Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([O-:10])=[O:9])(=[O:3])[CH3:2].[Na+].[CH3:19][C:20]([O:23][C:24]([C:26]1[N:27]2[C@H:30]([S:31][CH2:32][C:33]=1[CH2:34]I)[C@H:29]([NH:36][C:37](=[O:46])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:28]2=[O:47])=[O:25])([CH3:22])[CH3:21].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH3:22][C:20]([O:23][C:24]([C:26]1[N:27]2[CH:30]([S:31][CH2:32][C:33]=1[CH2:34][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([O:14][C:15](=[O:17])[CH3:16])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)[CH:29]([NH:36][C:37](=[O:46])[CH2:38][O:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:28]2=[O:47])=[O:25])([CH3:19])[CH3:21]
Reactant: CC(=O)Oc1ccc(C(=O)[O-])cc1OC(C)=O
Reactant: CC(C)(C)OC(=O)C1=C(CI)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Oc1ccc(C(=O)OCC2=C(C(=O)OC(C)(C)C)N3C(=O)C(NC(=O)COc4ccccc4)C3SC2)cc1OC(C)=O
Reaction time: 2 h

Procedure:
By following the procedures and conditions described in Example 4, 2.33 g (8.95 mmol) of sodium 3,4-diacetoxybenzoate in 100 mL of DMF added to 4.75 g (8.95 mmol) of (6R-trans)-3-(iodomethyl)-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 50 mL of DMF, followed by stirring for 2 hours, gave 3.36 g (58.5%) of a cream colored solid after silica gel chromatography (6:4 hexane/EtOAc).
Reaction SMILES: [NH2:1][C@@:2]1([CH3:30])[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[C:3]1([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:27][O:26][C:23]1[N:22]=[CH:21][C:20]([C:18]2[CH:19]=[C:9]3[C:8]([NH:7][C@@H:4]4[CH2:5][CH2:6][C@:2]([CH3:30])([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[C:3]4([CH3:29])[CH3:28])=[C:13]([C:14]([NH2:16])=[O:15])[CH:12]=[N:11][N:10]3[CH:17]=2)=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cc3c(N[C@@H]4CC[C@](C)(N)C4(C)C)c(C(N)=O)cnn3c2)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(N[C@@H]4CC[C@](C)(NS(C)(=O)=O)C4(C)C)c(C(N)=O)cnn3c2)cn1
Reaction time: 1 h
Yield: 37.4 %

Procedure:
4-(N,N-dimethylamino)pyridine (15.7 mg, 0.129 mmol) was added to a solution of 4-((1R,3S)-3-amino-2,2,3-trimethylcyclopentylamino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (97.5 mg, 0.138 mmol, from Example 232), N,N-diisopropylethylamine (0.080 mL, 0.458 mmol) and methanesulfonyl chloride (0.030 mL, 0.385 mmol) in dichloromethane (1 mL). After 1 h at room temperature, the mixture was purified by silica gel chromatography, eluting with 0-10% methanol in dichloromethane. The fractions containing the desired product were concentrated. The material was further purified with reverse phase HPLC (Waters Xbridge 19×100 mm), eluting with 20-80% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), to give 6-(6-methoxy-3-pyridinyl)-4-(((1R,3S)-2,2,3-trimethyl-3-((methylsulfonyl)amino)-cyclopentyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide as white solid (25.1 mg, 37% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.47 (1 H, d, J=1.98 Hz), 8.15 (1 H, s), 8.07 (1 H, dd, J=8.58, 2.42 Hz), 7.95 (1 H, d, J=1.76 Hz), 7.15 (1 H, d, J=1.54 Hz), 6.94 (1 H, d, J=8.58 Hz), 4.58 (1 H, t, J=8.25 Hz), 3.98 (3 H, s), 3.06 (3 H, s), 2.42-2.53 (2 H, m), 1.93-2.05 (1 H, m), 1.73-1.84 (1 H, m), 1.53 (3 H, s), 1.16 (3 H, s), 1.04 (3 H, s); MS (ES+) m/z: 487.3 (M+H); LC retention time: 3.843 min (analytical HPLC Method F).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9]CC)=[O:8])=[C:2]=[S:3].[N-:15]=[N+:16]=[N-:17].[Na+]>O>[C:7]([C:6]1[CH:5]=[C:4]([N:1]2[C:2]([SH:3])=[N:17][N:16]=[N:15]2)[CH:14]=[CH:13][CH:12]=1)([OH:9])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cccc(N=C=S)c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(-n2nnnc2S)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a mixture of 69 g of ethyl m-isothiocyanatobenzoate and 26 g of sodium azide was added 500 ml of water and the mixture was refluxed for 2 hours. After removing deposited insoluble matter by filtration, the filtrate was acidified by the addition of concentrated hydrochloric acid (pH about 2), and crystals of 1-(3-ethoxycarbonylphenyl)-5-mercaptotetrazole thus deposited were collected by filtration, mixed with 30 g of sodium hydroxide and 300 ml of water, and the mixture was stirred for 30 minutes at 70° C. The reaction mixture was neutralized by concentrated hydrochloric acid and crystals thus deposited were collected by filtration. The crude crystals were recrystallized from methanol to provide 32 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole. The yield was 42% and the mleting point of the product was 181°-182° C.
Reaction SMILES: [C:1]12([CH2:14][CH2:13][CH2:12][CH2:11]1)[C:9]1[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:3](=[O:10])[CH2:2]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[N+:15]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[C:1]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:2][C:3]2=[O:10])([O-:17])=[O:16]
Reactant: O=C1CC2(CCCC2)c2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CC2(CCCC2)c2ccc([N+](=O)[O-])cc21
Reaction time: 1 h
Yield: 9210.9 %

Procedure:
To a chilled solution of spiro(cyclopentane-1,1'-indan)-3'-one (16.7 g; 0.09 moles) in conc. sulphuric acid (100 ml) there are added in portions under agitation a solution of potassium nitrate (10 g) in conc. sulphonic acid (30 ml). The temperature should not exceed 10°-15° C. The mixture is kept cold for 1 hour and then put on ice. The crude product is sucked off and thoroughly washed with water. After drying there are obtained 1917 g of a yellow powder (yield 95%), mp. 104° C. A sample is recrystallized from N-hexane and melts at 110° C.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].[Na].Cl>C1COCC1.[Na]>[OH:10][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:13][CH2:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCOCCOCCO
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To triethyleneglycol (17.6 g, 117.20 mmol, 3.00 equiv) in anhydrous THF (70 mL), was added sodium (30 mg, 1.25 mmol, 0.03 equiv). Tert-butyl acrylate (5.0 g, 39.01 mmol, 1.00 equiv) was added after the sodium had dissolved. The resulting solution was stirred overnight at room temperature and then neutralized with 1.0 N hydrogen chloride. After removal of the solvent, the residue was suspended in 50 mL of brine and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the tert-butyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate (9.6 g) was isolated as a colorless oil, which was used directly for the next reaction step without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([O:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:21]=[N:22][CH:23]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Cl)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 500-mL round-bottomed flask was added (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (2.5 g, 12.42 mmol) in DMF (80 mL) at 0° C. NaH (1.080 mL, 24.84 mmol) was added slowly and the mixture was stirred at 0° C. for 15 min. 2,6-dichloropyrazine (1.851 g, 12.42 mmol) was added and the mixture was warmed to RT and stirred for 2 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with water, brine, dried, filtered and concentrated to give the crude title compound. The material was used in the next step without further purification
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31]Br)=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.Cl>C(O)C.[OH-].[Na+].O>[CH:20]1[C:21]2[CH:22]([CH2:24][O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([OH:10])=[O:9])=[O:27])[C:23]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NCCCBr)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NCCCSc1ccccc1C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of thiosalicylic acid (500 mg) in ethanol (15 ml) and 2N sodium hydroxide aqueous solution (3.2 ml) was added 3-(9-fluorenylmethoxycarbonylamino)-propyl bromide at ambient temperature and the suspension was stirred for 2 hours. The resulting clear solution was diluted with water (20 ml) and acidified with 1N hydrochloric acid (6.5 ml). White crystals were collected by filtration and the solid was washed with ethanol-water (1:3, 15 ml) and then with n-hexane - diethyl and either (2:1, 15 ml) to give 2-[3-(9-fluorenylmethoxycarbonylamino)-propylthio]benzoic acid (1.07 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:64]1[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.O>ClCCl>[OH:48][CH:29]([CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](=[O:45])[N:64]1[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1)/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH:27]([CH:12]1[O:13][C:14](=[O:26])[C:15]([O:24][CH3:25])=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]([CH3:22])[CH:20]([OH:21])[CH:3]([CH2:1][CH3:2])[CH:4]([OH:53])[CH:5]([CH3:52])[CH2:6][C:7]([CH3:51])=[CH:8][CH:9]=[CH:10][CH:11]1[O:49][CH3:50])[CH3:28]
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reactant: C1CCNCC1
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCCCC1)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCCCC1)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBt (2 mg) were added. After 20 min, piperidine (1.3 mg) was added. The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated. Reaction mixture was extracted with dichloromethane (3×5 mL). The combined organic layer was washed with water (2×5 mL). The organic layer was dried over sodium sulphate, and was concentrated. The crude product was purified by preparative HPLC [Eurospere-100, C18 column (250 mm×8 mm), mobile phase: acetonitrile-water (1:1 isocratic)] to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][Cl:17])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH3:28])=[CH:25][C:24]([OH:29])=[CH:23][CH:22]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:17][CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:29][C:24]3[CH:25]=[C:26]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([CH3:18])=[C:27]4[CH3:28])=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCCCl
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (5.0 g), prepared as described in Example 7, 2,3-dimethyl-5-hydroxyindole (3.5 g), (Arch. Pharm. 1972, 305, 159), and potassium carbonate (4.0 g) in DMF (70 ml) was stirred and heated at 90° C. for 3 hours. The mixture was filtrated and the solvent was removed by evaporation under vacuum. The residue was purified by column chromatography on silica using the solvent mixture dichloromethane/ethyl acetate/methanol (50/48/2). The solvent was evaporated under vacuum to give 7-(2-chloroethoxy)-4-[(2,3-dimethyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (4.9 g) as a beige solid.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][CH2:12][NH2:13].C(N(CC)CC)C.Cl>ClCCl.O>[CH2:1]([NH:3][C:4]([NH:13][CH2:12][CH2:11][C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)=[S:5])[CH3:2]
Reactant: NCCc1cccs1
Reactant: CCN=C=S
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=S)NCCc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Ethyl isothiocyanate (1.3 g, 15.0 mmol) was slowly added dropwise to a solution of thiopheneethylamine (1.3 g, 10.2 mmol) in dichloromethane (150 mL). Triethyl amine (3.8 mL, 20.4 mmol) was added dropwise to the mixture and stirred at room temperature for 2 h. After completion of the reaction, pH of the resulting solution was adjusted to about 7 using aqueous 1N HCl, to which water was added. The resulting mixture was extracted with dichloromethane. The residue was purified by flash column chromatography (ethyl acetate:hexanes=1:3), to give the title compound (1.9 g, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:20])[C:13]([CH3:19])([CH3:18])[C:14]([O:16]C)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:20])[C:13]([CH3:19])([CH3:18])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C(=O)O
Temperature: 65 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of (R)-methyl 3-(((benzyloxy)carbonyl)amino)-2,2-dimethylbutanoate (2.2 g, 7.88 mmol) in methanol (25 mL) was KOH (3.54 g, 63.0 mmol) solution and stirred at 65° C. for overnight. Reaction mass was concentrated under reduced pressure to remove methanol. The residue was diluted with water (50 mL) and acidified to pH 5 using 1.5N HCl solution and extracted with ethyl acetate (2×200 mL), the combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield (R)-3-(((benzyloxy) carbonyl)amino)-2,2-dimethylbutanoic acid (1.2 g, 56.9%) as colorless oil. 1HNMR (400 MHz, DMSO-d6) δ ppm: 12.23 (bs, 1H), 7.30-7.39 (m, 5H), 5.03 (s, 2H), 3.92-3.98 (m, 1H), 0.98-1.09 (m, 9H). LCMS conditions: Column: Ascentis C18 (5×2.1 mm-2.7 μm); Mobile Phase A: 2% ACN-98% H2O-10 mM NH4COOH; Mobile Phase B: 98% CAN-2% H2O-10 mM NH4COOH, Flow: 1.0 mL/min, Retention Time: 1.639 min, Purity: 86.5% (m/z=266.2 M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[Li][CH2:12][CH2:13]CC.C(Br)=C>C1COCC1.[Br-].[Zn+2].[Br-].[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH2:13])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: [Li]CCCC
Agent: Cl[Ni]Cl
Agent: C=CBr
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(F)c(F)c(F)c1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 mol of 3,4,5-trifluorobromobenzene and 3 l of THF is admixed at -70° C. with 1 mol of BuLi. Subsequently, a mixture of 0.5 mol of zinc bromide in 1 l of THF is added to the reaction mixture, and this mixture is stirred for 30 minutes at -65° C. Then 1 mol of vinyl bromide and 0.022 mol of nickel(II) chloride/TPP is added.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23]S(C)(=O)=O.[CH2:28](O)[CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36]
Reactant: OCCOCCOCCO
Reactant: COCCOCCOCCOCCOCCOCCOCCOS(C)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO

Procedure:
Monodispersed compound 32 was prepared from compound 31 and monodispersed triethylene glycol using the procedure described above in Example 17. Oil; Rf 0.41 (methanol:chloroform=6:10); MS m/z calc'd for C21H44O11 472.29 (M++1), found 472.29.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:8][NH:9]2)=[CH:5][C:4]=1[C:21]([NH2:23])=[NH:22].CN(C)[CH:26]=[CH:27][CH:28]=O>N1C=CC=CC=1>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:8][NH:9]2)=[CH:5][C:4]=1[C:21]1[N:23]=[CH:28][CH:27]=[CH:26][N:22]=1
Reactant: N=C(N)c1cc2c(/C=C/c3ccc(F)cc3)n[nH]c2cc1F
Reactant: CN(C)C=CC=O
Agent: Cl
Solvent: c1ccncc1
Product: Fc1ccc(/C=C/c2n[nH]c3cc(F)c(-c4ncccn4)cc23)cc1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
36 mg of 6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxamidine hydrochloride obtained by Example 599 and 15 μl of 3-dimethylaminopropenal were dissolved in 1 mL of pyridine, and stirred at 120° C. for 7 hours. After distilling off the solvent, purification by LC-MS was conducted, to give 0.61 mg of the title compound.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[NH:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13].C(N(CC)CC)C>C(Cl)Cl>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13])=[O:9]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC[C@@H](C(=O)N2CCC[C@H]2CO)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
L-pyroglutamic acid (100 g, 0.775 mol), L-prolinol (78.3 g, 0.775 mol) and triethylamine (322 ml) are dissolved in methylene chloride (2.5 l), and a solution of DMC (196.5 g, 1.163 mol) in methylene chloride (600 ml) is added dropwise over a period of forty minutes under water-cooling. The mixture is stirred for a further 3 hours at room temperature, and the reaction liquid is filtered to remove insolubles. The filtrate is concentrated to dryness under reduced pressure, and the residue is crystallized from dioxane-ether to give L-pyroglutamyl-L-prolinol (38.4 g, 23.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([NH2:25])[C:21]([Cl:24])=[N:22][CH:23]=1.O.C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:24][C:21]1[C:20]([N:25]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:19][C:18]([CH3:17])=[CH:23][N:22]=1
Reactant: Cc1cnc(Cl)c(N)c1
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cnc(Cl)c(N=C(Cc2ccc(F)cc2)c2ccncc2)c1
Yield: 64 %

Procedure:
A mixture of p-toluenesulfonic acid (500 mg), 2-(4-fluorophenyl)-1-(pyridine-4-yl)ethanone (10 g, 46 mmoles) and 5-methyl-3-amino-2-chloropyridine (8.6 g, 60 mmoles) in 350 mL of toluene was refluxed overnight with a Dean-Stark removal of water/toluene azeotrope. The reaction mixture was further concentrated, the brown residue suspended in an ethyl acetate/hexane mixture (9/1) and filtered. The solid was solubilised in ethyl acetate and purified by chromatography on silica gel (ethylacetate/hexane 1/1) to give 10 g of (2-Chloro-5-methyl-pyridin-3-yl)-[2-(4-fluoro-phenyl)-1-pyridin-4-yl-ethylidene]-amine as a brown solid.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=CC=CC=1[N+]([O-])=O>>[N+:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:26][CH:25]=1)([O-:35])=[O:34]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccccc2[N+](=O)[O-])o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: O=[N+]([O-])c1ccccc1I
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccccc2[N+](=O)[O-])o1
Yield: 97 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(2-nitrophenyl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (75 mg, 0.113 mmol) and 1-iodo-2-nitrobenzene following General Procedure A. Flash chromatography (3-10% EtOAc/hexanes) yielded the title compound as a yellow oil (58 mg, 97%): 1H NMR (CDCl3, 300 MHz) δ 7.82 (dd, 1 H, J=9.2, 6.3 Hz), 7.70 (dd, 1H, J=9.3, 6.0 Hz), 7.67-7.64 (m, 1H), 7.51-7.49 (m, 1H), 7.32-7.25 (m, 3H), 7.19-7.16 (m, 3H), 4.82 (t, 1H, J=6.7 Hz), 2.60 (t, 2H, J=7.5 Hz), 1.88-1.86 (m, 2H), 1.64-1.60 (m, 2H), 1.35-1.26 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 171.5, 152.5, 151.1, 148.0, 137.6, 134.6, 134.5, 133.6, 133.4, 131.3, 130.7, 129.6, 127.1, 73.8, 41.6, 41.1, 36.6, 34.3, 34.3, 30.9, 30.1, 23.4, 0.2, 0.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH:9]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 70 °C
Reaction time: 0.12 h

Procedure:
To a solution of (3-Hydroxy-phenyl)-carbamic acid tert-butyl ester (2.4 g, 11.4 mmol) in 5 ml of dry DMF, anhydrous potassium carbonate (7.9 g, 57.416 mmol) was added. The mixture stirred for 5-10 minutes, added ethyl-2-bromo-isobutyrate (4.5 g, 22.9 mmol). The resulting mixture was heated at 70° C. for 12 hours. Upon completion (˜25 h), the solution was diluted with EtOAc (25 ml) and washed with saturated NH4Cl (5 ml). The aqueous layer was then extracted for two additional times with EtOAc (10 ml) and the combined organic fractions were washed with brine (2×5 ml). The solution was then dried over Na2SO4 and concentrated to give brown oil. Purification on silica gel (hexanes/acetone) yielded 1.8 g (49%). 1H-NMR (400 MHz, CDCl3): δ 1H NMR (400 MHz, CDCl3): 1.26 (t, J=7.2 Hz, 3H), 1.50 (s, 9H), 1.59 (s, 6H), 6.43 (s, 1H), 6.47-6.50 (m, 1H), 6.96 (t, J=8.4 Hz, 2H), 7.11 (t, J=8.0, 1H).