Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS([Cl:29])(=O)=O>C(Cl)Cl>[Cl:29][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 6-hydroxymethylpyridine-2-carboxylate (1.34 g) and diisopropylethylamine (1.24 g) were dissolved in 30 mL of methylene chloride, 0.54 mL of methanesulfonyl chloride was added dropwise thereto at ice temperature, and the mixture was stirred at room temperature overnight. The solvent was removed from the reaction mixture, and then the residue was purified by chromatography on silica gel (hexane-ethyl acetate=5:1) to give t-butyl 6-chloromethylpyridine-2-carboxylate as a yellow powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:52]1[CH2:56][CH2:55][CH:54]([CH2:57][OH:58])[CH2:53]1>CN(C)C=O>[OH:58][CH2:57][CH:54]1[CH2:55][CH2:56][N:52]([C:10]([C:9]2[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:53]1
Reactant: OCC1CCNC1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(CO)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.01 mol 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (CAS: 845616-82-2) in 40 ml N,N-dimethylformamide were added successively 3.57 g TBTU, 8.5 ml N-ethyldiisopropylamine and 1 g rac-pyrrolidin-3-yl-methanol (CAS: 5082-74-6). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The mixture was taken in ethyl acetate and washed twice with water and twice with saturated NaHCO3. The organic phase was dried over Na2SO4 and filtered. The solvent was evaporated. The crude oil was purified on silica gel (eluent: ethyl acetate) to yield the title compound as an off white foam. MS (m/e): 396.1 (M+H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc(Br)cc1F
Product: Cc1ccc(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1F

Procedure:
The title compound was prepared from (3R)(+)-3-(tert-butoxycarbonylamino)pyrrolidine and 4-bromo-2-fluorotoluene using the procedure outlined for Description 11.
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:22]([C:24]1[N:25]=[C:26]([CH2:35][CH3:36])[O:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:23])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:21]=[C:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[O:13][CH:14]=[C:10]([NH:9][C:22]([C:24]2[N:25]=[C:26]([CH2:35][CH3:36])[O:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:23])[N:11]=1
Reactant: CCc1nc(C(=O)N(C(=O)OC(C)(C)C)c2coc(CCCCC(C)=O)n2)c(-c2ccccc2)o1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc(C(=O)Nc2coc(CCCCC(C)=O)n2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-ethyl-5-phenyl-oxazole-4-carbonyl)-[2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (43 mg, 0.09 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.07 mL, 0.90 mmol). After stirring at rt for 4 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a white solid. LC-MS-conditions 01: tR=1.05 min, [M+H]+=382.12.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38](/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:36]=[CH:37][C:38](/[CH:41]=[CH:42]/[CH2:43][CH2:44][O:45][S:54]([CH3:53])(=[O:56])=[O:55])=[CH:39][CH:40]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCO)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCOS(C)(=O)=O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[(E)-4-hydroxybut-1-enyl]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1.2 mmol) in dichloromethane (50 mL) and triethylamine (3.6 mmol) at room temperature, add methanesulfonyl chloride (1.56 mmol) dropwise over 5 minutes. Stir at room temperature for 1 hour, then dilute the reaction with dichloromethane (100 mL). Wash the organics with water (2×100 mL) followed by brine (100 mL). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure to yield the title compound as a light yellow foam (0.84g, 1.2 mmol). Use this material in the next step (Scheme II, step B) without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:19]1[CH:29]=[N:28][C:22]2[NH:23][C:24](=[O:27])[O:25][CH2:26][C:21]=2[CH:20]=1.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])/[CH:4]=[CH:5]/[C:19]1[CH:29]=[N:28][C:22]2[NH:23][C:24](=[O:27])[O:25][CH2:26][C:21]=2[CH:20]=1
Reactant: O=C1Nc2ncc(Br)cc2CO1
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)COC(=O)N2
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a stirred solution of N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (1.19 g, 5.2 mmole) in propionitrile (50 mL) was added 6-bromo-2-oxo-1,4-dihydro-2H-pyrido[2,3-d]-1,3-oxazine (1.1 g, 4.9 mmole), DIEA (1.75 mL, 10 mmole), palladium(II) acetate (112 mg, 0.5 mmole), and tri-o-tolylphosphine (304 mg, 1.0 mmole). The reaction was purged with argon and heated at reflux for 16 hr, then was cooled to RT and concentrated under vacuum. The residue was taken up in CHCl3 and the solution was filtered through a pad of silica gel (3% methanol/CHCl3). The filtrate was concentrated and the residue was triturated with ethyl acetate, collected by suction filtration, and dried under vacuum gave the title compound (1.02 g, 55%) as an off-white solid: LCMS (ES) m/e 377 4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]2([CH2:39][OH:40])[CH2:38][CH2:37][CH2:36][CH2:35]2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:40][CH2:39][C:34]1([NH:33][S:30]([C:26]2[CH:25]=[C:24]([NH:23][C:20]([C:19]3[CH:18]=[N:17][N:11]4[C:12]([CH:14]5[CH2:16][CH2:15]5)=[CH:13][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[N:9][C:10]=34)=[O:22])[CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:31])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-N-(1-hydroxymethyl-cyclopentyl)-benzenesulfonamide (example B.13) according to general procedure II. Pale-yellow solid. MS (ISP) 566.3 [(M+H)+]; mp 255-257° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:21][C:22]1([CH3:38])[O:27][CH:26]([C:28]([NH:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:29])[C:25]([CH3:37])([CH3:36])[CH2:24][O:23]1>>[CH3:21][C:22]1([CH3:38])[O:27][CH:26]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:34])=[O:29])[C:25]([CH3:37])([CH3:36])[CH2:24][O:23]1
Reactant: CCCCCCCCCCCCCC(=O)NCCCO
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 88 %

Procedure:
N-(3-Hydroxypropyl)tetradecanamide (2.87 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 4.63 g of the title compound (yield: 88%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[C:4]([F:17])[CH:3]=1.CC(C)([O-])C.[Na+].Cl[C:25]1[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)=[CH:27][N:26]=1.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:25]3[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[N:36]4)=[CH:27][N:26]=3)[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: Clc1ncc(CCCCn2ccnn2)cn1
Reactant: OCc1coc(C=Cc2ccc(Cl)cc2F)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)ccc1C=Cc1nc(COc2ncc(CCCCn3ccnn3)cn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.100 g, 0.39 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.046 g, 0.47 mmol). After stirring for 15 min at r.t. 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.085 g, 0.36 mmol) is added slowly and stirred for further 3 h at r.t. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 98:2) 2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine is obtained as a colorless solid. Yield 0.125 g (77%).
Reaction SMILES: [NH2:1][C:2]1([NH:7][C:8](=[O:28])[CH:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:5][NH:4][C:3]1=[O:6].N1C=CC=CC=1.[C:35](OC=O)(=[O:37])C>ClCCl>[CH:35]([NH:1][C:2]1([NH:7][C:8](=[O:28])[CH:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:5][NH:4][C:3]1=[O:6])=[O:37]
Reactant: NC1(NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccsc2)CNC1=O
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CNC1(NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccsc2)CNC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
The amine (42) (490 mg) in dry dichloromethane was cooled to 0° C. and treated with pyridine (211 mg) followed by formic-acetic anhydride (117 mg). The mixture was stirred at 0° C. for 5 minutes then allowed to warm to room temperature. After 1/2 hour the solvent was evaporated and the residue dried in vacuo. The solid was triturated with dry ether, filtered off, and washed with more ether before drying in vacuo to give the product (43) (510 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:6]=1)[CH3:3].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][S:40][CH2:41][CH2:42][NH:43][C:44](SC)=[CH:45][N+:46]([O-:48])=[O:47]>C(OCC)(=O)C>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:44]([NH:43][CH2:42][CH2:41][S:40][CH2:39][C:35]2[O:34][CH:38]=[CH:37][CH:36]=2)=[CH:45][N+:46]([O-:48])=[O:47])=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccco1
Reactant: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCCCCCCCCCCN)o1
Solvent: CCOC(C)=O
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCCCCCCCCCCNC(=C[N+](=O)[O-])NCCSCc2ccco2)o1
Yield: 69.8 %

Procedure:
A mixture of N-[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine (0.8 g.) and N-2-[[(2-furanyl)methyl]thio]ethyl-1-(methylthio)-2-nitroethenamine (0.57 g.) in ethyl acetate (8 ml.) was evaporated and the residue heated at 98°-100° for 2 hours. The oily residue was dissolved in methanol (10 ml.) and evaporated to dryness (×2). The oily residue was triturated with ethyl acetate (30 ml.), the solid which separated was washed with ethyl acetate and dried to give the title compound (0.82 g.), m.p. 69°-72°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:38][C:39]1[N:44]=[C:43]([N:45]([CH3:47])[CH3:46])[CH:42]=[CH:41][CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[C:43]([N:45]([CH3:47])[CH3:46])[N:44]=2)[CH:27]=1)[C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(CCl)n1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccc(N(C)C)n3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 43.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.78 g) and 6-chloromethyl-2-(dimethylamino)pyridine (0.46 g) as starting materials, 5-benzyloxy-N-({1-[(6-dimethylaminopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]N=C(CC)CC)=[CH:6][CH:5]=[CH:4][N:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:5]([CH3:4])=[C:6]([CH2:7][CH3:2])[NH:8][C:7]=12
Reactant: CCC(CC)=NNc1cccnc1Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1[nH]c2c(Cl)nccc2c1C
Temperature: 25 °C
Yield: 143.2 %

Procedure:
A solution of N-(2-chloropyridin-3-yl)-N'-(1-ethylpropylidene)-hydrazine (1.3 g, 6.1 mmol) prepared in Step 2 in diphenyl ether was stirred for 3 hours at 300° C. The reaction mixture was cooled to room temperature and then purified with silica gel column chromatography to give 850 mg of the titled compound as a pale yellow solid. (Yield: 72%).
Reaction SMILES: [N+:1]([O-])([O-])=O.[Na+].[NH:6]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[NH2:7]>O.C(O)(=O)C>[CH3:23][CH:22]([CH3:24])[CH2:21][N:20]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]3[N:1]=[N:7][N:6]=[C:8]3[C:17]=2[N:18]=[CH:19]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)Cn1cnc2c(NN)nc3ccccc3c21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cn1cnc2c1c1ccccc1n1nnnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 375.5 %

Procedure:
A solution of sodium nitrate (2.0 g, 3 mmole) in water (5 mL) was added to a solution of 4-hydrazino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (4.0 g, 15.7 mmole, Example 7) in a mixture of acetic acid (5 mL) and water (50 mL). The reaction mixture was stirred at ambient temperature for 15 minutes. A precipitate was isolated by filtration, washed with water then air dried to provide 4.1 g of crude product. This material was recrystallized from dichloromethane/ethanol to provide 3.0 g of 6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a cream colored crystalline solid, m.p. 208-212° C. Analysis: Calculated for C14H14N6: %C, 63.14; %H, 5.30; %N, 31.56; Found: %C, 62.60; %H, 5.2; %N, 31.5.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1)#[N:41]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:46]=[CH:47][C:42]([C:40]#[N:41])=[CH:43][CH:44]=2)[CH2:53][CH2:52]1
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(C2CCC(=CCC3OCCCO3)CC2)cc1
Yield: 56 %

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer, was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.2 g, 27 mmols), followed by adding tetrahydrofuran (200 ml), suspending, stirring the suspension under ice cooling till the liquid temperature reached 10° C., adding to the reaction mixture, potassium t-butoxide (30 g, 27 mmols), elevating the temperature up to room temperature under ice cooling for one hour, stirring the mixture for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(4-cyanophenyl)cyclohexanone (5.0 g, 25 mmols) from the dropping funnel over 30 minutes. The reaction mixture was stirred for 5 hours after completion of the dropwise addition, followed by adding ether (100 ml), allowing the mixture to stand, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure, and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(4-cyanophenyl)cyclohexane (4.1 g, 14 mmols).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>O.CO>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccn(-c2cccc(F)c2)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccn(-c2cccc(F)c2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 1-(3-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylate 89-2 (50 mg, 0.202 mmol) in water (0.5 mL) and methanol (0.5 mL) was added LiOH (20 mg, 0.835 mmol). After stirring at room temperature for 30 minutes, the mixture was concentrated with rotavap and the residue extracted with ethyl acetate, which was then evaporated to give crude 1-(3-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid 89-3.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10]([C:12]1[C:13]([S:23](Cl)(=[O:25])=[O:24])=[N:14][N:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]=12)#[N:11]>N1C=CC=CC=1.CC(O)C>[C:10]([C:12]1[C:13]([S:23]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])(=[O:24])=[O:25])=[N:14][N:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]=12)#[N:11]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)c(C#N)c2n1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)c(C#N)c2n1
Temperature: 70 °C
Reaction time: 24 h
Yield: 55.4 %

Procedure:
A solution of 0.67 g (4.1 mmole) of 2,6-dichloroaniline was stirred at room temperature as a solution of 1.1 g (4.1 mmole) of 3-cyano-5,7-dimethylpyrazolo-[1,5-a]pyrimidine-2-sulfonyl chloride in 3 ml pyridine was added. The mixture was heated at 70° C. for 15 hours, then at 130° C. for 24 hours, and cooled to room temperature. The mixture was diluted with 2-propanol and stirred at room temperature for 1 hour. The tan solid was collected by filtration, washed well with 2-propanol and dried to give 0.9 g tan powder. This was completely dissolved in 2N NaOH and extracted with CH2Cl2. The aqueous layer was separated and acidified with glacial HOAc, which gave a precipitate. This was collected by filtration, washed well with water and dried to give 0.2 g (12.3 -percent) of the product as an off-white solid, m.p. 280°-285° C. (decomposition and degassing). 1H NMR (DMSO-d-6): 11.1 (br., 1H, NH), 7.5-7.4 (m, 3H, benzene), 7.5 (s, 1H, pyrazolopyrimidinyl H-6), 2.67 (s, 3H, CH3), 2.63 (s, 3H, CH3) 13C NMR (DMSO-d-6): 165, 156, 150, 148, 136, 130, 129, 114, 111, 80, 24, 16. IR (KBr): 3220, 2240, 1620, 1540, 1440, 1355, 1170 cm-1.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.CO[C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20].[NH4+].[Cl-]>C1COCC1>[OH:21][C:12]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]
Reactant: Fc1ccc(Br)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCCCCCCBr)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
7.65 g (313.8 mmol) magnesium shavings are placed under protective gas atmosphere and 55.1 g (314.8 mmol) 4-bromofluorobenzene dissolved in 250 ml abs. THF are added dropwise so that the reaction mixture boils gently. After complete addition, the mixture is heated for 30 minutes under reflux, and, afterwards, the suspension is cooled. While cooling in an ice bath, a solution of 25.0 g (105.4 mmol) 8-bromoctanoic acid methyl ester in 100 ml abs. THF is added dropwise. Subsequently, the mixture is heated for a further 30 minutes under reflux. After cooling, NH4Cl-solution is added to the reaction and this is extracted by diisopropyl ether by shaking. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with petroleum ether/acetic acid ethyl ester (20/1 to 10/1): Yield 36.4 g (87%).