Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[CH2:32]([O:31][C:29]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])=[O:30])[CH3:33]
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(OC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-methoxybenzyl)phenyl β-D-glucopyranoside (0.075 g) in 2,4,6-trimethylpyridine (2 mL) was added ethyl chloroformate (0.04 mL) at room temperature. After the mixture was stirred at room temperature for 16 hours, a saturated aqueous solution of citric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give an amorphous form of 2-(4-methoxybenzyl)phenyl 6-O-ethoxycarbonyl-β-D-glucopyranoside (0.032 g). As a result of X-ray powder diffraction analysis, the amorphous substance shows no distinct peak. 1H-NMR (CD3OD) δ ppm: 1.23 (3H, t, J=7.1 Hz), 3.30-3.65 (4H, m), 3.74 (3H, s), 3.93 (1H, d, J=15.1 Hz), 4.02 (1H, d, J=15.1 Hz), 4.05-4.20 (2H, m), 4.29 (1H, dd, J=6.4,11.7 Hz), 4.45 (1H, dd, J=2.2, 11.7 Hz), 4.89 (1H, d, J=7.4 Hz), 6.75-6.85(2H, m), 6.85-7.05 (2H, m), 7.05-7.2 (4H, m)
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:10]2)[N:3]=1.[CH3:24][O-:25].[Na+].CO>COCCOC>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:9]([C:4]2[N:3]=[C:2]([O:25][CH3:24])[C:7]([F:8])=[CH:6][N:5]=2)[CH2:10]1
Reactant: C[O-]
Reactant: Fc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1nc(N2CCC(NCc3ccc(Cl)cc3Cl)C2)ncc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Dissolve (S)-[1-(4-chloro-5-fluoropyrimidin-2-yl)-pyrrolidin-3-yl]-(2,4-dichlorobenzyl)-amine (318 mg, 0.84 mmol) in dry 1,2-dimethoxyethane (20 mL) and add dropwise sodium methoxide in methanol (25% w/v, 1.9 mL, 8.46 mmol). Stir at 70° C. overnight. Add aqueous 2 N hydrochloric acid to a pH of about 6-7 and extract with 30:70 isopropanol:chloroform. Combine the organic layers, wash with saturated aqueous sodium chloride, dry (magnesium sulphate), filter, and concentrate to give a residue. Chromatograph the residue on silica gel to give the title compound (130 mg, 41%). Dissolve the title compound in methanol and add 1 M hydrogen chloride in diethyl ether (350 μL, 0.35 mmol), triturate, and concentrate to give the hydrochloride salt of the title compound. 1H NMR (400 MHz, MeOH-d4) δ 7.96 (1H, s), 7.65-7.76 (2H, m), 7.51 (1H, dd, J=8.2, 1.6 Hz), 4.45-4.56 (2H, m), 4.17 (2H, d, J=6.4 Hz), 3.99-4.10 (2H, m), 3.85-3.95 (4H, m), 2.61 (1H, d, J=6.4 Hz), 2.39 (1H, d, J=6.1 Hz); MS (ES): m/z=371 [M+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:38](=[O:50])([O:46][CH:47](I)[CH3:48])[O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.Cl>CN(C)C(=O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH2:48][CH2:47][O:46][C:38]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:50])=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Reactant: CC(I)OC(=O)OC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)OCCOC(=O)OC4CCCCC4)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
To a solution of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (300 mg) in N,N-dimethylacetamide (6 ml) was added potassium carbonate (81.8 mg) under ice-cooling. After stirring at room temperature for 30 minutes, cyclohexyl 1-iodoethyl carbonate (371.47 mg) was added thereto under ice-cooling. The mixture was stirred at the same temperature for 30 minutes, poured into a mixture of water and ethyl acetate and adjusted to pH 5 with 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to give (cyclohexyloxycarbonyloxy)ethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (15.8 mg).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:33])([F:32])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1.O.CO>C1COCC1>[F:33][C:5]([F:4])([F:32])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1
Reactant: O=C([O-])COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Lithium hydroxide monohydrate (0.622 g, 14.81 mmol) was added to 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (1.29 g, 2.96 mmol) in a mixture of THF (20 mL), water (10 mL) and MeOH (5 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The solvents were evaporated then the residues were suspended in water and acidified to pH 4 with 1M citric acid. The resulting precipitate was collected by filtration, washed with water and dried to afford 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (1.020 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[OH:14][C@@H:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:25][CH2:24][C:23]3([CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[C:22]2=[O:31])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([N:27]2[CH2:28][CH2:29][CH2:30][C:23]3([C:22](=[O:31])[N:21]([C@H:18]4[CH2:17][CH2:16][C@@H:15]([OH:14])[CH2:20][CH2:19]4)[CH2:25][CH2:24]3)[CH2:26]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCCNC2
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCCC2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Reaction time: 1 h

Procedure:
A solution of 3-chloro-2-methylbenzenesulfonyl chloride (0.050 g, 0.22 mmol) in CH2Cl2 (110 mL) was slowly added to a mixture of 2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (0.060 g, 0.2 mmol) and DIPEA (0.10 mL, 0.6 mmol) in CH2Cl2 (110 mL) at 0° C. and the reaction was stirred for 1 h. The mixture was diluted with ethyl acetate and then washed with diluted HCl, water and brine, dried and concentrated. The product was purified by CombiFlash eluted with CH2Cl2/EtOAc. LC-MS: 441.2/443.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.[S:23](=O)(=[O:26])([OH:25])[OH:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:13]=[C:12]([S:23]([OH:26])(=[O:25])=[O:24])[S:11][CH:10]=2)=[O:8])=[CH:14][CH:15]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C(=O)c2ccsc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2csc(S(=O)(=O)O)c2)cc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
9.7 g (0.05 mol) of product from Step A was dissolved in 75 ml CH2Cl2 and cooled to -10° C. Then, 15.3 g (0.15 mol) acetic anhydride was added dropwise followed by the dropwise addition of 5.9 g (0.06 mol) concentrated sulfuric acid. The resulting mixture was stirred at room temperature overnight.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[N:22][C:17]2=[N:16][CH:15]=1)CCC>>[CH3:8][C:4]1[N:3]=[C:2]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[N:22][C:17]3=[N:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Cc1cccc(Br)n1
Product: Cc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 36.5 %

Procedure:
2-Bromo-6-methylpyridine (367 mg, 2.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-(6-methylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (142 mg) as a white solid: δH (400 MHz, DMSO) 2.62 (3H, s), 7.26 (1H, d, J 7.4), 7.70 (1H, d, J 7.4), 7.86 (1H, t, J 7.8), 7.94 (1H, s), 8.83 (1H, s), 10.55 (1H, d, J 7.8); m/z (ES+) 279 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl[C:9]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.CO.N>ClCCl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:9]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1cc(Cl)nc2ccccc12
Reactant: NCCCCCN
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NCCCCCN)nc2ccccc12

Procedure:
The title compound was prepared by an analogous procedure to that described in example 1a from 1,5-diaminopentane (5 g, 49 mmol) and 2-chloro-4-methoxyquinoline (0.93 g, 4.8 mmol) to yield, after chromatography over silica gel eluting with an increasing concentration of 9:1 methanol/ammonia in dichloromethane, a cream coloured solid (30%). δH (CDCl3) 1.0-1.8 (8H, envelop), 2.72 (2H, t), 3.4-3.5 (2H, m), 3.97 (3H, s), 4.6-4.79 (1H, m), 5.94 (1H, m), 7.18 (1H, t), 7.51 (1H, t), 7.60 (1H, d), 7.96 (1H, d). MS (ES+) 260 (90%) MH+.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([O:13]CC)=[O:12])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.O1CCOCC1.[OH-].[Li+].Cl>O>[C:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([OH:13])=[O:12])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C)n(C(C)(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc(C(=O)O)nn1C(C)(C)C
Temperature: 40 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylate (0.60 g, 2.85 mmol) in a mix of ethanol:water:dioxane (1:1:1, 9 mL) was added lithium hydroxide (0.48 mg, 11.4 mmol). The mixture was stirred at 40° C. for 5 hours. The solution was checked by LC-MS and diluted with water (10 mL) and the pH adjusted to 2 with 1N HCl. The solution was extracted with EtOAc (2×10 mL) and the combined organic phases washed with brine (20 mL), dried (NaSO4), and concentrated in vacuo to obtain 1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylic acid (0.50 g, 96% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.4 (s, 1H), 5.47 (s, 1H), 2.42 (s, 3H), 1.56 (s, 9H); MS (ESI) m/z: 183.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:14][C:13]3=[CH:15][S:16][CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]([N:11]2[C:12]3=[CH:17][S:16][CH:15]=[C:13]3[N:14]=[C:10]2[S:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:20])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(CSc2nc3cscc3[nH]2)nc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(CSc2nc3cscc3n2C(=O)Oc2ccc([N+](=O)[O-])cc2)nc1

Procedure:
The title compound was prepared in analogy to Example 17 from 2-(5-methyl-2-picolylmercapto)-1H-thieno[3,4-d]imidazole and p-nitrophenyl chloroformate. After working up and chromatography on silica gel using toluene/ethyl acetate (1:1), the appropriate fractions were crystallized from ethyl acetate, and the title compound was obtained. Melting point 165°-168° C.
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:16]([CH2:15][C:14]2[CH:30]=[CH:31][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=2)[C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:26])([CH3:27])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)CCC2CCCC2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure B using 6-[(4-dec-1-ynylbenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropanoyl chloride (purification by flash chromatography on SiO2 EtOAc/c-Hex 20/80) as a colorless oil (97%). 1H NMR (CDCl3) δ: 7.68 (d, J=2.3 Hz, 1H), 7.30 (d, J=7.7 Hz, 2H), 7.09 (d, J=7.7 Hz, 2H), 7.06-6.99 (m, 1H), 6.90 (d, J=8.7 Hz, 1H), 4.85 (s, 2H), 2.39 (t, J=7.2 Hz, 2H), 2.13-2.01 (m, 2H), 1.75 (s, 6H), 1.70-1.20 (m, 21H), 1.04-0.83 (m, 5H). HPLC, Rt: 6.6 min (purity: 99.7%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.Br[C:25]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:33]2[C:28](=[CH:29][C:30]([Cl:35])=[C:31]([Cl:34])[CH:32]=2)[NH:27][C:26]1=[O:36]>C(Cl)(Cl)Cl.C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:25]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[C:33]3[C:28](=[CH:29][C:30]([Cl:35])=[C:31]([Cl:34])[CH:32]=3)[NH:27][C:26]2=[O:36])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2C1(Br)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CCNC2(c3ccccc3Cl)C(=O)Nc3cc(Cl)c(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A solution of 1.05 g of 4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperidine and 0.46 g of triethylamine in 10 ml of chloroform is added at RT to a solution of 1.8 g of the compound obtained in step C in 50 ml of THF and the mixture is stirred for 2 hours at RT. It is concentrated under vacuum, the residue is taken up with a 5% solution of potassium carbonate and extracted with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl, boiling THF is added to the organic phase, the latter is dried over sodium sulfate and the solvents are partially evaporated off. The crystalline product formed is filtered off to give 1.94 g of the expected product. M.p.=248°-249° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([NH:13][C:14](=[O:23])[C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(N(CC)CC)C.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[O:8]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH:10][C:11]([NH:13][C:14](=[O:23])[C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])=[O:12])=[CH:5][C:6]=1[Cl:9])[Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(O)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1c(Cl)cc(NC(=O)NC(=O)c2c(F)cccc2F)cc1Cl
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
Into a homogeneous solution of 1-(3,5-dichloro-4-hydroxyphenyl)-3-(2,6-difluorobenzoyl)urea (3.13 grams, 8.66 mmol) in dimethylformamide (25 milliliters) was added triethylamine (1.75 grams, 17.3 mmol), and the resulting mixture was stirred for 5 minutes. Tertiary-butyldimethylsilyl chloride (3.92 grams, 26.0 mmol) was then added, and a thick precipitate formed immediately. This heterogeneous mixture was then diluted with ethyl acetate (200 milliliters), washed with saturated sodium bicarbonate (twice with 150 milliliters) and then washed with a brine solution (150 milliliters). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid. The solid was washed with cold ether and vacuum dried to afford 1-(4-tert-butyldimethylsiloxy-3,5-dichlorophenyl)-3-(2,6-difluorobenzoyl)urea (2.71 grams, 5.70 mmol) having a melting point of 184° C.-186° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[N:9][C:8]=1[C:12]([Cl:14])=[O:13])=[O:5])[CH3:2].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:17]=1>O1CCOCC1>[ClH:14].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([N:30]2[CH2:35][CH2:34][N:33]([C:12]([C:8]3[N:9]=[N:10][S:11][C:7]=3[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:13])[CH2:32][CH2:31]2)[N:17]=1
Reactant: CCOC(=O)Nc1snnc1C(=O)Cl
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: C1COCCO1
Product: CCOC(=O)Nc1snnc1C(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Product: Cl
Reaction time: 18 h

Procedure:
A solution of 5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carbonyl chloride (5.17 g., 0.022 mole) in dioxane (35 ml. was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (6.35 g., 0.022 mole) in dioxane (190 ml.). The resultant mixture was stirred at reflux for 1 hour, and then at 23° C. for 18 hours. Filtration gave the title compound; m.p. 281°-284° C. (dec.) after crystallization from methanol.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.[CH:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[OH:48])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: O=Cc1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 1 g, 2.0 mmol) in anhydrous THF (10 mL), s-butyllithium (4.5 ml, 1.4M in cyclohexane, 6.3 mmol) was added and stirred for 2 h at −78° C. Benzaldehyde (685 mg, 0.0064 mmol) in THF (5 mL) was added dropwise and the solution was stirred for additional 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried (Na2SO4), and solvent was removed. The residue was purified over a silica gel chromatography column using ethyl acetate-pet. ether gradient, providing the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:26](OC)([N:28](C)C)[CH3:27].[NH2:33]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:33][NH:28][C:26]([CH3:27])=[C:10]2[N:9]=1
Reactant: COc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Product: COc1cc2c(cc1C#N)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVb) was prepared by reacting 0.0016 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-thione (IIb) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=364.
Reaction SMILES: CCOCC.Br[CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH2:24]([NH:26][C:27](=[O:30])[CH2:28][SH:29])[CH3:25]>C(Cl)Cl>[CH2:24]([NH:26][C:27](=[O:30])[CH2:28][S:29][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:25]
Reactant: CCNC(=O)CS
Reactant: CCCCCCCCC#CCC#CCC#CCBr
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCC#CCC#CCC#CCSCC(=O)NCC
Reaction time: 1 h

Procedure:
The ether solution of 1-bromo-2,5,8-heptadecatriyne, prepared according to the above operating procedure, is added dropwise under an inert atmosphere to a stirred solution, at 0° C., of sodium thiolate of N-ethylthioglycolamide prepared according to operating procedure b) above. The mixture obtained is stirred for 1 hour after the addition is finished. The solvents are then removed by evaporation under vacuum. The product obtained is dissolved in 100 cm3 of methylene chloride. The organic phase is washed with water, dried over magnesium sulphate, concentrated and then deposited onto a silica gel column. The expected amide is eluted with a mixture of methylene chloride and ethyl acetate (97-3). After evaporation of the eluent, 6 g of product are isolated and are recrystallized from isopropyl ether. 4 g of N-ethyl 3-thia-5,8,11-eicosatriynamide are obtained in the form of beige crystals having a melting point of 59° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[O:16][C:15]([C:17]3([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:26][OH:27].C(N(CC)CC)C>O1CCCC1.CO>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[O:16][C:15]([C:17]3([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14][C:13]=2[CH3:24])[CH:7]=[CH:6][C:3]=1[C:4]([NH:26][OH:27])=[NH:5]
Reactant: NO
Reactant: Cc1nc(C2(C)CCCCC2)oc1COc1ccc(C#N)c(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(C2(C)CCCCC2)oc1COc1ccc(C(=N)NO)c(Cl)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
1.24 g 2-Chloro-4-[4-methyl-2-(1-methyl-cyclohexyl)-oxazol-5-ylmethoxy]-benzonitrile were dissolved in a mixture of 20 ml tetrahydrofuran and 20 ml methanol. 5.0 g hydroxylamine hydrochloride were added followed by the addition of 10.0 ml triethylamine. The reaction mixture was stirred at 65° C. overnight. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 1.39 g 2-Chloro-N-hydroxy-4-[4-methyl-2-(1-methyl-cyclohexyl)-oxazol-5-ylmethoxy]-benzamidine as an oil.