Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.O1CCCC1.[H-].[Na+].[CH2:18]([Sn:22]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23]I)[CH2:19][CH2:20][CH3:21]>C(OCC)(=O)C.O.CN(C)C=O>[CH3:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][CH2:23][Sn:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6]1
Reactant: CN1CCN(CCO)CC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To a mixture of 1-(2-hydroxyethyl)-4-methylpiperazine (1.0 g, 6.9 mmol) and tetrahydrofuran (15 ml) was added sodium hydride (60%, 277 mg, 6.9 mmol) at 0° C. (external temperature), and the reaction mixture was stirred at room temperature for 30 minutes. Then, to the reaction mixture was added dropwise a mixture of tributyl-iodomethyl-tin (2.0 g, 4.6 mmol) and N,N-dimethylformamide (15 ml) at 0° C. (external temperature). Then, the reaction mixture was stirred at room temperature for 1.5 hours. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1, NH silica gel) to obtain the title compound (1.9 g, 4.2 mmol, 92%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH2:39]([CH2:41][NH2:42])[OH:40].CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([NH:42][CH2:41][CH2:39][OH:40])[N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: NCCO
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(NCCO)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, ethanolamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76 to give 2-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-ylamino]-ethanol. MS (ES+): 433.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:8]([C:12]([O:14]C)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[C:16]([C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][C:10]2[C:5]([C:6]=1[OH:20])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1c(C(=O)O)nc2cc(Cl)ccc2c1O
Temperature: 60 °C
Yield: 94.5 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (1.0 g, 3.38 mmol) in water (20 mL) was added an aqueous solution of sodium hydroxide (0.27 g, 6.75 mmol). Upon addition, the suspension dissolved. The reaction mixture was warmed to 60° C. for 1 hour. After this time the reaction was cooled to room temperature and acidified with concentrated hydrochloric acid. The product was then extracted into diethyl ether and ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide the title compound as a solid (900 mg). This material was purified by recrystalization employing an ethyl acetate/hexane co-solvent system to provide the title compound (571 mg, 60%) as a white solid mp 296° C. (dec); MS (CI)=238 (M+H). Analysis for C12H8NO5Cl.0.45 CH3CO2CH2CH3.0.10H2O: Calc'd: C, 51.30; H, 3.68; N 4.34, Found: C, 51.28; H, 3.62; N 3.97 1H NMR 8.22 (d, J=8.7 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.28 (dd, J=8.7, 1.8 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [H-].[Na+].C[CH2:4][CH:5](C(OCC)=O)[C:6](OC)=[O:7].Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[N+:23]([O-])=O>CS(C)=O>[Br:22][C:19]1[CH:18]=[C:17]2[C:16]([CH:5]([CH3:4])[C:6](=[O:7])[NH:23]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(CC)C(=O)OC
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1C(=O)Nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride (3.9 g) was suspended in dimethyl sulfoxide (24 mL), and diethyl methyl malonate (16 mL) was added at 0° C., and then the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was heated to 100° C., and a solution of 2,5-dibromonitrobenzene (15.3 g) in dimethyl sulfoxide (17 mL) was added at 100° C., and then the reaction mixture was stirred at 100° C. for 5 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (75 mL), and tin (11.5 g) was added at room temperature. Concentrated hydrochloric acid (45 mL) was added at 0° C., and then the reaction mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (4.9 g) as a brown solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]2[C:8]([C:9](=[O:25])[C:10]([CH3:24])=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:12]2)=[CH:7][CH:6]=1.[C:26]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)#[N:27]>C(O)C.O>[CH3:24][C:10]1[C:9](=[O:25])[C:8]2[C:13](=[C:14]([C:15](=[O:17])[CH:16]=[CH:32][C:31]3[CH:34]=[CH:35][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[O:12][C:11]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-methoxy -8-acetyl-3methylflavone (2.31 g, 0.0075 mol) and 4-cyanobenzaldehyde (0.98 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 2.1 g of product m.p. 223-224C, 1H-NMR (CDCl3)δ:2.18 (s, 3H), 3.96 (s, 3H), 7.04-8.36 (m, 13H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[N:21]1([S:18]([C:15]2[CH:16]=[CH:17][C:8]([O:7][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])(=[O:20])=[O:19])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCOCC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
K2CO3 (138 mg, 1.00 mmol) was added to a stirred solution of methyl 2-hydroxy-5-(4-morpholinylsulfonyl)benzoate (may be prepared as described in Description 64; 300 mg, 1.00 mmol) in acetone (20 ml), followed by the addition of (bromomethyl)benzene (170 mg, 1.00 mmol). The mixture was heated to reflux for 16 h, and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated to yield the title compound as a colourless oil. 380 mg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8](=[O:23])[CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])[CH2:2]1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([CH2:9][C:8]([NH:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:2]3)=[O:23])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CC(=O)NC1CCCNC1
Product: COC(=O)c1cccc(N2CCCC(NC(=O)Cc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 58.5 %

Procedure:
Using N-(piperidin-3-yl)-2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]acetamide (200 mg, 0.572 mmol) and 3-(methoxycarbonyl)phenylboric acid (205 mg, 1.14 mmol), the same procedure was followed as in Example 2 to give 162 mg (59%) of the desired compound as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[N:5][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:8]=1)#[N:2].[OH-].[Li+].CO>C1COCC1>[C:1]([C:3]1[C:4]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[N:5][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:8]=1)#[N:2]
Reactant: CCOC(=O)COc1nc(Nc2cc3ccccc3cn2)cnc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ncc(Nc2cc3ccccc3cn2)nc1OCC(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
Ethyl 2-(3-cyano-6-(isoquinolin-3-ylamino)pyrazin-2-yloxy)acetate (35 mg, 0.099 mmol) was dissolved in THF (1 mL) and lithium hydroxide (2.4 mg, 0.099 mmol) added. The reaction was stirred at room temperature for 15 hours. Methanol (1 mL) was added and the reaction mixture was stirred for a further 24 hours and then concentrated to dryness. Purification by preparative HPLC afforded the title compound (10.8 mg, 0.0336 mmol, 34%). 1H NMR (MeOD, 400 MHz) δ 9.04 (s, 1H), 8.53 (s, 1H), 8.14-8.10 (m, 2H), 7.97 (d, 1H, J=8.0 Hz), 7.72-7.67 (m, 1H), 7.53-7.48 (m, 1H), 4.96 (br s, 2H), 2.67 (s, 1H). LC-MS (2) Rt=1.46 min; No ionization.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[N:59]1([CH2:65][CH2:66]O)[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:66][CH2:65][N:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: OCCN1CCCCC1
Reactant: O=S(=O)(NCCc1ccccc1O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(NCCc1ccccc1OCCN1CCCCC1)c1ccc(Oc2ccc(F)cc2)cc1
Yield: 69 %

Procedure:
200 mg (0.516 mmol) of 4-(4-fluorophenoxy)-N-[2-(2-hydroxyphenyl)ethyl]benzene-sulfonamide are reacted in 20 ml of THF with 230 mg (0.878 mmol) of triphenyl-phosphine, 141 μl (0.774 mmol) of DEAD and 0.165 ml (1.239 mmol) of 2-piperidin-1-ylethanol in analogy to the method described under 3C, resulting in the title compound in a yield of 69%.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([S:14][CH3:15])[CH:8]=2)=[O:4].[OH-].[Na+]>>[CH3:15][S:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([C:3]([OH:4])=[O:2])[NH:6]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(SC)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc2cc(C(=O)O)[nH]c2c1
Yield: 90.8 %

Procedure:
A mixture of methyl-6-methylsulfanyl-1H-indole-2-carboxylate (11.2 g, 51 mmol) and 2N NaOH (125 ml) was heated to reflux temperature for 30 minutes. The clear solution was cooled, and extracted with EtOAc. The aqueous fraction was acidified with concentrated HCl to pH=1, and the precipitate which formed, was filtered and dried to give 6-Methylsulfanyl-1H-indole-2-carboxylic acid (9.6 g, 91.0%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C@@H:10]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:11]([O:13]CC)=[O:12])=[CH:4][C:3]=1[Cl:37].CO.C1COCC1.[OH-].[Li+]>O>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C@@H:10]([NH:16][C:17]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:23][CH2:24]2)=[O:18])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[Cl:37]
Reactant: CCOC(=O)[C@@H](Cc1cc(C)c(N)c(Cl)c1)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1N
Temperature: 40 °C
Reaction time: 20 h

Procedure:
The mixture of 4.1 g (7.8 mmol) ethyl (R)-3-(4-amino-3-chloro-5-methyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionate, 60 ml of methanol and 60 ml THF was combined with a solution of 1.5 g (36.8 mmol) lithium hydroxide in 30 ml of water and stirred for 20 hours at 40° C. The reaction mixture was evaporated down under reduced pressure, the residue was taken up in 50 ml of water and acidified by the addition of 2-molar hydrochloric acid solution. The resulting precipitate was suction filtered and dried at 35° C. in the circulating air dryer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CC(C)(C)OC(=O)NC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-4-yl-carbamic acid tert-butyl ester according to conditions described in general procedure C. Mp: 211-212° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18-1.14 (m, 2 H), 1.34 (s, 9H), 1.57-1.61 (m, 8 H), 2.80 (t, J=12.8 Hz, 2 H), 3.21-3.34 (m, 6 H), 4.19 (bs, 1 H), 6.19 (d, J=5.5 Hz, 1 H), 6.76 (d, J=7.6 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.14 (d, J=9.1 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.54-7.61 (m, 3 H), 7.81-7.83 (m, 1 H), 7.96-7.99 (m, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[F:26][C:27]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28]1.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:29]2[CH2:30][CH2:31][C:27]([F:32])([F:26])[CH2:28]2)[CH2:5][CH2:4]1
Reactant: FC1(F)CCNC1
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N2CCC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (190 mg, 0.50 mmol), 3,3-difluoro-pyrrolidine×HCl (143 mg, 1.00 mmol), DIPEA (0.34 mL, 2.0 mmol) and dioxane (10 mL).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.Cl[CH2:11][CH:12]=O.C([O-])(=O)C.[Na+].CN(C=O)C>O>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[C:5]2[CH:12]=[CH:11][NH:8][C:6]=2[N:7]=1
Reactant: O=CCCl
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2[nH]ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.3 %

Procedure:
A mixture of 2,4-diamino-6-hydroxypyrimidine (300 g, 2.37 mol), chloroacetaldehyde (50% aq. solution, 382 g, 2.43 mol, 303 mL, 1.02 eq.), sodium acetate (195 g, 2.37 mol), DMF (2.5 L), and water (360 mL) was stirred mechanically at rt for 2 days. The resulting solid was collected by filtration, and washed with water (50 mL×3). The mother liquor was concentrated to give additional material which was washed with water (50 mL×3). The combined solid materials were recrystallized from MeOH to give the title compound as a white powder (186 g, 52% yield, HPLC purity: 100%). tR: 2.21 min. 1H-NMR (DMSO-d6) δ 11.00 (br. s, 1H), 10.33 (br. s, 1H), 6.63 (q, 1H), 6.21 (q, 1H), 6.12 (br. s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:8](=[N:12][O:13][CH3:14])[C:9](O)=[O:10])=[C:4]([F:23])[CH:3]=1.S(Cl)([Cl:26])=O>>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:8](=[N:12][O:13][CH3:14])[C:9]([Cl:26])=[O:10])=[C:4]([F:23])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(=O)O
Product: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(=O)Cl

Procedure:
The title compound is prepared by reaction of 3-(4-bromo-2-fluorobenzyl)-2-methoxyimino-4-oxooctanoic acid (from Step F) with thionyl chloride according to the procedure of Example 4, Step D. The material is used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[S:6][C:7]([C:9]3[C:18]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]C)=[O:25])[CH:15]=4)[N:10]=3)=[CH:8][C:4]=2[CH:3]=1.[OH-].[Na+].O>O1CCCC1>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[S:6][C:7]([C:9]3[C:18]([N:19]([CH:21]([CH3:22])[CH3:23])[CH3:20])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[CH:15]=4)[N:10]=3)=[CH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4s3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of methyl 2-(5-fluorobenzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (148 mg, 0.36 mmol) in tetrahydrofuran (25 mL) was added sodium hydroxide (43.4 mg, 1.08 mmol) and water (2 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3N). The solids were collected by filtration to afford 2-(5-fluorobenzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid (69 mg, 49%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(#N)C>S(Cl)(Cl)=O>[NH:2]1[CH:3]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:13])[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Reactant: c1ccc(C2CCCN2)nc1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCCC1c1ccccn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.075 g, 0.39 mmol) was suspended in thionyl chloride (1 mL) and the mixture heated at 60° C. for 1 hour. The mixture was cooled and concentrated by evaporation, azeotroping with toluene (×3). 2-Pyrrolidin-2-yl-pyridine (0.173 g, 1.17 mmol) and acetonitrile (1.5 mL) were added and the reaction mixture stirred for 30 minutes and then the solvent was removed by evaporation. The crude material was purified by HPLC, eluting with 5%-95% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were evaporated, azeotroping with methanol (×3), to give the title compound as a foam (0.025 g). LCMS m/z 325.18 [M+H]+ R.T.=5.07 min (Analytical Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:10][C:11]=2[C:12]2[N:16](COCC[Si](C)(C)C)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:10][C:11]=2[C:12]2[NH:13][CH:14]=[N:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3ncnn3COCC[Si](C)(C)C)s2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a solution of N-{4-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-5-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.112 g, 0.207 mmol) in dichloromethane (2.0 mL) at room temperature was added trifluoroacetic acid (3.1 mL, 40 mmol). The mixture was then stirred at room temperature for 4 hours. The solvent was evaporated and the excess trifluoroacetic acid was removed by azeotroping with toluene. Column chromatography was performed to yield the title compound (0.0520 g, 61%). LCMS: (FA) ES+, 411. 1H NMR (400 MHz, d6-DMSO) δ: 14.46 (s, 1H), 10.69 (s, 1H), 8.80-8.73 (m, 1H), 8.64-8.60 (m, 1H), 8.43-8.37 (m, 1H), 7.59-7.54 (m, 1H), 7.37-7.28 (m, 4H), 4.66 (s, 2H), 2.12 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14]O)=[O:6])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:33])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14][F:33])=[O:6])[CH2:3][CH2:2]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCF)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (0.40 g) obtained in Example 113 in dichloromethane (4.5 ml) was added diethylaminosulfur trifluoride (0.18 ml) at −78° C. The reaction mixture was stirred for 5 hr while gradually heating to room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=6/4 to ethyl acetate). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (0.024 g, 6%).