Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:10]=3[O:20][C:7]=2[C:6]([O:21][CH3:22])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>O.CC(C)=O>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:9]2[C:8]3[C:7](=[C:6]([O:21][CH3:22])[CH:5]=[CH:4][C:3]=3[C:1]([OH:25])=[O:2])[O:20][C:10]=2[CH2:11]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C=O)c23)C1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)O)c23)C1
Yield: 41 %

Procedure:
Ethyl 5-formyl-8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (from step 6) (0.310 g, 1.02 mmol) was taken in acetone water mixture. To this was added sulphamic acid (0.148 g, 1.53 mmol) and sodium chlorite (0.157 g, 1.73 mmol) and stirred for half an hour. After removing acetone under diminished pressure and dilution with water, it yielded 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylic acid (41%) which was filtered out, washed with water and dried.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:37])[C:35]=1[F:36])[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:33]=[C:34]([F:37])[C:35]([F:36])=[C:28]([F:27])[CH:29]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1cc(F)c(F)c(F)c1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cc(F)c(F)c(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 67.2 %

Procedure:
A mixture of intermediate 59 (0.5 g, 1.36 mmol), 3,4,5-trifluorobenzylamine (0.66 g, 4.0 mmol) and MeOH (0.2 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and the mixture is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-50:50) gives 0.44 g of the product 83. 1H NMR (CDCl3) δ 7.59 (s, 1 H), 7.20-7.05 (m, 2 H), 7.05-6.90 (m, 8 H), 6.80-6.70 (m, 2 H), 5.45-5.30 (m, 2 H), 4.70-4.50 (m, 2 H), 1.16 (s, 9 H); MS: m/z 482 (M++1).
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Li])CCC.[CH3:12][C:13]1([CH3:25])[C:22]2[C:17](=[C:18]([CH:23]=[O:24])[CH:19]=[CH:20][CH:21]=2)[O:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1>[C:5]([CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[O:16][CH2:15][CH2:14][C:13]2([CH3:25])[CH3:12])[OH:24])#[CH:6]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCOc2c(C=O)cccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1cccc2c1OCCC2(C)C
Yield: 132.1 %

Procedure:
7.6 ml (54.0 mmol) of trimethylsilylacetylene and 50 ml of THF are introduced into a three-necked flask. A solution of 22 ml (54.0 mmol) of n-butyllithium (2.5M in hexane) is added dropwise at -78° C. under a stream of nitrogen and the mixture is allowed to return to room temperature. The reaction mixture is introduced dropwise into a cold (-78° C.) solution composed of 9.30 g (49.0 mmol) of 4,4-dimethylchroman-8-carbaldehyde and of 50 ml of THF. The reaction mixture is allowed to return to room temperature, poured onto an aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 14.00 g (100%) of the expected compound are obtained in the form of a yellow oil. 3.00 g (10.0 mmol) of this oil are mixed with 50 ml of THF, and 11.5 ml (12.6 mmol) of a tetrabutylammonium fluoride solution (1.1M in THF) are added dropwise. The reaction mixture is stirred at room temperature for one hour, is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 2.30 g (100%) of the expected compound are collected in the form of a colourless oil.
Reaction SMILES: C([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])=[CH:13][C:8]=2[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[C:38]#[N:39])=[CH:27][CH:26]=2)[CH2:6]1)CCC.[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+]>>[CH2:13]([C:6]1[N:7]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[C:38]3[NH:39][N:42]=[N:41][N:40]=3)=[CH:29][CH:30]=2)[C:8]2[CH:13]=[C:12]([NH:14][C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])[CH:11]=[CH:10][C:9]=2[N:5]=1)[CH2:8][CH2:9][CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCN1CN(Cc2ccc(-c3cc(Cl)ccc3C#N)cc2)c2cc(NC(=O)NC3CCCCC3)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCCc1nc2ccc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2cc(Cl)ccc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 59 from 4'-[(3-n-butyl-6-(N-cyclohexylaminocarbonylamino)-benzimidazol-1-yl)-methyl]-5-chloro-2-cyano-biphenyl and sodium azide/ammonium chloride.
Reaction SMILES: C(N(CC)CC)C.[ClH:8].Cl.[NH2:10][CH2:11][CH2:12][C:13]1[CH:45]=[CH:44][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]([CH2:32][CH:33]5[S:37][C:36](=[O:38])[NH:35][C:34]5=[O:39])=[CH:30][CH:29]=4)[N:23]([CH3:42])[C:22]=3[CH:43]=2)=[CH:15][CH:14]=1.[C:46]([C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:58]=1[OH:59])[C:53](O)=[O:54])([CH3:49])([CH3:48])[CH3:47].CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[ClH:8].[C:60]([C:57]1[CH:56]=[C:52]([CH:51]=[C:50]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:58]=1[OH:59])[C:53]([NH:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:41]=[CH:40][C:31]([CH2:32][CH:33]5[S:37][C:36](=[O:38])[NH:35][C:34]5=[O:39])=[CH:30][CH:29]=4)[N:23]([CH3:42])[C:22]=3[CH:43]=2)=[CH:44][CH:45]=1)=[O:54])([CH3:63])([CH3:62])[CH3:61]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNC(=O)c4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)cc3)cc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 42.4 %

Procedure:
A mixture of anhydrous triethylamine (0.106 g), 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), anhydrous N,N-dimethylformamide (10 ml), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.13 g) and 1-ethyl-3-[(3′-dimethylamino)propyl]carbodiimide hydrochloride (WSC.HCl, 0.13 g) was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by liquid chromatography on a silica gel column using ethyl acetate:n-hexane=4:1 as the eluant. To a solution of the glassy product in ethyl acetate (15 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was crystallized in acetone to afford the title compound (0.17 g, pale yellow powder, mp 164-168° C.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:1][C:2](=[O:3])[C:4]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=3[O:11]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(O)ccc1O2
Yield: 82.6 %

Procedure:
A solution of 2,5-dihydroxyacetophenone (15 g, 98 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g, 100 mmol) and pyrrolidine (21 mL, 260 mmol) in methanol (146 mL) was stirred at reflux for 23 h and concentrated under vacuum to produce a red oily crude material. The oily crude material was purified by ISCO (330 g column) chromatography using 27 to 80% ethyl acetate in hexane to afford the product of step 1 (27 g, 82%), mp 72-74° C. (ethyl acetate, ether and hexane), MS m/z=332 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH:5]=[N:6][OH:7].ClN1C(=O)CCC1=O.[OH:20][CH2:21][C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:28][C:22]([CH2:21][OH:20])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:7][N:6]=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: C=C(CO)C(=O)OCC
Reactant: ON=Cc1cc(Cl)cc(Cl)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CO)CC(c2cc(Cl)cc(Cl)c2)=NO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.00 g (15.8 mmol) of 3,5-dichlorobenzaldehyde oxime were stirred in 100 ml of DMF together with 2.21 g (16.6 mmol) of N-chlorosuccinimide at RT for 4 h. 3.08 g (23.7 mmol) of ethyl 2-(hydroxymethyl)acrylate and 2.40 g (23.7 mmol) of triethylamine were then added, and the mixture was stirred at RT for 18 h. The reaction solution was concentrated under reduced pressure, and CH2Cl2 and water were then added. The aqueous phase was re-extracted once with CH2Cl2, and the combined organic phases were washed twice with water, dried over Na2SO4, filtered and concentrated. After chromatography on silica gel using n-heptane:ethyl acetate (3:1), the product was obtained. Yield: 3.10 g (62%)
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[O:8][C:5]1[N:4]=[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])[C:2]([F:1])=[CH:7][N:6]=1)[CH3:26]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ncc(F)c(N=CN(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (0.10, 0.54 mmol) in CH2Cl2 (2 mL) were added triethylamine (0.20 g, 2.0 mmol) and ethyl chloroformate (0.065 g, 0.60 mmol), and the mixture was agitated on an orbital shaker at room temperature overnight. The reaction was diluted with CH2Cl2 and the solution was washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether gradient) to yield 0.031 g (22%) of the title compound as a white solid: mp 124-126° C.; 1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.19 (d, J=2.2 Hz, 1H), 4.35 (q, J=7.14 Hz, 2H), 3.21 (s, 6H), 1.40 (t, J=7.14 Hz, 3H); HPLC-MS (ESI) m/z 258 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:41][C:39]([CH3:42])([CH3:40])[CH2:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:30])=[N:34]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (62 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 114.06 mg, 0.3 mmol) and iPr2NEt (0.1 mL, 0.6 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (23.1 mg, 20.8%) as an off-white powder. HRMS (ES+) m/z Calcd for C30H33Cl2F2N5O2S+H [(M+H)+]: 604.2052. found: 604.2052.
Reaction SMILES: Cl.[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:26]1[CH:31]=[N:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>ClCCl>[N:30]1[CH:31]=[CH:26][CH:27]=[C:28]([NH:32][C:33]([N:11]2[CH2:12][CH:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:4]=3)[CH2:10]2)=[O:34])[CH:29]=1
Reactant: O=C=Nc1cccnc1
Reactant: c1ccc(-c2ccc(OC3CNC3)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CC(Oc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
3-(Biphenyl-4-yloxy)azetidine hydrochloride (3 g, 11.47 mmol) was suspended in dichloromethane (45 mL) under a nitrogen atmosphere, treated with triethylamine (4.0 mL, 28.68 mmol) and stirred for 10 minutes at room temperature. The mixture was cooled to 0° C. and treated portionwise with pyridine-3-isocyanate (1.15 g, 9.56 mmol). Stirred at 0° C. for 10 minutes, then at rt for 16 hours. The solution was diluted with further dichloromethane (200 mL), washed with H2O (2×100 mL), followed by brine (50 mL), dried (over MgSO4), and solvent evaporated in vacuo to yield an off-white solid. The solid was triturated with diethyl ether, then stirred for 3 days with MP-isocyanate resin in a dichloromethane/methanol/acetonitrile mixture. The mixture was filtered and reduced to dryness in vacuo. The resulting solid was triturated successively with diethyl ether, then acetonitrile and filtered to give the urea (1.2 g, 36%) as a white solid; Rf 0.10 (5% MeOH-DCM); LCMS retention time 2.08 minutes, m/z 346.2 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ 8.97 (s, 1H), 8.75 (d, 1H, J=2.3 Hz), 8.21 (d, 1H, J=4.7 Hz), 8.05-8.01 (m, 1H), 7.65-7.60 (m, 4H), 7.44 (t, 2H, J=7.9 Hz), 7.39 (dd, 1H, J=8.3 and 4.7 Hz), 7.32 (t, 1H, J=7.3 Hz), 6.96 (d, 2H, J=8.8 Hz), 5.14-5.08 (m, 1H), 4.49 (dd, 2H, J=9.5 and 6.5 Hz) and 3.97 (dd, 2H, J=9.5 and 3.8 Hz); 13C nmr (100 MHz; DMSO-d6) 156.2 (C), 155.9 (C), 141.4 (CH), 139.6 (C), 138.9 (CH), 137.3 (C), 133.4 (C), 128.9 (CH), 128.1 (CH), 126.9 (CH), 126.8 (CH), 126.3 (CH), 123.9 (CH), 115.1 (CH), 65.6 (CH) and 56.4 (CH2).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])=[O:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])=[O:28]
Reactant: COc1ccccc1C(=O)CN
Reactant: COC(=O)CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(=O)NCC(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.2 %

Procedure:
Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.57 g, 18.62 mmol), 4-(dimethylamino)pryidine (463.8 mg, 3.79 mmol) and adipic acid monomethyl ester (2.97 g, 18.55 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(2-methoxy-phenyl)-ethanone hydrochloride (3.74 g, 18.55 mmol) and triethylamine (3.75 g, 37.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 22 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 NHCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter the drying agent and concentrate in vacuo to afford 4.57 g of the titled product (80%): mass spectrum: m/z 308.1 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[C:17]([CH2:18][OH:19])[CH:20]=[CH:21][CH:22]=2)[N:4]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1cccc(CO)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (22.3 g), 3-hydroxybenzyl alcohol (10.0 g), potassium carbonate (11.14 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 4 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:1, v/v) to give (3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol as colorless crystals (12.75 g, yield 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[CH:4]=1.[N+:11]([O-])([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[CH3:1][S:2][C:3]1[S:7][C:6]2[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[S:10][C:5]=2[CH:4]=1
Reactant: CSc1cc2sccc2s1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CSc1cc2sc([N+](=O)[O-])cc2s1
Temperature: -20 °C

Procedure:
1.0 g (5.4 mmol) of 2-methylthiothieno[3,2-b]thiophene is dissolved in 20 ml of acetic anhydride, and the solution is cooled to -20° C. At this temperature, a mixture of 0.6 ml of 70% nitric acid in 5 ml of acetic anhydride is added dropwise. The mixture is then allowed to warm to room temperature. For working up, the mixture is added to ice water end extracted several times with diethyl ether, and the organic phase is washed with saturated sodium hydrogen carbonate solution until neutral and dried with anhydrous magnesium sulfate. After removal of the solvent in a rotary evaporator under reduced pressure, the orange-yellow crude product obtained is purified by preparative column chromatography (SiO2 //2:1 cyclohexane/ethyl acetate, Rf : 0.62) and recrystallized from cyclohexane.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:4]=[C:5]([C:11]2[N:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:12]=2)[S:6][C:7]=1[N+:8]([O-:10])=[O:9].N(C)C.[OH2:28]>>[N+:8]([C:7]1[S:6][C:5]([C:11]2[N:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:12]=2)=[CH:4][C:3]=1[CH:2]=[O:28])([O-:10])=[O:9]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc(C(Cl)Cl)c([N+](=O)[O-])s2)n1
Reactant: O
Agent: CNC
Product: C[Si](C)(C)CCOCn1cnc(-c2cc(C=O)c([N+](=O)[O-])s2)n1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-[4-(dichloromethyl)-5-nitro-2-thienyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (1.00 g, 2.44 mmol) and Me2NH (40% wt, 15.00 mL, 118 mmol) was stirred at 60° C. for 15 min. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered, and evaporated. Purification of the crude residue by flash chromatography (0-50% EtOAc/hexanes) provided the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[N:18]([C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[C:19]=[O:20]>O1CCCC1>[F:28][C:27]([F:29])([F:30])[C:25]1[CH:26]=[C:21]([NH:18][C:19]([N:1]2[CH2:4][CH:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:2]2)=[O:20])[CH:22]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CNC2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of the compound prepared in Example 2 (986 mg) in tetrahydrofuran (12 mL) was dropwise added 1-isocyanato-3,5-bis(trifluoromethyl)benzene (0.85 mL), and the mixture was stirred for 30 minutes. The reaction solution was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the compound of the present invention (1.413 g) having the following physical data.
Reaction SMILES: [Cl-].[CH:2]1([CH2:5][NH2+:6][CH2:7][CH2:8]Cl)[CH2:4][CH2:3]1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N:18]=[C:19]=[S:20]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N:18]=[C:19]1[N:6]([CH2:5][CH:2]2[CH2:3][CH2:4]2)[CH2:7][CH2:8][S:20]1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: ClCC[NH2+]CC1CC1
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2CC2CC2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][S:17][CH2:18][C:19]1[C@H:24]([C:25]([OH:27])=[O:26])[N:23]2[C:28](=[O:40])[C@@H:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:22]2[S:21][CH:20]=1>O1CCOCC1.C(O)(=O)C>[C:1]1([CH:7]([O:27][C:25]([C@@H:24]2[N:23]3[C:28](=[O:40])[C@@H:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C@H:22]3[S:21][CH:20]=[C:19]2[CH2:18][S:17][CH3:16])=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSCC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CSCC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
A solution of 0.39 g of diphenyldiazomethane in 5 ml of petroleum ether is added dropwise over the course of half an hour to a solution of 0.5 g of 3-methylthiomethyl-7β -phenylacetylamino-2-cephem-4α-carboxylic acid in 20 ml of dioxane, while stirring. The solution is stirred for a further 15 hours at room temperature, treated with a few drops of glacial acetic acid and concentrated under reduced pressure. The residue is recrystallised from methyl acetate and gives pure 3-methylthiomethyl-7β-phenylacetylamino-2-cephem-4α-carboxylic acid diphenylmethyl ester which is dried for 16 hours at room temperature in a high vacuum. Melting point 175-177° C; thin layer chromatogram (silica gel): Rf = 0.77 (system: chloroform/methanol, 1:1); Rf = 0.17 (system: toluene/acetone, 2:1); [α]D20 + 342° ± 1° (c = 1.011 in dioxane); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): λmax = 255 mμ (ε = 7,800) and λmin = 244 mμ (ε = 7,200), infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.92μ, 5.61μ, 5.73μ, 5.92μ, 6.25μ and 6.67μ.