Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl.[NH2:20][CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)CC)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:24][C:22](=[O:23])[CH2:21][NH:20]/[C:11](/[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][OH:1])=[CH:12]\[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: NCC(N)=O
Reactant: CCOC(=O)CC(=O)c1ccccc1OCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C(\NCC(N)=O)c1ccccc1OCCO
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate (2 g, 7.94 mmol) and glycinamide hydrochloride (3.5 g, 31.7 mmol) in methanol (20 mL) was added triethylamine (3.21 g, 31.7 mmol) at room temperature. The mixture was stirred at 40° C. for 20 min. Acetic acid (1.9 g, 31.7 mmol) was added, and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature and saturated sodium bicarbonate (200 mL) was added. The organic layer was separated, dried (Na2SO4) and concentrated to give a yellow solid. The solid was washed with EtOAc (20 mL), and the residue was dried under reduced pressure to give the title compound as a white solid. This material was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][NH2:14].C(N(C(C)C)CC)(C)C.C(#N)C>ClCCl.[OH-].[Na+]>[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][NH:14][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)CCN
Reactant: ClCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)CCNCCN1CCOCC1

Procedure:
Into a microwave reactor was placed 4-(2-chloroethyl)-morpholine (1.5 g, 8.1 mmol), 3,3-dimethylbutylamine (2.2 mL, 16 mmol), diisopropylethylamine (3.1 mL, 18 mmol), and acetonitrile (30 mL). The resulting mixture was microwaved at 130° C. for 30 minutes and then diluted with dichloromethane and 1N sodium hydroxide. The layers were separated, and the organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield an orange oil. The oil was purified on a silica gel column, eluting with 15% of 10:1 (MeOH:NH4OH) in EtOAc to yield a yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1.[Li]CCCC.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1.[C:1]([NH:5][C:6](=[O:7])[O-:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)NC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[O-]
Product: NS(=O)(=O)C1(Cl)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
step 3.8a) To a solution of cyclopropylsulfonylamine tert-butyl carbamate (1.0 g, 4.52 mmol) dissolved in THF (10 mL) cooled to −78° C., was added n-BuLi (6.4 mL, 10.2 mmol, 1.6 M in hexane) and the reaction mixture was stirred for 1 h. To this solution was added a THF (10 mL) solution of NCS (0.86 g, 6.34 mmol). After stirred for 5 min, the bath was changed to ice bath and the mixture was stirred for 3 h at the temperature. The reaction mixture was diluted with ice water, the pH was adjusted to <4. The aqueous mixtire was extracted with EtOAc. The combined extracts were dried (MgSO4), concentrated and purified by flash chromatography over SiO2 using EtOAc/hexanes (0% to 60%) as the eluent to afford 0.98 g (67%) of 1-chloro-cyclopropanesulfonamide-tert-butylcarbamate as a white solid: 1H NMR (CDCl3) δ ppm 1.51 (m, II H), 2.01 (m, 2H), 7.60 (s, 1H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C@H:4]([C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])[NH2:5].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[ClH:21].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31]([NH:5][C@@H:4]([C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH2:12][CH2:13]1)=[O:7])[CH2:3][S:2][CH3:1])=[O:32])=[CH:25]2
Reactant: CSC[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: CSC[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(=O)N1CCC(C2CCN(C)CC2)CC1
Product: Cl

Procedure:
Prepared from 1-(S-methyl-D-cysteinyl)-4-(1-methyl-piperidin-4-yl)piperidine and 5-chloroindole-2-carboxylic acid using methods substantially equivalent to General Coupling Method 1. The HCl salt is prepared following General Salt Formation Method 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:13]=O.C1(P(=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[C:11]([C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[C:5]2/[CH:13]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc(F)cc2c(C=O)c[nH]c12
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c[nH]c2c(C#N)cc(F)cc12
Yield: 63.8 %

Procedure:
To a mixture of 5-fluoro-3-formyl-1H-indole-7-carbonitrile (D133) (8 g) in CH3CN (80 mL) was added ethyl (triphenylphosphoranylidene)acetate (30 g). The reaction was heated to reflux overnight. After the mixture was filtered, the filtrate was concentrated and purified by column chromatography to afford ethyl (2E)-3-(7-cyano-5-fluoro-1H-indol-3-yl)-2-propenoate (D134) (7 g) as a light yellow solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([OH:18])[CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1.O>ClCCl>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][C:2](=[O:3])[O:18][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCC1
Temperature: 25 °C

Procedure:
A solution of 4-nitrophenyl chloroformate (6.00 g) in dichloromethane (12 mL) is added dropwise to an ice-cooled mixture of cyclobutanol (2.00 g), and pyridine (2.4 mL) in dichloromethane (10 mL). The resulting mixture is stirred over night at room temperature. Water and dichloromethane are added and the organic phase is separated, washed with brine and dried over MgSO4. The solvent is evaporated leaving the title compound as an oil, which is used without further purification. Yield: 6.61 g (crude); LC (method 2): tR=1.30 min; Mass spectrum (ESI+): m/z=260 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:3]=1[C:4]([S:26]([O-:29])(=[O:28])=[O:27])=[C:5]([S:22]([O-:25])(=[O:24])=[O:23])[C:6]([S:18]([O-:21])(=[O:20])=[O:19])=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=[CH:13]2.[Na+:30].[Na+].[Na+].[C:33](OC(=O)C)(=[O:35])[CH3:34].C([O-])(=O)C.[Na+]>CN(C)C=O>[Na+:30].[Na+:30].[Na+:30].[C:33]([O:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:3]=1[C:4]([S:26]([O-:29])(=[O:28])=[O:27])=[C:5]([S:22]([O-:25])(=[O:23])=[O:24])[C:6]([S:18]([O-:21])(=[O:20])=[O:19])=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=[CH:13]2)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)([O-])c1c(S(=O)(=O)[O-])c2ccc3cccc4cc(O)c(c1S(=O)(=O)[O-])c2c34
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cccc3ccc4c(S(=O)(=O)[O-])c(S(=O)(=O)[O-])c(S(=O)(=O)[O-])c1c4c32

Procedure:
10 grams of trisodium hydroxypyrenetrisulfonate, 50 mls of acetic anhydride and 1.6 grams of sodium acetate are added to 200 mls of dimethylformamide in a 500 ml flask. The flask is equipped with a condenser having a drying tube and a stirring bar. The contents of the flask are stirred at 50° to 70° C. for one to two hours. The reaction mixture is filtered and the filtrate collected. The filtrate is vacuum evaporated to yield a crude solid product. This crude solid product is extracted into boiling methanol. The volume of the methanol is reduced to 100 mls and cooled. The first batch of product crystallizes out and is filtered. The methanol is again reduced to approximately 20 mls to yield a second crop of product. This is filtered and combined with the first batch and dried for twenty to forty minutes at 60° C.
Reaction SMILES: [C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=C(O)C(O)=O)([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:18]>O=[Mn]=O>[C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=O
Reactant: CC(C)(C)c1ocnc1C=C(O)C(=O)O
Agent: O=[Mn]=O
Product: CC(C)(C)c1ocnc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of oxazole alcohol 3 (9.9 g, 64 mmol) in acetone (200 mL, Aldrich, Cat. No. 179124) was added MnO2 (27.7 g, 319 mmol, 5 equiv., Wako Pure Chemical, Osaka, Japan, Cat. No. 138-09675), and the mixture was stirred at room temperature overnight. After celite filtration to remove MnO2, the solvent was removed by evaporation, and the residual pale brown oil was dissolved in CHCl3 and applied to silica-gel column chromatography (prepared with CHCl3), then eluted with CHCl3:MeOH (100:1 to 50:1), to give an pale yellow oil of aldehyde 4 (5.54 g, 57% (38% in two steps)). Rf 0.65 (CHCl3:MeOH=10:0.5), 1H NMR (300 MHz CDCl3) δ 10.10 (s, 1H), 7.77 (s, 1H), 1.47 (s, 9H); HRMS (EI): m/z 153.0794 (M+) (Calcd for C8H11NO2: 153.0790).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][NH2:15]>C(Cl)Cl>[CH3:14][NH:15][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chlorosulfonylbenzoic acid (5.8 g, 25.2 mmol) in DCM (200 mL), a solution of methylamine (52.15 mL, 2 M in THF) is added. The mixture is stirred overnight at rt before the solvent is evaporated. The residue is dissolved in sat. aq. NH4Cl solution and extracted with EA. The organic extract is washed with water, dried over MgSO4, filtered and the solvent of the filtrate is evaporated to give 4-methylsulfamoyl-benzoic acid (3.77 g) as a white solid; LC-MS: tR=0.64 min.
Reaction SMILES: [OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[CH3:17][O:18][C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:17][O:18][C:19]([O:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)/C=C/C(C)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)/C=C/C(C)OC(=O)OC
Temperature: 1 °C

Procedure:
rac-Ethyl (2E)-4-hydroxypent-2-enoate (21) (10.09 g, 70 mmol), DMAP (1.71 g, 14 mmol) and pyridine (17 mL, 210 mmol) are dissolved in THF (400 mL). The solution is cooled to 1° C. Methylchloroformate (16.1 mL, 210 mmol) in THF (50 ml) is then added dropwise over 3 hours under stirring at 1° C. After 2 hours methylchloroformate (199 ml, 2.50 mol) in THF (150 ml) is added dropwise in four portions. After every portion, the reaction mixture is stirred for 5 hours at 1° C. The reaction mixture is quenched with 10% HCl (0.5 l) and extracted with tBuOMe (1.5 and 0.5 l). The organic phases are washed with 10% HCl (0.6 l), saturated NaHCO3 (0.3 l) and brine (2×0.2 l) successively. The combined organic phases are dried with N2SO4 and evaporated under reduced pressure. The residue is purified by flash chromatography (tBuOMe:heptane fraction 15:85 to 25:75) and yields 1 (rac-Ethyl (2E)-4-(methoxycarbonyloxy)pent-2-enoate) (8.64 g, 61%) as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([Sn:14]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])N(C)C)[CH2:11][CH2:12][CH3:13]>>[CH2:22]([Sn:14]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:23][CH2:24][CH3:25]
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Product: CCCC[Sn](C#Cc1ccc(Cl)cc1)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A mixture of commercially available 1-chloro-4-ethynylbenzene (4 g, 29 mmol) and 1,1,1-tributyl-N,N-dimethylstannanamine (9.79 g, 29.3 mmol) was stirred at RT for 2 hours. The reaction was concentrated to afford the desired product tributyl((4-chlorophenyl)ethynyl)stannane 18A (13.1 g, 27.7 mmol, 95% yield) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH2:7]([O:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:15])[CH:6]=1
Reactant: CCOC(=O)C=C(C)C
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)(C)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-bromo-1H-pyrazole (3.42 g, 23.43) and 3-methyl-2-butenoic acid ethyl ester (1 g, 7.81 mmol) in DMF (50 mL) was treated with cesium carbonate (10.1 g, 31.07) and allowed to stir for 3 hours at room temperature. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined extracts were dried over sodium sulfate and concentrated to afford the desired product, 1.1 g (51%) yield. 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.45 (s, 1H), 3.98-4.05 (m, 2H), 2.82 (s, 2H), 1.62 (s, 6H), 1.18-1.10 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH:3]([O:2][CH:22]([CH3:21])[CH3:16])([CH3:9])[CH3:4].[CH3:20][C:19]1[CH:21]=[CH:22][C:16]([S:13]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)OC(C)C
Product: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 151.9 %

Procedure:
50 g of 4-methoxy-2-nitroaniline are stirred at 0° C. in 300 ml of pyridine. 56.7 g of tosyl chloride are added in portions at 0° C. and the mixture is then stirred for two hours at room temperature, left to stand overnight and poured into an ice/water mixture. The crystals obtained are filtered off and washed with water and then with isopropyl ether to give 72.8 g of 2-(4-methylbenzenesulfonylamino)-5-methoxynitrobenzene in the form of crystals melting at 99° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:26]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:27]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C(=O)C1CCCCC1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.72 mmol), cyclohexanecarbonyl chloride (0.22 g, 1.5 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.20 g, 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1.[CH3:24][O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:25][C:26](=[O:31])[C:27]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:3]2[C:2]([CH3:23])([CH3:1])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:9]=3)[NH:4]2)[CH:17]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)Br
Reactant: CC1(C)Cc2cc(C(F)(F)F)ccc2NC1c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(F)(F)F)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 20.2 %

Procedure:
A mixture of 3-(3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (1.5 g, 4.7 mmol), 2-bromo-2-methyl-propionic acid methyl ester (2.55 g, 14.1 mmol) and potassium carbonate (3.24 g, 23.5 mmol) in N,N-dimethylformamide (12 mL) was stirred at 25° C. for 5 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(30% ethyl acetate/hexanes) to afford 2-[3-(3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (400 mg, 20%) as a brown oil. LC/MS m/e calcd for C23H27F3N2O2 (M+H)+: 421.48, observed: 421.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[C:15]([CH2:18][OH:19])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O1CCCC1.C(O)C.[C].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:20]([O:22][CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)=CS[C@H]12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)CS[C@H]12
Yield: 56.4 %

Procedure:
A suspension of 10% palladium-carbon (30 g.) in acetic acid (300 ml.) was added to a solution of diphenylmethyl 7-(2-phenylacetamido)-3-hydroxymethyl-2-cephem-4-carboxylate (30.0 g.) in tetrahydrofuran (500 ml.) and ethanol (100 ml.), and the mixture was subjected to catalytic reduction under hydrogen pressure of 10 kg/cm2 at 50°-55° C. for 4 hours. After removing the insoluble substance from the resultant mixture by filtration, the filtrate was concentrated under reduced pressure. Ethyl acetate (500 ml.) was added to a residue and adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give diphenylmethyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (17 g.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(N(CCCC)CCCC)CCC.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH2:35])=[CH:32][CH:31]=1.Cl>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:35][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Reactant: C=Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1ccc(C=Cc2ccc(F)cc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A mixture of dimethyl 4-bromoisophthalate (54.75 g., 200.5 mmol), water (330 ml), tributylamine (55.63 g., 300.7 mmol), 4-fluorostyrene (55.63 g., 300.7 mmol) and bis(triphenylphoshine)palladium(II)chloride (2.81 g., 4.01 mmol) was heated at reflux with stirring under an inert atmosphere for 6 hours. The reaction was cooled to ambient temperature and acidified to pH 2 with 2M HCl (700 ml). The aqueous layer was removed and the residual solid washed with water (2 L), dissolved in dichloromethane (1 L) and passed through a pad of silica, eluting with more dichloromethane (2 L). Evaporation of the dichloromethane gave a solid, which was further washed with iso-hexane (1 L), and dried to give methyl 4-[2-(4-fluorophenyl)ethenyl]-3-methoxycarbonylbenzoate (56.75 g) as a pale yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=1)=O)(C)(C)C.[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][C@@H:9]([C:24]([O:26][CH3:27])=[O:25])[NH2:8])=[CH:12]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCn1cc(C[C@H](N)C(=O)OC)c2ccccc21
Yield: 63 %

Procedure:
The same procedures as in Example 143 were carried out from the compound obtained in Example 142 (4.2 g), 4 mol/L of hydrogen chloride-dioxane solution (14.0 mL), and methylene chloride (140 mL), to give the captioned compound (2.2 g, 63%) as crystals.
Reaction SMILES: C1COCC1.C[O:7][C:8](=[O:49])[C:9]([CH3:48])([CH3:47])[CH:10]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)=[CH:31][CH:30]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1.O[Li].O.[Li+].[OH-]>CO>[CH3:47][C:9]([CH3:48])([CH:10]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)=[CH:31][CH:30]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1)[C:8]([OH:49])=[O:7]
Reactant: COC(=O)C(C)(C)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Li+]
Agent: [Li]O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 24 h
Yield: 40.8 %

Procedure:
To a solution in methanol (8 mL) and THF (4 mL) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid methyl ester (0.4 g, 0.69 mmol), prepared as in step 2, was added LiOH.H2O (4 ml, 4 mmole, 1M solution) dropwise, and the mixture was stirred overnight after which an additional 2 mL of the LiOH solution was added and the mixture was stirred an additional 24 hours. The mixture was concentrated to dryness, acidified with excess 0.5M citric acid, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (7% MeOH/CH2Cl2) provided 0.16 g (40%) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid as a white solid: mp 124°-127° C. Anal. Calc'd. for C37H32 N2O4 : C, 78.14; H, 5.67; N 4.92. Found C, 77.45; H, 5.74; N, 4.67.