Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][O:42][CH:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][O:42][CH:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: CCC(CC)OCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CCC(CC)OCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 47.4 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 0.70 g (1.01 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(1-ethylpropoxymethyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 65-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 0.27 g of the title compound was obtained as a white solid. (Yield: 476)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7](C)=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:12]C1C(C#N)=NC=CC=1C.CC1C(C)=CN=C(C#N)C=1.C(C1C=C(Cl)C=CN=1)(=O)C>>[C:1]([C:4]1[C:9]([CH3:12])=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(C)cn1
Reactant: Cc1ccnc(C#N)c1C
Agent: CC(=O)c1cc(Cl)ccn1
Agent: Cc1cnc(C#N)cc1C
Product: CC(=O)c1nccc(C)c1C

Procedure:
The title compound was prepared along with 2-acetyl-4,5-dimethylpyridine from 3,4-dimethylpyridine-2-carbonitrile including 4,5-dimethylpyridine-2-carbonitrile in the ratio of 5.5 to 1 according to the procedure for preparing 2-acetyl-4-chloropyridine described in Example 33.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[S:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([NH:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[S:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:17])[CH3:16]
Reactant: CSc1c(N)cnc2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CSc1c(NC(C)=O)cnc2ccccc12
Yield: 90 %

Procedure:
22.67 g (0.1 mole) of 3-amino-4-methylthio-quinoline-hydrochloride [or 19.02 g (0.1 mole) of the corresponding base] are dissolved in 125 ml of pyridine, whereupon 10.7 g (0.105 mole) of acetic anhydride are added at 10°-15° C. When the yellow colour of the solution has disappeared, the reaction mixture is poured into 1000 ml of water. The precipitated white crystals are filtered. Thus 20.9 g of 3-acetylamino-4-methylthio-quinoline are obtained, yield 90%, m.p.: 137°-138° C. (after crystallization from ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(C(F)(F)F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3cc(F)cc(C(F)(F)F)c3)C2)o[nH]1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
Trans-methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.255 g, 0.63 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 5 mL, 71.37 mmol) and stirred at room temperature for 1 week. The solvents were evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (172 mg, 79%). 1H NMR (600 MHz, dmso) δ 1.43-1.51 (m, 1H), 1.62-1.80 (m, 3H), 2.51-2.58 (m, 1H), 2.71-2.82 (m, 3H), 2.86-2.94 (m, 1H), 3.07-3.14 (m, 1H), 5.72 (s, 1H), 7.37-7.46 (m, 3H). HRMS Calculated for [C16H16F4N2O2+H]+: 345.1226. Found: 345.1241
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[N:4][NH:5][C:6]=1[CH3:7].[H-].[Na+].I[CH:17]([CH3:19])[CH3:18].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[N:4][N:5]([CH:17]([CH3:19])[CH3:18])[C:6]=1[CH3:7]
Reactant: Cc1[nH]nc(-c2ccc(Cl)s2)c1Br
Reactant: CC(C)I
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1c(Br)c(-c2ccc(Cl)s2)nn1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
4-Bromo-3-(5-chloro-2-thienyl)-5-methyl-1H-pyrazole (36.0 mmol) was dissolved in 30 mL dry N,N-dimethylformamide and cooled to 0° C. under nitrogen atmosphere. Sodium hydride (37.8 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. After stirring for 30 min, 2-iodopropane (43.2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was poured into saturated aqueous ammonium chloride solution and extracted with diethyl ether, dried over MgSO4, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane:dichloromethane 50:50) to afford 10.0 g 4-bromo-3-(5-chloro-2-thienyl)-1-isopropyl-5-methyl-1H-pyrazole (87% yield)
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]([CH2:19][OH:20])=[CH:12]3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]([CH:19]=[O:20])=[CH:12]3)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1c(CO)cc2cc(NC(=O)c3ccc(Br)cc3)ccc21
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cn1c(C=O)cc2cc(NC(=O)c3ccc(Br)cc3)ccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 92.2 %

Procedure:
To a solution of 4-bromo-N-[2-(hydroxymethyl)-1-methyl-1H-indol-5-yl]benzamide (13.63 g) obtained in Example 20 in DMSO (136 mL) were added triethylamine (21.1 mL) and pyridine-sulfur trioxide complex (24.16 g), and the mixture was stirred at room temperature for 22 hr. The reaction mixture was poured into ice water (400 mL), and the precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (12.49 g, yield 92%) as a pale-brown solid. The solid was used without purification for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5]>CO.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:2]([F:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(CNC(=O)c1cc([N+](=O)[O-])ccc1F)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)c(C(=O)NCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a stirred solution of benzyl 2-(2-fluoro-5-nitrobenzamido)acetate (120 mg) in methanol (10 mL) was added Pd/C (100 mg) at rt and stirred under the atmosphere of H2 gas at rt for 30 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale brown color solid (50 mg, 65%), mp 252-254° C. 1H NMR (400 MHz, DMSO-d6): δ 7.71-7.73 (1H, m), 7.00-7.02 (1H, m), 6.94 (1H, t, J=10.0 Hz), 6.65-6.67 (1H, m), 5.15 (2H, br s), 3.64 (2H, br s); LC-MS (negative ion mode): m/z 211 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Cl)cnc1CCCCN
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Product: Cc1ccc(Cc2cnc(NCCCCc3ncc(Cl)cc3C)[nH]c2=O)cn1
Yield: 28.3 %

Procedure:
Reaction of 5-chloro-2-(4-aminobutyl)-3-methyl-pyridine [from Example 5(a)] (1.0 g) with 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.23 g) under conditions analogous to those described in Example 1(f) gave 2-[4-(5-chloro-3-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.53 g) m.p. 140°-141° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[OH-].[Na+]>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CC2=CCCCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N[C@H]1CCN(CC2=CCCCC2)C1
Yield: 95.6 %

Procedure:
A mixture of tert-butyl N-[(3S)-1-(cyclohex-1-en-1-ylmethyl)pyrrolidin-3-yl]carbamate obtained in Example 9a (1.3 g, 4.64 mmol) and ethanol (9.2 ml) was stirred under ice-cooling, a 5 N aqueous hydrochloric acid solution (9.28 ml, 46.4 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours and 30 minutes. The reaction mixture was stirred under ice-cooling, a 5 N aqueous sodium hydroxide solution (9.28 ml, 46.4 mmol) was added, and the solvent was distilled off. Ethanol was added to the residue, the precipitated solid was filtered off, and the solvent in the filtrate was distilled off. Ethanol was further added to the residue, the precipitated solid was filtered off, and the solvent in the filtrate was distilled off to give the title compound (0.8 g, yield 95.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31](=[O:46])[CH:32]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:29][O:30][C:31](=[O:46])[CH:32]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:14][CH:13]=2)=[CH:38][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N(C)C(=O)OC(C)(C)C)cc2)cc1
Reactant: COCCOC(Cc1ccc(O)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)OC
Yield: 57 %

Procedure:
2-[4-{tert-Butoxycarbonyl(methyl)amino}phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.50 g; 1.26 mmole), 3-(4-hydroxyphenyl)-2-(2-methoxyethoxy)propanoic acid methyl ester(0.32 g; 1.26 mmole) and potassium carbonate (0.35 g; 2.64 mmole) were mixed in acetonitrile (20 ml) and refluxed over night. Water was added, acetonitrile evaporated and the residue extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated. Purification of the crude product with preparativ HPLC (Kromasil C8, 7 μm, 50×250 mm) using acetronitrile (50-70%) in ammonium acetate buffer (pH 7) as mobil phase gave 0.34 g (58% yield) of 3-[4-(2-(4-tert-butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2-methoxyethoxy)propanoic acid methyl ester
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1C2C(=CC=CC=2)C=C[CH:15]=1>Cl.O>[C:15]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])#[N:14]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: c1ccc2ncccc2c1
Agent: Cl
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Yield: 48 %

Procedure:
4-Chloro-3-nitrobenzoic acid (5.84 g, 29 mM), cuprous cyanide (5.2 g, 58 mM), cuprous chloride (0.96 g, 9.7 mM), and quinoline (6.9 ml, 58 mM) were heated under an argon atmosphere at 180′ for 3.5 hours. After cooling, the mixture was dissolved in concentrated hydrochloric acid (60 ml), diluted with water (80 ml), and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with aqueous NaH2PO4, brine, and dried over MgSO4. Crude product was purified by chromatography on silica, eluting with a mixture of dichloromethane/acetic acid (98:2), to give 4-cyano-3-nitrobenzoic acid (2.65 g, 48%). Nmr (DMSO-d6): δ 8.31 (d, 1H); 8.41 (dd, 1H); 8.68 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:31][CH3:32])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33])[CH3:2].[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45](Br)[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([C:18]2[CH:19]=[CH:20][C:15]([C:12]([CH2:13][CH3:14])([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([CH2:34][CH3:35])([OH:36])[CH2:1][CH3:2])=[C:7]([CH3:33])[CH:8]=3)[CH2:31][CH3:32])=[CH:16][C:17]=2[CH3:30])[CH:46]=1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)CC
Temperature: 140 °C
Yield: 72.2 %

Procedure:
A solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 28; 49.3 mg, 0.1 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 34.7 mg, 0.15 mmol), tetrakistriphenylphosphine palladium (16.2 mg, 0.014 mmol) and potassium phosphate (31.9 mg, 0.15 mmol) in N,N-dimethylformamide (0.27 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (37.1 mg, 71%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:27][C:26]2[N:22]([C:23]([C@H:28]3[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]3)=[N:24][N:25]=2)[C:21]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:20]=2[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:27][C:26]2[N:22]([C:23]([CH:28]3[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]3)=[N:24][N:25]=2)[C:21]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:20]=2[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](O)CC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCC(=O)CC2)C1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To a solution of oxalyl chloride (0.11 ml, 1.3 mmol) in dichloromethane (8 ml) was added dimethylsulfoxide (0.21 ml, 2.6 mmol) at −60° C. The mixture was stirred for 5 minutes at −50° C. A solution of cis/trans-8-chloro-1-(4-hydroxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (0.046 g, 1.1 mmol) in dichloromethane (3 ml) was added at −65° C. Stirring for 30 minutes was followed by addition of triethylamine (0.77 ml, 5.5 mmol). The cooling bath was removed 5 minutes after completed addition, and the reaction mixture was stirred for 1 h. The reaction mixture was washed with one portion of aqueous saturated ammonium chloride solution. The aqueous layer was extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.41 g, 90%) as white solid. MS m/e: 417 ([[M+H]]+)
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C:14]([C:15]2[N:16]=[C:17]([S:20][C:21]3[C@H:27]([CH3:28])[C@H:26]4[N:23]([C:24](=[O:36])[C@@H:25]4[C@H:29]([O:31][Si](C)(C)C)[CH3:30])[C:22]=3[C:37]([O:39]CC=C)=[O:38])[S:18][CH:19]=2)=[CH:13][CH2:12][N:11]1[CH3:43])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:31][C@@H:29]([C@H:25]1[C:24](=[O:36])[N:23]2[C@@H:26]1[C@@H:27]([CH3:28])[C:21]([S:20][C:17]1[S:18][CH:19]=[C:15]([C:14]3[C@H:10]([CH2:9][OH:8])[N:11]([CH3:43])[CH2:12][CH:13]=3)[N:16]=1)=[C:22]2[C:37]([OH:39])=[O:38])[CH3:30]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C)[C@H]3CO[Si](C)(C)C(C)(C)C)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(Sc3nc(C4=CCN(C)[C@H]4CO)cs3)[C@H](C)[C@H]12
Reaction time: 1 h

Procedure:
A solution of allyl (4R,5S,6S)-3-({4-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(106 mg, 0.16 mmol) in THF (2.7 ml) was cooled at 0° C. and to the solution were added acetic acid (0.073 ml, 1.28 mmol) and tetrabutylammonium fluoride in THF (1M, 0.64 ml, 0.64 mmol). The solution was stirred at the same temperature for 1 hour and then was allowed to stand in a refrigerator for 63 hours. To the reaction mixture was added water, and the solution was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography and then was subjected to de-allyl reaction in the same manner as Example 1.c) to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({4-[(2R)-2-hydroxymethyl-1-methyl-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Reaction SMILES: C([NH:4][S:5]([C:8]1[C:9]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:10]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])(=[O:7])=[O:6])(=O)C.Cl.[OH-].[Na+]>C(O)C>[CH2:18]([NH:17][C:10]1[CH:11]=[C:12]([CH:16]=[C:8]([S:5](=[O:7])(=[O:6])[NH2:4])[C:9]=1[O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:13]([OH:15])=[O:14])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccccc1

Procedure:
A mixture of 5-acetylsulphamyl-3-benzylamino-4-phenoxy-benzoic acid (1 g), ethanol (20 ml), and 4N hydrochloric acid (5ml) was refluxed for 2.5 hours. Then 2N sodium hydroxide (15 ml) was added, and the reaction mixture was heated on a steam bath for 30 minutes. After cooling, the pH was adjusted to 2.5 by addition of 4N hydrochloric acid, and the precipitated 3-benzylamino-4-phenoxy-5-sulphamyl-benzoic acid was isolated by filtation. After recrystallization from aqueous ethanol and drying, the compound was obtained with a melting point of 264°-265° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=1[Cl:33])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CCOC(C)=O>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:2]2[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=2)=[CH:28][C:27]=1[Cl:33])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: N#Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1c(Cl)ncnc1Nc1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
A solution of 4,6-dichloro-pyrimidine-5-carbonitrile Compound 2a (82 mg, 0.47 mmol), Et3N (0.13 mL, 0.94 mmol) and 4-benzyloxy-3-chloro-phenylamine Compound 2b (110 mg, 0.47 mmol) in THF (4.7 mL) was stirred at 25° C. for 3 hours. The reaction mixture was diluted with EtOAc (50 mL), washed with water (1×50 mL) and concentrated to afford 4-(4-benzyloxy-3-chloro-phenylamino)-6-chloro-pyrimidine-5-carbonitrile Compound 2c (175 mg, 100%) as an off-white solid; 1H NMR (300 MHz, CD3OD) δ 8.42 (s, 1H), 7.63 (s, 1H), 7.52-7.40 (m, 7H), 7.12 (m, 1H), 5.22 (s, 2H), 5.19 (s, 2); MS (ESI) m/z: 373 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:17][CH3:18])=[N:4][N:5]2[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([C:13](=[O:16])[CH2:14][CH3:15])[C:6]=12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:17][CH3:18])=[N:4][N:5]2[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([C:13](=[O:16])[CH:14]([CH3:15])[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:6]=12
Reactant: CCC(=O)c1ccc(OC)n2nc(CC)c(Cl)c12
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nn2c(OC)ccc(C(=O)C(C)CC(=O)OC(C)(C)C)c2c1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The compound of Example 145 (280 mg) was dissolved in tetrahydrofuran (12 mL) in an argon atmosphere. While the solution was kept at −78° C., 1 mol/L lithium bis(trimethylsilyl)amide/tetrahydrofuran solution (1.23 mL) was added and the mixture was stirred at −78° C. to room temperature for 30 min. t-butyl bromoacetate (181.6 μL) was then added at −78° C. and the mixture was stirred at room temperature for 7 hours. Subsequently, the reaction was terminated by adding a saturated aqueous solution of ammonium chloride and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=1:1) afforded the title compound as a green powder (237.1 mg).
Reaction SMILES: C(OCC)(=O)C.C(=O)([O-])O.[K+].[CH:12]#[C:13][CH:14]([OH:17])[CH2:15][CH3:16].[Br:18][C:19](Br)=[N:20][OH:21]>O>[Br:18][C:19]1[CH:12]=[C:13]([CH:14]([OH:17])[CH2:15][CH3:16])[O:21][N:20]=1
Reactant: ON=C(Br)Br
Reactant: C#CC(O)CC
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(O)c1cc(Br)no1

Procedure:
Added to 800 ml of ethyl acetate were 8 ml of water, 60.0 g (0.6 mol) of potassium hydrogencarbonate and 73.5 g (0.88 mol) of 1-pentyn-3-ol. Under stirring, 40.5 g (0.2 mol) of dibromoformaldoxime were added at room temperature over 3 hours. After the resultant mixture was stirred at room temperature for 16 hours, water was added and the reaction product was extracted with ethyl acetate. Subsequent to concentration, 3-bromo-5-(1-hydroxypropyl) isoxazole was obtained as oil. It was distilled to collect a fraction at 97°-102° C./2 mmHg. Analytical results of the fraction obtained: Yield: 18 g (74%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)=[CH:21][CH:20]=1)[CH3:17]
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Reactant: CCOc1ccc(I)cc1
Product: CCOc1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 1-ethoxy-4-iodo-benzene. MS (ESI) 322.2 (M•)+.