Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[N:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[F:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([NH2:3])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CON=C(Cc1cccc(F)c1)c1cccc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NC(Cc1cccc(F)c1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 51.9 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-1-(3-trifluoromethyl-phenyl)-ethanone O-methyl-oxime (1.00 g, 3.20 mmol) in Et2O at 0° C. was added LAH (1.0 M in THF, 3.20 mL, 3.20 mmol). The reaction mixture was stirred for a few minutes, and then refluxed for 30 hours. The resulting mixture was cooled to 0° C. and quenched with a few drops of H2O. The mixture was filtered through a pad of celite, concentrated and purified by column chromatography using hexane:EtOAc (1:1) as eluant to give 470 mg of the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 1.47-1.62 (m, 2 H), 2.84-2.93 (m, 1 H), 2.98-3.07 (m, 1 H), 4.28-4.35 (m, 1 H), 6.99-7.11 (m, 3 H), 7.16-7.27 (m, 1 H), 7.39-7.46 (m, 1 H), 7.52 (t, J=7.62 Hz, 2 H), 7.61 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:10][C:11]([C:14]3[N:15](C(OC(C)(C)C)=O)[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:14]1[C:11]1[O:10][C:9]([NH:8][C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)=[N:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(O)c3)o2)cc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cccc(Nc2ncc(-c3cc4ccccc4[nH]3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a stirred solution of tert-butyl 2-(2-((3-hydroxyphenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 22 (0.125 g, 0.319 mmol) in anhydrous CH2Cl2 (20 mL) was added 1:1 mixture of CH2Cl2:Trifluoroacetic acid (5 mL) at 0° C. Reaction was stirred for 1 hour at ambient temperature. It was quenched with aq. saturated NaHCO3 and CH2Cl2 layer was separated. After evaporation of solvent, crude product was purified using preparative-TLC to obtain 3-((5-(1H-indol-2-yl)oxazol-2-yl)amino)phenol 23 (0.027 g, 16% yield).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC([O-])(C)C.[Na+].Br[C:15]1[C:16]([CH:25]2[CH2:27][CH2:26]2)=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:25]1([C:16]2[C:15]([N:1]3[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:24]3[C:19]([CH:20]=[CH:21][CH:22]=[N:23]3)=[CH:18][CH:17]=2)[CH2:27][CH2:26]1
Reactant: C1CNCCNC1
Reactant: Brc1c(C2CC2)ccc2cccnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cnc2c(N3CCCNCC3)c(C3CC3)ccc2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A mixture of homopiperazine (0.965 g, 9.6 mmol), NaOt-Bu (0.323 g, 3.4 mmol), (±)-BINAP (0.40 g, 0.64 mmol), and Pd2(dba)3 (0.22 g, 0.24 mmol) in toluene (10 mL) was heated to 110° C. and 8-bromo-7-cyclopropylquinoline (0.60 g, 2.4 mmol) was added. After 2 h, the reaction was cooled to rt, quenched with 50 mL of water, and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over anhydrous Na2SO4, concentrated, and purified by SiO2 chromatography with a gradient elution of 0.25-2.2% NH4OH and 2.5-22% MeOH/CH2Cl2 to yield 7-cyclopropyl-8-(1,4-diazepan-1-yl)quinoline (0.33 g, 51% yield).
Reaction SMILES: O=[CH:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[NH2:13][CH2:14][C@H:15]([OH:17])[CH3:16].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CO.[Pd]>[OH:17][C@H:15]([CH3:16])[CH2:14][NH:13][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: C[C@@H](O)CN
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CO
Product: C[C@@H](O)CNC[C@H](C)NC(=O)OC(C)(C)C
Yield: 98.5 %

Procedure:
(S)-tert-butyl 1-oxopropan-2-ylcarbamate (Boc-L-Alaninal) (3.0 g, 17.32 mmol) and (R)-1-aminopropan-2-ol (1.95 g, 25.98 mmol) in anhydrous methanol (120 mL) was hydrogenated at 1 atmosphere overnight using palladium, 10% wt. on activated carbon (900 mg) as catalyst. Reaction was complete as determined by TLC using CAN spray to visualize. The reaction mixture was then filtered through a celite bed. After solvent evaporation crude product was diluted with ethyl acetate, washed with saturated NAHCO3 (aq.) and dried over MgSO4. Solvent evaporation afforded tert-butyl (S)-1-[(R)-2-hydroxypropylamino]propan-2-ylcarbamate] in 98.5% yield (3.95 g). It was carried to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](O)=[O:8].[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([NH:28][C:7]([C:6]1[C:5]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)=[CH:13][C:4]=2[O:3][C:2]=1[CH3:1])=[O:8])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Product: CCCCNC(=O)c1c(C)oc2cc(Oc3ccnc4ccsc34)ccc12

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic acid 100 and butylamine in a similar manner as that described for example 102. 1H NMR (CD3CN) δ 8.48 (1H,d, J=5.3 Hz), 7.91 (1H, d, J=5.6 Hz), 7.81 (1H, d, J=8.6 Hz), 7.53 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=2.3 Hz), 7.20 (1H, dd, J=8.6, 2.3 Hz), 6.62 (1H, d, J=5.3 Hz), 6.62 (1H, bm), 3.40 (2H, q, J=6.9 Hz), 2.65 (3H, s), 1.60 (2H, m), 1.42 (2H, m), 0.97 (3H, t, J=7.3 Hz).
Reaction SMILES: C[Si](Cl)(C)C.BrCCBr.[CH:10]1(I)[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1>CN(C)C(=O)C.[Zn].[Cu]I>[Cl:16][C:17]1[C:22]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: IC1CCCC1
Reactant: Clc1nccnc1Cl
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: Clc1nccnc1C1CCCC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a suspension of zinc dust (2.00 g, 30.6 mmol) in N,N-dimethylacetamide (20 mL) was added a mixture of trimethylsilyl chloride and 1,2-dibromoethane (7:5, v/v, 0.95mL total volume) dropwise over 5 minutes. The mixture was stirred for 15 min before cyclopentyl iodide (5.00 g, 25.5 mmol) was added dropwise over 15 min. This mixture was stirred for an additional 15 min and then was added via syringe over 5 min to a mixture of copper(I) iodide (0.30 g, 1.60 mmol), dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (0.65 g, 0.80 mmol), and 2,3-dichloropyrazine (1.66 mL, 16.0 mmol) in N,N-dimethylacetamide (30 mL) under argon atmosphere. The mixture was heated to 80° C. for 7 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The resulting layers were separated and the aqueous layer was extracted with ethyl acetate (1×). The combined extracts were washed with water (2×), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 2-chloro-3-cyclopentylpyrazine.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:35])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(F)cc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.80 mmol) and 4-fluorophenylisocyanate (0.25 g, 1.80 mmol) in acetonitrile (20 mL), was added triethylamine (0.51 mL, 3.60 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-fluoro-phenyl)-urea as an off-white solid (0.51 g, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.13 min (98.98%); mp: 262-264° C.; 1H NMR (DMSO-d6) δ 1.92-2.13 (m, 1H), 2.29-2.47 (m, 1H), 2.54-2.69 (m, 1H), 2.82-3.00 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.37-4.55 (m, 3H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 6.73 (t, J=5.9 Hz, 1H), 7.06 (t, J=8.9 Hz, 2H), 7.37-7.48 (m, 3H), 7.52 (s, 1H), 7.70 (d, J=7.9 Hz, 1H), 8.67 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.6, 115.1 (d, J=22.0 Hz), 119.4 (d, J=6.6 Hz), 121.9, 122.9, 126.9, 130.3, 136.8, 142.4, 144.9, 155.3 (d, J=4.4 Hz), 158.5, 168.0, 171.0, 172.9; LCMS: MH=411; Anal Calcd for C21H19FN4O4: C, 61.46; H, 4.67; N, 13.65. Found: C, 61.44; H, 4.53; N, 13.46.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:15]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)nc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)nc1

Procedure:
6-(bromomethyl)pyridine-3-carboxylic acid was coupled to 4-chloro-3-(pyridin-2-yl)aniline as described in general procedure E to yield 6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH:9]=1.S(OC)(OC)(=O)=O.Cl>CN(C)C=O>[CH3:1][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]2
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
Potassium carbonate (1.244 g) was added to a solution of commercially available 2,6-dihydroxynaphthalene (961 mg) in N,N-dimethylformamide (100 ml), and the admixture was stirred at room temperature for 30 minutes. Dimethyl sulfate (1.14 ml) was slowly added dropwise to the mixture and the resulting mixture was further stirred at room temperature overnight. The reaction mixture thus prepared was neutralized with a 2N HCl solution and then partitioned between water and ethyl acetate, and the ethyl acetate layer was dried with anhydrous magnesium sulfate. After removing the solvent by distillation under reduced pressure, the resulting residue was purified by column chromatography on silica gel (eluting with chloroform/ethyl acetate) to obtain 307 mg of the title compound (yield: 29%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:26][CH2:27][O:28][CH3:29])[CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[OH-].[Na+]>C(O)C>[CH3:29][O:28][CH2:27][CH2:26][N:19]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:30])=[O:2])[CH2:12][CH2:13]2)=[CH:18]1
Reactant: COCCn1cc(C2CCN(Cc3cccc(C(=O)OC)c3)CC2)c2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCn1cc(C2CCN(Cc3cccc(C(=O)O)c3)CC2)c2cccnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.66 g (1.62 mmol) of 3-{4-[1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-ylmethyl}-benzoic acid methyl ester were dissolved in 0.8 ml of ethyl alcohol and 2.43 ml of 2 N sodium hydroxide were added. After stirring at room temperature for 20 hours, the solvent was evaporated under reduced pressure and the residue dissolved in water. The mixture was neutralised with 2 N hydrochloric acid and extracted twice with dichlormethane. The organic phase was washed with water and brine, dried with magnesium sulphate, filtrated and evaporated. The crude material weighed 0.46 g and was purified by flash chromatography over silica gel affording 0.2 g (31% of yield) of the expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:9]/[C:10]([O:12]C)=O.CC(C)([O-])C.[K+]>C1COCC1>[OH:12][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)/C=C(\SCc1ccccc1)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(O)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of methyl Z-3-(2'methylphenyl)-3-benzylthio-2-propenoate (575 mg, 1.93 mmol) in 6.0 mL of THF was added through a double ended needle to a solution of potassium tert-butoxide (650 mg, 5.79 mmol) in 8.0 mL of THF at ambient temperature. An additional 2×1 mL of THF was used to rinse the ester into the reaction. The bright orange-green reaction as stirred 20 minutes at 25° C., then cooled in an ice bath and quenched by the addition of 3.5 mL of 2.0 N aqueous hydrochloric acid. The reaction was poured into 25 mL of saturated aqueous sodium chloride and extracted with 2×25 mL of ethyl acetate. The ethyl acetate layers were washed in succession with 25 mL of saturated aqueous sodium chloride, combined, dried over sodium sulfate, decanted, and evaporated. Flash column chromatography on 15 g of silica gel eluted with 500 mL of 3% ethyl acetate in hexane followed by 200 mL of 6% ethyl acetate in hexane gave 3-hydroxy-5-(2'-methylphenyl)-2-phenylthiophene as 385 mg of pale yellow viscous oil (75% yield). The product could be distilled bulb to bulb, bp (0.4 mm) 140° -150° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20](=O)[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:69]=[N:70][N:71]([CH3:73])[N:72]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:69]=[N:70][N:71]([CH3:73])[N:72]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1nnc(SCSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3S(=O)C2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnc(SCSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)n1
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyltetrazol-5-yl thiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (1.38 g: 1.31 mMol.) in dimethylformamide (15 ml) at -20° C. is added phosphorus trichloride (0.33 ml: 3.28 mMol.), and the mixture is stirred at the same temperature for 20 minutes. The reaction mixture is poured into cold two layers of aqueous sodium hydrogen carbonate and ethyl acetate and stirred. The organic layer is taken, washed with water and brine, dried over sodium sulfate and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=5:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyltetrazol-5-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.20 g) as yellow foam. Yield: 88%.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].O>CN(C)C=O.CCCCCC>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][C:4]3[CH:17]=[CH:18][S:19][C:3]=3[C:2](=[O:1])[C:8]=2[CH:9]=1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)COC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A mixture of 12.54 g (0.046 m) of 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid in 100 ml of dimethylformamide (DMF) and 3.18 g (0.033 m) of K2CO3 was warmed to 60° C. for 1 hour in an atmosphere of nitrogen. To this mixture 7.7 g (0.05 m) of methyl bromoacetate was added dropwise and the mixture was held at 60° C. overnight (about 16 hours). The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5% NaHCO3 and water, dried over Na2SO4, filtered and evaporated to give an oil which solidified. Trituration with hexane gave 12.5 g (78%) of methyl(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)acetoxyacetate, m.p. 78°-80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[C:5](=N)[NH:6][C:7]2=[NH:14].[ClH:16].[CH3:17][CH:18]([CH2:27][CH3:28])[CH2:19][NH:20][C:21]1[S:22][CH2:23][C:24](=[NH:26])[N:25]=1.N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:16].[NH:14]=[C:7]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])[C:5](=[C:23]2[S:22][C:21]([NH:20][CH2:19][CH:18]([CH3:17])[CH2:27][CH3:28])=[N:25][C:24]2=[NH:26])[NH:6]1
Reactant: COc1ccc(OC)c2c1C(=N)NC2=N
Reactant: CCC(C)CNC1=NC(=N)CS1
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: CCC(C)CNC1=NC(=N)C(=C2NC(=N)c3c(OC)ccc(OC)c32)S1

Procedure:
When equivalent amounts of 4,7-dimethoxy-1,3-diiminoisoindoline and 2-(2-methylbutylamino)-4-imino-2-thiazoline hydrochloride are substituted for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, in the procedure described in Example 9, part B above, there is obtained as the product 1-imino-4,7-dimethoxy-3-[2-(2-methylbutylamino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B(OC)(OC)OC.CO>O1CCCC1>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: COB(OC)OC
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
To a solution of 2-amino-4-trifluoromethylbenzoic acid (4.56 g, 22.2 mmol), prepared in the step (a), in tetrahydrofuran (100 ml) were added 10 M borane-dimethyl sulfide complex (4.4 ml, 44.0 mmol) and trimethyl borate (10 ml). The mixture was stirred under ice cooling for 10 min, at room temperature for 15 min, and at 45° C. for 17 hr. Subsequently, 2 ml of 10 M borane-dimethyl sulfide complex was added thereto, and a reaction was allowed to proceed at 45° C. for 15 hr. Thereafter, methanol was added to the reaction mixture under ice cooling to terminate the reaction. The reaction mixture was concentrated under reduced pressure, and the resultant powder was collected by filtration, washed with hexane, and then dried to give 2-amino-4-trifluoromethyl-1-hydroxymethylbenzene (4.08 g, 96%) as yellowish green powder.
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH2:10][NH2:11].CCN(C(C)C)C(C)C.Cl[C:24]1[N:29]=[C:28]([Cl:30])[C:27]([C:31]#[N:32])=[CH:26][N:25]=1>CN(C=O)C>[Cl:30][C:28]1[C:27]([C:31]#[N:32])=[CH:26][N:25]=[C:24]([NH:11][CH2:10][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[C:3]([F:12])([F:2])[F:13])[N:29]=1
Reactant: NCc1cnccc1C(F)(F)F
Reactant: N#Cc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(NCc2cnccc2C(F)(F)F)nc1Cl
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To (4-(trifluoromethyl)pyridin-3-yl)methanamine hydrochloride (1.0 equiv.) in DMF (1.0 M) was added DIEA (2.5 equiv.). The reaction was cooled to −20° C. (ice/brine bath) then added 2,4-dichloropyrimidine-5-carbonitrile (1.0 equiv.). The reaction mixture was stirred for 10 min, then removed from the ice bath and allowed to stir for 30 min. The reaction mixture was diluted with ethyl acetate and partitioned with water. The organic layer was separated and volatile solvents were removed under reduced pressure. The residue was purified using silica gel chromatography (5-50% ethyl acetate in hexanes). The desired fractions were combined and volatile solvents were removed under reduced pressure. The residue was triturated in 10% ethyl acetate in hexanes, filtered, washed with hexanes, and dried in vacuo to afford 4-chloro-2-(((4-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrimidine-5-carbonitrile (43.0% yield) as a pale tan solid; MS (ESI) m/z 314.0 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1.O>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone (150 mg, 0.64 mmol) dissolved in 750 uL pyridine was added 4-tert-butylbenzenesulfonyl chloride (225 mg, 0.97 mmol) and the mixture stirred at 60° C. overnight. The reaction mixture was diluted with 1.0 mL H2O and the precipitate formed was collected by vacuum filtration. The crude product was recrystallized from EtOAc/hexane yielding 190 mg of pure title compound. 1H NMR (CDCl3) δ 9.87 (s, 1H), 8.79 (d, J=4.8 Hz, 1H), 8.52 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.52 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.40 (dd, J=7.6 Hz, 4.8 Hz, 1H), 7.33-7.31 (m, 3H), 1.22 (s, 9H). MS: m/z=429.0 (M++1).