Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[ClH:1].[CH2:36]([O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reactant: CCCCCCCBr
Agent: Cl
Product: CCCCCCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)CNC2(c3cccc(C(C)C)c3)CCCCC2)c1
Yield: 34 %

Procedure:
Using methods analogus to those previously described, hydrochloride 11 (0.4 mmol) is reacted with 1-bromoheptane to afford the title compound 59 (0.14 mmol, 34%) as a glass, which can be pulverized to an off-white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.49 (s, 1H), 7.37 (m, 2H), 7.27 (m, 1H), 6.51 (s, 1H), 6.45 (s, 1H), 6.43 (s, 1H), 4.05 (m, 1H), 3.98 (m, 1H), 3.88 (t, J=6.5 Hz, 2H), 2.96 (hept, J=7 Hz, 1H), 2.84 (m, 1H), 2.6 (3H obscured by solvent), 2.36 (m, 1H), 2.16 (m, 2H), 2.01 (s, 3H), 1.85-1.75 (m, 4H), 1.58 (m, 1H), 1.5-1.26 (m, 18H), 0.89 (t, J=6.6 Hz, 3H); MS (CI) m/z 555.5 (MH+).
Reaction SMILES: [CH3:1][C:2]1([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([CH3:35])=[CH:32][CH:33]=5)[NH:28][N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH3:35][C:31]1[CH:30]=[C:29]2[C:34]([C:26]([C:23]3[N:24]=[C:25]4[C:17]([C:15]([NH:14][C:2]5([CH3:1])[CH2:6][CH2:5][NH:4][CH2:3]5)=[O:16])=[CH:18][NH:19][C:20]4=[N:21][CH:22]=3)=[N:27][NH:28]2)=[CH:33][CH:32]=1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C)CCN(C(=O)OC(C)(C)C)C5)c4n3)n[nH]c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C)CCNC5)c4n3)n[nH]c2c1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a stirred solution of tert-butyl 3-methyl-3-(2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)pyrrolidine-1-carboxylate (76 mg, 0.16 mmol) in 6 mL of dichloromethane was added trifluoroacetic acid (3 mL) in one portion at room temperature and stirred for one hour. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 20% acetonitrile/80% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 45% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-methyl-1H-indazol-3-yl)-N-(3-methylpyrrolidin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate (18 mg, 22.9%) as a white solid. MS: (M+H)+=376; 1H NMR (300 MHz, DMSO): δ 13.43 (s, 1H), 9.17 (s, 1H), 8.80 (brs, 1H), 8.49 (s, 1H), 8.38 (d, 1H, J=8.1 Hz), 8.29 (s, 1H), 7.47 (s, 1H), 7.16 (d, 1H, J=8.4 Hz), 3.94 (d, 1H, J=12.0 Hz), 3.51-3.20 (m, 3H), 2.57 (s, 3H), 2.30-2.17 (m, 2H), 1.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[OH:20][CH2:21][C:22]([NH:25][S:26]([C:29]1[CH:30]=[N:31][CH:32]=[C:33](Br)[CH:34]=1)(=[O:28])=[O:27])([CH3:24])[CH3:23]>>[OH:20][CH2:21][C:22]([NH:25][S:26]([C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:18]#[C:17][C:14]2[N:12]3[CH:13]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:9]=[C:10]([CH3:19])[C:11]3=[N:16][CH:15]=2)[CH:34]=1)(=[O:28])=[O:27])([CH3:24])[CH3:23]
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3cncc(S(=O)(=O)NC(C)(C)CO)c3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (270 mg, 1 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) (282 mg, 0.9 mmol) according to general procedure II. Obtained as a light yellow solid (180 mg, 35%). MS (ISP) 495.0 [(M+H)+], 497 [(M+2+H)+]; mp 215-217° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:14][OH:15].CC([O-])=O.[Na+]>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[N:14][OH:15])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCc2cc(Br)ccc2C1
Temperature: 25 °C

Procedure:
To a mixture of 6-bromo-3,4-dihydro-1H-naphthalen-2-one (5.370 g, 23.86 mmol) and hydroxylamine hydrochloride (2.487 g, 35.79 mmol) in EtOH (80 mL) was added a solution of NaOAc (5.871 g, 71.57 mmol) in H2O (20 mL). The mixture was heated to reflux for 2 h. The reaction was cooled to RT and concentrated in vacuo. The residue was suspended in H2O and filtered. The pad was washed with H2O (2×50 mL) and Et2O (2×50 mL) and the solids were dried in vacuo to furnish the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:22][S:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:29]4[CH2:30][CH2:31][N:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:27][CH2:28]4)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CS(=O)(=O)N1CCNCC1
Product: Cn1c(-c2cncc(CN3CCN(S(C)(=O)=O)CC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and 1-methanesulfonyl-piperazine are processed according to the method described in Example 170 to give 6-chloro-2-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 (t, J=4.5 Hz, 4H), 3.14 (t, J=4.5 Hz, 4H), 3.30 (s, 3H), 3.72 (s, 2H), 3.80 (s, 3H), 7.36 (dd, J=8.5, 1.9 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 8.06 (t, J=2.0 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 444.1265 [(M+H)+ Calcd for C22H25ClN5: 444.1261].
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:29])[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:11]([O:10][C:3](=[O:9])[C:4](=[O:6])[CH2:28][C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:29])[CH3:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Yield: 70.9 %

Procedure:
To a solution of 1-(2-hydroxy-phenyl)-ethanone (5 g, 0.03672 mole) in DMF (75 mL) was added NaH (60% w/w dispersion in oil) (1.66 g, 0.0416 mole) and the resulting mixture was stirred at ambient temperature for 15 minutes. Benzyl bromide (7.23 g, 0.0422 mole) was then added and the mixture as stirred for an additional 4 hours. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 8.4 g (100%) of 1-(2-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 84.14%. To a mixture of THF (200 mL) and NaH (60% w/w dispersion in oil) (4.4 g, 0.11 mole) cooled to 0° C. was added diethyl oxalate (10.73 g, 0.07345 mole). The resulting mixture was heated to reflux for 15 minutes. After cooing to ambient temperature, 1-(2-benzyloxy-phenyl)-ethanone (8.3 g, 0.0376 mole) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 8.7 g (71%) of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 78.6%. A solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole), acetic acid (20 mL) and hydrazine hydrate (0.632 g, 0.01264 mole) was heated to reflux for 3 hours. The reaction mixture was then poured into iced water basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.703 g (100%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 97.14%.
Reaction SMILES: Cl[C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[Cl:18][C:14]1[C:15]([O:17][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16][C:11]([N:3]2[CH:2]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)=[C:12]([F:19])[CH:13]=1
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(-n2cc3c(n2)CCCC3)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a solution of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (30 mg) in dimethylformamide (1 ml), there were added potassium carbonate (10 mg) and ethyl bromoacetate (20 mg), and the mixture was stirred at 80° C. for 3 hours. After cooling, water was added to the reaction mixture, followed by extraction with ether. The ether layer was washed with water twice, dried and concentrated. The residue was purified by thin layer chromatography to give 1.8 mg of 3-chloro-2-(4-chloro-2-fluoro-5-ethoxycarbonylmethoxyphenyl-4,5,6,7-tetrahydro-2H-indazole (Compound No. 1) as a glassy substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=1)[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[Se](=O)=[O:20]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=1)[N:8]=[C:7]([CH:18]=[O:20])[CH:6]=[CH:5]2
Reactant: COCCCOc1cc(F)cc2ccc(C)nc12
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: COCCCOc1cc(F)cc2ccc(C=O)nc12
Yield: 87.3 %

Procedure:
To a solution of 6-fluoro-8-(3-methoxypropoxy)-2-methylquinoline (0.22 g, 0.87 mmol) in dioxane (20 mL) and water (0.2 mL) was added selenium dioxide (0.12 g, 1.0 mmol) and the resultant mixture was heated at reflux for 5 hours. The cooled reaction mixture was filtered through a plug of Celite®, washing the solids with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to provide the title compound (0.20 g, 89%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[NH:15][NH2:16].C(O[CH:20]=[C:21]([C:27]#[N:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(O)C>[NH2:28][C:27]1[N:15]([C:3]2[C:2]([F:1])=[C:7]([F:8])[C:6]([C:9]([F:12])([F:11])[F:10])=[C:5]([F:13])[C:4]=2[F:14])[N:16]=[CH:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(F)c(F)c(C(F)(F)F)c(F)c2F)c1N
Yield: 87.3 %

Procedure:
40 g (0.161 mol) of 2,3,5,6-tetrafluoro-4-trifluoromethylphenylhydrazine and 27.8 g (0.161 mol) of ethyl ethoxymethylenecyanoacetate are dissolved in 70 ml of ethanol and the solution is warmed under reflux for 10 hours. The solvent is distilled off in vacuo, the residue is suspended in 100 ml of diethyl ether, the suspension is filtered and the solid is dried. 52.2 g (87.4% of theory) of 5-amino-4-ethoxycarbonyl-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 175° C.-176° C. are obtained.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:10][C:9]=1[OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([O:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)/[CH:42]=[CH:43]/[CH2:44]O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:23]([O:22][C:11]1[CH:12]=[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]([OH:30])[C:10]=1[CH2:44]/[CH:43]=[CH:42]/[C:41]1[CH:46]=[CH:47][C:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[C:39]([O:38][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:40]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Oc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1Cc1ccccc1
Reactant: OC/C=C/c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: ClCCl
Product: Oc1c(C/C=C/c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)c(OCc2ccccc2)cc(OCc2ccccc2)c1Cc1ccccc1
Reaction time: 8 h
Yield: 46 %

Procedure:
At rt under an N2 atmosphere, 25% H2SO4/SiO2 (1.6 g, 4 mmol) was added in one batch to the stirred mixture of 2-benzyl-3,5-bis(benzyloxy)phenol (3.96 g, 10 mmol) and (E)-3,4-bis(benzyloxy)cinnamyl alcohol (3.46 g, 10 mmol) in dry CH2Cl2 (80 mL). The resulting mixture was starred at rt overnight. After filtration and evaporation, the residue was purified by column chromatography on silica gel (EtOAc/n-hexane=1/7 v/v) and recrystallized from EtOAc and n-hexane to give a white solid, (3.4 g, 46.0% yield): mp 93-95° C.; 1H NMR (CDCl3, 400 MHz) δ 7.41-7.22 (m, 30H), 6.92 (s, 1H) 6.79 (s, 1H), 6.78 (d, J=4.0 Hz, 1H), 6.35 (A of AB, J=15.8 Hz, 1H), 6.26 (s, 1H), 6.13-6.07 (B of ABt, J=15.8, 5.0 Hz, 1H), 5.08 (s, 2H), 5.07 (s, 2H), 4.99 (s, 4H), 4.02 (s, 2H), 3.55 (d, J=5.0 Hz, 2H); 13C NMR (CDCl3, 400 MHz) δ 156.1, 155.6, 154.0, 148.9, 148.2, 141.1, 137.2, 137.1, 131.0, 130.1, 128.5, 128.4, 128.2, 127.8, 127.7, 127.6, 127.3, 127.2, 127.1, 126.5, 125.7, 119.7, 114.9, 112.4, 109.6, 107.3, 91.4, 71.1, 70.5, 70.3, 28.8, 26.6; HRMS (ESI): calcd for C50H44O5Na (M+Na) 747.3086, found 747.3096.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[O:5][C:4]([C:21]([O:23]CC)=[O:22])=[CH:3]1.O>C(O)(=O)C.Cl>[O:1]=[C:2]1[C:7]2[N:8]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[O:5][C:4]([C:21]([OH:23])=[O:22])=[CH:3]1
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2-c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(=O)c2c(o1)c1ccccc1n2-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.0 g (0.0033 mole) of ethyl 4,5-dihydro-4-oxo-5-phenylpyrano[3,2-b]indole-2-carboxylate in 10 ml glacial acetic acid and 2.0 ml conc. hydrochloric acid was stirred at reflux for 41/2 hr, then cooled and added to 75 g ice--H2O. The solid was filtered, washed with cold water, then added to a mixture of 35 ml 5% aqueous sodium carbonate and 250 ml water. After filtering by gravity, the aqueous solution was washed three times with 75 ml chloroform, cooled in ice, and acidified with 4.0 N hydrochloric acid. The orange precipitate was filtered, digested 15 min on the steam bath with 25 ml water and re-filtered warm. Recrystallization from DMF-water yielded an off-white solid of mpt. >290°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([O:16]CC)=O)[NH:12][CH:13]=1.ClC1C=CC=CC=1C1C=C(C(OC)=O)[NH:29][N:30]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([NH:29][NH2:30])=[O:16])[NH:12][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)n[nH]1
Reactant: CCOC(=O)c1cc(-c2cccc(C)c2C)c[nH]1
Product: Cc1cccc(-c2c[nH]c(C(=O)NN)c2)c1C
Yield: 59 %

Procedure:
According to the same procedure as in the Step 22-1-3 except that ethyl 4-(2,3-dimethylphenyl)-1H-pyrrole-2-carboxylate obtained in the Step 24-1-3 was used instead of methyl 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate, the title compound (25 mg, 59%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:15][O:16][C:17]1[CH:57]=[CH:56][C:20]([CH2:21][N:22]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([C:30]3[C:31]([NH:38][C:39]4[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=4)=[N:32][CH:33]=[C:34]([CH:37]=3)[CH:35]=[O:36])[N:24]=2)=[CH:19][CH:18]=1>>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][N:22]([CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:57][CH:56]=2)[C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([C:30]3[CH:37]=[C:34]([CH:35]([OH:36])[C:9]4[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:14])[CH3:1])(=[O:5])=[O:4])=[CH:7][CH:8]=4)[CH:33]=[N:32][C:31]=3[NH:38][C:39]3[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[N:24]=2)=[CH:53][CH:52]=1
Reactant: CN(C)S(=O)(=O)c1ccc([Mg]Br)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 16 h
Yield: 73.8 %

Procedure:
(4-(N,N-Dimethylsulfamoyl)phenyl)magnesium bromide (0.48 M in THF) (2545 μL, 1.222 mmol) was added to 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (176.4 mg, 0.305 mmol) to give a deep orange solution. The solution was stirred for 16 h and then quenched with MeOH (1.0 mL). The product was extracted into DCM from water, dried (MgSO4), and purified by flash chromatography (0 to 10% to 20% to 30% EtOAc/DCM) to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-N,N-dimethylbenzenesulfonamide (171.5 mg, 0.225 mmol, 73.6% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.51 (s, 1H); 8.74 (s, 1H); 8.30 (dd, J=4.11, 2.54 Hz, 2H); 7.85 (d, J=2.35 Hz, 1H); 7.55-7.72 (m, 4H); 7.26 (d, J=8.22 Hz, 2H); 7.19 (d, J=8.41 Hz, 2H); 6.90 (d, J=8.41 Hz, 2H); 6.83 (d, J=8.61 Hz, 2H); 6.74 (d, J=9.00Hz, 1H); 6.19 (d, J=3.91 Hz, 1H); 5.86 (d, J=4.11 Hz, 1H); 4.68-4.91 (m, 4H); 3.82 (s, 3H); 3.74 (s, 3H); 3.70 (s, 3H); 2.56 (s, 6H); 2.54 (s, 3H). m/z (ESI, +ve ion) 763.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccccc2c1

Procedure:
In an analogous manner to that described in Example 14(a), by alkylating ethyl 4-hydroxy-naphthalene-2-carboxylate [J. Agric. Chem Soc. Japan 24, 313 (1950)] with benzyl bromide there was obtained ethyl 4-benzyloxy-naphthalene-2-carboxylate as an almost colourless solid, Rf : 0.53 (SiO2, hexane:ethyl acetate=4:1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH2:33])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH2:33])[N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(N)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 6-1 (46 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 6-2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.[CH3:27][N:28](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:27]#[N:28])[CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
2-[(E)-2-(2,4-Difluorophenyl)vinyl]-5-[(3-bromophenyl)sulfonyl]pyridine (Example 27, 340 mg, 0.779 mmol) and zinc cyanide (110 mg, 0.93 mmol) were combined in N,N-dimethylformamide (5 mL) and degassed. Tetrakis-(triphenyl phosphine)palladium(0) (68 mg, 0.059 mmol) was added and the reaction heated at 100° C. under nitrogen for 6 hours. Further tetrakis(triphenylphosphine)palladium(0) (60 mg) was added and heating continued for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried over MgSO4 and concentrated in vacuo. The residue was purified by mass-triggered preparative HPLC (Nebula) to give the title compound as a beige solid (56 mg, 19%). This was purified further by recrystallisation from isopropyl alcohol/dichloromethane. δH (500 MHz, d6 DMSO): 9.16 (1H, s), 8.57 (1H, s), 8.40 (1H, dd, J=2.2, 8.4 Hz), 8.33 (1H, d, J=8.2 Hz), 8.18 (1H, d, J=78 Hz), 7.96-7.82 (3H, m), 7.76 (1H, d, J=8.3 Hz), 7.46 (1H, d, J=16.1 Hz), 7.36-7.31 (1H, m), 7.20-7.16 (1H, m); m/z (ES+) 383 [MH+].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][CH:4]=1.[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19].O>O1CCCC1>[CH2:19]([N:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4]1)[C:18]#[CH:17]
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCn1cc(C(=O)OCC)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
1 g of ethyl 3-trifluoromethyl-1H-pyrrole-4-carboxylate of Step A was introduced into 10 ml of tetrahydrofuran, followed, at 0° C. by 240 mg of sodium hydride at 50% in vaseline oil in small portions. After stirring for 30 minutes at 20° C. and cooling to 0° C., a solution of 0.45 ml of propargyl bromide in 1 ml of tetrahydrofuran was added with stirring for 30 minutes at 0° C., then for 1 hour at 20° C., followed by cooling again to 0° C. A little sodium hydride was added then 0.45 ml of propargyl bromide in solution in 1 ml of tetrahydrofuran with stirring at 0° C. The mixture was poured into water and extracted with methylene chloride. The extracts were concentrated to dryness by distilling under reduced pressure and the residue was chromatographed over silica. Elution with a mixture of hexane and ethyl acetate (8-2) yielded 0.950 g of ethyl 1-(2-propynyl)-3-trifluoromethyl-1H-pyrrole-4-carboxylate melting at 58° C.