Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Reactant: O=C1Cc2cc(F)ccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.3 g of 5-fluoro-3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]#[N:11])=[CH:5][CH:4]=1.CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15].CN(C)C=O>CO>[CH3:17][N:16]([CH3:18])[C:14]([CH3:15])=[CH:9][C:7]1[C:6]([C:10]#[N:11])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: COC(C)(OC)N(C)C
Reactant: COc1ccc(C#N)c(C)n1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(C=C(C)N(C)C)n1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
A mixture containing 47.2 g of 6-methoxy-2-methyl-3-pyridinecarbonitrile, 100 ml of dimethylacetamide dimethyl acetal and 100 ml of dimethylformamide was heated with stirring in an oil bath at 130° C. for 1 hour and 45 minutes. The temperature of the oil bath was raised to 150° C. and the methanol formed by the reaction was distilled off using a 12" distillation column (Vigreux) while continuing the heating at 150° C. for 14 hours. The reaction mixture was concentrated, 50 ml of ether was added to the concentrated solution whereupon the product crystallized out. The mixture was chilled and the crystalline solid collected. The solid was washed with cold ether, dried and recrystallized from ethyl acetate using decolorizing charcoal to yield 33.5 g of 2-[2-(dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile, m.p. 103°-104° C.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH2:31])[CH2:29][OH:30].CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH:31][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:29][OH:30]
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NC(CO)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CO)c2ccc(F)cc2F)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(2,4-difluoro-phenyl)-2-hydroxy-ethylamine and DIEA to give 2-[1-(2,4-difluoro-phenyl)-2-hydroxy-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 455 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:20]2[CH:24]=[N:23][N:22]=[C:21]2[CH2:25][N:26]2[C:30](=[O:31])[C:29]3=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]3[C:27]2=[O:36])=[C:8]([CH:19]=1)[C:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])=[O:10])([O-:3])=[O:2].[Cl:37]NC(=O)C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:20]2[C:21]([CH2:25][N:26]3[C:27](=[O:36])[C:28]4=[CH:35][CH:34]=[CH:33][CH:32]=[C:29]4[C:30]3=[O:31])=[N:22][N:23]=[C:24]2[Cl:37])=[C:8]([CH:19]=1)[C:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])=[O:10])([O-:3])=[O:2]
Reactant: O=C(c1cc([N+](=O)[O-])ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F
Reactant: CC(=O)NCl
Product: O=C(c1cc([N+](=O)[O-])ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F

Procedure:
Following the procedure of Example 1, 5-nitro-2-[3-phthalimidomethyl-4H- 1,2,4-triazol-4-yl]-2',6'-difluorobenzophenone is reacted with N-chloroacetamide to form 5-nitro-2-[3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]-2',6'-difluorobenzophenone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][O:15][CH2:16][CH3:17].Cl.[CH:20]([O:23][NH2:24])([CH3:22])[CH3:21]>C(O)C>[CH2:16]([O:15][CH2:14][C:13]1[N:24]([O:23][CH:20]([CH3:22])[CH3:21])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)[CH3:17]
Reactant: CC(C)ON
Reactant: CCOCC(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1OC(C)C
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A solution of N-(4-chloroquinolin-3-yl)-2-ethoxyacetamide (7.3 g, 28 mmol) and O-isopropylhydroxylamine hydrochloride (3.3 g, 0.030 mol) in ethanol (150 mL) was heated at reflux for two hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 4% methanol in dichloromethane containing 3 mL of aqueous ammonium hydroxide per liter of eluent) to provide 2.15 g of 2-(ethoxymethyl)-1-isopropoxy-1H-imidazo[4,5-c]quinoline as a dark oil that crystallized upon standing.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([C:20]1[O:24][N:23]=[C:22]([OH:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CS(C)=O.C(=O)(O)[O-].[Na+]>O.CO>[C:16]([C:20]1[O:24][N:23]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[C:22](=[O:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ccc(-n2oc(C(C)(C)C)cc2=O)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
413.3 g of ethyl 4-chloro-3-nitrobenzoate, 305 g of 5-t-butyl-3-hydroxyisooxazole and 1 liter of dimethyl sulfoxide were mixed, and stirred. Thereto was added 300 g of sodium bicarbonate, and the reaction was run at 90° C. for 8 hours. Thereafter, the reaction mixture was cooled, and thereto were added 1.5 liters of methanol, and further 3 liters of water to precipitate crystals. These crystals were filtered off. Yield: 560.7 g, Percent yield: 93.2%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([CH:18]=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[BH4-].[Na+].Cl.[CH3:25]O>>[CH3:25][O:19][CH2:18][C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12
Reactant: O=Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COCc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1.35 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carboxaldehyde in 90 ml. of absolute methanol is treated with 0.175 g. of sodium borohydride. After stirring for 2 hours at room temperature, excess 1 N aqueous hydrochloric acid is added and the mixture with the methanol is concentrated under reduced pressure. The solid that separates is dissolved in methylene chloride and this solution is washed with a saturated sodium bicarbonate solution and then dried (sodium sulfate). Addition of hexane to this refluxing solution causes the desired compound to crystallize, m.p. 114°-116° C.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:14][C:15](=[CH:17][CH2:18][CH2:19]/[C:20](=[CH:22]/[CH2:23]O)/[CH3:21])[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH3:21][C:20]([CH2:19][CH2:18][CH:17]=[C:15]([CH3:16])[CH3:14])=[CH:22][CH2:23][O:6][C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CCCCCCC(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCC(=O)CCC(=O)OCC=C(C)CCC=C(C)C
Yield: 218.8 %

Procedure:
A solution of 5.2 g 4-oxo-decanoic acid, 13.5 g geraniol, 17.5 g N,N′-dicyclohexyl-carbodiimide and 1.0 g 4-pyrrolidinopyridine in 250 ml of dichloromethane was stirred for 24 hours at room temperature. The precipitate was filtered off, the filtrate was diluted with ether, washed with aqueous hydrochloric acid, saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The resulting oil-cristall mixture was purified by chromatography to yield 19.7 g of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:14])=O.CN(C)C=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cncc1Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1c(Cl)cncc1Cl

Procedure:
Thus obtained 3,5-dichloropyridine-4-carboxylic acid (384 mg, 2 mmol) was dispersed in 1,2-dichloroethane (30 mL) to prepare a slurry, added with thionyl chloride (0.44 mL, 5 mmol), further added with dimethylformamide (0.3 mL), and the mixture was refluxed under heating for 1 hour. The solvent was evaporated under reduced pressure to thereby obtain a crude product of 3,5-dichloropyridine-4-carbonylchloride. 3-(4-aminophenyl)-2-{3-[(2,2-dimethyl propionyl)isobutylamino]-4-methoxyphenyl}propionic acid ethyl ester (2.04 g, 4.5 mmol) obtained in Example 38 was then dissolved in 1,2-dichloroethane (30 mL), and added with pyridine (0.57 mL, 7 mmol). To the mixture, the 1, 2-dichloroethane solution (10 mL) of 3,5-dichloro pyridine-4-carbonylchloride obtained in the above was added, and the mixture was stirred for 1 hour. The reaction solution was treated with water (15 mL), extracted with chloroform, dried over anhydrous sodium sulfate, evaporated under reduced pressure so as to remove the solvent, and the resultant residue was purified through silica gel column chromatography (hexane:ethyl acetate (v/v)=3:2) to thereby obtain 3-[4-(3,5-dichloropyridine-4-carbonylamino) phenyl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionic acid ethyl ester (yield: 2.77 g, yield ratio: 98%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:19])[CH3:18].[H][H]>C(OCC)(=O)C>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:19])[CH3:18]
Reactant: COc1cc(OC)c(C(C)=O)c(O)c1CC=C(C)C
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(C(C)=O)c(O)c1CCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
An ethyl acetate solution of 22.2 g of 2'-hydroxy-4',6'-dimethoxy-3'-(3-methyl-2-butenyl)acetophenone was added into a sufficiently hydrogen gas-absorbed suspension of 1.5 g of 5% palladium-carbon in 20 ml of ethyl acetate, and the mixture was stirred at room temperature for 2 hours in a hydrogen gas atmosphere. After the reaction, the reaction mixture was filtered and the solvent was removed by distillation. The residue was recrystallized from n-hexane to obtain 20.4 g (yield=91.2%) of 2'-hydroxy-3'-isopentyl-4',6'-dimethoxyacetophenone in the form of a colorless needle.
Reaction SMILES: [CH2:1]([N:4]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]1[C:10](=[O:11])[N:9]2[C@H:12]([C:15]([OH:17])=O)[CH2:13][CH2:14][C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+].CCN=C=NCCCN(C)C>CCOC(C)=O.C(Cl)Cl.CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[C:10](=[O:11])[N:9]2[C@H:12]([C:15](=[O:17])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:13][CH2:14][C:8]2=[N:7][CH:6]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)O)CC2
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)Nc1ccccc1)CC2
Temperature: 25 °C

Procedure:
To a solution of 18a (5.50 g, 14.89 mmol) and aniline (1.93 mL, 22.3 mmol) in 75 mL 5:1 CH2Cl2/DMF at 0° C., was added HOAT (2.23 g, 16.4 mmol), NaHCO3 (2.50 g, 29.8 mmol), and EDCI (4.00 g, 20.8 mmol). The mixture was stirred and allowed to warm to rt over 72 h. The reaction was diluted with EtOAc and the organic phase was washed with H2O, 1N HCl, H2O, and brine. The organic phase was dried (Na2SO4) and concentrated. The residue obtained was purified by flash chromatography (80 to 90% EtOAc/hexanes) to afford 3.825 g (58%, 2 steps) of 18b as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([NH2:27])=[O:26])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:6]=2[N:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[C:3]([C:25]([NH2:27])=[O:26])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH2:15][OH:16])[C:6]=2[N:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1cc2c3ccccc3n(CCO)c2nc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-9-(2-(tert-butyldimethylsilyloxy)ethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (xxv-a, 360 mg, 1.06 mmol) was dissolved in tetrahydrofuran (3 mL). A solution of tetrabutylammonium fluoride (1.0 M in THF, 1.3 mL, 1.4 mmol) was added. The resulting solution was stirred at room temperature 3 h. The solution was concentrated under reduced pressure. The residue was triturated with methylene chloride. The resulted solids were dissolved in tetrahydrofuran and washed with brine. The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g silica, methylene chloride to 3% methanol in methylene chloride gradient). The product 9 was isolated as a yellow solid (30 mg, 10% for 2 steps). NH4OAc standard conditions. DAD retention time=5.02 min. M+H=271. 1H NMR (300 MHz, DMSO-d6): 8.66 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.59-7.50 (br s, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.25 (ddd, J=1.7, 7.0, 8.2 Hz, 1H), 7.11 (dd, J=7.0, 7.0 Hz, 1H), 4.30-4.23 (m, 2H), 3.72-3.66 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH3:34][NH:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][N:35]([CH3:34])[C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Reactant: CNCCO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N(C)CCO
Yield: 79.9 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with 2-(methylamino)ethanol (0.35 ml, 4.3 mmol) to give the title compound as a solid (173 mg, 79%), except that the mixture was heated at 45° C. for 24 hours and purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum (2 rotamers) 1.60-1.63 (m, 3H), 3.18 and 2.93 (s, 3H), 3.41-3.65 (m, 4H), 5.01 and 4.75 (br s, 1H), 5.81 and 5.91 (q, 1H), 6.04 (s, 2H), 7.30-7.36 (m, 2H), 7.66 (s, 1H), 7.71-7.78 (m, 3H), 8.84-8.90 (m, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.55 and 8.58 (s, 1H), 11.12 (br s, 1H); Mass spectrum MH+ 504.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].O1CCOCC1.[Br:16]N1C(=O)CCC1=O>O>[Br:16][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: CCc1cccnc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Br)cnc1N
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a solution prepared by dissolving 360 mg of 3-ethylpyridine-2-amine (synthesized according to the method disclosed in International Publication WO2006/025567, page 142) in a mixed solvent of 12 mL of 1,4-dioxane and 4 mL of water, 553 mg of N-bromosuccinimide was added at 0° C., and the mixture was stirred for 1.5 hours at the same temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer thus obtained was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. Thereafter, the insolubles were filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=75/25), to obtain 394 mg of 5-bromo-3-ethylpyridine-2-amine [33-1] (hereinafter, referred to as the compound [33-1]).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.Cl[O-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: OC(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F

Procedure:
2.75 g (0.01 mol) of 2-(2,2,2-trifluoroethoxy)-5-(2,2,2-trifluoro-1-hydroxyethyl)-pyridine and 0.17 g (0.0005 mol) of tetrabutylammonium bromide are dissolved in 25 ml of methylene chloride at room temperature. 12.2 ml (0.012 mol) of an approximately 6% strength sodium hypochlorite solution are metered in within 10 minutes with vigorous stirring and the mixture is stirred for a further 8 hours during which the reaction temperature rises to 27° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.3 mbar, 100°-120° C. bath temperature), 1.31 g (48% of theory) of 2-(2,2,2-trifluoroethoxy)-5-trifluoroacetylpyridine are obtained.
Reaction SMILES: NC1N(C2C=CC=CC=2[O:13]C)N=CC=1C(N)=O.[NH2:18][C:19]1[N:23]([CH2:24][C:25]([F:28])([F:27])[F:26])[N:22]=[CH:21][C:20]=1[C:29]#[N:30]>>[NH2:18][C:19]1[N:23]([CH2:24][C:25]([F:28])([F:27])[F:26])[N:22]=[CH:21][C:20]=1[C:29]([NH2:30])=[O:13]
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Reactant: N#Cc1cnn(CC(F)(F)F)c1N
Product: NC(=O)c1cnn(CC(F)(F)F)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbonitrile provided the tile compound. 400 MHz 1H NMR (DMSO) δ 7.75 (s, 1H), 7.30 (brs, 1H), 6.78 (brs, 1H) 6.58 (m, 2H), 4.88 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([O:35]CC)=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[Li+].[OH-]>O1CCOCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Temperature: 80 °C

Procedure:
Ethyl 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylate from example D.b1 (15.28 g; 29.0 mmol) is dissolved in 1,4-dioxane (150 mL) and aqueous LiOH (prepared from 1.04 g; 43.5 mmol; and 75 mL of water). The stirred reaction mixture is heated to 80° C. until the starting material is consumed according to LC-MS. The mixture is concentrated under reduced pressure, and diluted with water. The product is precipitated by addition of 2M citric acid to adjust pH to 5, isolated by suction filtration, washed with several small portions of water and dried in high vacuo at 40° C. to yield the title compound as pale yellow solid.
Reaction SMILES: [C:1](C1[N-]C=CN=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:24][CH2:25][CH2:26][N:27]=1>C1(C)C=CC=CC=1>[C:1]([N:27]1[CH2:26][CH2:25][N:24]=[C:23]1[NH:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: O=C(c1cccnc1)c1ncc[n-]1
Solvent: Cc1ccccc1
Product: O=C(c1cccnc1)N1CCN=C1Nc1c(Cl)cccc1Cl
Yield: 43.3 %

Procedure:
4.15 g (24 millimoles) of nicotinoylimidazolide and 4.6 g (20 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute toluene are refluxed for 3 hours. The mixture is then concentrated to dryness on a rotary evaporator and the residue is worked up as described in Example 41. 2.9 g of pure 1-nicotinoyl-2-(2',6'-dichlorophenylamino)-2-imidazoline of melting point 172.5°-173.5° C. are obtained; the material is identical with the product obtained according to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][C@H:35]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:37]([C:47]([O:49][CH3:50])=[O:48])[CH2:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:34][C@@H:35]5[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[C@@H:37]([C:47]([O:49][CH3:50])=[O:48])[CH2:36]5)=[O:30])=[CH:32][CH:33]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CN1C(=O)OC(C)(C)C
Yield: 84.9 %

Procedure:
4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (400 mg, 0.834 mmol), (2S,4R)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (224 mg, 0.917 mmol), PyBOP (651 mg, 1.250 mmol), and Hunig's Base (0.728 mL, 4.17 mmol) were stirred in DCM (Volume: 10 mL) for 3 days. The solvent was removed and the crude material was purified by silica gel chromatography using 60% EtOAc/hexanes to give (2R,4S)-1-tert-butyl 2-methyl 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-1,2-dicarboxylate (500 mg). 1H NMR (400 MHz, MeOD) δ ppm 1.33-1.41 (m, 4H), 1.43 (s, 9H), 2.25-2.48 (m, 2H), 3.39-3.47 (m, 1H), 3.78 (s, 3H), 3.81-3.90 (m, 1H), 4.46 (td, J=7.7, 4.8 Hz, 1H), 4.64 (qd, J=5.8, 5.6 Hz, 1H), 4.85-4.93 (m, 2H), 7.20-7.32 (m, 4H), 7.58-7.71 (m, 3H), 7.76-7.92 (m, 1H); LC-MS (Condition A), MS m/z (M++H) 706.1.