Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20]>CN(C=O)C>[CH2:18]([NH:21][C:4]1[C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:19]=[CH2:20]
Reactant: Clc1nc(Cl)c2scc(-c3ccccc3)c2n1
Reactant: C=CCN
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(-c3ccccc3)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.4 %

Procedure:
In 1 ml of DMF, 176 mg (0.63 mmol) of 2,4-dichloro-7-phenylthieno[3,2-d]pyrimidine was dissolved, and then 79 mg (1.4 mmol) of allylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (30 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 168 mg (yield: 88.9%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1)[NH2:23]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2)cn1
Yield: 64 %

Procedure:
6-Chloro-N-[4-(trifluoromethyl)phenyl]nicotinamide (0.49 g) and hydrazine monohydrate (4 mL) were suspended in ethanol (8 mL), and the suspension was heated to reflux for 15 hours. The reaction solution was concentrated under reduced pressure, and the obtained solid was then collected by filtration and washed with ethyl acetate. The solid was dried under reduced pressure to obtain the title compound (0.31 g) as a white solid (yield: 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[C:14](Cl)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][NH2:21].[ClH:22].CO>CO.C(OCC)C>[ClH:18].[ClH:22].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:21][CH3:20])[N:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(Cl)c2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Cl)n1
Yield: 41 %

Procedure:
0.11 g (0.00035 mol) of 4-amino-N-(2,6-dichloro-pyridin-4-yl)-benzenesulfonamide was stirred in 25 ml of liquid methylamine in an autoclave at 130° C. for 72 hours. After removal of the methylamine the residue was taken up in 5 ml of dichloro-methane/methanol 1:1, filtered and, after removal of the solvent, chromatographed on silica gel with hexane/ethyl acetate 3:1, 2:1 and finally 1:1. The product, obtained as a white, amorphous solid substance, was dissolved in 2 ml of methanol, treated with 2 ml of 2N HCl/methanol, diluted with 20 ml of diethyl ether and filtered off under suction. The material on the suction filter was washed well with diethyl ether and dried in a high vacuum. There was obtained 0.055 g (41%) of 4-amino-N-(2-chloro-6-methylamino-pyridin-4-yl)-benzenesulfonamide dihydrochloride (1:2) as white crystals; m.p.: >215° C. (dec.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39](O)=[O:40])(=[O:13])=[O:12].ON1C=CC=CC1=O.CCN=C=NCCCN(C)C.[NH2:61][CH2:62][C:63]1[NH:67][N:66]=[N:65][N:64]=1>C(Cl)Cl.CN(C=O)C>[NH:64]1[C:63]([CH2:62][NH:61][C:39]([C@@H:15]2[CH2:16][C@@H:17]([S:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18][N:14]2[S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])=[O:40])=[N:67][N:66]=[N:65]1
Reactant: O=C(O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: NCc1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: O=c1ccccn1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1nnn[nH]1)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A solution of 200 mg (0.34 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid and 42 mg (0.38 mmol) N-hydroxy-2-pyridone in 15 ml CH2Cl2 were treated at 0° C. with 72 mg (0.38 mmol) of EDCI. After 3.5h at RT, it was cooled (0° C.) and treated with 37 mg (0.38 mmol) of 5-aminomethyl-tetrazol. The reaction was stirred over night at RT, 2 ml DMF were added and after 4 h at RT the reaction was extracted with EtOAc/aqueous saturated NaHCO3. The organic phase was washed with aqueous 10% KHSO4, dried over Na2SO4 and purified by flash-chromatography on silicagel (CH2Cl2/MeOH 9:1) to give 100 mg (44%) of (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid (1H-tetrazol-5-ylmethyl)-amide, mp: 135-145 slow dec, MS: 661 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[N:9]2)=[CH:5][CH:4]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:46](=[O:47])[C:45]([C:48](O)=[O:49])=[CH:44][CH:43]=[N:42]2)=[CH:37][CH:36]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:48]([C:45]2[C:46](=[O:47])[N:41]([C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)[N:42]=[CH:43][CH:44]=2)=[O:49])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=3)[N:9]=[C:10]([C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(-c3nccn3C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(-c3nccn3C)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (143.2 mg, 0.322 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (377.3 mg, 1.61 mmol, prepared in Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (308.8 mg, 1.61 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (217.7 mg, 1.61 mmol), N-ethyl-N-isopropylpropan-2-amine (208.2 mg, 1.61 mmol) and CH2Cl2 (5 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (127 mg, 59.67%). LRMS (APCI pos): >99% purity, 254 nm, m/e 661 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[O:31]=[C:26]1[NH:27][C:28](=[O:30])[C:29](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:5][CH2:4][CH2:3][CH2:8][CH3:7])[C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=3)=[CH:5][CH:4]=2)[S:25]1
Reactant: O=Cc1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Reactant: O=C1CSC(=O)N1
Product: CCCCCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Yield: 180.6 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 320 mg (0.8 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)benzamide with 100 mg (0.8 mmol) of 2,4-thiazolidine dione, 350 mg (87%) of the expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][CH:32]=[CH:31]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCOc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCOc4ccc5[nH]ccc5c4)CC3)noc2c1
Yield: 123.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.6 g, 11.8 mmol), K2CO3 (1.6 g, 11.6 mmol), KI (200 mg), 5-(3-chloropropoxy)indole (2.2 g, 10.5 mmol) and CH3CN (100 ml) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed 2 times with H2O, 2 times with brine and after drying with MgSO4 the solvent was removed in vacuo to yield 5.1 g of a dark oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500, using 2 silica gel columns and 4% MeOH--CH2Cl2 as eluent) to afford 2.65 g (65%) of a beige solid. Recrystallization from ethanol gave 2.2 g (54%) of a beige powder, m.p.=118-121° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13].O>C(O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:13][CH3:12])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Solvent: CCO
Solvent: O
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 2,4-dibromo-1-nitro-benzene (2.0 g, 7.14 mmol) in ethanol (50 mL) was added a 40% aqueous solution of methylamine (50 mL). The reaction mixture was stirred at 80° C. in a closed vessel for 3 h, then cooled to 0° C. Water was added and the precipitate was filtered, washed with water, and dried in vacuo to give 1.26 g of (5-bromo-2-nitro-phenyl)-methyl-amine as an orange solid (76% yield): 1H NMR (CDCl3) δ 3.04 (s, 3H), 6.79 (dd, 1H), 7.03 (d, 1H), 8.05 (d, 1H), 8.0-8.1 (broad s, 1H); MS (m/z) 231, 233 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:39].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:39])=[O:26])[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: Cc1ccc(F)cc1C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(F)cc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 100 %

Procedure:
In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(hydroxycarbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione g, 0.19 mmol) prepared in example 55d was reacted with cyanuric fluoride (51 mg, 0.38 mmol) (Alfa) and pyridine (45 mg, 0.57 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 0.1 g, 100%).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.O.[NH2:14]N>C(O)C>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[CH:4]=[CH:3][NH:2][N:14]=1
Reactant: CN(C)C=CC(=O)c1cccs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-thienyl)prop-2-en-1-one (193 mmol) and hydrazine hydrate (396 mmol) in 50 mL ethanol was refluxed for 18 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized (dichloromethane/cyclohexane) to afford 26.0 g 3-(2-thienyl)-1H-pyrazole (90% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:14]=3[OH:24])[C:11]=2[CH3:12])=[O:6])[CH2:3][CH2:2]1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][F:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:14]=3[O:24][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][F:31])[C:11]=2[CH3:12])=[O:6])[CH2:3][CH2:2]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(O)c1
Reactant: FCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(OCCCCCF)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-5-methyl-1H-1,2,3-triazole-4-carboxamide (0.17 g) obtained in Example 141 in DMF (5 ml) were added 1-bromo-5-fluoropentane (0.11 g) and potassium carbonate (0.07 g), and the mixture was stirred at 50° C. overnight. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane (2:1). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate) to give the title compound as a pale-yellow amorphous substance (0.16 g, 77%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)[CH3:17]>CC#N>[C:1]([C:5]1[CH:10]=[C:9]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH2:16][CH3:17])[CH:24]=2)[C:8]([NH2:12])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Solvent: CC#N
Product: CCOc1cccc(-c2cc(C(C)(C)C)c(O)cc2N)c1

Procedure:
2-tert-Butyl-4-(3-ethoxyphenyl)-5-aminophenol (C-16) was synthesized following the general scheme above starting from 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) and 3-ethoxyphenyl boronic acid. HPLC ret. time 2.77 min, 10-99% CH3CN, 5 min run; ESI-MS 286.1 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([B:7]([OH:9])[OH:8])=[CH:4][CH:3]=1.O[C:11]([C:14](O)([CH3:16])[CH3:15])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[S:6][C:5]([B:7]2[O:9][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1ccc(Cl)s1
Product: CC1(C)OB(c2ccc(Cl)s2)OC1(C)C
Yield: 50 %

Procedure:
The title compound (50%, oil) was prepared from 5-chlorothiophen-2-boronic acid and pinacol.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH3:13])=[N+:9]([O-])[CH:10]=1)=[N+:2]=[N-:3].[CH3:14][N:15](C)C(Cl)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[N:1]([CH2:4][C:5]1[C:10]([C:14]#[N:15])=[N:9][C:8]([CH2:12][CH3:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: CN(C)C(=O)Cl
Reactant: CCc1ccc(CN=[N+]=[N-])c[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1ccc(CN=[N+]=[N-])c(C#N)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 90.5 %

Procedure:
After dissolving 5-(azidomethyl)-2-ethyl-1-pyridiniumolate (2.16 g, 12.1 mmol) in acetonitrile (25 ml), 1.77 ml of trimethylsilylnitrile (13.3 mmol) and 1.23 ml of dimethylcarbamoyl chloride (13.3 mmol) were added under a nitrogen stream and the mixture was stirred at room temperature for 66 hours. Saturated aqueous sodium hydrogencarbonate was added for treatment and extraction was performed with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (2.05 g) as a colorless oil. (90.4% yield)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:13][C:10]1[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 57.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (260 mg, 1.2 mmol), 2-nitrobenzene-1-sulfonyl chloride (597 mg, 2.69 mmol), DMAP (cat) and pyridine (0.3 ml, 3.67 mmol) in DCM (5 ml) gave the title compound (275 mg, 56%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[S:10][CH:9]=1)[C:5]([OH:7])=O.[NH2:18][CH:19]1[C:30](=[O:31])[N:21]2[C:22]([C:27]([OH:29])=[O:28])=[C:23]([CH3:26])[CH2:24][S:25][C@H:20]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[S:10][CH:9]=1)[C:5]([NH:18][CH:19]1[C:30](=[O:31])[N:21]2[C:22]([C:27]([OH:29])=[O:28])=[C:23]([CH3:26])[CH2:24][S:25][C@H:20]12)=[O:7]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc2cc(Cl)ccc12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)c1csc2cc(Cl)ccc12
Yield: 7959.2 %

Procedure:
Following the general procedure of Example 36, 2.8 g (10.39 mM) of α-methoxyimino-α-(6-chloro-3-benzothienyl)acetic acid were converted to the acid chloride and reacted with 2.33 g (10.91 mM) of 7-amino-3-methyl-3-cephem-4-carboxylic acid to provide 385 g (80% yield) of 7-[α-methoxyimino-α-(6-chloro-3-benzothienyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. NMR (CDCl3): δ 2.02 and 2.21 (two s, 3H); δ 3.1-3.85 (m, 2H); δ 4.01 (s, 3H); δ 5.06 (d, 1H); δ 5.86 (dd, 1H); δ 7.2-7.8 (m, 4H); δ 8.3-8.7 (m, 2H).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1.IC>O1CCCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:1])[C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a solution of lithium diisopropylamide (2 mol/L, 22 mL, 44 mmol) in tetrahydrofuran (80 mL) was dropwise a solution of methyl 2-(4-bromophenyl)acetate (10 g, 44 mmol) in tetrahydrofuran (20 mL) at −78° C. The mixture solution was stirred for 0.5 hour at that temperature, then iodomethane (8 g, 56 mmol) was added. The mixture was stirred for 10 minutes at −78° C., then was removed from the cooling bath and stirred for 0.5 hour. The reaction was quenched with sat. ammonium chloride, then diluted with ethyl acetate, washed with water, The organic layer concentrated to dry, purified by column chromatography (silica-gel, petroleum:ethyl acetate=20:1) to give methyl 2-(4-bromophenyl)propanoate as a colorless oil (10 g, 91%). 1H NMR (300 MHz, CDCl3): δ 7.44 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 3.65-3.70 (m, 4H), 1.48 (d, J=6 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[C:11]2[CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](=[O:17])[CH2:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(O)(=O)C(C(C(O)=O)O)O.CCOCC.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37]>O1CCOCC1>[C:36]([NH:40][CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[C:11]2[CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](=[O:17])[CH2:16][C:10]=2[CH:9]=[CH:8][CH:7]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC1(C)CCc2c(cccc2OCC(O)CCl)CC1=O
Reactant: CC(C)(C)N
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)NCC(O)COc1cccc2c1CCC(C)(C)C(=O)C2

Procedure:
2,2 g crude 1-(3-chloro-2-hydroxypropoxy)-6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-6-one in 20 ml dioxane and 10 ml tert-butylamine are heated at 130° for 20 hours in an autoclave. The reaction mixture is divided between 10% (w/w) aqueous tartaric acid solution and ether. The aqueous phase is made alkaline and extracted with ether. Evaporation of the ether phase yields the title compound (M.pt of hydrogen maleate 186°-188° after crystallization from ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH:13]1([C:16]2[C:17]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:17]3[C:16]([CH:13]4[CH2:15][CH2:14]4)=[CH:21][C:20]([C:22]([F:25])([F:23])[F:24])=[CH:19][N:18]=3)[CH2:27][CH2:28]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Product: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 85.5 %

Procedure:
Using 4-bromo-2-fluorobenzoyl chloride (2.5 g) and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine hydrochloride (3.2 g) described in Preparation Example 89 and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (4.2 g) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:52])[CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[S:16][CH:17]=1)C>ClCCl>[CH3:8][O:10][C:11](=[O:52])[CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:40])([CH3:41])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[S:16][CH:17]=1
Reactant: CCOC(=O)Cc1csc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2nc(CC(=O)OC)cs2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Trifluoroacetic acid (0.15 mL) was added to a solution of {2-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-thiazol-4-yl}-acetic acid ethyl ester (Example 63-(1); 20.7 mg, 0.0318 mmol) in dichloromethane (0.75 mL) at room temperature, and the mixture was stirred at room temperature for one hour and 30 minutes. The solvent in the reaction solution was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (15.9 mg, 93%).