS (ISP): 327.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Br)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.[CH2:16]([O:18][P:19]([O:23]CC)[O:20][CH2:21][CH3:22])[CH3:17]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11]([CH2:12][P:19]([O:20][CH2:21][CH3:22])([O:18][CH2:16][CH3:17])=[O:23])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([CH3:14])[CH:8]=2)[N:3]=1
Reactant: CCOP(OCC)OCC
Reactant: Cc1cc2cc(CBr)c(Br)nc2cc1Cl
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc2cc(C)c(Cl)cc2nc1Br)OCC

Procedure:
A mixture of 2-bromo-3-bromomethyl-7-chloro-6-methylquinoline (4.2 g, 12 mmol), toluene (50 ml) and triethylphosphite (4.2 ml) was refluxed for 20 h. After cooling the solution was concentrated in vacuum and the product precipitated by the addition of hexane. The crystals were filtered off, washed with hexane and dried in vacuo to give 4.5 g of 2-bromo-7-chloro-3-diethylphosphonomethyl-6-methylquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2.[OH-].[K+]>C(O)(C)C.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl.N[C@H](C1C=CC=CC=1)[C@H](NS(C1C=CC(C)=CC=1)(=O)=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1CC(=O)CC2
Agent: Cl[Ru]Cl
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(C)O
Solvent: c1ccccc1
Product: COc1cccc2c1C[C@H](O)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.2 %

Procedure:
N-((1R,2R)-2-amino-1,2-diphenylethyl)-4-methylbenzenesulfonamide (0.333 g, 0.908 mmol) and benzene ruthenium(II) chloride dimer (0.113 g, 0.226 mmol) in 80 mL isopropanol were stirred at 80° C. for 30 minutes, then cooled to room temperature. A solution of 8-methoxy-2-tetralone (4.0 g, 23 mmol) in isopropanol (400 mL) was added, followed by potassium hydroxide (0.038M in isopropanol, 120 mL, 4.56 mmol). The reaction mixture was stirred at 50° C. for 1.5 hours, at which time the starting material had been consumed. The isopropanol was evaporated, the residue was taken up in ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel (15 to 30% ethyl acetate-hexane, eluant) to afford 3.0 g (74% yield) of the title compound as a fluffy off-white solid. Analytical chiral HPLC (Chiralcel OJ 4.6×25 mm, 20% isopropanol/hexane, 23° C., 0.5 mL/min) showed the isolated material to be >98% ee. 1H NMR (300 MHz, DMSO-d6) δ 7.04 (t, J=7.8 Hz, 1H), 6.68 (m, 2H), 4.72 (d, J=3.7 Hz, 1H), 3.87 (m, 1H), 3.74 (s, 3H), 2.57-2.91 (m, 3H), 2.33 (m, 1H), 1.81 (m, 1H), 1.59 (m, 1H). MS (DCI+) m/z 196 (M+NH4)+.
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[CH:33]1([CH2:38][CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1.C(O)C>[CH:33]1([CH2:38][CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37]1.[CH:33]1([CH2:38][CH2:39][C:40]([NH:42][C:43]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:16]3[C:15]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=4)[N:19]=[CH:18][CH:17]=3)=[CH:27][CH:28]=2)=[S:44])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-cyclopentylpropanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 57%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:3]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCBr
Reactant: Brc1ccsc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccsc1
Yield: 84.9 %

Procedure:
Dried ethyl ether (40 ml) was added to activated magnesium (1.22 g; 50 mmol), and 1-bromododecane (12.46 g; 50 mmol) was added thereto to prepare a Grignard reagent. Then, Ni(dppp)Cl2 (33 mg) was added thereto, and 3-bromothiophene (8 g; 49 mmol) dissolved in 10 ml of ether was slowly added dropwise. The reaction solution was refluxed for one day, and then a mixture of 2N HCl/ice (50 ml) was added to terminate the reaction. The resultant was extracted by using ethyl ether, and the solvent was distilled off under reduced pressure. The residue was dissolved in DMF (50 ml) and filtered to remove remaining paraffin. The filtrate was concentrated, and then the residue was distilled off under vacuum to obtain a colorless liquid of 3-dodecylthiophene (10.5 g; 85%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([CH3:13])[CH:12]=1.CN([CH:19]=[O:20])C.[Cl-].[Na+]>C1COCC1>[CH3:15][O:14][C:10]1[CH:9]=[CH:8][C:7]([CH:19]=[O:20])=[CH:12][C:11]=1[CH3:13]
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1C
Reaction time: 1.17 h
Yield: 91.4 %

Procedure:
A stirred solution of 180 mL (1.6 Molar in hexane: 0.29 mole) of n-butyllithium in 250 mL of THF was cooled to below −60° C., and a solution of 50 grams (0.26 mole) of 5-bromo-2-methoxytoluene (commercially available) was added at a rate to maintain the reaction mixture temperature below −55° C. Upon completion of addition, the reaction mixture was cooled to about −60° C. to −70° C. where it stirred for 70 minutes. After this time, 80 mL (0.99 mole) of DMF was added to the reaction mixture at a rate to maintain the reaction mixture temperature below −50° C. Upon completion of addition, the reaction mixture was poured into an aqueous dilute sodium chloride solution, and then it was extracted with two portions of diethyl ether. The combined extracts were washed with one portion of an aqueous dilute sodium chloride solution, with one portion of an aqueous saturated sodium chloride solution, and then dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 35.7 grams of a residual oil. The oil was purified by column chromatography on silica gel using mixtures of hexane and ethyl acetate as eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 23.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C)C=O>[F:20][CH:16]([F:21])[O:14][C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2cc(OC(F)F)cnc12
Temperature: 100 °C
Yield: 15.8 %

Procedure:
A solution of 8-nitro-quinolin-3-ol (CAS25369-37-3) (500 mg, 2.63 mmol) in dimethylformamide (5 ml) was treated with sodium chlorodifluoroacetate (481 mg, 3.15 mmol). The mixture was heated to 100° C. overnight under a nitrogen atmosphere. For the workup, the reaction mixture was cooled to room temperature, then saturated aqueous sodium carbonate solution and dichloromethane were added. The organic layer was separated, dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a gradient of cyclohexane/ethyl acetate=9:1 to 8:1 as the eluent yielding 100 mg (16%) of the 3-difluoromethoxy-8-nitro-quinoline as a yellow solid; (calculated) C10H6F2N2O3 [240.2]; (found) [M+H]+=241.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[NH:9][C:10](=[O:12])[CH3:11])([O-:5])=[O:4].I[CH3:17].Cl>CN(C)C=O>[CH3:17][N:9]([C:10](=[O:12])[CH3:11])[C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1
Reactant: CC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% in oil, 5.19 g) in N,N-dimethylformamide (30 ml) was added a solution of 3′-nitroacetanilide (214 mg) in N,N-dimethylformamide (30 ml) at 0° C. The mixture was stirred at room temperature for 30 minutes, then iodomethane (3.59 ml) was added. After 30 minutes, 1N hydrochloric acid was poured into the mixture and extracted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give N-methyl-3′-nitroacetanilide (4.64 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH:8]1([O:11][N:12]=[C:13]([C:52]2[N:53]=[C:54]([NH:57][CH:58]=[O:59])[S:55][CH:56]=2)[C:14]([NH:16][C@@H:17]2[C:50](=[O:51])[N:19]3[C:20]([C:34]([O:36]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:35])=[C:21]([CH2:24][N+:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][CH:26]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[CH2:10][CH2:9]1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1.C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([O:11][N:12]=[C:13]([C:52]2[N:53]=[C:54]([NH:57][CH:58]=[O:59])[S:55][CH:56]=2)[C:14]([NH:16][C@@H:17]2[C:50](=[O:51])[N:19]3[C:20]([C:34]([O-:36])=[O:35])=[C:21]([CH2:24][N+:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][CH:26]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[CH2:9][CH2:10]1
Reactant: NC(=O)c1cc[n+](CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3SC2)cc1
Reactant: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: NC(=O)c1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3SC2)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a suspension of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate trifluoroacetate (syn isomer) (2.7 g) in a mixture of anisol (5 ml) and methylene chloride (10 ml) was added trifluoroacetic acid (10 ml) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. The mixture was poured into diisopropyl ether (800 ml) and the resulted precipitate was collected and dried over phosphorus pentoxide to give trifluoroacetic acid salt of 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (1.63 g).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:4][N:3]=1.O.[NH2:15][NH2:16]>CO>[NH:15]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:4][N:3]=1)[NH2:16]
Reactant: NN
Reactant: COc1cc(S(N)(=O)=O)cnc1Cl
Solvent: CO
Solvent: O
Product: COc1cc(S(N)(=O)=O)cnc1NN

Procedure:
2-Chloro-3-methoxy-5-sulfamoylpyridine (0.3 g, 1.35×10-3 mole) and hydrazine hydrate (0.53 g, approximately 0.01 mole) were added to methanol (20 ml). After refluxing overnight, the reaction mixture was stripped of methanol in vacuo to yield an oil which was cooled in an ice bath and triturated with water (5 ml). The precipitate was collected by filtration and air dried; yield, 0.22 g (75 percent).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:4]=1.Cl[C:39]1[CH:40]=[CH:41][C:42]2[O:55][CH2:54][N:45]3[C:46]4[CH:47]=[CH:48][CH:49]=[C:50]([F:53])[C:51]=4[CH:52]=[C:44]3[C:43]=2[N:56]=1.C([O-])([O-])=O.[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:1][CH:2]([F:37])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19]([C:39]4[CH:40]=[CH:41][C:42]5[O:55][CH2:54][N:45]6[C:46]7[CH:47]=[CH:48][CH:49]=[C:50]([F:53])[C:51]=7[CH:52]=[C:44]6[C:43]=5[N:56]=4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:4]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2ccc(C(F)F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(C(F)F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a degassed solution of 2-(4-(difluoromethyl)phenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.18 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (50 mg, 0.20 mmol), Na2CO3 (39 mg, 0.37 mmol), in 1,4-dioxane (3 mL) and H2O (0.1 mL) were added Pd2(dba)3 (5 mg) and X-Phos (5 mg) under N2. Then the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O and dried over Na2SO4. After being concentrated, the residue was purified by prep-HPLC to give the product of 2-(4-(difluoromethyl)phenyl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, yield: 41%). 1H-NMR (CDCl3, 400 MHz) δ 8.08 (d, J=7.6 Hz, 2H), 8.05 (s, 1H), 7.73 (s, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.53 (s, 2H), 7.30 (s, 1H), 7.25 (d, J=2.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.88˜6.93 (m, 1H), 6.75 (s, 1H), 6.09 (d, J=4.4 Hz, 1H), 6.04 (s, 2H), 3.41 (s, 3H), 3.04 (d, J=4.8 Hz, 3H), 2.79 (s, 3H). MS (M+H)+: 647.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[NH:4][N:3]=1.[CH3:10]OS(OC)(=O)=O>[OH-].[Na+]>[NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[N:4]([CH3:10])[N:3]=1
Reactant: COS(=O)(=O)OC
Reactant: N#Cc1c(N)n[nH]c1N
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(N)c(C#N)c1N
Yield: 20.8 %

Procedure:
3,5-Diamino-4-cyanopyrazole (6.1 g) was dissolved in 1 M sodium hydroxide solution (50 ml), and dimethylsulphate (6.2 g) was added. The mixture was heated at reflux for 21/2 hours and then evaporated to dryness. The residue was extracted with 2-methoxyethanol, and the extracts were evaporated. The residue was triturated with a small amount of water to give 3,5-diamino-4-cyano-1-methylpyrazole (1.4 g), m.p. 194°-196° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:14])[C:9]([CH3:13])([CH3:12])[C:10]#[N:11].B.O1CCCC1>O1CCCC1>[NH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[OH:14]
Reactant: CC(C)(C#N)C(O)c1ccccc1F
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CN)C(O)c1ccccc1F
Temperature: 75 °C
Yield: 84.9 %

Procedure:
To a stirring solution of 3-(2-fluoro-phenyl)-3-hydroxy-2,2-dimethyl-propionitrile (1.5 g, 7.76 mmol) in tetrahydrofuran was added a solution of borane-tetrahydrofuran complex (17 mL, 17.0 mmol, 1M in tetrahydrofuran). After bubbling ceased, the reaction mixture was heated to 75° C. for 4 hours and then allowed to cool to ambient temperature. Methanol (9 mL) was added dropwise followed by hydrogen chloride (9 mL, 4N in 1,4-dioxane). The resulting mixture was heated to reflux for 2 hours, allowed to cool to ambient temperature and then concentrated at reduced pressure. To the residue was added aqueous hydrochloric acid (5 mL, 1 N) followed by ethyl acetate (20 mL). The layers were separated and the aqueous layer was basified with aqueous lithium hydroxide (6 mL, 1 N) and this aqueous phase was extracted with dichloromethane (3×75 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (20 mL) and concentrated at reduced pressure to give the product as a colorless oil (1.3 g, 85%). 1H NMR (CDCl3) δ 7.53 (m, 1H), 7.25-7.05 (m, 2H), 6.94 (m, 1H), 5.06 (br s, 1H), 2.83 (q, J=12.5 Hz, 2H), 0.86 (d, J=8.5 Hz, 6H).