Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.CC([O-])(C)C.[K+].Cl.Br[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.[NH4+].[Cl-]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:25]1[CH:26]=[CH:27][C:22]([CH:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=2)[C:10]#[N:11])=[CH:23][CH:24]=1
Reactant: Brc1ccncc1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: COCCOC
Product: N#CC(c1ccncc1)c1ccc(C(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
A dried flask was charged with 2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (1.0 g, 5.38 mmol) in DME (20 ml). The mixture was degassed and filled with N2, then t-BuOK (30 ml, 30 mmol, 1M in THF), 4-bromopyridine hydrochloride (2.1 g, 10.7 mmol) and Pd(dppf)Cl2 (39.6 mg, 0.538 mmol) was added. The mixture was stirred at 60° C. for 3 h. After cooling to room temperature, sat.aq NH4Cl (15 ml) was added and the solution was extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine and dried over Na2SO4, concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc: Petroleum ether=4:1) to give 2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (360 mg, yield: 25.7%). 11-1 NMR (CDCl3 400 MHz): δ8.75 (d, J=1.6; Hz, 1H), 8.71 (d, J=6.0; Hz, 2H), 7.90 (dd, J=8.0; Hz, 2.0; Hz, 1H), 7.77 (d, J=8.4; Hz, 1H), 7.31 (d, J=6.0; Hz, 2H), 5.26 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:7]([OH:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[S:4]1(=[O:20])=[O:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([N:11]1[N:12]=[N:13][C:9]([C:8]2[N:3]([CH2:1][CH3:2])[S:4](=[O:19])(=[O:20])[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]=2[OH:14])=[N:10]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCN1C(c2nnn[nH]2)=C(O)c2ccccc2S1(=O)=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(c2nnn(Cc3ccccc3)n2)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of 2-ethyl-4-hydroxy-3-(tetrazol-5-yl)-1,2-benzothiazine 1,1-dioxide (0.5 g), potassium carbonate (0.120 g) and benzylbromide (0.21 ml) in dimethylformamide was stirred at room temperature for 16 hours, then poured into water (30 ml). The resulting solids were filtered off, washed with water and dried in vacuo to give crude product (0.638 g), which was recrystallized from toluene to afford the title compound (0.457 g, 70%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[CH:6]=2)[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:33]([NH2:35])[CH3:34])[CH:30]=[CH:31][CH:32]=1>CN1C(=O)CCC1>[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:33]([NH:35][C:7]2[CH:6]=[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=2)[CH3:34])[CH:30]=[CH:31][CH:32]=1
Reactant: C[C@H](N)c1cccc(Cl)c1
Reactant: CS(=O)(=O)c1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1)c1cccc(Cl)c1
Temperature: 120 °C

Procedure:
To (Z)-5-((7-(cyclopropylamino)-5-(methylsulfonyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (step c) (10 mg, 0.0275 mmol) in 200 uL NMP, was added (S)-1-(3-chlorophenyl)ethanamine (23.2 ul, 0.165 mmols) and the reaction mixture was heated in the microwave at 120° C. for 20 minutes. The mixture was concentrated and diluted with MeOH and purified by preparative HPLC to yield (S,Z)-5-((5-(1-(3-chlorophenyl)ethylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione LCMS (M+1=438)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18](O)=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN.O[N:34]1[C:38]2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH:34][CH3:38])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of 5-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-4-methylpyridine-2-carboxylic acid (88 mg, 0.20 mmol) in methylene chloride (2 ml), methylamine hydrochloride (15 mg, 0.22 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 4-methylmorpholine (0.048 ml, 0.44 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg, 0.22 mmol) were added at room temperature. After stirring for 5 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=3:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of diethyl ether and hexane and then collected by filtration to obtain the title compound (73 mg, 0.16 mmol, 81%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([O:31][CH2:32][CH:33]([OH:46])[CH2:34][N:35]5C(=O)C6C(=CC=CC=6)C5=O)=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1>CCO>[NH2:35][CH2:34][CH:33]([OH:46])[CH2:32][O:31][C:29]1[CH:28]=[CH:27][C:26]2[C:19]3[C:18]([NH:17][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=5)=[C:2]([Cl:1])[CH:3]=4)=[N:23][CH:22]=[N:21][C:20]=3[S:24][C:25]=2[CH:30]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(O)COc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CCO
Product: NCC(O)COc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 12.1 %

Procedure:
To a solution of crude material 2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-benzo[4,5]thieno[2,3-d]pyrimidin-7-yloxy}-2-hydroxy-propyl)-isoindole-1,3-dione (216 mg, 0.33 mmol, from Step 1) in EtOH (5 mL) was added hydrizine (1 mL) under nitrogen. The reaction was stirred at rt for 15 h. The solvent was removed in vacuo. The crude material was purified by preparative HPLC to give 1-amino-3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]oxy}propan-2-ol as a white solid (21 mg, 12%). 1H-NMR (CD3OD) δ 8.23 (s, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.31 (dd, J=2.7, 9.0 Hz, 1H), 7.26 (m, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.11 (d, J=9.7 Hz, 1H), 7.03 (dd, J=2.3, 9.0 Hz, 1H), 6.96 (d, J=9.2 Hz, 1H), 6.92 (td, 1H), 5.04 (s, 2H), 3.94 (m, 3H), 2.81 (m, 2H), LCMS RT=2.84 min, [M+H]+=525.1.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][O:21][C:22]1[CH:51]=[CH:50][C:25]([CH2:26][O:27][C:28](=[O:49])[C@H:29]([N:36]2[CH2:40][C@H:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:38]([CH:47]=O)[CH2:37]2)[CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28](=[O:49])[C@H:29]([N:36]2[CH2:40][C@H:39]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@@H:38]([CH2:47][N:10]3[CH2:9][CH2:8][CH:7]([N:5]4[C:4](=[O:13])[C:3]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[C:2]([CH3:1])[NH:6]4)[CH2:12][CH2:11]3)[CH2:37]2)[CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:50][CH:51]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: Cc1[nH]n(C2CCNCC2)c(=O)c1-c1ccccc1
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4[nH]c(C)c(-c5ccccc5)c4=O)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 91.3 %

Procedure:
When 0.070 g of 4-(5-methyl-4-phenyl-1H-pyrazol-3(2H)-on-2-yl)-piperidine and 0.043 g of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid 4-methoxybenzyl ester were used in the procedure of Example 124, Step C, there was obtained 0.061 g of α-(R)-(3-(S)-((4-(5-methyl-4-phenyl-1H-pyrazol-3(2H)-on-2-yl)-piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid 4-methoxybenzyl ester after chromatography on silica gel (20 mL column—elution with 3% MeOH in dichlormethane). ESI-MS 677.3 (M+H); TPLC A: 2.85 min.
Reaction SMILES: [C:1]1([C:13]([OH:15])=[O:14])([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH2:16]1[O:18][CH2:17]1>C(C(C)=O)C(C)C>[OH:8][CH2:7][CH2:2][O:14][C:13]([C:1]1([C:10]([O:12][CH2:17][CH2:16][OH:18])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:1][CH2:10][OH:11])=[O:8])=[O:15]
Reactant: C1CO1
Reactant: O=C(O)C1CCCCC1(C(=O)O)C(=O)O
Solvent: CC(=O)CC(C)C
Product: O=C(OCCO)C1CCCCC1(C(=O)OCCO)C(=O)OCCO

Procedure:
Cyclohexanetricarboxylic acid was allowe to react under pressure with ethylene oxide and 0.15% of the catalyst of Example II (based on the total wt. of system) in the presence of methyl isobutyl ketone at 150°-160° C for 2 hours. A viscous oil of good purity was obtained after charcoal treatment and evaporation of a methyl isobutyl ketone solution. The infrared spectra and elements analysis were consistent with the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].S(Cl)([Cl:18])(=O)=O>C(Cl)Cl.CCOC(C)=O>[Cl:18][CH:8]([C:7](=[O:14])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)COCCOC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)C(=O)COCCOC
Reaction time: 6 h
Yield: 70.8 %

Procedure:
Ethyl 4-(2-methoxyethoxy)-3-oxobutanoate (Intermediate 123) (0.5 g) was dissolved in anhydrous DCM (5 ml). Sulfuryl chloride (430 mg) was added dropwise at room temperature. The mixture was stirred for 6 h. The crude mixture was diluted with EtOAc (50 ml) and washed well with water and brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light orange oil (414 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[C:24]([NH2:25])=[C:23]2[O:26][CH2:27][O:28][C:22]2=[C:21]([I:29])[CH:20]=1>>[Cl:18][C:19]1[C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:23]2[O:26][CH2:27][O:28][C:22]2=[C:21]([I:29])[CH:20]=1
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Product: COc1cc2ncc(C#N)c(Nc3c(Cl)cc(I)c4c3OCO4)c2cc1OC
Yield: 72.6 %

Procedure:
Using an analogous procedure to that described in the portion of Example 1 that is concerned with the preparation of starting materials, 4-chloro-3-cyano-6,7-dimethoxyquinoline (1.74 g) was reacted with 6-chloro-4-iodo-2,3-methylenedioxyaniline (2.5 g) to give 4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline as a solid (2.59 g) which gave the following characterising data; NMR Spectrum: (DMSOd6) 4.0 (s, 6H), 6.18 (s, 2H), 7.38 (s, 1H), 7.48 (s, 1H), 7.88 (s, 1H), 8.44 (s, 1H), 9.45 (s, 1H); Mass Spectrum: M+H+ 510.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1.[CH:29](=O)[CH3:30].[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([CH2:29][CH3:30])[CH2:21][CH2:22]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1
Reactant: CC=O
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCNCC2)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(CC)CC2)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
To a solution of 4-amino-5-chloro-2-ethoxy-N-[{4-(4-piperidinylmethyl)-2-morpholinyl}-methyl]benzamide (Example 22) (1.0 g) and TEA (0.49 g) in methanol (10 ml) was added acetaldehyde (0.21 g) under ice-cooling. The mixture was stirred at the same temperature for 2 hours, and then thereto was gradually added sodium borohydride (92 mg). After completion of addition, the mixture was stirred at the same temperature for 1 hour, and warmed to room temperature to stir overnight. The reaction solution was dried under reduced pressure to be solidified, and the residue was dissolved in chloroform, washed with water, then brine, and dried over anhydrous magnesium sulfate. Then, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (1.2 g) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13].[N+]([O-])([O-])=O.[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1cccc2c(Cl)nccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-chloroisoquinoline (6.0 g, 0.037 mol) in conc. H2SO4 (35 mL) was treated with a solution of fuming HNO3 (10 mL) and potassium nitrate (4.0 g, 0.040 mol) in conc. H2SO4 (35 mL) at 0-5° C. The mixture was stirred at 0° C. for a further 90 min, and then poured into ice. The precipitate was collected, washed and dried to give the product as a yellow solid. LC-MS: 3.68 min, 209.2 & 211.1 (M+1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:6]1)=[O:4].Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.[OH-].[Na+].Cl>C(O)CCC.Cl.O1CCOCC1.CO>[Cl:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([C:16]4[CH:17]=[CH:18][C:13]([C:11]([C@@H:7]5[CH2:8][CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]5)=[O:12])=[CH:14][CH:15]=4)=[CH:24][CH:23]=3)[S:28][C:29]=2[CH:35]=1
Reactant: COC(=O)C1CCCC(C(=O)c2ccc(-c3ccc(N)cc3)cc2)C1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CCC[C@@H](C(=O)c2ccc(-c3ccc(Nc4nc5ccc(Cl)cc5s4)cc3)cc2)C1
Temperature: 90 °C
Yield: 8.6 %

Procedure:
To a solution of 3-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid methyl ester (100 mg, 0.3 mmol) in butanol (5 mL), 2,6-dichloro-benzothiazole (60 mg, 0.3 mmol) and 5 drops of 4 M HCl in dioxane were added, and the reaction mixture was heated at 90° C. for 5 h. An additional sample of 2,6-dichlorobenzothiazole (60 mg, 0.3 mmol) and 5 drops of 4 M HCl in dioxane were then added, and the reaction mixture was heated overnight at 90° C. The solvent was removed by rotary evaporation, the residue was dissolved in DMF (2 mL), 1 N aqueous NaOH (0.3 mL, 0.3 mmol) was added, and the mixture was heated at 75° C. overnight. A solution of 1 N aqueous HCl (0.3 mL, 0.3 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford cis-3-[4′-(6-chloro-benzothiazol-2-ylamino)-biphenyl-4-carbonyl]-cyclohexanecarboxylic acid as a white solid (12.6 mg, yield 23.4%). 1H NMR (300 MHz, DMSO) δ 8.05 (d, 2 H), 7.75–8.00 (m, 7 H), 7.50 (d, 1 H), 7.35 (d, 1 H), 3.25 (m, 1 H), 2.50 (m, 1 H), 2.20–1.90 (m, 4 H), 1.70–1.50 (m, 4 H); LC-MS ret. time 3.99 min (method 2), m/z 491.11 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:30]=[CH:29][C:28](Cl)=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:30]=[CH:29][C:28]([NH:42][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)c1ccc(N2C(c3ccc([N+](=O)[O-])cc3)CCC2c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(C(C)(C)C)cc3)cc2[N+](=O)[O-])cc1
Temperature: 145 °C
Reaction time: 1.5 h
Yield: 31.3 %

Procedure:
The product from Example 179C (13.2 g, 27.5 mmol) and 4-methoxybenzylamine (18 mL, 139 mmol) were combined and stirred at 145° C. for 1.5 h. The mixture was cooled to rt, and CH2Cl2 was added. The resulting precipitate was filtered off, and the filtrate was washed successively with 1N aq. HCl and saturated aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-25% EtOAc in hexane to give the title compound (5.0 g, 31%).
Reaction SMILES: [OH:1][C:2]([CH3:11])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O>[CH3:11][C:2]([O:1][Si:23]([CH3:26])([CH3:25])[CH3:24])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)(O)C(=C)CCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC(C)(O[Si](C)(C)C)C(=C)CCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 25.77 g. of 4-hydroxy-4-methyl-5-methylene-1-octyne and 28.6 g. of imidazole in 50 ml. of dimethylformamide is added 22.9 g. of chlorotrimethylsilane. The mixture is stirred at room temperature for 40 minutes, poured into cold water and extracted with petroleum ether. The extract is washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and the solvent is removed. The residue is distilled and the desired product recovered at 85°-87° C. (0.45 mm.) as a colorless liquid.
Reaction SMILES: CN1CCOCC1.[CH2:8]([O:15][C:16](=[O:31])[CH2:17][CH2:18][C@@H:19]([C:28](O)=O)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:33]([O:35][CH2:36]C(C)C)=[O:34].[N+](=C)=[N-].CCOCC.C(N(CC)CC)C>C(OCC)(=O)C.CO.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[C:9]1([CH2:8][O:15][C:16](=[O:31])[CH2:17][CH2:18][C@H:19]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:28][C:33]([O:35][CH3:36])=[O:34])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: [Ag+]
Agent: C=[N+]=[N-]
Agent: O=C([O-])c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)C[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
4-Methylmorpholine (2 ml) was added to a solution of t-butoxycarbonyl-L-glutamic acid 5-benzyl ester (6.75 g,20 mmol) in ethyl acetate (60 ml) at 0° C. i-Butyl chloroformate (2.61 ml,20 mmol) was then added to give a precipitate and the mixture was stirred for 15 min at 0° C. before filtering through celite into a flask at 0° C. The pad was washed with precooled ethyl acetate. The combined filtrate and wash was treated with diazomethane in ether (30 mmol in 100 ml) over 5 min and the reaction left at 0° C. for 3h before warming to room temperature. Excess diazomethane was removed by bubbling nitrogen through the solution which was then concentrated to give a yellow gum. The gum was dissolved in methanol (100 ml), treated with silver benzoate (1 g, 4.4 mmol) and triethylamine (10 ml,70 mmol) then stirred for 2.5h at room temperature. The black solution was concentrated under reduced pressure and the residue taken up in ethyl acetate (100 ml) then washed with saturated aqueous sodium bicarbonate solution (100 ml), water (100 ml), 1M aqueous potassium hydrogen sulphate solution (2×100 ml) and brine (100 ml). The dried (MgSO4) organic phase was evaporated to leave a yellow oil which was purified by column chromatography on flash silica eluting with a gradient of 15-50% ethyl acetate in cyclohexane to give the title compound (1.972 g) as a white solid which crystallised from cyclohexane m.p.60-61° C., [α]D -21° (CHCl3 c=1%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](Cl)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C=O)C.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>[Cl-].[Na+].O.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: C1CCNC1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N3CCCC3)CS[C@H]12
Reaction time: 1 h

Procedure:
To a solution of 0.988 g. (2 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate in 10 ml. of dry DMF maintained at ice-bath temperature were added 0.375 ml. (4.4 mmole) of pyrrolidine. The reaction mixture was allowed to stir for about one hour and the mixture was then diluted with brine and ethyl acetate. The ethyl acetate was washed with brine several times and dried over magnesium sulfate. Evaporation of the dried extract gave 845 mg. of product.
Reaction SMILES: [BrH:1].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11](O)[C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1>C1(C)C=CC=CC=1.ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([Br:1])[C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C(O)c1ccc2c(c1)OCO2
Reactant: Br
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)C(Br)c1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
62% Aqueous hydrobromic acid (220 ml) was added slowly to a stirred suspension of 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetic acid (see J Org Chem, 50(23), 4523-6, 1985; 82.4 g) in a mixture of toluene (500 ml) and dichloromethane (1 liter). The mixture was stirred vigorously for 4 h. The aqueous layer was separated and removed and the organics were dried (MgSO4) and concentrated to give a brown oil. The oil crystallised over a 24 h period to give 105.3 g of the title compound.