Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)[S:7](=[O:24])(=[O:23])[C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C.[Pd]>[O:30]1[C:29]2[CH:33]=[CH:34][C:26]([CH2:25][N:6]3[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([C:39]4[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:37]([O:36][CH3:35])[CH:38]=4)[C:9]4[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=4[S:7]3(=[O:23])=[O:24])=[CH:27][C:28]=2[O:32][CH2:31]1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(c2cc(OC)c(OC)c(OC)c2)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
2-Benzo[1,3]dioxol-5-ylmethyl-1,1-dioxo-4-(trifluoromethanesulfonyloxy)-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester was taken up in toluene/DMF (10 mL/2 mL) and treated with (3,4,5-trimethoxy)phenylboronic acid (0.35 g, 1.65 mmol), potassium carbonate (0.23 g, 1.67 mmol), and Pd° (PPh3)4 (0.19 g, 0.16 mmol). The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with sat. aq. NaHCO3, brine, dried over magnesium sulfate, and the solvent evaporated. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate 1:1. The resulting oil was treated with diethyl ether, the precipitated solid collected, and dried to give the product as an off-white solid;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:12][CH:11]=[CH2:10])[CH:3]=1
Reactant: BrCc1cccc(Br)c1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCc1cccc(Br)c1
Yield: 88.9 %

Procedure:
To a solution of 1-bromo-3-(bromomethyl)benzene (10.0 g, 40.0 mmol) in tetrahydrofuran (50 mL), under an inert atmosphere was added allylmagnesium bromide (1.0 M in diethyl ether, 40.0 mL, 40.0 mmol). The reaction was allowed to reflux overnight. The reaction was quenched with sulfuric acid (2 M, 45 mL). The resulting biphasic solution was solution was partitioned. The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography using 100% hexanes as eluent providing the title compound as a clear liquid (7.51 g, 71%, ˜80% pure): 1H NMR (400 MHz, DMSO-d6) δ 7.42 (ddd, J=2.1, 1.4, 0.7 Hz, 1H), 7.37 (dt, J=7.1, 2.1 Hz, 1H), 7.28-7.18 (m, 2H), 5.81 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.09-4.90 (m, 2H), 2.67 (dd, J=8.6, 6.8 Hz, 2H), 2.32 (tdt, J=7.7, 6.5, 1.5 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 144.35, 137.61, 131.05, 130.28, 128.62, 127.44, 121.53, 115.37, 34.59, 33.91; EIMS m/z 210 ([M]+).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([CH2:11][CH2:12][CH:13]([CH3:17])[C:14](O)=[O:15])([O:9][CH3:10])=[O:8]>C(Cl)Cl>[C:7]([CH2:11][CH2:12][CH:13]([CH3:17])[C:14]([Cl:4])=[O:15])([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CCC(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)CCC(C)C(=O)Cl

Procedure:
9.64 g of oxalyl chloride are added to the solution of 6.1 g of 4-carbomethoxy-2-methylbutanoic acid (U.S. Pat. No. 4,052,511) in 50 ml of methylene chloride. The mixture is refluxed for two hours and evaporated, to yield the 4-carbomethoxy-2-methylbutanoyl chloride, which is used as such without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[CH3:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH:19]=O)[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>CC#N.C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[CH3:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCC=O)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CCCCN2CCN(C)CC2)c1F
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-(4-oxo-butyl)-3H benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11n (15 mg, 0.030 mmol) is dissolved in MeCN (500 μL) and methylpiperazine (10 μl, 0.089 mmol) is added followed by AcOH (5 μL, 0.089 mmol). After 5 minutes, tetramethylammonium triacetoxyborohydride (12 mg, 0.045 mmol) is added. After 5 minutes, the reaction mixture is diluted with ethyl acetate and washed with NaHCO3 and brine. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to give 12 mg (69%) of pure desired product as a white solid. MS APCI (−) m/z 587, 585 (M−1 Br pattern) detected; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.98 (s, 1H), 7.30 (d, 1H), 7.08 (dd, 1H), 6.30 (d, 1H), 6.1 (broad singlet, 1H), 4.26 (t, 2H), 3.64 (d, 2H), 3.37 (s, 1H), 2.45 (broad, 8H), 2.41 (s, 3H), 2.38 (t, 2H), 2.28 (s, 3H), 1.95 (quin, 2H), 1.55 (quin, 2H), 0.98 (m, 1H), 0.50 (qt, 2H), 0.22 (qt, 2H).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[S:24][C:23]([NH2:25])=[N:22][CH:21]=3)[C:15](=[O:27])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[CH3:28][N:29]1[C:33]([S-:34])=[N:32][N:31]=[N:30]1.[K+].C(=O)(O)[O-].[Na+]>P([O-])([O-])([O-])=O>[CH3:28][N:29]1[C:33]([S:34][CH2:5][C:6]2[CH2:7][S:8][C@@H:9]3[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[S:24][C:23]([NH2:25])=[N:22][CH:21]=4)[C:15](=[O:27])[N:10]3[C:11]=2[C:12]([OH:14])=[O:13])=[N:32][N:31]=[N:30]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(N)s3)[C@H]2SC1
Reactant: Cn1nnnc1[S-]
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cnc(N)s3)[C@H]2SC1
Yield: 49.4 %

Procedure:
A solution of 3-acetoxymethyl-7-(2-aminothiazol-5-yl)acetamido-3-cephem-4-carboxylic acid (2 g.) and potassium 1-methyl-1H-tetrazole-5-thiolate (0.7 g.) in pH 6.4 phosphate buffer (50 ml.) was stirred for 4 hours with continuous introduction of nitrogen gas while the reaction mixture was kept to pH 6.4 to 7 with sodium bicarbonate. After the reaction, the reaction mixture was cooled and then filtered. The filtrate was adjusted to pH 2.5 with diluted hydrochloric acid under ice-cooling, and the precipitates were collected by filtration and then purified similarly as that of Example 6 to give light brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-(2-aminothiazol-5-yl)acetamido-3-cephem-4-carboxylic acid (1.05 g.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH2:10][C@H:11]([CH2:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:10][CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:16][OH:17])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: O=Cc1cccc(Br)n1
Solvent: ClCCl
Product: CC(C)CC(CO)NCc1cccc(Br)n1

Procedure:
2] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.16 mmol) was added L-leucinol (0.42 mL, 3.24 mmol) in dry CH2Cl2 (10 mL) to give 2-[(6-bromo-pyridin-2-ylmethyl)-amino]-4-methyl-pentan-1-ol as brown solid. MS m/z: 287.6 (M+H). Calc'd for Cl2H19BrN2O: 287.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:15]([CH:16]=[O:17])=[C:14]([OH:18])[C:13]([O:19][CH3:20])=[CH:12][CH:11]=1.O.C(OCC)(=O)C>C(#N)C>[Br:1][C:11]1[CH:12]=[C:13]([O:19][CH3:20])[C:14]([OH:18])=[C:15]([C:10]=1[F:9])[CH:16]=[O:17]
Reactant: COc1ccc(F)c(C=O)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Br)c(F)c(C=O)c1O
Yield: 71.9 %

Procedure:
After adding 3.11 g of N-bromosuccinimide to a solution of 2.98 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No. 457628-15-8] in 15 ml of acetonitrile, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3.13 g of 5-bromo-6-fluoro-2-hydroxy-3-methoxybenzaldehyde (crude product).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].[C:14](#[N:16])[CH3:15]>C1(C)C=CC=CC=1>[O:9]=[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][C:14]#[N:16]
Reactant: CC#N
Reactant: CCOC(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCC(=O)c1cccnc1
Temperature: 90 °C

Procedure:
To a solution of ethyl nicotinate (30.24 g, 0.20 mol) in toluene (anhydrous, 200 mL) was added NaH (18.64 g, 0.47 mol, 60% in mineral oil). The resulting suspension was heated at 90° C. and acetonitrile (anhydrous, 24.74 ml, 0.47 mol) was added into this suspension via syringe under nitrogen and the reaction was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature and the resulting solid material was collected by filtration. The crude product was dried in vacuo and used directly in the next step. For analytical purposes, the solid was dissolved in water. The pH was adjusted to 5 by aqueous HCl and the solution extracted with DCM. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo to afford a sample of the product for characterization. 1H NMR(CDCl3): δ9.2(s, 1H), 8.8(d, 1H), 8.2(d, 1H), 7.5(dd, 1H), 4.1 (s, 2H)
Reaction SMILES: [CH3:1][C:2]([CH:11]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[N+:23]([O-])=O)([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][C:2]([CH:11]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=1[NH2:23])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
α-Methyl-[2-(2-nitro-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (6.80 g; 14.9 mmole) was dissolved in methanol (200 ml) under argon at room temperature. Powdered stannous chloride dihydrate (17.48 g; 77.5 mmole) was added, followed by concentrated hydrochloric acid (19 ml) with stirring. After 1.5 hours, Celite, ethyl acetate and saturated potassium carbonate solution were added with stirring (the potassium carbonate was added portionwise). The suspension was filtered through a Celite pad. The pad was then rinsed with ethyl acetate (three times). The filtrate was concentrated and the resulting white solid was triturated with 10% methanol:water and dried giving 6.02 g of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:13][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.Cl.[OH-].[Na+]>C1COCC1>[CH3:13][C:8]1([C:11]#[N:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
Treat a 0° C. solution of 1,4-dioxa-spiro[4.5]decane-8-carbonitrile (1 g, 5.98 mmol) in THF (12 mL) drop-wise with lithium bis(trimethylsilyl)amide (1M, 6.88 mL, 6.88 mmol), stir at 0° C. for 1 h, add iodomethane (0.374 mL, 5.98 mmol) drop-wise and stir at 0° C. Add satd. NH4Cl, then brine, extract with EtOAc (2×), dry the combined organics over MgSO4 and concentrate to dryness to afford crude 8-methyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.33 g, 123%). Add THF (15 mL) and HCl (3M, 15 mL, 45 mmol), heat the mixture at 50° C. for 5 h, cool to RT, make basic with 3M NaOH, extract with DCM (3×), dry the combined organics over Na2SO4 and concentrate to dryness to afford the title compound (700 mg, 85%, 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 2.48-2.41 (m, 2H), 2.30-2.23 (m, 2H), 2.19-2.12 (m, 2H), 1.84 (td, J=13.3, 4.5 Hz, 2H), 1.41 (s, 3H); MS(ESI) m/z: 138.1 (M+H+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][C@@H:16]1[C@@:36]2([CH3:37])[C:20](=[CH:21][CH2:22][C@@H:23]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:31])[CH2:29][OH:30])[CH2:19][C@@H:18]([O:39][C:40](=[O:42])[CH3:41])[CH2:17]1)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:15][C@@H:16]1[C@@:36]2([CH3:37])[C:20](=[CH:21][CH2:22][C@@H:23]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:31])[CH2:29][O:30][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:19][C@@H:18]([O:39][C:40](=[O:42])[CH3:41])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
A solution of 55.1 mg of p-toluenesulphonyl chloride in 0.2 ml. of dry pyridine was added at 0° C. to a solution of 100 mg of (20S)-1α,3β-diacetoxy-21-hydroxy-20-methyl-pregn-5-ene in 0.5 ml. of dry pyridine. After standing at 0° C. for 6 hours, the mixture was poured on to ice-water and extracted with ether. The extract was washed successively with 2-N hydrochloric acid, water, saturated sodium bicarbonate solution and water. The residue obtained after drying over sodium sulphate and concentration was chromatographed on 3.5 g of silica gel using hexane/ether (4:1) for the elution, there being obtained 100 mg of uniform (20S)-1α,3β-diacetoxy-20-methyl-21-(p-toluene-sulphonyloxy)-pregn-5-ene. After recrystallisation from ether, the product melted at 168°-170° C.; [α]D =-20.8° (c=0.5 in chloroform).
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(Cl)=O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[NH2:18].[F:37][C:38]([F:51])([F:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46]>C1(C)C=CC=CC=1.C(O)C>[F:50][C:38]([F:37])([F:51])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46].[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:48]([NH:47][C:45](=[O:46])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([F:37])([F:51])[F:50])=[S:49])[CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(N=C=S)c1ccccc1C(F)(F)F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C(F)(F)F)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
2-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-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 2-(trifluoromethyl)-1-benzenecarbonyl 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 (61 mg, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CCN1CC(OC2C=CC([Cl:48])=C(Cl)C=2)C1)CO>>[Cl:48][C:29]1[CH:28]=[C:5]([CH:4]=[CH:3][C:2]=1[Cl:1])[O:6][CH:7]1[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]2[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=2)=[O:18])[CH2:14][OH:15])[CH2:10]1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)c(Cl)c3)C2)n(C)n1

Procedure:
This compound is prepared in a manner analogous to that used to prepare 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(3,4-dichloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.N1CCCC1>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1/[CH:13]=[CH:20]/[C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1)([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=Cc1ccncc1
Solvent: C1CCNC1
Product: O=[N+]([O-])c1ccc(/C=C/c2ccncc2)c([N+](=O)[O-])c1

Procedure:
1.4 g (7.7 mmol) of 2,4-dinitrotoluene, 0.82 g (7.7 mmol) of pyridine-4-carboxaldehyde and 0.2 mL of pyrrolidine were charged to a round-bottomed flask. The flask was fitted with a splash protector and then irradiated for 20 seconds in a domestic microwave oven (850 watt). The mixture was then allowed to cool, and the product was caused to precipitate by addition of 20 mL of acetone. Suction-filtration and drying at 40° C. under vacuum have 0.9 g of product (43% of the theoretical).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])C=C[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>CC(C)=O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][SH:8]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7]1)[CH3:16]
Reactant: Sc1cccc(Cl)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(C[SH]1C=CC(Cl)=C1)OCC
Temperature: 23 °C
Reaction time: 17 h

Procedure:
A three-neck round bottom flask was charged with 3-chloro-thiophenol (20.0 g, 0.138 mol) and potassium carbonate (21 g, 0.15 mol) in acetone (220 ml) and treated with a dropwise addition of bromoacetaldehyde diethyl acetal. After stirring for 17 hours at 23° C., the slurry was filtered through a small plug of celite, the filtrate evaporated under reduced pressure and the residue diluted with diethyl ether and water. The organics were washed with brine, dried over sodium sulfate, and evaporated to a rust-colored oil weighing 35.1 g (97%). FDMS m/e=260 (M+).
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC2C=CC([N+]([O-])=O)=CC=2)=[O:26])[CH2:9][N:8]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)(=[O:3])[NH2:2].P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[C:1]([CH2:4][S:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([OH:27])=[O:26])[CH2:9][NH:8]1)(=[O:3])[NH2:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSCC(N)=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CSCC(N)=O)C3)[C@H](C)[C@H]12
Yield: 66.9 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(carbamoylmethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin -4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.42 g), 20% palladium hydroxide on carbon (0.4 g), 0.05M phosphate buffer (pH 6.3, 20 ml), and tetrahydrofuran (20 ml) was stirred at ambient temperature for 4 hours under atmospheric pressure of hydrogen. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to remove the organic solvent. The resulting residue was washed twice with ethyl acetate (20 ml) and the aqueous layer was concentrated under reduced pressure to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (20 ml) eluting in turn with water (100 ml) and 5% aqueous acetone (100 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(carbamoylmethyl)thiomethylpyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]1([N:29]2[C:33]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)=[CH:32][C:31]([C:44]([CH3:50])([CH3:49])[C:45]([F:48])([F:47])[F:46])=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:33]2[N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:30]=[C:31]([C:44]([CH3:50])([CH3:49])[C:45]([F:48])([F:47])[F:46])[CH:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1)C(F)(F)F
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-ylcarbamate (104 mg, 0.3 mmol) described in the previous step. The reaction mixture was stirred at rt overnight, then concentrated under reduced pressure. The crude was purified by silica gel chromatography (hexane/ethyl acetate 25-100%) and triturated in diethyl ether to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)urea (103 mg, 62%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.56 (s, 6H), 4.02 (s, 6H), 6.55 (s, 1H), 6.94 (d, J=9 Hz, 1H), 7.17 (d, J=9 Hz, 1H), 7.34-7.57 (m, 9H), 8.55-8.59 (m, 2H), 9.28 (s, 1H); LC-MS (ESI) m/z 593 (M+H)+.