Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:5][C:6]([CH:9]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][OH:11])=[CH:7][N:8]=1.Cl[C:33]1[C:37]2[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:36]=2[O:35][N:34]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]2[O:35][N:34]=[C:33]([O:11][CH2:10][CH:9]([C:6]3[S:5][C:4]([CH3:3])=[N:8][CH:7]=3)[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:37]=2[CH:38]=1
Reactant: Clc1ccc2onc(Cl)c2c1
Reactant: Cc1ncc(C(CO)NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(C(COc2noc3ccc(Cl)cc23)NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1

Procedure:
To a solution of 0.24 g of 60% sodium hydride in 10 ml of N,N-dimethylformamide are dropwise added 2.0 g of 2-(2-methyl-1,3-thiazol-5-yl)-2-tritylaminoethanol, a solution of 10 ml of N,N-dimethylformamide at room temperature, and the temperature is gradually elevated to 80° C. after which 1.03 g of 3,5-dichloro-1,2-benzoisoxazole is added. They are subjected to reaction at the same temperature for one hour. After cooling, water and ethyl acetate are added, and the crystals precipitated are collected by filtration. The organic layer of the filtrate is separated, washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The crystals obtained are combined with the crystals previously collected by filtration to obtain 1.81 g of colorless, crystalline 5-chloro-3-[2-(2-methyl-1,3-thiazol-5-yl)-2-tritylaminoethoxy]-1,2-benzoisoxazole.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:28][N:29]1[CH:33]=[N:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:38][C:37]3[CH:36]=[CH:35][C:34]([C:30]4[N:29]([CH3:28])[CH:33]=[N:32][N:31]=4)=[CH:40][CH:39]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cn1cnnc1-c1ccc(N)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cnnc1-c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 100 mg; 0.36 mmol) in DCM (4 ml) was treated with polymer-supported Mukaiyama reagent (400 mg) followed by triethylamine (100 mL; 0.73 mmol) and 4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (Maybridge, 63.2 mg; 0.36 mmol). After stirring at RT for 24 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH3:46][O:47][C:48](=[O:56])[C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[N:51][CH:50]=1.N1C=CC=CC=1>C(Cl)Cl.O>[CH3:46][O:47][C:48](=[O:56])[C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:51][CH:50]=1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(N)nc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
A solution of triphenylphosphine (1.23 g, 4.69 mmol) in methylene chloride (15 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (947 mg, 5.32 mmol). The resulting brown-purple solution was stirred at 0° C. for 5 min and then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared in Example 54, 900 mg, 3.13 mmol). The reaction mixture was stirred at 0° C. and then allowed to warm to 25° C. over 45 min. The reaction mixture was then treated with 6-aminonicotinic acid methyl ester (620 mg, 4.07 mmol) and pyridine (0.38 mL, 4.7 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester (1.10 g, 84%) as a white foam: [α]23589=−68.0° (c=0.128, chloroform); FAB-HRMS m/e calcd for C21H22Cl2N2O3 (M+H)+ 421.1086, found 421.1079.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1O)(=[O:3])[CH3:2].[CH2:16]([NH2:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:29](Cl)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:16]([N:28]([CH:6]1[O:8][C@H:9]([CH2:14][OH:15])[C@@H:10]([OH:13])[C@H:11]([OH:12])[C@H:5]1[NH:4][C:1](=[O:3])[CH3:2])[C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O

Procedure:
Preparation in analogy to Example 54 from N-acetylglucosamine, dodecylamine and dodecanoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[C:26]([O:30][C:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([NH:42][CH2:43][CH3:44])=[N:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([N:42]([C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=3)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH2:43][CH3:44])=[N:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCNc1nn(C(=O)OC(C)(C)C)c2ccccc12
Solvent: C1CCOC1
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1nn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl chloride (100 mg, 0.24 mmol), 3-ethylamino-indazole-1-carboxylic acid tert-butyl ester (62.6 mg, 0.24 mmol), and TEA (0.64 mL) in THF (1 mL) was stirred at 60° C. for 2 hours and then purified by flash column to give 3-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37]>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=3[CH3:33])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: Cc1ccccc1C(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)S(C)(=O)=O

Procedure:
Compound 2 was coupled with 2-methylbenzoic acid by procedure K. LC-MS showed the product had the expected M+H+ of 574. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H) 8.2 (s, 1H) 8.0 (d, 1H) 7.6 (m, 2H) 7.3 (m, 7H), 6.8 (d, 2H), 4.4 (s, 2H), 3.7 (t, 2H), 3.3 (d, 2H), 3.2 (d, 2H) 2.84 (s, 3H), 2.3 (s, 3H), 1.8 (m, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([C:28]2[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH2:35])[N:29]=2)[C:15]([NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)=[N:16][CH:17]=1)[CH3:11])(C(C)(C)C)(C)C>C1COCC1>[NH2:35][C:30]1[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:14]2[CH:13]=[C:12]([CH:10]([CH3:11])[CH2:9][OH:8])[CH:17]=[N:16][C:15]=2[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)[N:29]=1
Reactant: COc1ncc(Nc2ncc(C(C)CO[Si](C)(C)C(C)(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)CO)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
Tetra(N-butyl)ammonium fluoride (1.0M in THF) (Fluka, St. Louis, Mo.; 1.206 mL, 1.206 mmol) was added to an orange solution of 4-(5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (241.0 mg, 0.482 mmol) in THF (5.0 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0 to 100% EtOAc/hexanes) to provide 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)propan-1-ol (139.0 mg, 0.361 mmol, 74.8% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.88 (s, 1H), 8.66 (d, J=2.5 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H), 8.35-8.40 (m, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.88 (br. s., 1H), 7.74 (br. s., 1H), 4.70 (br. s., 1H), 3.93 (s, 3H), 3.49 (d, J=6.5 Hz, 2H), 2.83 (sxt, J=6.9 Hz, 1H), 2.44 (s, 3H), 1.22 (d, J=7.0 Hz, 3H). 19F NMR (376 MHz, d6-DMSO) δ −139.83 (d, J=13.0 Hz, 1F). m/z (ESI, +ve) 386.2 (M+H)+.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@@H:9]([C:11](=[O:22])[NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[C:15]([Cl:21])[CH:14]=1)[CH3:10])(C)(C)C.C(Cl)Cl>O.CO>[NH2:8][C@H:9]([CH3:10])[C:11]([NH:12][C:13]1[CH:14]=[C:15]([Cl:21])[C:16]([F:20])=[C:17]([Cl:19])[CH:18]=1)=[O:22]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C[C@@H](N)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a solution of hydrochloric acid (12 M, 266 mL, 3.19 mol) in water (272 mL) and MeOH (135 mL) was added a solution of crude [(R)-1-(3,5-dichloro-4-fluoro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (208.6 g, max. 594 mmol) in MeOH (600 mL) via an addition funnel over 30 min. CH2Cl2 (300 mL) was then added and the reaction mixture was stirred at room temperature overnight. An additional portion of HCl (12 M, 100 mL) was added and stirring was continued for another 20 h. The volatile solvents were removed in vacuo and the remaining aqueous mixture was cooled to −15 to −20° C. Toluene (400 mL) was added followed by the addition of NaOH solution (50% aqueous, 300 mL), which was added at a rate to keep the internal temperature below 25° C. The layers were separated and the aqueous layer was extracted with toluene (2×1 L). The combined organic layers were dried with Na2SO4 and concentrated to give 158.3 g of the title compound as a dark brown oil that solidifies slowly in the freezer, m/z 251.1 [M+H]+. This crude material was used without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCCCO
Product: CON=C1C[C@@H](C(=O)NCCCCO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 4-amino-1-butanol, the title compound was obtained in 68% purity by HPLC. MS(ESI+): m/z=410.
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[N+:13]([C:16]1[CH:23]=[CH:22]C(CN)=[CH:18][CH:17]=1)([O-:15])=[O:14].NC1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1>[OH-].[Na+]>[N+:13]([C:16]1[CH:17]=[CH:18][C:10]([CH2:9][NH:8][C:6](=[O:7])[NH:3][CH2:2][C:1]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:22][CH:23]=1)([O-:15])=[O:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCc1ccc(C(=O)O)cc1)NCc1ccc([N+](=O)[O-])cc1
Yield: 75.6 %

Procedure:
N,N-carbonyldiimidazole (1.62 g, 10 mmol), 4-nitrobenzyl amine (1.52 g, 10 mmol), p-aminobenzoic acid (1.52 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide solution are used according to the method for the production of compound III in Method two to obtain 2.49 g of 4-[(4-nitrobenzylureido)methyl]benzoic acid (intermediate M-36) as a yellow solid, with a yield of 75.4%.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[OH-].[Na+].[CH2:14]=O.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([S:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[Na+].Cl>C1(C)C=CC=CC=1.O>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:14][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: C=O
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)Cc2c(C(F)(F)F)nn(C)c2O)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
5-Hydroxy-1-methyl-3-trifluoromethylpyrazole (1.7 g (10 mmol)) synthesized in Reference Example 1 and 0.6 g (15 mmol) of sodium hydroxide were dissolved in 10 mL of toluene. While stirring the resulting solution at room temperature, 1.7 g of paraformaldehyde was charged thereto, followed by stirring at the same temperature for 24 hours. Furthermore, 1.8 g (10 mmol) of sodium p-toluenesulfinate was charged thereto at room temperature, and the obtained mixture was stirred for 8 hours. After the reaction, 5.0 g (50 mmol) of 35% hydrochloric acid was added dropwise thereto, 30 mL of water was further added, and the precipitated crystal was collected by filtration, washed twice with 5 mL of water and dried by a hot air drier to obtain 3.0 g (yield: 88.2%) of the title compound as a pale yellow crystal. The 1H-NMR spectrum agreed with that of Example 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][CH3:12])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:13].Cl[C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:10]([O:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]2[C:5]([CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[O:13]2)=[CH:6][CH:7]=1)[CH2:11][CH3:12]
Reactant: CCCOc1cccc(O)c1OC
Reactant: C#CC(C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc2c(c1OC)OC(C)(C)C=C2
Reaction time: 20 h
Yield: 79.2 %

Procedure:
A suspension of 5.5 g (30 millimoles) of 2-methoxy-3-n-propoxy-phenol, 6.5 g (60 millimoles) of 3-chloro-3-methyl-but-1-ine, 5 g of potassium carbonate, 8 g of potassium iodide and 50 ml of anhydrous acetone is heated to boiling under stirring for 20 hours. The inorganic salt is filtered off, the filtrate evaporated and the residue heated to boiling in 100 ml of N,N-dimethyl aniline for 8 hours. The reaction mixture is worked up in the usual manner and the product is purified as described in Example 3. Thus 5.9 g of the title compound are obtained in the form of a colorless oil, yield 80%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:26]CC4C=CC(OC)=CC=4)[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:12]=3[F:14])[C:7](=[O:36])[CH:6]=[C:5]2[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:26][C:9]1[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:36])[CH:6]=[C:5]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(=O)c2c(NCc3ccc(OC)cc3)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(=O)c2c(N)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of ethyl 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-(4-methoxybenzylamino)-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (577 mg, 1.02 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. and treated dropwise with trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for over night. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3, brine, and dried over anhyd Na2SO4 followed by the removal of CH2Cl2. The crude product was purified by column chromatography (Hexane:EtOAc 1:1) to yield ethyl 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (336 mg, 74%) as a orange amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12.[H-].[Na+].Br[CH2:29][CH2:30][OH:31]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[N:12]([CH2:29][CH2:30][OH:31])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12
Reactant: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1CCO
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (0.0041 M) of 11b-(2-chlorophenyl)-10-nitro-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 30 ml of dry N,N-dimethylformamide was treated with 0.34 g (0.008 M) of a 57% dispersion of sodium hydride in mineral oil with stirring under nitrogen. After 30 min, 1.5 g (0.012 M) of 2-bromoethanol was added and the reaction was heated to 90° for 3 hr. The solvent was removed under vacuum, and the residue was dissolved in 50 ml of dichloromethane which was then washed with 50 ml of water, 25 ml of a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether, and recrystallized from a mixture of dichloromethane and methanol to give the product as pale yellow prisms, m.p. 185°-190°(dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH2:10][C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=[O:22])([O-])[O-].[K+].[K+].C=O.[C:27]([O-])(O)=[O:28].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH2:19][OH:22])([CH2:27][OH:28])[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C(=O)Cc2ccc(Cl)cc21
Reactant: O=C([O-])O
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)C(CO)(CO)c2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2.7 g, 10.1 mmol), potassium carbonate (4.2 g, 30.3 mmol), THF (150 mL) and paraformaldehyde (7.2 g, 0.24 mol) was stirred at 20° C. for 2 h then was poured onto ice (100 g) and saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (4×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. Chromatography (SiO2; gradient elution with 30-100% EtOAc in petrol) gave an orange solid (3.7 g). Crystallisation from EtOAc and petrol gave the title compound (1.23 g). Chromatography of the mother liquor gave further product (0.978 g). MS: [M-tert-Bu]+=272 (fragment ion).
Reaction SMILES: [OH2:1].[F:2][C:3]([F:13])([F:12])[C:4]([F:11])([F:10])[C:5]([F:9])([F:8])[CH:6]=[O:7].[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[OH-].[Na+]>O>[F:8][C:5]([F:9])([C:4]([F:10])([F:11])[C:3]([F:2])([F:13])[F:12])[CH:6]([C:15]1[NH:14][C:18]([CH:6]([OH:7])[C:5]([F:8])([F:9])[C:4]([F:10])([F:11])[C:3]([F:12])([F:13])[F:2])=[CH:17][CH:16]=1)[OH:1]
Reactant: c1cc[nH]c1
Reactant: O=CC(F)(F)C(F)(F)C(F)(F)F
Reactant: O
Agent: [Na+]
Agent: [OH-]
Product: OC(c1ccc(C(O)C(F)(F)C(F)(F)C(F)(F)F)[nH]1)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 48 h

Procedure:
Heptafluorobutyraldehyde hydrate (5.0 g, 23 mmol) was placed in a 100 mL Schlenk flask. This was frozen with liquid nitrogen and an inert atmosphere was established. Against an outflow of nitrogen, dried pyrrole (0.694 mL, 10 mmol) and sodium hydroxide (2.25 g, 56 mmol) were added. The flask was wrapped in foil and the mixture was stirred for 2 days. The volatiles were removed by vacuum, leaving a light brown, oily solid. The solid was dissolved in 40 mL of water and the solution was extracted (4×50 ml) with methylene chloride. The organic layers were dried over sodium sulfate and then evaporated to dryness under vacuum to an oily brown solid (38%), which proved to be a diastereomeric mixture of the desired products. 1H NMR of recrystallized product (CDCl3, 360 MHz) d 8.78 (broad s, 1 H); 6.28 (d, 2H, J=2.8 Hz); 5.128 (dd, 2 H, J1=117 Hz, J2=8 Hz); 2.53 (broad s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[N:42]1([CH2:47][CH2:48][NH2:49])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:49][CH2:48][CH2:47][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:40])=[CH:18][CH:17]=1
Reactant: NCCN1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (5 ml), and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (77 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-tetrahydro-1H-1-pyrrolyl-1-ethanamine (30 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (8 mg, yield 9%).