Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[N:26]1[CH:27]=[C:28]([CH:35]=O)[N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12>O1CCCC1.C(OCC)(=O)C>[N:26]1[CH:27]=[C:28](/[CH:35]=[CH:6]/[C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12
Reactant: O=Cc1cnc2ccccn12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc2ccccn12
Temperature: 65 °C
Yield: 51.4 %

Procedure:
(Ethoxycarbonylmethylene)triphenylphosphorane (0.72 g, 2.05 mmol) was added to a solution of imidazo[1,2-a]pyridine-3-carbaldehyde (0.25 g, 1.71 mmol) in anhydrous tetrahydrofuran (THF) (20 mL) at room temperature. The reaction mixture was heated overnight at 65° C. After completion of the reaction as indicated by HPLC, the reaction mixture was diluted with ethyl acetate (EtOAc) (20 mL) and quenched with a saturated solution of ammonium chloride (10 mL). The organic layer was washed with water (3×20 mL) and brine (15 mL). It was dried over anhydrous Na2SO4, filtered and evaporated to get the crude product. This crude was purified by silica gel column chromatography using 50-80% EtOAc in Hexanes to provide pure (E)-ethyl 3-(imidazo[1,2-a]pyridin-3-yl)acrylate (0.19 g) as a white solid. ES+(M+H)+217.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:5]=2[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(OCC)C>[N:15]1([C:2]2[S:3][C:4]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:5]=3[N:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c2nc(Cl)sc12
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(Cl)c2nc(N3CCCCC3)sc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 64.2 %

Procedure:
Under a nitrogen atmosphere a solution of 1.7 grams (6.8 mmole) of 2,4-dichloro-7-nitrobenzothiazole in 150 mL of diethyl ether was stirred as 1.2 grams (13.7 mmole) of piperidine was added via syringe over a ten minute period. The reaction mixture, which had spontaneously warmed, was cooled with ice-water to ambient temperature, where it stirred for 40 minutes. The resulting precipitate was collected by filtration and washed with 50 mL of ethyl acetate. The filtrate was washed with aqueous 0.1N hydrochloric acid and two 50 mL portions of water. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a bright yellow-orange solid, which was combined with a material prepared by a similar route and purified by column chromatography on silica gel. Elution was accomplished with 7:1 followed by 5:1 hexane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.3 grams of 2-(1-piperidinyl)-4-chloro-7-nitrobenzothiazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16](O)=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2].[F:38][C:39]([F:46])([F:45])[CH2:40][S:41]([NH2:44])(=[O:43])=[O:42].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([NH:44][S:41]([CH2:40][C:39]([F:46])([F:45])[F:38])(=[O:43])=[O:42])=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: NS(=O)(=O)CC(F)(F)F
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)NS(=O)(=O)CC(F)(F)F)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
A solution of [6-(4-cyanophenyl)-5-(2-furoyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (Example 29A) (75 mg, 0.15 mmol), 2,2,2-trifluoroethane-sulfonamide (23 mg, 0.16 mmol), 1,3-dicyclohexylcarbodiimide (33 mg, 0.16 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) in dichloromethane (4 ml) is stirred at room temperature for 4 days. The product is extracted with dichloromethane (100 ml), washed with 2 N hydrochloric acid and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 30:70→90:10). The title compound is isolated as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH3:28][O:29][CH2:30][CH2:31][CH2:32][NH2:33]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[NH:33][CH2:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: COCCCN
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: COCCCNC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 3-methoxypropan-1-amine (23 μl, 0.23 mmol) via procedure W to afford 68 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(3-methoxypropyl)carbamimidoyl)-benzamide. MS (Q1) 423 (M)+.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[N+:40]([O-:42])=[O:41])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](=[O:36])(=[O:35])[NH2:34])=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[N+:40]([O-:42])=[O:41])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:36])=[O:35])=[O:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
In a stream of nitrogen and at 0° C., 0.24 ml (1.16 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 435 mg (1.02 mmol) of 3-benzyloxy-4-nitro-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 3 and 274 mg (2.23 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 490 mg (yield: 83.0%) of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:14]3[CH:15]=[C:16]4[CH:22]=[CH:21][N:20]([S:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:17]4=[N:18][CH:19]=3)=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1.Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:26]1([S:23]([N:20]2[C:17]3=[N:18][CH:19]=[C:14]([C:10]4[C:9]([C:7]5[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=5)=[CH:13][N:12]([CH2:33][C:34]#[N:35])[N:11]=4)[CH:15]=[C:16]3[CH:22]=[CH:21]2)(=[O:24])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CSc1nccc(-c2c[nH]nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cn(CC#N)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Temperature: 75 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
To a solution of the 5-{4-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazol-3-yl}-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (C-1-3) (638 mg, 1.42 mmol) and bromoacetonitrile (0.5 mL, 7 mmol) in DMF was added freshly ground Potassium Carbonate (254 mg, 1.84 mmol). The resulting suspension was stirred at 75° C. for 18 hr. LCMS showed complete consumption of starting material. The mixture was partitioned between ethyl acetate and saturated aqueous NaCl. The aqueous layer was extracted with ethyl acetate twice. The combined organics were washed with water twice, saturated aqueous NaCl, dried over MgSO4 and reduced to minimum volume. The residue was purified on silica gel using a gradient of 25 to 100% methyl tert-butyl ether in hexanes as eluent to give [3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-methylsulfanyl-pyrimidin-4-yl)-pyrazol-1-yl]-acetonitrile (C-1-4) (440 mg, 63%) as a crisp foam. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.46 (d, J=2.02 Hz, 1H), 8.36 (d, J=5.31 Hz, 1H), 8.31 (s, 1H), 8.11-8.16 (m, 2H), 8.09 (d, J=2.02 Hz, 1H), 7.83 (d, J=4.04 Hz, 1H), 7.64-7.71 (m, 1H), 7.57 (t, J=7.71 Hz, 2H), 7.01 (d, J=5.31 Hz, 1H), 6.75 (d, J=4.04 Hz, 1H), 5.26 (s, 2H), 1.88 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH3:16])[C:8](=[O:17])[NH:7][C:6]1=[O:18].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>C1COCC1>[CH3:16][C:15]1[CH:14]=[CH:13][S:12][C:11]=1[C:9]1[C:8](=[O:17])[NH:7][C:6](=[O:18])[N:5]([CH2:4][CH2:3][CH:2]=[O:1])[CH:10]=1
Reactant: Cc1ccsc1-c1cn(CCCO)c(=O)[nH]c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccsc1-c1cn(CCC=O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
1-(3-Hydroxy-propyl)-5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 28.36 mg, 0.13 mmol) was dissolved in dry THF (5 mL), the solution was cooled to 0° C. and then Dess-Martin periodinane (97 mg, 0.22 mmol) was added under nitrogen. The mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added and the solution was washed with aqueous saturated NaHCO3 solution. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (7-3) to give 17 mg of the title compound (50% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=3)[CH:14]=2)[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[C:8]=1[OH:9].[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>ClCCCl>[N+:10]([C:7]1[C:8]([OH:9])=[C:3]([OH:2])[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[N:20]=3)[CH:14]=2)[CH:6]=1)([O-:12])=[O:11]
Reactant: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)cc(O)c1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-methoxy-5-nitro-3′-(6-(trifluoromethyl)pyridin-2-yl)biphenyl-4-ol (0.288 g, 0.738 mmol) in 1,2-dichloroethane (10 mL) cooled in an ice-water bath was added aluminium chloride (0.123 g, 0.922 mmol) in one portion followed by pyridine 0.233 g, 2.95 mmol) dropwise. The resulting red suspension was stirred at 80° C. for two hours, then cooled to room temperature and poured onto cold 2 N aqueous hydrochloric acid (100 mL). The precipitate was filtered off, washed with water and dried to give 5-nitro-3′-(6-(trifluoromethyl)pyridin-2-yl)biphenyl-3,4-diol, 0.164 g, (59%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C([Cl:91])N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:91])[N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Reactant: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1cc2nc3c(Cl)n2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Yield: 42 %

Procedure:
Prepared in 42% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.45-7.36 (m, 3H), 7.32 (s, 1H), 5.91-5.64 (m, 1H), 4.65 (d, J=4.8 Hz, 1H), 4.01-3.86 (m, 2H), 3.55-3.48 (m, 1H), 3.40-3.30 (m, 1H), 2.55 (s, 1H), 2.43 (br. s., 3H), 2.33 (br. s., 1H), 2.00-1.48 (m, 10H), 1.19 (br. s., 3H), 1.17 (s, 9H), 1.06 (d, J=5.9 Hz, 3H) LCMS (ESI, M): 695.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)([OH:12])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Fc1ccc(CBr)cc1
Product: CCOC(=O)N1CCC(O)(Cc2ccc(F)cc2)CC1

Procedure:
The title compound was prepared from 1-ethoxycarbonyl-4-piperidone and 4-fluoro-benzylbromide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].Cl.[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:34])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg), glycine ethyl ester hydrochloride (135 mg) and triethylamine (450 mg) were added to pyridine (1,000 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 4 times repeatedly. Ethanol (1 ml) and distilled water (1 ml) were added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain an about 1:1 mixture (106 mg) of the title compound and 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is the raw material, as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1I.[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[CH:18].C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:18]#[C:17][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Reactant: C#CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C#CC1CCCCC1
Reaction time: 8 h

Procedure:
tert-Butyl 4-chloro-3-iodopyridin-2-ylcarbamate (1.0 g, 2.82 mmol) in 10 mL tetrahydrofuran was treated with copper(I) iodide (0.027 g, 0.141 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.099 g, 0.141 mmol) and the mixture was purged with nitrogen for 5 minutes. Ethynylcyclohexane (0.472 mL, 3.67 mmol) and triethylamine (1.179 mL, 8.46 mmol) were added and the mixture was stirred overnight under nitrogen. The mixture was filtered through diatomaceous earth and the filtrate washed with aqueous citric acid (once), water (twice), and brine (once), dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) provided the title compound. MS (DCI) m/e 335/337 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:9][N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH:11]=2)=[CH:3][CH:2]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:34][C:25]4[CH:26]=[N:27][C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:24]=4)=[CH:21][CH:22]=3)=[N:9][N:10]([CH2:12][C:13]([F:15])([F:16])[F:14])[CH:11]=2)=[CH:3][CH:2]=1
Reactant: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)cc1
Reactant: OCc1cnc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Temperature: 60 °C
Yield: 47.3 %

Procedure:
To a solution of 4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol (79 mg) and Quinoxalin-2-yl-methanol (50 mg) in dioxane (2 ml) was added triphenylphosphine (105 mg) and di-t-butyldiazacarboxalate (92 mg) and the reaction mixture heated at 60° C. After 18, the reaction mixture was poured into 1N NaOH, extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated. Purification with MPLC biotage eluting with 2% methanol/0.5% ammonium hydroxide/60% ethyl acetate/hexanes provided the title compound (54 mg). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.52 (m, 2H), 8.13 (m, 1H), 8.10 (m, 1H), 7.79 (m, 2H), 7.73 (s, 1H), 7.40 (d, J=8.7, Hz, 2H), 7.24 (m, 2H), 7.04 (d, J=8.7 Hz, 2H), 5.32 (s, 2H), 4.79 (q, J=8.3 Hz, 2H); MS: (M+H m/z=462.1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[C@H:8]([NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]1[O:32][CH2:31][CH2:30][O:29]1>C(#N)C.O>[O:29]1[CH2:30][CH2:31][O:32][CH:28]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C@H:7]1[C@@H:8]([NH:11][C:12](=[O:21])[CH2:13][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9](=[O:10])[NH:6]1
Reactant: COc1ccc(CN2C(=O)[C@H](NC(=O)COc3ccccc3)[C@@H]2c2ccccc2C2OCCO2)c(OC)c1
Solvent: CC#N
Solvent: O
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1c1ccccc1C1OCCO1

Procedure:
The product of Example 4 (1.56 g, 3 mmol) was dissolved in a mixture of acetonitrile (120 ml) and distilled water (30 ml), degassed with argon for 30 minutes, and brought to reflux. A degassed solution of K2S2O8 (5.67 g, 21 mmol) and Na2HPO4.7H2O (2.81 g, 10.5 mmol) in distilled water (120 ml) was added in 8 equal portions at 4 minute intervals to the refluxing solution, the reaction being kept at pH >6 by the addition of solid Na2HPO4.7H2O. The acetonitrile was evaporated and the residue was extracted with ethyl acetate. The extracts were washed with brine, dried, and evaporated to an oil, 2.07 g. The oil was extracted with petroleum ether to remove the dimethoxybenzaldehyde and then was triturated with ethyl acetate-ether. It was cooled in ice and the resulting solid product was collected; 0.54 g (49%), mp 137-138° dec.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>ClCCl.C(OCC)(=O)C.[Pt]>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cc(Br)ccc12
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A solution of tert-butyl 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propylcarbamate (56.4 g, 133 mmol) in dichloromethane (150 mL) and ethyl acetate (500 mL) and 5% platinum on carbon (15.52 g, 79.56 mmol) were added to a hydrogenation vessel, which was placed under hydrogen pressure (50 psi, 3.4×105 Pa) and shaken overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to provide 52.17 g of tert-butyl 3-[(3-amino-7-bromoquinolin-4-yl)amino]propylcarbamate.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].Cl.[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=NO)c1ccnnc1
Agent: Cl
Agent: N
Product: c1cncc(-c2nc(-c3ccnnc3)no2)c1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and nicotinoyl chloride hydrochloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.75 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 8.32 (dd, J=5.3, 2.2 Hz, 1H), 8.61 (dt, J=8.2, 1.8 Hz, 1H), 8.93 (dd, J=5.1, 1.7 Hz, 1H), 9.39 (dd, J=2.2, 0.8 Hz, 1H), 9.55 (dd, J=5.4, 1.4 Hz, 1H), 9.85 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z 226 (M+H)+.