Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:7][C:6]4[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:10]([F:13])([F:12])[F:11])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: FC(F)(F)c1ccc(Cl)cc1CCl
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-chloro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (48% yield).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCCC1.CO.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)co2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(-c2coc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of tert-butyl 4-(4-phenyl-1,3-oxazol-2-yl)piperazine-1-carboxylate (590 mg, 1.79 mmol) in tetrahydrofuran (4 ml) and methanol (4 ml) was added a solution of 4 N hydrogen chloride in ethyl acetate (4 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was poured to an aqueous 1 N sodium hydroxide solution (10 ml) and extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 370 mg (90.0%) of the desired product as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1.Cl.CCOCC>C1COCC1.C(Cl)Cl.C([O-])(O)=O.[Na+].CC#N>[Cl:21][C:22]1[N:27]=[C:26]([N:11]([C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH3:3])[C:12]2[NH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Cc1cccc(C)c1Nc1nc2ccccc2[nH]1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cccc(C)c1N(c1ccnc(Cl)n1)c1nc2ccccc2[nH]1
Temperature: 0 °C

Procedure:
A 3-neck round bottom flask was charged with NaH (60% dispersion in mineral oil, 0.41 g, 10.1 mmol, 1.2 eq.) under N2. The mineral oil was removed by stirring in n-heptane (3×10 mL) and decanting the supernatant liquid. The NaH was suspended in anhydrous THF (20 mL) and cooled to 0° C. A solution of 2-(2,6-dimethylphenylamino)-1H-benzimidazole (2.0 g, 8.4 mmol) in anhydrous THF (15 mL) was added slowly and the reaction was stirred at 0° C. for 0.5 h. A solution of 2,4-dichloropyrimidine (1.89 g, 12.7 mmol, 1.5 eq.) in anhydrous THF (15 mL) was added and the reaction was stirred at 0° C. for 0.5 h under N2, then warmed to RT and stirred for 18 h. The reaction was diluted with CH2Cl2 and sat. aq. NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was taken up into IPA and triturated with 1M HCl in Et2O (16 mmol). The resulting precipitate was separated by filtration and rinsed with n-heptane and n-heptane/EtOAc (1:1) to yield off-white crystals of a mixture of regioisomers as the HCl salts. The salts were suspended in hot CH3CN and filtered. The solids, a mixture of regioisomers, was taken up into CH2Cl2 and free-based with sat. aq. NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo to afford a fluffy white solid. The solids were dissolved in CH2Cl2, adsorbed onto silica and purified by column chromatography (silica; n-heptane:EtOAc; 4:1). The product fractions were combined and the solvent removed in vacuo to afford 2-(N-(2-chloropyrimid-4-yl)-2,6-dimethylphenylamino)-1H-benzimidazole as a white solid. MS m/z=350 (M+H). Calc'd for C19H40N8O3=349.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[CH2:10][CH2:11]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Clc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
60 mg of the target compound (0.17 mmol, 20.7%) was obtained using 1-(2-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[Cl:13][C:14]1[N:15]=[N:16][C:17]([NH:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([CH3:12])[CH3:11])=[CH:18][CH:19]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(CN)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(Cl)nn1)c1ccc(F)cc1
Yield: 105.8 %

Procedure:
A solution of (2-(4-fluorophenyl)-2-methylpropan-1-amine (27 g, 160 mmol, 1.6 equiv), 3,6-dichloropyridazine (15 g, 100 mmol, 1.0 equiv) and K2CO3 (42 g, 302 mmol, 3.0 equiv) in isopropanol (15 mL) was stirred at 100° C. for 36 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was dried over Na2SO4 and concentrated in vacuo. Partial purification over silica gel using a 30-75% gradient of EtOAc/hexanes gave the desired product (29.6 g, 103%) which was used without further purification.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>>[C:27]([C:26]1[CH:25]=[C:24]([NH:23][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)(=[O:13])=[O:12])=[CH:22][CH:21]=2)[CH:31]=[CH:30][CH:29]=1)#[N:28]
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: N#Cc1cccc(N)c1
Product: N#Cc1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-aminobenzonitrile (29 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-cyanophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 12 mg (12%). 1H-NMR: 10.76 (s, 1H), 8.23-8.20 (m, 1H), 8.07 (d, J=8.5 Hz, 2H), 8.03-7.98 (m, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.61-7.58 (m, 2H), 7.23-7.18 (m, 1H), 7.11-7.07 (m, 2H), 3.85-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.68-1.59 (m, 2H).
Reaction SMILES: ClC1N=C(/C=C(/C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)\O)C=CN=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[S:48]([NH:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34])(=[O:50])=[O:49]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: COC(=O)c1cccc(N)c1
Agent: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1
Yield: 73.8 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step A using methyl 3-aminobenzoate (16 g, 105.9 mmol) in DCM (150 mL) and 2,5-difluorobenzene-1-sulfonyl chloride (24.7 g, 116.5 mmol) the title compound was obtained (25.6 g, 73.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.06-11.13 (br, 1H), 7.42-7.52 (m, 2H), 7.52-7.77 (m, 4H), 7.78-7.80 (m, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:7]=1[O:13][C:14]([F:17])([F:16])[F:15])(=[O:5])=[O:4].C([O-])(=O)C.[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40](I)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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].[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>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:18])[CH3:1])(=[O:5])=[O:4])=[C:7]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=4)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N(C)C)c(OC(F)(F)F)c4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 83.5 %

Procedure:
A mixture of 0.477 g of N,N-dimethyl-4-bromo-2-trifluormethoxybenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2for 19 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 120° under N2 for 5.5 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30-26:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.425 g of the title compound as a solid of m.p. 145-146° C. The mass spectrum shows the molecular peak MH+ at 522.3 Da.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:17])[NH:5][C:6]2[CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH:12]=1)#[N:2].[OH-:18].[Na+]>S(=O)(=O)(O)O>[CH:12]1[C:11]2[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:17])[C:3]=1[C:1]([NH2:2])=[O:18]
Reactant: N#Cc1cc2c([nH]c1=O)CCc1ccccc1-2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1cc2c([nH]c1=O)CCc1ccccc1-2
Temperature: 0 °C

Procedure:
Heat 5.5 gm 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)one in 50 ml of 90% sulfuric acid at 100° for 11/2 hours. Cool the reaction mixture, pour into ice water and basify the aqueous mixture with 50% sodium hydroxide to give a tan precipitate. Filter the mixture and recrystallize the solid (dimethylformamide:acetonitrile) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)(O)[CH:16]([CH3:18])[CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN(C=O)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:16]([CH3:18])[CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccncc2)C(C)C)CCN(C)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-3-methyl-2-(pyridin-4-yl)butan-2-ol (0.2 g, 0.55 mmol) was dissolved in dry DCM and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.194 g, 1.65 mmoL) dissolved in dry DCM (1 mL) was added. Stirring was continued for 1 h at 0° C. and for 2 h at RT. Volatiles were removed under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate, and the product was extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.42 (d, 2H), 7.50 (d, 2H), 7.12 (s, 1H), 7.10 (d, 1H), 6.90 (d, 1H), 5.22 (d, 2H), 4.60 (d, 1H), 4.22 (d, 1H), 3.82 (m, 1H), 3.50 (m, 1H), 3.16 (m, 2H), 3.05 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H), 1.65 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23]CCO)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH:45]([N:48]=[C:49]=[O:50])([CH3:47])[CH3:46].C(O)C(N)(CO)CO.C([O-])(=O)C.[NH4+]>CO.O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][C:49](=[O:50])[NH:48][CH:45]([CH3:47])[CH3:46])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reactant: CC(C)N=C=O
Agent: CC(=O)[O-]
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: NC(CO)(CO)CO
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)OCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 436.7 %

Procedure:
A solution of (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 15, intermediate b) (0.01 g, 0.03 mmol) and DCM (1 mL) was added to PS-BEMP (2.2 mmol/g, 0.03 g, 0.06 mmol). The mixture was shaken at room temperature for 5 min, isopropyl isocyanate (17 μL, 0.15 mmol) was added, the mixture was heated at 40° C. and left to shake for 24 h. PS-Trisamine (4.7 mmol/g, 0.06 g, 0.3 mmol) and DCM (1 mL) were added and the reaction mixture was left to shake at room temperature for 4 h. The reaction mixture was filtered and the solid washed with DCM (3 mL). The filtrate was evaporated and the crude product purified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 μm 60 Å 30 mm×300 mm column, UV detection at 254 nm, mobile phase 95:5 methanol:water and 10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to afford the title compound (0.053 g, 44% yield) as a pale yellow oil: m/z 405.29 (MH+); NMR δH (400 MHz, CDCl3) 1.15 (6H, d, J 6.5 Hz), 1.24 (3H, d, J 6.5 Hz), 1.47 (9H, s) 2.50–2.60 (2H, m), 3.0–3.1 (2H, m), 3.8–3.9 (1H, m), 3.9–4.1 (2H, m), 4.5–4.6 (2H, m), 4.7–4.8 (1H, br s), 5.04 (2H, s), 6.50 (1H, d, J 7.0 Hz) and 7.18 (1H, d, J 7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][C@H:9]1[C:14](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]2[C:32](=[O:33])[NH:34][C:14]([C@@H:9]3[CH2:10][CH:11]=[CH:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:25][C:26]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC=CC[C@H]1C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=CC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a mixture of (2S)-1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (1.16 g), triethylamine (1.42 mL) and tetrahydrofuran (12 mL) was added 2-methylpropyl chlorocarbonate (0.662 mL) with stirring at room temperature. After 1 hr, 3-amino-5-bromothiophene-2-carboxamide (752 mg) produced in Example 1, step D, was added, and the mixture was stirred in a microwave reactor at 100° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL), 2M aqueous sodium hydroxide solution (10.2 mL) was added, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was ice-cooled, and 6M hydrochloric acid (3.33 mL) was added dropwise. The reaction mixture was poured into brine, and extracted with 3:1 ethyl acetate/tetrahydrofuran mixture. The extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (851 mg) as a white solid. The optical purity was 51.1% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK IC (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1 ml/min, column temperature: 30° C., detection 220 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](O)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][C:24]([CH3:25])([CH3:26])[C:27]([NH:57][S:54]([CH3:53])(=[O:56])=[O:55])=[O:28])=[C:16]([CH:15]2[CH2:14][C:13](=[O:30])[NH:12][CH:11]([C:31]3[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:40])[CH:21]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(C)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-methyl-2-methoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (70 mg, 0.12 mmol) and CDI (39 mg, 0.24 mmol) in dry DMF (2 mL) was heated at 65° C. for 2 h. In a separate flask a mixture of methanesulfonamide (91 mg, 0.962 mmol) and NaH (60% in mineral oil) (38 mg, 0.95 mmol) (Aldrich) in DMF (3 mL), was stirred at room temperature for 2 h, then was added slowly to the above solution. The reaction mixture was stirred at room temperature for 2 h, then poured into water (3 mL) and the aqueous phase was acidified to “pH” 1-2 by addition of concentrated HCl. The mixture was extracted with EtOAc (20 mL) twice. The combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and the residue was purified by Prep-HPLC to give the title compound as a white solid (8.5 mg).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:11].C[O:13]B(OC)OC.C([Li])(C)(C)C>>[F:11][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[CH:8][S:9][C:10]=2[C:2]=1[OH:13]
Reactant: COB(OC)OC
Reactant: Fc1ccc2ccsc2c1Br
Agent: [Li]C(C)(C)C
Product: Oc1c(F)ccc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
(Ref: Briner, K; Burkholder, T. P; Conway, R. G; Cunningham, B. E; Finley, D. R; Heinz, L. J; Jesudason, C. D; Kohlman, D. T; Liang, S. X; Xu, Y. C. Preparation and use of serotonergic benzothiophenes. WO 0109126 A1. Chem. Abs. 134:162912). To a solution of 7-bromo-6-fluoro-1-benzothiophene (0.2 g, 0.9 mmol) and trimethylborate (0.2 mL, 1.8 mmol) at −78° C. was added tert-butyllithium dropwise. After 10 mins at −78° C. the reaction was quenched by pouring onto saturated ammonium chloride. This was extracted with ethyl acetate (3×10 mL) and the solvent removed in vacuo from the combined organic extracts. The residue was taken up in ethyl acetate (4 mL) and 10% aqueous hydrochloric acid (4 mL) was added, the mixture was stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo. The residue was taken up in TBF (10 mL), water (2 mL) and cooled to 0° C. then 10% aqueous sodium hydroxide (2 mL) and 28% hydrogen peroxide (1 mL) were added to this and stirred for 0.5 h at 0° C. The mixture was warmed to room temperature and stirred for 2 hours, before a acetic acid (3 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL), dried (MgSO4) and the solvent removed in vacuo, to give a purple solid. This was purified by flash chromatography with a gradient of 0-20% ethyl acetate in iso-hexane to give the title compound (56 mg, 38%); δH (300 MHz, CDCl3) 7.41 (4H, m, ArH).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH2:19]([N:22]1[C:26]([SH:27])=[N:25][N:24]=[N:23]1)[C:20]#[CH:21].B(F)(F)F.CCOCC.N>C(#N)C.O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:26]3[N:22]([CH2:19][C:20]#[CH:21])[N:23]=[N:24][N:25]=3)[CH2:15][S:14][C@H:9]12
Reactant: C#CCn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: N
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 47 °C
Reaction time: 1.5 h
Yield: 79.5 %

Procedure:
To a suspension of 7-aminocephalosporanic acid (0.35 g) and 1-(2-propynyl)-1H-tetrazole-5-thiol (0.20 g) in acetonitril (1.8 ml) was added boron trifluoride etherate (0.55 g) at room temperature and the resulting mixture was stirred for 1.5 hours at 47° C. To the reaction mixture was added water (1.8 ml) and the mixture was adjusted to pH 3.5 with conc. aqueous ammonia under ice-cooling. The precipitates were collected by filtration, washed successively with water and acetone and then dried to give 7-amino-3-[1-(2-propynyl)-1H-tetrazole-5-yl]thiomethyl-3-cephem-4-carboxylic acid (0.36 g).