Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[S:14])=[CH:4][CH:3]=1.[C:15]([NH:18][C@@H:19]1[C@@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][OH:39])[O:32][C@H:20]1[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][C:23]=1[O:30][CH3:31])(=[O:17])[CH3:16].C([O-])(=O)C.[NH4+]>C(O)C>[C:15]([NH:18][C@@H:19]1[C@@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][OH:39])[O:32][C@H:20]1[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[C:11]2[S:10][C:9](=[S:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[C:12]2=[O:13])=[CH:24][C:23]=1[O:30][CH3:31])(=[O:17])[CH3:16]
Reactant: O=C1CSC(=S)N1c1ccc(O)cc1
Reactant: COc1cc(C=O)ccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(C=C2SC(=S)N(c3ccc(O)cc3)C2=O)ccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Yield: 82.9 %

Procedure:
3-(4-Hydroxyphenyl)-2-thioxothiazolidin-4-one (0.23 g, 1.0 mmol) was added to a stirred suspension of 4-formyl-2-methoxyphenyl 2-acetamido-2-deoxy-β-D-glucopyranoside (1b)(0.32 g, 0.9 mmol) in absolute ethanol (10 ml) containing ammonium acetate (0.08 g, 1.0 mmol) and the pale yellow heterogeneous reaction mixture boiled gently. After 5 h the mixture was cooled in ice and the yellow product was filtered off and washed well with methanol and acetone to give 5b (0.42 g, 74%), m.p. 234°-236° C., [α]D +2.5° (c 0.81, DMOS) Found: C, 53.62; H, 4.65; N, 4.73, C25H26N2O9S2 calc: C, 53.38; H, 4.63; N, 4.98).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]2[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Br:15][C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.O>[Br:15][C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:14][CH:12]([OH:13])[CH2:11][CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=[N+]([O-])c1cn(CCC2CO2)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cn(CCC(O)COc2ccc(Br)nc2)c(Cl)n1
Temperature: 83.5 °C
Reaction time: 28 h
Yield: 36.9 %

Procedure:
A mixture of epoxide 129 (see Example 2AA) (1.004 g, 4.61 mmol), 6-bromo-3-pyridinol (4.015 g, 23.1 mmol) and powdered K2CO3 (3.319 g, 24.0 mmol) in anhydrous 2-butanone (10 mL) under N2 was stirred at 82-85° C. for 28 h. The resulting cooled mixture was diluted with water (100 mL) and extracted with 25% EtOAc/CH2Cl2 (3×100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-40% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 40% EtOAc/petroleum ether gave 1-[(6-bromo-3-pyridinyl)oxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-butanol (137) (667 mg, 37%) as a cream solid: mp (MeOH/CH2Cl2/pentane) 112-114° C.; 1H NMR [(CD3)2SO] δ 8.56 (s, 1H), 8.12 (d, J=3.1 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.39 (dd, J=8.8, 3.2 Hz, 1H), 5.28 (br d, J=4.5 Hz, 1H), 4.24 (dd, J=14.0, 5.8 Hz, 1H), 4.18 (dd, J=14.2, 7.3 Hz, 1H), 3.99 (dd, J=10.0, 4.9 Hz, 1H), 3.96 (dd, J=10.0, 5.5 Hz, 1H), 3.82 (m, 1H), 2.06 (dtd, J=13.9, 7.7, 3.4 Hz, 1H), 1.90 (ddt, J=13.7, 9.2, 6.7 Hz, 1H); HRESIMS calcd for C12H13BrClN4O4 m/z [M+H]+ 394.9754, 392.9782, 390.9803. found 394.9753, 392.9777, 390.9797.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([O:12][CH3:13])[N:5]=1.[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]=[C:28]=[O:29])(=[O:26])=[O:25])(=[O:17])=[O:16]>C(Cl)Cl>[CH3:11][O:10][C:8]1[N:7]=[C:6]([O:12][CH3:13])[N:5]=[C:4]([N:3]([O:2][CH3:1])[C:28]([NH:27][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:15]([CH3:14])(=[O:17])=[O:16])(=[O:26])=[O:25])=[O:29])[N:9]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CONc1nc(OC)nc(OC)n1
Solvent: ClCCl
Product: COc1nc(OC)nc(N(OC)C(=O)NS(=O)(=O)c2ccccc2S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of N,4,6-trimethoxy-1,3,5-triazin-2-amine (0.01 mol) in dry methylene chloride (24 ml) is added 2-methylsulfonylbenzenesulfonyl isocyanate (0.014 mol). The mixture is stirred at ambient temperature for 24 hours. The solvent is then evaporated under reduced pressure. The residue is stirred in 1-chlorobutane (50 ml) for 5 hours. The solid is then filtered, washed with ether and dried to yield N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)(methoxy)aminocarbonyl]-2-(methylsulfonyl)benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F.Cl>CS(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: COc1ccc[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccn(-c2ccc([N+](=O)[O-])cc2Cl)c1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
15 g (120 mmol) of 3-methoxypyridone are dissolved in 120 ml of anhydrous dimethyl sulfoxide and admixed with 16.1 g (144 mmol) of potassium tert-butoxide with stirring. After 30 min, 21.0 g (120 mmol) of 3-chloro-4-fluoronitrobenzene are added and the mixture is heated to 80° C. After 16 h, the mixture is allowed to cool, admixed with 1N hydrochloric acid and extracted repeatedly with dichloromethane. The combined dichloromethane phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting residue is stirred with tert-butyl methyl ether and filtered. The solid is dried under reduced pressure. 22.8 g (60% of theory) of the desired compound are obtained.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:24][CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15]1.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:20]([O:19][C:17]([CH:16]1[CH2:22][CH2:23][CH2:24][N:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C1CCCNC1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1CCCN(c2ccc(C#N)c3ccccc23)C1
Temperature: 115 °C
Reaction time: 20 h
Yield: 68.3 %

Procedure:
1-Cyano-4-fluoronaphthalene(1.0 g, 5.84 mmol) and ethyl nipecotate (3.63 mL, 23.4 mmol) were dissolved in pyridine (5 mL) and stirred at 115° C. for 20 hours. After cooling to rt ethyl acetate (50 mL) was added and the solution washed with HCl (0.4 M, 2×30 mL). The combined aqueous layers were extracted with ethyl acetate (30 mL). The combined organic layers were washed with sat. sodium hydrogen carbonate (30 mL), brine (30 mL), dried and evaporated. The crude product was purified by silica gel column chromatography eluted with a stepwise gradient of 0-70% ethyl acetate in n-heptane to give the title compound (1.23 g, 68%) as a yellowish oil
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:13]2[C:14]([C:19]([OH:21])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=O)[N:4]=1.S(Cl)([Cl:24])=O>C(Cl)(Cl)(Cl)Cl>[Cl:24][C:11]1([C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:19](=[O:20])[O:21]1
Reactant: COc1cc(OC)nc(C(=O)c2cccnc2C(=O)O)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(OC)nc(C2(Cl)OC(=O)c3ncccc32)n1
Temperature: 70 °C

Procedure:
45.53 g of 3-[(4,6-dimethoxy-2-pyrimidinyl)carbonyl]-2-pyridinecarboxylic acid are suspended in 700 ml of carbon tetrachloride and 186.4 g of thionyl chloride added with stirring. The suspension is heated to 70° C. for 4 hrs and the reaction mixture then cooled to RT and the excess thionyl chloride and carbon tetrachloride evaporated off to give the title compound as a tan solid m.p. 146°-148° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](B(O)O)=[CH:9]3)=[CH:4][C:3]1=2.[CH3:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1I)[C:26]([O:28][CH3:29])=[O:27]>>[CH3:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:12]3[C:13]([CH3:17])([CH3:16])[CH2:14][CH2:15][C:2]([CH3:21])([CH3:1])[C:3]=3[CH:4]=2)[CH:9]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: CC1(C)CCC(C)(C)c2cc3cc(B(O)O)ccc3cc21
Reactant: COC(=O)c1ccc(I)c(C)c1
Product: COC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)c(C)c1
Yield: 52.9 %

Procedure:
Following the basic procedure of Example 7(f), by reacting 2.8 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthrylboronic acid with 1.84 g (6.7 mmol) of methyl 3-methyl-4-iodobenzoate, 1.37 g (53%) of methyl 3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate was obtained in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:11])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C([Li])CCC.[C:17](=[O:19])=[O:18]>C1COCC1.CCCCCC>[Cl:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=1)[NH:9][N:8]=[CH:7]2
Reactant: O=C=O
Reactant: Clc1cc(Br)c2[nH]ncc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1cc(Cl)cc2cn[nH]c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
463 mg (2 mmol) of 7-bromo-5-chloro-1H-indazol were dissolved in 12 ml THF. The so-lution was cooled to −78° C. under argon. 3.75 ml (6 mmol) of a 1.6 M butyl lithium solution in hexane were added slowly within 10 min. The reaction mixture was warmed to 5° C. and stirred for 30 min at this temperature. A suspension was obtained, which was cooled to −78° C. Solid carbon dioxide was added and the reaction mixture was warmed to rt. At 10° C. the suspension became a clear solution. The solvent was evaporated and the residue was treated with water and diethyl ether. The aqueous layer was extracted once with diethyl ether, acidified with 1N aqueous HCl solution. A white solid precipitated, which was filtered off and washed with water. The solid was suspended in diethyl ether/heptane in order to remove pentanoic acid. 130 mg (33%) of 5-chloro-1H-indazole-7-carboxylic acid were obtained as a white solid after filtration and drying. MS (ISP) 195.1 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([OH:16])=[O:15])=[C:9]([OH:17])[CH:8]=[CH:7]2)(=[NH:3])[NH2:2].CS([O-])(=O)=O.N1C=CC=CC=1.Cl.[NH2:30][N:31]=[CH:32][NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>O>[NH2:30][N:31]=[CH:32][NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([O:17][C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=3)[C:10]=2[C:14]([OH:16])=[O:15])=[O:39])=[CH:36][CH:35]=1
Reactant: N=C(N)c1ccc2c(C(=O)O)c(O)ccc2c1
Reactant: NN=CNc1ccc(C(=O)Cl)cc1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)c1ccc2c(C(=O)O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To 930 mg of 6-amidino-1-carboxy-2-naphthol.methanesulfonate were added 10 ml of anhydrous pyridine and then 667.5 mg of 4-aminoiminomethylaminobenzoic acid chloride.hydrochloride, followed by stirring for 2 hours under cooling with ice and then 48 hours under cooling with water. The precipitate was collected by filtration and washed with a small amount of pyridine. To the collected precipitated were added 20 ml of warm DMF and then 0.6 ml of methanesulfonic acid. The resulting solution was added dropwise to 600 ml of ether, followed by stirring for 1 hour under cooling with ice. The supernatant liquid was decanted, and 20 ml of methanol was added to the residue. This solution was added dropwise to 450 ml of acetone, followed by stirring for 15 minutes under cooling with ice. Then, the precipitate was collected by filtration and washed with a small amount of acetone to obtain 869 mg of the desired product.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([NH:13][C:14]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:29])(=[O:26])=[O:25])=[C:20]2[C:15]=1[CH2:16][CH2:17][CH2:18][CH2:19]2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]>S(=O)(=O)(O)O>[C:6]([NH:13][C:14]1[C:23]([N+:1]([O-:4])=[O:2])=[CH:22][C:21]([S:24]([NH:27][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:29])(=[O:26])=[O:25])=[C:20]2[C:15]=1[CH2:16][CH2:17][CH2:18][CH2:19]2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7]
Reactant: CCOC(=O)C(=O)Nc1ccc(S(=O)(=O)NC(=O)C(=O)OCC)c2c1CCCC2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(S(=O)(=O)NC(=O)C(=O)OCC)c2c1CCCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Potassium nitrate (0.24 g, 2.3 mmol) was added to a solution of 5-ethoxalylamino-8-ethoxalylaminosulfonyl-1,2,3,4-tetrahydronaphthalene (1.0 g, 2.3 mmol) in 12 ml of conc. sulfuric acid with stirring at 0° C. Stirring was continued for 2 h at this temperature, and then the mixture was poured into 75 ml of ice-water. The separated product was isolated by suction and washed repeatedly with water to give 0.64 g (58%) of sufficiently pure title compound. M.p. 140°-142° C. (ethanol); 1H-NMR (DMSO-d6): 1.20 (t,J=7Hz, 3H, CH3), 1.30 (t,J=7Hz, 3H, CH3), 1.58-1.90 (m, 4H, 2CH2), 2.60-2.90 (m, 2H, CH2), 3.05-3.33 (m, 2H, CH2), 3.95-4.60 (m, 4H, 2CH2), 8.27 (s, 1H, ArH), 10.9 (broad s, 1H, NH, only one exchangeable proton could be seen).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]3[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C@H:17]([N:18]([CH3:28])[C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]4)=[CH:5][CH:4]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].N1C=CC=CC=1>C(Cl)Cl>[C:31]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]3[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C@H:17]([N:18]([CH3:28])[C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]4)=[CH:29][CH:30]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc(N)cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(O[C@H]2CC[C@H]3[C@@H]4CC[C@H]5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 17β-(4-aminophenoxy)-4-methyl-5α-4-azaandrostan-3-one hydrochloride (7 mg) in CH2Cl2 (100 μl) was added acetic anhydride (30 μl) followed by adding pyridine (50 μl). The mixture was stirred at room temperature for 1 hr and then concentrated to dryness. The residue was purified via a silica gel plate developed with 5% MeOH-EtOAc (Rf=0.3) to give the title product, mp. 340° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:13]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccccn2)sc2ccccc12
Yield: 43.8 %

Procedure:
Methyl thiosalicylate (1.6 g, 9.51 mM) and 2-cyanopyridine (1.0 g, 9.60 mM) were dissolved in toluene (2 ml), and then triethylamine (2 ml, 14.4 mM) was added thereto. After heating the mixture under reflux for 8 hours, and the toluene was distilled away. Ethanol was added to the residues, and the resulting precipitates were collected by filtration to give crude crystals (1.7 g). The product was purified by silica gel column chromatography (hexane:chloroform=5:1→chloroform) to give the title compound as crystals (1.0 g, 43.4%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+]>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:23]=[N:24][C:25]([Br:1])=[C:26]([O:28][CH3:29])[CH:27]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cnc1Br
Reaction time: 2 h

Procedure:
A mixture of 3-chloro-5-methoxypyridine (40.0 g, 0.279 mol), piperazine (48.0 g, 0.557 mol), potassium-tert-butoxide (62.5 g, 0.557 mol) and tetrakis-(triphenylphosphine)palladium(0) (1.6 g, 1.39 mmol) was refluxed for 2 hours. The workup procedure was performed according to method A. 1-(5-Methoxy-3-pyridyl)piperazine fumaric acid salt was isolated as intermediate product. Yield 22.6 g (26%). A mixture of 1-(5-methoxy-3-pyridyl)-piperazine fumaric acid salt (23.1 g, 74.7 mmol), aqueous sodium hydrogen carbonate (224 ml, 1 M), di-tert-butyldicarbonate (16.3 g, 74.7 mmol) and dichloromethane (200 ml) was stirred at room temperature for 1 hour. The phases were separated. The organic phase gave 4-tert-butoxycarbonyl-1-(5-methoxy-3-pyridyl)-piperazine in quantitative yield. N-Bromosuccinimide (1.82 g, 10.2 mmol) was added to a mixture of 4-tert-butoxycarbonyl-1-(5-methoxy-3-pyridyl)-piperazine (3.0 g, 10.2 mmol) and acetonitrile (50 ml) at 0° C. The reaction was allowed to reach room temperature and was stirred for 2 hours. Aqueous sodium hydroxide (100 ml, 4 M) was added followed by extraction twice with ethyl acetate (2×100 ml). Chromatography on silica gel with ethyl acetate:petroleum (1:3) gave 4-tert-butoxycarbonyl-1-(6-bromo-5-methoxy-3-pyridyl)-piperazine as free base. Yield 2.6 g, 68%. This compound (2.32 g, 6.23 mmol) was deprotected by stirring with a mixture of trifluoroacetic acid (4.8 ml) and dichloromethane (30 ml) for 6 hours. The mixture was evaporated, and aqueous sodium hydroxide (100 ml, 1 M) was added. The mixture was extracted three times with ethyl acetate (3×100) and gave the title compound as the free base. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid in quantitative yield. Mp 202-218° C.
Reaction SMILES: [C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][Si](C)(C)C)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](I)[CH:26]=1>>[C:1]([C:5]1[N:19]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:25]3[CH:24]=[N:23][CH:22]=[C:21]([Cl:20])[CH:26]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2ncc(C#C[Si](C)(C)C)cn2n1
Reactant: Clc1cncc(I)c1
Product: CC(C)(C)c1nc2ncc(C#Cc3cncc(Cl)c3)cn2n1

Procedure:
The title compound, a light yellow solid, MS: m/e=312.2/314.1 (M+H+), can be prepared in accordance with the general method of example 43, step 2 from 2-tert-butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 43, step 1) and 3-chloro-5-iodopyridine.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:6][C:3]=1[CH:4]=[CH2:5].C(Cl)Cl.ClCCl.C(OCC)(=[O:33])C>>[F:1][C:2]12[O:33][C:3]1([CH:6]=[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:9]2[F:10])[CH:4]=[CH2:5]
Reactant: C=Cc1cc(OCOCCOC)c(OCOCCOC)c(F)c1F
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: C=CC12C=C(OCOCCOC)C(OCOCCOC)=C(F)C1(F)O2

Procedure:
Using the procedure of Stage D of Example 40, 32 g of the product of Stage E were reacted to obtain 33.5 g of the expected product with a Rf=0.14 (CH2Cl2 --AcOEt 8-2).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([OH:14])=[O:13]>>[CH2:10]([O:9][C:7]([C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: CCOC(=O)C(=Cc1ccc(C(=O)O)cc1)C(=O)C(C)C
Yield: 94 %

Procedure:
29.0 g of ethyl isobutyrylacetate and 33.0 g of 4-carboxybenzaldehyde are heated with a water trap for 6 h. The reaction solution is concentrated, taken up in ethyl acetate and extracted with 20% strength ammonium chloride solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, concentrated and directly reacted further to 45. 50.0 g of an oil are obtained. C16H18O5 (290.3): MS (ESI+): 291.1 (M+H)+, tR=1.42 min (Gradient 2).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1cc(Cl)ccc1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,5-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,5-dichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1>>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[CH:24][N:23]=1
Reactant: COc1ccc(N)cn1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cn1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 5-amino-2-methoxypyridine (35 mg, 0.288 mmol) similar to Example 180 and was isolated as a solid (30 mg, 45%). 1H NMR (CDCl3): 9.65 (brs, 1H), 8.72-8.69 (m, 2H), 8.26 (d, J=2.7 Hz, 1H), 7.71 (d, J=6.9 Hz, 1H), 7.44-7.40 (m, 2H), 6.86 (d, J=9.0 Hz, 1H), 6.74 (s, 1H), 3.98 (s, 3H).
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[C:9]([O:13][C:14]([N:16]1[C@H:21]([C:22](=[O:33])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[F:32])[CH2:20][C@:19]2([CH2:34]OS(C)(=O)=O)[C@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].O>C1COCC1>[C:9]([O:13][C:14]([N:16]1[C@H:21]([C:22](=[O:33])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[F:32])[CH2:20][C@:19]2([CH3:34])[C@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(COS(C)(=O)=O)C[C@@H]12
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(C)C[C@@H]12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Lithium triethylborohydride (1N in THF, 2.06 mL, 2.06 mmol) was added at 0° C. to a solution of (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-methanesulfonyloxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (385 mg, 0.67 mmol) in THF (6.8 mL) under argon atmosphere. The solution was stirred 10 min at 0° C., then poured into cold water and extracted with EtOAc (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 75:25). TLC, Rf (c-hexane/EtOAc 1:1)=0.55; MS (UPLC/MS): 383.3/385.3 [M+H]+, 427.5/429.4 [M+HCOO]−; tR (HPLC conditions f): 2.24 min.