Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC2N(C3C[O:13][CH2:12]3)C(CCl)=NC=2C=1.[Cl:17][C:18]1[CH:47]=[CH:46][C:21]2[N:22]([C@@H:39]3[CH2:43][CH2:42]S(=O)(=O)C3)[C:23]([CH2:25][N:26]3[C:30]4=[CH:31][N:32]=[CH:33][CH:34]=[C:29]4[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:27]3)=[N:24][C:20]=2[CH:19]=1.CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:17][C:18]1[CH:47]=[CH:46][C:21]2[N:22]([CH2:39][CH:43]3[CH2:12][O:13][CH2:42]3)[C:23]([CH2:25][N:26]3[C:30]4=[CH:31][N:32]=[CH:33][CH:34]=[C:29]4[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:27]3)=[N:24][C:20]=2[CH:19]=1
Reactant: ClCc1nc2cc(Cl)ccc2n1C1COC1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCS(=O)(=O)C2)c2cnccc12
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CC2COC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-oxetan-3-yl-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole (Example 2-1) instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [OH:1][C:2]1([C:18]([F:21])([F:20])[F:19])[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH2:3]1.C1CCCCC=1>CCO.[Pd]>[F:21][C:18]([F:19])([F:20])[C:2]1([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: OC1(C(F)(F)F)CCNCC1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a stirred solution of benzyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (347 g, 1.15 mole) in EtOH (1.2 L) was added Pd—C (Degussa type, 10 wt. % Pd, 50% H2O, 26.0 g, 12.2 mmol) and cyclohexene (850 mL, 8.39 mol). The mixture was heated to a gentle reflux for 1 hour resulting in a slight exotherm and the vigorous evolution of gas. Upon cooling to ambient temperature, the mixture was filtered through Celite®, and the filtrate was concentrated. The resulting residue was dissolved in CH2Cl2 (500 mL), dried (Na2SO4), filtered, and concentrated to give an orange solid. The crude material was crystallized from MTBE to give 160 g (83%) of product as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 5.71 (br s, 1H), 2.74 (m, 4H), 2.42 (br s, 1H, overlaps DMSO), 1.53 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.I[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (952 mg, 3.96 mmol), ethyl 2-iodoacetate (1.27 g, 5.93 mmol) in DMF (14 ml) was added K2CO3 (1.64 g, 11.9 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to remove DMF. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed successively with water and saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated in vacuo to give a crude solid. The residual solid was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 1:1) to afford a pale yellow solid. The solid was triturated with hexane/ethyl acetate (4:1), collected by filtration, rinsed with hexane/ethyl acetate (5:1) and dried to afford ethyl 2-(2-chloro-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate (953 mg, 2.92 mmol, 74% yield) as a white solid. MS [M+H] found 327.
Reaction SMILES: CN1C(=O)CC(=O)N(C)C1=O.[Cl:12][C:13]1[CH:18]=[C:17]([N:19](CC=C)CC=C)[CH:16]=[CH:15][C:14]=1[CH:26]([CH3:40])[C:27]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([Cl:39])[CH:34]=1)([OH:32])[C:28]([F:31])([F:30])[F:29].[OH-].[Na+]>C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:19][C:17]1[CH:16]=[CH:15][C:14]([CH:26]([CH3:40])[C:27]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([Cl:39])[CH:34]=2)([OH:32])[C:28]([F:29])([F:30])[F:31])=[C:13]([Cl:12])[CH:18]=1
Reactant: C=CCN(CC=C)c1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Yield: 76.5 %

Procedure:
A solution of 1,3-dimethylbarbituric acid ([CAS Reg. No. 769-42-6], 828 mg), tetrakis(triphenylphosphine) palladium (0) (230 mg) and 3-(2-Chloro-4-diallylamino-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (590 mg) in DCM (120 ml) was heated under reflux for 3 h. NaOH (1N aq) was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 0:100-50:50) to give the title compound as a light yellow gum (370 mg). MS (m/e)=365.0 [M+H+].
Reaction SMILES: [CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3C(OC(C)(C)C)=O)=[CH:29][CH:28]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)[C:48]([OH:50])=[O:49]>C(Cl)Cl>[CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:31]([C:48]([OH:50])=[O:49])[CH:32]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Solvent: ClCCl
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3)c(C(=O)O)c1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of ethyl 2-n-propyl-3-{2'-(tert-butoxycarbonyl)biphenyl-4-yl}methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (657 mg), trifluoroacetic acid (3 ml) and methylene chloride (10 ml) is stirred overnight at room temperature. The reaction mixture is washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated to remove the solvent. The crude residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-3-(2 -carboxybiphenyl-4-yl)methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (516 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH2:38][CH:39]([CH2:42][OH:43])[CH2:40][OH:41].[I-].[Na+]>CN(C=O)C>[OH:41][CH2:40][CH:39]([NH:38][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH2:42][OH:43]
Reactant: NC(CO)CO
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCNC(CO)CO)CC3)n[nH]c12
Temperature: 120 °C
Reaction time: 0.02 h
Yield: 27 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indazole-7-carboxamide i (Intermediate 22) (19 mg, 0.0413 mmol) in DMF (1 mL) was added K2CO3 (25 mg, 0.165 mmol), 2-amino-1,3-propanediol (20 mg, 0.2065 mmol) and sodium iodide (1.0 mg). The reaction mixture was heated to 120° C. for 14 hrs. The solution was filtered and concentrated. The residue was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 80% B in 10 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (5.8 mg, 27%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.C(OCC)(=O)C>[CH3:21][C:6]1[C:5]([CH2:4][CH2:3][OH:2])=[CH:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=2)[N:7]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
2.6 g (8.40 mmol) of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester in 15 ml of dry tetrahydrofuran were added under an argon atmosphere within 15 minutes to a stirred suspension of 0.38 g (10 mmol) of lithium aluminium hydride in 5 ml of tetrahydrofuran. The reaction was exothermic. Subsequently, the mixture was stirred at room temperature for 1 hour. Then, 1 ml of ethyl acetate was dropped to the reaction mixture, followed by water, drop after drop, under argon, with stirring and cooling until the gas evolution ceased. The reaction mixture was diluted with 50 ml of ethyl acetate, dried with anhydrous sodium sulfate and filtered. The filtrate was evaporated and the residue was chromatographed on silicagel with a mixture of dichloromethane and tert.-butyl methyl ether (4:1 vol./vol.) as eluent. 1.88 g (79.5% of theory) of 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol was obtained as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]([N:27]([CH3:26])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Reactant: CNCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)C(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid (50 mg, 0.14 mmol), N-methylbenzylamine (0.022 mL, 0.17 mmol), iPr2NEt (0.07 mL, 0.50 mmol) in DMF (3 mL) was added HATU (68 mg, 0.18 mmol) and stirred at rt overnight. The reaction mixture was poured into ice-water, and the solid was collected by filtration. The solid was re-dissolved in CH2Cl2 and purified by preparative TLC (CH2Cl2-MeOH-Hexane, 8:2:2) affording the product as a light yellow powder. LC-MS: 467 (M++1). 1H NMR (CDCl3): δ 2.92 and 3.00 (each s, 3H), 3.05˜3.12 (m, 4H), 3.62˜3.72 (m, 4H), 4.12˜4.20 (m, 2H), 4.52 and 4.62 (each s, 2H), 5.08 (br.s, 2H), 5.94 (m, 1H), 6.15 (m, 1H), 7.14˜7.24 (m, 3H), 7.26˜7.40 (m, 3H), 7.58˜7.62 (m, 1H), 7.68˜7.72 (m, 1H).
Reaction SMILES: CC(C)C(P(=O)O)NC(=O)CCC1C=CC=CC=1.C(OC([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]([OH:45])[C:35]([O:37]CC1C=CC=CC=1)=[O:36])=O)C1C=CC=CC=1>ClCCl>[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:45])[C:35]([OH:37])=[O:36]
Reactant: O=C(NCCCC[C@H](O)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CC(C)C(NC(=O)CCc1ccccc1)[PH](=O)O
Solvent: ClCCl
Product: NCCCCC(O)C(=O)O

Procedure:
Under an argon atmosphere, a dichloromethane (15 ml) solution of the 2-methyl-1-(3-phenylpropanoylamino)propylphosphinic acid (162 mg) obtained in the above step (a) was added with benzyl (S)-6-benzyloxycarbonylamino-2-hydroxyhexanoate (228 mg) which was obtained from 6-amino-2-hydroxyhexanoic acid described in Chem. Pharm. Bull., 621(1976) in a conventional manner, N-(dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (180 mg), and dimethylaminopyridine (38.7 mg), and then the mixture was stirred at room temperature for 16 hours. The organic substances were extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (10 g, chloroform:methanol=10:1) to obtain benzyl (S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)phosphinoyloxy)hexanoate (117 mg, 31%). This compound was subjected to the measurement of molecular weight and then used in the following reaction.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:9]([CH3:15])=[N:10]2)=[O:4].[C:22]([O:26][C:27]([NH:29][C@H:30]([CH3:39])[C:31](=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][CH:30]([CH3:39])[C:31](=[O:38])[CH:32]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:9]([CH3:15])=[N:10]2)=[O:4])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NCC(F)(F)F
Reactant: CCOC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NCC(F)(F)F)nc12)C(=O)C(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A mixture of 2-bromo-1-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)ethanone (616) (300 mg, 0.83 mmol), ethyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (602) (258 mg, 0.99 mmol) and K2CO3 (286 mg, 2.07 mmol) in DMF (2.75 mL) was stirred at RT for 1 h. The reaction mixture was concentrated. Saturated NH4Cl (aq.) and EtOAc was added and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (293a) (285 mg, 64% yield). m/z (ESI, +ve) 541.1 (M+H)+. This material was put into a sealed tube with 2 mL of EtOH. AcOH (1 mL) and NH4OAc (511 mg, 6.63 mmol) were added and the mixture was stirred at 60° C. overnight (21 h). The reaction mixture was concentrated. The residue was put into solution with EtOAc and water. The layers were separated and the organic layer was washed with water, 1 M NaOH (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (293b) (215 mg, 0.41 mmol, 50% yield) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dt, J=7.53, 0.73 Hz, 1H), 7.29-7.44 (m, 2H), 7.12 (d, J=2.54 Hz, 1H), 5.00 (br. s., 1H), 4.25-4.53 (m, 4H), 2.14-2.30 (m, 2H), 1.64 (s, 3H), 1.58 (d, J=7.24 Hz, 3H), 1.36-1.48 (m, 12H). 19F NMR (377 MHz, CDCl3) δ ppm −70.80. m/z (ESI, +ve) 522.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)([Cl:18])=O.CN(C)C=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([Cl:18])=[O:15])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (100 mg, 0.50 mmol) in thionyl chloride (110 μL, 1.5 mmol) was added N,N-dimethylformamide (20 μL, 0.26 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Excess thionyl chloride and N,N-dimethylformamide were removed in vacuo and the resulting acid chloride was used directly in next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2Br)([CH3:18])[CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(B(O)O)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:20]3[C:19](=[CH:24][C:23]([F:25])=[CH:22][CH:21]=3)[C:16]([CH3:18])([CH3:17])[C:15]2=[O:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)NC1CCN(Cc2ccccc2)CC1)c1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: CC1(C)C(=O)N(C2CCN(Cc3ccccc3)CC2)c2ccc(F)cc21
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A mixture of N-(1-benzylpiperidin-4-yl)-2-(2-bromo-5-fluorophenyl)-2-methylpropanamide (275 mg, 0.635 mmol, EXAMPLE 44, Step 2), palladium acetate (14 mg, 0.063 mmol), phenyl boronic acid (15 mg, 0.13 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (30 mg, 0.063 mmol), potassium carbonate (220 mg, 1.6 mmol) and t-butyl alcohol (15 mL) was refluxed under nitrogen atmosphere for 14 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (8-66% ethyl acetate in hexane) to give the title compound (171 mg, 76%).
Reaction SMILES: C([C:5]1[N:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][N:6]=1)(C)(C)C.[C:20]1(C2CC(C3C=CC=CC=3)=C(C3C=CC=CC=3)C=2C2C=CC=CC=2)C=CC=C[CH:21]=1>CN(C=O)C.C[Rh](Cl)(C)(C)(C)(C)C1C=CC=C1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:9]1[C:8]2[C:11]3[N:15]([CH:20]=[CH:21][C:7]=2[N:6]=[CH:5][N:10]=1)[C:14]1[C:13](=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:12]=3
Reactant: c1ccc(C2=C(c3ccccc3)C(c3ccccc3)=C(c3ccccc3)C2)cc1
Reactant: CC(C)(C)c1ncc(-c2nc3ccccc3[nH]2)cn1
Agent: C[Rh](C)(C)(C)(C)(Cl)C1C=CC=C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)nc1c3cncnc3ccn21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Preparation analogous to N. Umeda et al., Angew. Chem. Int. Ed. 2008, 47, 4019: a solution of 25.2 g (100 mmol) of 2-(2-tert-butylpyrimidin-5-yl)benzimidazole (S48) and 110 mmol of the alkyne in 400 ml of DMF is initially introduced in a pressure Schlenk tube, 1.5 g (4 mmol) of tetraphenylcyclopentadiene, 547 mg (1 mmol) of pentamethylcyclopentadienyl-rhodium chloride dimer and 21.0 (105 mmol) of copper(II) acetate monohydrate are added, and the mixture is stirred in the sealed tube at 100° C. for 18 h. After cooling, the DMF is removed in vacuo, the residue is taken up in 1000 ml of THF and filtered through a short silica-gel column. After removal of the THF in vacuo, the oily residue is taken up in hot methanol (about 75 ml). After cooling, the crystals formed are filtered off with suction and recrystallised again from methanol with addition of a little ethyl acetate. The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 180-220° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>[OH-].[Na+].C(Cl)Cl>[CH2:22]([N:24]([CH2:25][CH3:26])[C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH3:23]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A solution of 25 g (110 mmol) 4-benzoylbenzoic acid [611-95-0] and 20 mL SOCl2 was allowed to reflux for 2 h then allowed to cool. The excess SOCl2 was evaporated off and the resulting clear oil was dissolved in 10 mL CH2Cl2 then slowly added to 12 mL (116 mmol) diethylamine in a mixture of 10 mL 3N NaOH and 50 mL CH2Cl2. The mixture was allowed to stir for 30 min then partitioned between H2O and CH2Cl2. The organic layer was washed with brine, dried over K2CO3, filtered and concentrated. The product precipitated from EtOAc/hexane to give 29.6 g (105 mmol) white crystals. MS m/z (MH+) 282.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][CH:20]1[CH:27]2[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:30]>C(O)(=O)C.O1CCOCC1>[ClH:30].[CH:21]12[CH2:29][CH:25]3[CH2:24][CH:23]([CH2:28][CH:27]([CH2:26]3)[CH:20]1[NH:19][C:17](=[O:18])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH2:8])[CH2:22]2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3

Procedure:
To a stirred solution of 100 g (0.25 mole) of the title product of Example 1 in 827 ml of acetic acid was added 413 ml (2.5 mole) of 6.07N hydrogen chloride in dioxane. After about thirty minutes the solution was concentrated in vacuo to a viscous oil. Trituration with diethyl ether afforded a solid which was collected by filtration, washed with diethyl ether, and air dried. Repetition of the trituration with diethyl ether afforded the title compound as an analytically pure solid. [α]D +47.5°; [α]365 +186.3° (methanol).
Reaction SMILES: NC1C(=O)N2C([C:16](O)=[O:17])=C(CSC3NN=NC=3)CS[C@H]12.[CH:21]1[C:26]([C@@H:27]([NH2:50])[C:28]([NH:30][C@@H:31]2[C:34](=[O:35])[N:33]3[C:36]([C:47]([OH:49])=[O:48])=[C:37]([CH2:40][S:41][C:42]4[N:46]=[N:45][NH:44][CH:43]=4)[CH2:38][S:39][C@H:32]23)=[O:29])=[CH:25][CH:24]=[C:23]([OH:51])[CH:22]=1>C(Cl)Cl>[CH:25]1[C:26]([C@@H:27]([NH2:50])[C:28]([NH:30][C@@H:31]2[C:34](=[O:35])[N:33]3[C:36]([C:47]([OH:49])=[O:48])=[C:37]([CH2:40][S:41][C:42]4[N:46]=[N:45][NH:44][CH:43]=4)[CH2:38][S:39][C@H:32]23)=[O:29])=[CH:21][CH:22]=[C:23]([OH:51])[CH:24]=1.[CH3:16][OH:17]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Agent: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3c[nH]nn3)CS[C@H]12)c1ccc(O)cc1
Solvent: ClCCl
Product: CO

Procedure:
The acylation of 7-amino-3-(1,2,3-triazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (7-TACA) to BL-S640 has been carried out in methylene chloride with D-(-)-p-hydroxyphenylglycyl chloride hydrochloride. The yield to BL-S640 methanol solvate was about 45% on a biopotency basis. There was about 15% activity in the mother liquor and about 25% insoluble solids which is unreacted 7-TACA and 7-TACA decomposition product with degraded β-lactam.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH:4]([CH2:21]Cl)[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH2:19][CH3:20])=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:2][CH2:3][CH:4]1[CH:5]2[C:14]3[C:9]([CH2:8][CH2:7][N:6]2[CH2:21]1)=[CH:10][C:11]([O:18][CH2:19][CH3:20])=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=3
Reactant: CCOc1cc2c(cc1OCC)C(C(CCl)CCl)NCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOc1cc2c(cc1OCC)C1C(CCl)CN1CC2
Reaction time: 2 h
Yield: 79 %

Procedure:
0.01 mole (3.69 g) of 1-[bis(chloromethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride is suspended in 50 ml of absolute benzene, and 5 ml of triethyl amine are added to the suspension. After standing for 2 hours the reaction mixture is evaporated to dryness. The residue is dissolved in water and extracted with three 50-ml portions of ether. The ethereal extract is dried and evaporated to yield the aimed compound as a crystalline residue. After recrystallization from ether the product melts at 91° to 93° C.