Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:20]([O:22]C)=O)[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[OH:32][C@@H:29]1[CH2:30][CH2:31][C@H:26]([N:25]2[CH2:2][CH2:3][C:4]3([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:11])[CH2:8][CH2:9]3)[C:20]2=[O:22])[CH2:27][CH2:28]1
Reactant: COC(=O)C1(CC=O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-benzyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (4.80 g, 0.0150 mol), cis-4-aminocyclohexanol hydrochloride (2.5 g, 0.016 mol) and triethylamine (3.3 mL, 0.024 mol) in 1,2-dichloroethane (30.0 mL) was stirred at room temperature for 30 min. To the mixture was added sodium triacetoxyborohydride (7.9 g, 0.038 mol) with stirring. The mixture was stirred at room temperature for 1 h, then was heated at 80° C. for 2 h. After cooling, the mixture was diluted with dichloromethane, and washed with IN HCl solution, NaHCO3 (7.5%), water, and brine successively, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give benzyl 2-(cis-4-hydroxycyclohexyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (4.20 g, 72.0%).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:16]([N:27]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:28][CH3:29])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=C(C#N)[CH:19]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[Li+].[OH-:46].[CH3:47][CH2:48][OH:49]>Cl.C(OCC)(=O)C>[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:16]([N:27]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:28][CH3:29])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:47]([C:48]([OH:46])=[O:49])[CH:19]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CCN(CC1CCCC1)c1nc2cc(C#N)ccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCN(CC1CCCC1)c1nc2cc(C(=O)O)ccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C

Procedure:
A suspension of 3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-2-[N′-(cyclopentylmethyl)-N′-ethylamino]quinoline-7-carbonitrile (40 mg, 0.06 mmol) and 2N LiOH aq. (2.0 mL) in EtOH (2 mL) is stirred and refluxed for 2 hours. The reaction mixture is cooled to room temperature and then diluted with 1N HCl and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated to give 3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-2-[N′-(cyclopentylmethyl)-N′-ethylamino]quinoline-7-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]#[N:8].C[O-].[Na+].[Cl-].[NH4+:13]>CO>[ClH:1].[Cl:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([NH2:13])=[NH:8]
Reactant: N#Cc1ncsc1Cl
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1ncsc1Cl

Procedure:
10 mmol 5-chloro-4-cyanothiazole was dissolved in 10 ml anhydrous methanol, and 10 mmol sodium methoxide was added. Upon complete reaction of the starting materials, 20 mmol ammonium chloride was added, to carry out reaction in closed state for 12 hr. The reaction product was filtered to remove inorganic salt, and then the resultant filtrate was concentrated to obtain 5-chloro-4-thiazolformamidine hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[CH2:22][C:23](O)=[O:24])([CH3:9])[CH3:8].[CH3:26][O:27][C:28](=[O:46])[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([O:38][S:39](=[O:42])(=[O:41])[NH2:40])=[C:31]([CH:43]([CH3:45])[CH3:44])[CH:30]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:26][O:27][C:28](=[O:46])[C:29]1[CH:30]=[C:31]([CH:43]([CH3:45])[CH3:44])[C:32]([O:38][S:39](=[O:41])(=[O:42])[NH:40][C:23](=[O:24])[CH2:22][C:11]2[C:10]([CH:7]([CH3:8])[CH3:9])=[CH:15][C:14]([CH:16]([CH3:18])[CH3:17])=[CH:13][C:12]=2[CH:19]([CH3:21])[CH3:20])=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:34]=1
Reactant: COC(=O)c1cc(C(C)C)c(OS(N)(=O)=O)c(C(C)C)c1
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(C)C)c(OS(=O)(=O)NC(=O)Cc2c(C(C)C)cc(C(C)C)cc2C(C)C)c(C(C)C)c1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Oxalyl chloride (1.12 mL, 12.8 mmol) was added dropwise to a solution of 2,4,6-triisopropylphenyl acetic acid (3.05 g, 11.6 mmol) in 150 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred overnight and then concentrated in vacuo. The residue was re-dissolved in 150 mL dichloromethane. 3,5-Bis(1-methylethyl)-4-(sulfamoyloxy)benzoic acid methyl ester (3.48 g, 11.6 mmol) and triethylamine (4.0 mL) were added and the resulting mixture was stirred for 2 hours. Washed with 1 M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give an off-white foam. Recrystallized (hexanes) to give 5.21 g of the title compound as a white solid; mp 144-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:31])=[O:30]
Reactant: Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)-benzenesulfonamide was synthesized (63%) from 3,5-dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236), 2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (br s, 1H), 9.19 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.74-7.68 (m, 2H), 7.60 (td, J=7.5, 1.0 Hz, 1H), 7.31 (s, 1H), 7.20 (s, 2H), 4.42 (s, 2H). MS (EI): m/z 509 (M−H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[OH2:14].Cl>NC[C@H](O)C>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:7][CH2:6][C@H:8]([OH:14])[CH3:9])[NH:7][C:6]=2[CH:8]=1
Reactant: O
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Agent: C[C@@H](O)CN
Agent: Cl
Product: C[C@@H](O)CNC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 74 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (200 mg, 0.78 mmol) in (R)-(−)-1-amino-2-propanol (1.0 ml) was stirred for 18 h at 100° C. in a sealed flask. The cooled solution was stirred with water (3 ml) at 0° C. followed by adjustment to pH 2 with 4M hydrochloric acid. The product was isolated by filtration, washed with water, and dried in vacuo at room temperature to give 170 mg (74%) of the pure title compound; mp 210-211° C.; 1H-NMR (DMSO-d6): δ1.08 (d, 3H), 3.0-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.72-3.82 (m, 1H), 4.91 (br s, 1H), 7.09 (s, 1H), 7.14 (br s, 1H), 10.95 (br s, 1H); MS: m/e 297/295(M+); (C8H10N3Cl1O3S2 .0.5 H2O) calc C, 31.53; H, 3.64; N, 13.79; found C, 31.57; H, 3.58; N, 13.58.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][C@H:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11][C:10]=2[CH:21]=1)#[N:2].[C:29]([N:31]=[C:32](OC1C=CC=CC=1)[NH:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][CH2:42][C@@H:41]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH2:40][CH2:39][C:38]=2[CH:49]=1)#[N:30].[NH:57]([C:59]1[N:64]=[N:63][C:62]2[C:65]3[CH:73]=[CH:72][CH:71]=[CH:70][C:66]=3[CH2:67][CH2:68][CH2:69][C:61]=2[CH:60]=1)[NH2:58]>>[N:63]1[C:62]2[C:65]3[CH:73]=[CH:72][CH:71]=[CH:70][C:66]=3[CH2:67][CH2:68][CH2:69][C:61]=2[CH:60]=[C:59]([N:57]2[C:1]([NH2:2])=[N:3][C:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[CH2:15][CH2:14][C@H:13]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[CH2:12][CH2:11][C:10]=4[CH:21]=3)=[N:58]2)[N:64]=1.[N:63]1[C:62]2[C:65]3[CH:73]=[CH:72][CH:71]=[CH:70][C:66]=3[CH2:67][CH2:68][CH2:69][C:61]=2[CH:60]=[C:59]([N:57]2[C:29]([NH2:30])=[N:31][C:32]([NH:33][C:34]3[CH:35]=[CH:36][C:37]4[CH2:43][CH2:42][C@@H:41]([N:44]5[CH2:45][CH2:46][CH2:47][CH2:48]5)[CH2:40][CH2:39][C:38]=4[CH:49]=3)=[N:58]2)[N:64]=1
Reactant: N#CN=C(Nc1ccc2c(c1)CC[C@@H](N1CCCC1)CC2)Oc1ccccc1
Reactant: NNc1cc2c(nn1)-c1ccccc1CCC2
Reactant: N#CN=C(Nc1ccc2c(c1)CC[C@H](N1CCCC1)CC2)Oc1ccccc1
Product: Nc1nc(Nc2ccc3c(c2)CC[C@@H](N2CCCC2)CC3)nn1-c1cc2c(nn1)-c1ccccc1CCC2
Product: Nc1nc(Nc2ccc3c(c2)CC[C@H](N2CCCC2)CC3)nn1-c1cc2c(nn1)-c1ccccc1CCC2

Procedure:
Phenyl (S)—N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate and phenyl (R)—N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate were treated with 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine in a similar manner as described above in Synthetic Example 2 to yield 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(S)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine and 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine. For example, a suspension of a single enantiomer of phenyl N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamimidate (0.06 g, 0.16 mmol) and 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (0.036 g, 0.16 mmol) in 1 mL of IPA was stirred at 90° C. for 18 h. After cooling to ambient temperature, the solvent was evaporated and the residue was purified by HPLC to provide enantiomerically pure 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine as a yellow solid (0.04 g, 50%). 1H NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 7.94 (s, 1H), 7.85 (br s, 2H), 7.72 (m, 1H), 7.46 (m, 3H), 7.37 (m, 2H), 7.06 (m, 1H), 3.46 (m, 4H), 3.12 (m, 2H), 2.72 (m, 4H), 2.61 (m, 3H), 2.25 (m, 5H), 2.09-1.82 (m, 5H) ppm; MS (ES) 507 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C=O)C.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1>CCOC(C)=O.O>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Nc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncccc1OCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To the mixture of 2-aminopyridin-3-ol (500 mg) and DMF (dry) (15 mL) was added NaH (60%, 200 mg) at room temperature and the mixture was stirred at room temperature for 20 min. 1-(Bromomethyl)-3-chlorobenzene (933 mg) was added and the mixture was stirred at the same temperature for 1 hr. Water and EtOAc were added and the extracted organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.01 g) as a brown crystalline solid.
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[CH2:2].Br[C:17]1[CH:18]=[C:19]([C:23]2[O:24][C:25]([CH3:46])=[C:26]([CH2:28][CH2:29][O:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[C@H:36]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:34]4)[N:27]=2)[CH:20]=[CH:21][CH:22]=1.ClCCl>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].C1(C)C=CC=CC=1>[CH3:46][C:25]1[O:24][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH:1]=[CH2:2])[CH:18]=2)=[N:27][C:26]=1[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C@H:36]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:34]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4cccc(Br)c4)oc3C)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=Cc1cccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)OCC)c(C)o2)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a mixture of vinyltributyltin (Aldrich, 65.0 mg, 0.21 mmol), ethyl ((1S)-5-{2-[2-(3-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (50 mg, 0.10 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (4.2 mg, 0.005 mmol) was added toluene (2 mL). The resulting solution was degassed with argon for 30 minutes, and then stirred at 110° C. for 16 h. The reaction mixture was cooled to rt and diluted with 10 mL ethyl acetate. The organic layer was filtered through a silica plug and the filtrate concentrated under reduced pressure. The crude was then redissolved in methanol and filtered through a silica-octyl plug before preparative HPLC purification using 30 to 100% acetonitrile in water (0.1% TFA) gradient to afford the desired product. 1H NMR (CD2Cl2) δ 8.03 (s, 1H), 7.86 (d, 1H), 7.39-7.51 (m, 2H), 7.04 (d, 1H), 6.68-6.84 (m, 3H), 5.88 ( (d, 1H), 5.31-5.35 (m, 1H), 4.10-4.23 (m, 4H), 3.48 (qr, 1H), 2.97 (t, 2H), 2.64-2.89 (m, 3H), 2.29-2.42 (m, 5H), 1.69-1.76 (m, 1H), 1.26 (t, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[C:35]([F:38])([F:37])[F:36])[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[C:35]([F:37])([F:38])[F:36])[CH2:24][C:23]2=[O:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3C(F)(F)F)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3C(F)(F)F)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-trifluoromethylphenyl)piperidin-3-ol (0.15 g) obtained in Step 1 in 3 ml of dimethyl sulfoxide (DMSO), was added 0.16 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.15 g) was added slowly to the reaction mixture, which was then stirred for about 4 hours at room temperature, diluted with 20 ml of ethyl acetate, washed with brine, and dried and concentrated. The resulting residue was purified with column chromatography to give 84 mg of the titled compound as white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16][N:15]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)=[N:3][CH:4]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1nc(N)cs1
Product: Cc1nc(Nc2ncc(-c3ccnc(Cl)c3)c3sc(C)nc23)cs1

Procedure:
The title compound, MS: m/e=374.0 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 2-chloropyridin-4-boronic acid and 4-amino-2-methylthiazole (Example C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:32]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(O)C.[NH:37]1[CH2:43][C:41](=[O:42])[NH:40][C:38]1=[O:39].N1CCCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:43]4[C:41](=[O:42])[NH:40][C:38](=[O:39])[NH:37]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=O)cnn23)c1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)c1cccc(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)c1
Temperature: 80 °C
Yield: 69 %

Procedure:
To the reaction flask, tert-butyl 3-(5-(3-chlorophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate (122 mg, 0.3 mmol) was added to ethanol (1.3 mL) along with hydantoin (26 mg, 0.3 mmol) and piperidine (26 μL, 0.3 mmol). The reaction was heated at 80° C. for 2 hours in the microwave then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 50% ethanol/water, and then 100% ethanol. The material was dried under vacuum overnight. The product, tert-butyl 3-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate, was recovered as a solid in 69% yield. LCMS (M+1=546)
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[CH:10]([C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1)=[CH2:11]>>[CH:12]1([CH2:10][CH2:11][CH:3]2[C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: C=CC1=CCCCC1
Product: CC1(C)CCC(=O)CC1CCC1CCCCC1
Yield: 75 %

Procedure:
Using 4,4-dimethylcyclohex-2-enone (53 μL, 0.40 mmol) as substrate and vinylcyclohexene (0.14 mL, 1 mmol, 2.5 eq) as reagent and following General Procedure 3 overnight gave the above product (72 mg, 0.30 mmol, 75%) as a colourless oil after purification by column chromatography (1:49 EtOAc/petrol). The product compound was characterised using 1H NMR and 13C NMR, IR and MS. The presence of an enantioexcess was determined by derivatization using the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[Cu](C#N)[C:11]#[N:12]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: Oc1ccc(Cl)cc1I
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1O
Yield: 79.7 %

Procedure:
4-Chloro-2-iodophenol (85 g, 0.33 mol) was dissolved in 150 ml of DMF, followed by the addition of 32.5 g (0.36 mol) of copper cyanide. The resulting mixture was refluxed for 2 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the thus-prepared solution was washed with water. Subsequent to elimination of an undissolved salt, the solution was concentrated under reduced pressure, whereby 40.4 g of 5-chloro-2-hydroxybenzonitrile were obtained (yield: 80%). Without purification, it was provided for use in the next step.
Reaction SMILES: C[Mg]Cl.[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14].[Cl-].[NH4+].[C:17](OCC)(=O)C>C1COCC1>[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:17])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: COc1cc(C=O)ccc1F
Reactant: CCOC(C)=O
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(C)O)ccc1F
Reaction time: 2 h

Procedure:
Methyl magnesium chloride (3 M tetrahydrofuran solution, 7.8 mL) was added to a solution of 4-fluoro-3-methoxybenzaldehyde (3 g) in THF (200 mL) while cooling with ice, and the reaction solution was stirred for 2 hours while cooling with ice. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system) to obtain 2.65 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)=[CH:18][CH:17]=1)[CH3:15]>C(OCC)(=O)C>[CH3:13][CH:14]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)=[CH:20][CH:21]=1)[CH3:15]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(C(C)C)cc2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(C(C)C)cc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-[4-(1-methylethyl)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.29 g, 42%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([OH:11])=O)=[O:7])=[CH:2]1.[NH2:12][CH:13]1[C:27](=[O:28])[N:15]2[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][S:21][CH2:22][CH3:23])[CH2:18][S:19][C@H:14]12>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([NH:12][CH:13]2[C:27](=[O:28])[N:15]3[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][S:21][CH2:22][CH3:23])[CH2:18][S:19][C@H:14]23)=[O:11])=[O:7])=[CH:2]1
Reactant: CCSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CS(=O)c1ccsc1
Product: CCSCC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)c3ccsc3)[C@H]2SC1

Procedure:
380 mg. of 3-thienylsulfinylacetic acid of the R form and 7-amino-3ethylthiomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 116 mg. of 7-(3-thienylsulfinylacetamido)-3-ethylthiomethyl-3-cephem-4-carboxylic acid of the R form were obtained.