Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].BrC(C)C>COCCOC>[Br:7][C:8]1[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH:2]([CH3:3])[CH3:1])[CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)Br
Product: CC(C)n1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
Potassium tert-butoxide (16.80 g, 18.63 mL, 142.2 mmol) was added to a suspension of 5-bromo-1H-pyridin-2-one (25 g, 142.2 mmol) in DME (247.5 mL) and the mixture stirred at ambient temperature for 30 minutes. To the mixture was added potassium carbonate (13.76 g, 99.54 mmol) and 2-bromopropane (34.98 g, 26.70 mL, 284.4 mmol) and the reaction mixture heated at reflux for 64 hours. The reaction mixture was filtered to remove the resultant precipitate and the filtrate concentrated in vacuo. The residue was recrystalised from DCM/hexane to give the sub-title product as an off-white solid (19.1 g 62% Yield). 1H NMR (400.0 MHz, CDCl3) δ 1.36 (d, 6H), 5.22 (dt, 1H), 6.49 (d, 1H), 7.31 (dd, 1H) and 7.41 (d, 1H) ppm; MS (ES+) 217.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
3-Cyano-4-fluorobenzenesulfonyl chloride (10 g, 45.53 mmol) was added portion wise to a solution of 2-aminothiazole (5 g, 50.13 mmol) in dichloromethane (50 mL) and pyridine (18.4 mL, 228 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 1 hour a precipitate was observed. The mixture was stirred for 18 hours at room temperature. The mixture was sonicated for 2.5 hours until the solid had dissolved, then left to stir at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and azeotropically dried with toluene (2×100 mL). The residue was diluted carefully with a 1M aqueous solution of hydrogen chloride and stirred for 1 hour at room temperature whereupon a precipitate formed. The brown solid was collected by filtration and triturated with dichloromethane to afford the title compound as a brown solid (7.8 g, 60%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:27])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[C:17]([F:26])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:25])=[CH:19]2)=O)C.CC(C[AlH]CC(C)C)C.C(O)C>C(Cl)Cl>[F:26][C:17]1[C:16]([O:15][C:9]2[C:8]3=[C:7]([CH3:27])[C:6]([CH2:4][OH:3])=[CH:14][N:13]3[N:12]=[CH:11][N:10]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:25])[NH:21]2
Reactant: CCOC(=O)c1cn2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2c1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc2c(F)c(Oc3ncnn4cc(CO)c(C)c34)ccc2[nH]1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
To a solution of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (68 mg 0.19 mmol) in anhydrous methylene chloride (2.0 mL) at −78° C. under argon was added DIBAL (0.48 mmol, 0.48 mL, 1.0M, 2.5 eq.) dropwise. After 5 minutes, the mixture was warmed to −15° C. and allowed to stir for an additional 15 minutes. A drop of ethanol was added to quench the reaction followed by IN sodium hydroxide (0.2 mL) and 1.0 mL of ethyl acetate and 1.0 mL of THF. After 30 minutes, the mixture was filtered to remove the resulting solid. The filtrate was dried, concentrated in vacuo, and chromatographed using silica gel eluting with 40-75% ethyl acetate in hexanes (gradient). Concentration of the desired fractions afforded the title compound (39 mg, 63%) as a clear oil. LC/MS; (M+H)+=327.3
Reaction SMILES: N1CCCCC1.C1C2C(COC([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30](=[O:49])[NH:31][CH2:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[NH:41][CH2:40][C:34]1[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=1[CH2:32][NH:31][C:30]([C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][NH:24]1)=[O:49])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
Piperidine (1.0 mL, 10.0 mmol) was added dropwise to a stirred solution of (S)-{9H-Fluoren-9-yl)methyl-2-[2-{(tert-butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]piperidine-1-carboxylate (0.89 g, 1.47 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 1 h. Solvent was removed under reduced pressure and the crude product was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound (0.45 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=3)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[CH3:42][CH:43]1[O:48][CH2:47][CH2:46][NH:45][CH2:44]1.[OH-].[Na+].Cl>CS(C)=O.CC(O)C>[CH3:42][CH:43]1[O:48][CH2:47][CH2:46][N:45]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:44]1
Reactant: CC1CNCCO1
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4CCOC(C)C4)n3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 90 °C
Reaction time: 30 h
Yield: 11.3 %

Procedure:
2-(Chloromethyl)-N-[6-{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.079 mmol) was added to 2-methylmorpholine (0.5 ml, 0.079 mmol). The reaction mixture was heated in the microwave for 15 min at 90° C. The solvent was blown off under nitrogen. IPA (2 ml) and 2M NaOH (2 ml) were added to the mixture. The reaction mixture was stirred for 30 hours, then neutralised with 2M HCl aqueous to pH 7. The solvent was blown off under nitrogen. The mixture was dissolved in 2 ml of DMSO. Insoluble matter was removed by filtration and purification was carried out by MDAP (Method E) to afford the title compound (5 mg).
Reaction SMILES: C([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][CH2:6][NH:7][C:8](=O)OC(C)(C)C)C.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)CBr>CN(C=O)C.C(OCC)(=O)C>[O:15]1[CH2:16][CH2:17][O:3][CH:4]1[CH2:5][CH2:6][NH:7][CH2:8][C:28]1[CH:27]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:29]=1
Reactant: CCOC(CCNC(=O)OC(C)(C)C)OCC
Reactant: COc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(CNCCC2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a stirred solution of tert-butyl (3,3-diethoxypropyl)carbamate (1.0 g, 4.05 mmol) in DMF (15 mL) was added sodium hydride (0.25 g, 6.25 mmol). The reaction mixture was stirred at room temperature for 30 minutes and 3-methoxybenzyl bromide (0.875 mL, 6.25 mmol) added. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate and washed with water and twice with brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was dissolved in ethanol (10 mL) and 4M hydrogen chloride in dioxane (10 mL) added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated at reduced pressure. The residue was loaded onto an SCX-2 cartridge and eluted with ethanol (4 column volumes) and then 10% triethylamine/ethanol (4 column volumes). The product containing fractions were combined and the solvent evaporated at reduced pressure to afford the title compound (0.543 g, 50%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1([S:13][CH2:12]1)[CH3:11]>CCOCC>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11]
Reactant: Nc1ccccc1N
Reactant: CC1(C)CS1
Solvent: CCOCC
Product: CC(C)(S)CNc1ccccc1N
Temperature: 80 °C
Yield: 26.4 %

Procedure:
o-Phenylenediamine (15.31 g, 1.42×10-1 mol, 100 M%) and 12.46 g (1.42×10-1 mol, 100 M%) isobutylene sulfide (Synder et al, J. Am. Chem. Soc. 69: 2672-2674, 1947) were mixed in a Parr bomb and heated in an oven at 80° C. for 18 hr. The bomb was cooled to room temperature and then opened. The crude brown oil contained some solid. The mixture was dissolved in 150 ml ether (some white solid did not dissolve), washed with saturated aqueous NaCl solution, and the solvent was removed on the rotary evaporator. The oily residue was placed on flash silic in a 600 ml sintered glass funnel and eluted with 500 ml portion of hexane, 90% hexane/ether, twice with 80% hexane/ether and twice with 50% hexane/ether. Evaporation of the first 50:50 hexane/ether fraction gave 7.36 g (26.5%) of 2-amino-1-(2-mercapto-2-methylpropylamino)benzene as a waxy crystalline product, mp 38°-40° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:25][OH:26])([CH3:24])([CH3:23])[CH3:22]>C1C=CC=CC=1>[CH3:16][O:15][CH2:14][O:13][C:12]1[C:11]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:10][C:7]([CH:8]=[N+:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[O-:26])=[CH:6][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NO
Reactant: COCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Solvent: c1ccccc1
Product: COCOc1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 69 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde (11.42 g, 40 mmol) in benzene (200 mL) was added tert-butylhydroxylamine (4.0 g, 50 mmol). The resulting solution was refluxed for 72 h until no more aldehyde was detected by TLC (Rf=0.56 for product and 0.78 for starting material in 1:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was suspended in hexane/EtOAc. The suspension was filtered, washed with hexanes and dried to afford the title compound (69% yield) as a white solid, m.p. 202.2-205.9° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([NH2:23])=[O:22]>>[N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([NH2:23])=[O:22])=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1sccc1N
Reactant: O=C(O)Cc1cccc2ncccc12
Product: NC(=O)c1sccc1NC(=O)Cc1cccc2ncccc12

Procedure:
The title compound was prepared from 2-(quinolin-5-yl)acetic acid and 3-aminothiophene-2-carboxamide using protocol B. Method[1], MS (ESI) 312.1 [M+H], Retention time=0.351 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=[O:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[N:6]=[C:5]2[CH:11]=[O:12]
Reactant: C1=COCCC1
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Yield: 62.5 %

Procedure:
A solution of 5-bromo-1H-indazole-3-carbaldehyde (1.00 g, 4.44 mmol), dihydropyran (912 uL, 10.0 mmol), and p-toluenesulfonic acid monohydrate (16.9 mg, 0.0889 mmol) in DCM (8.8 mL) was stirred at room temperature for 24 h. The reaction was poured into saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (3×5 mL). The combined organic fractions were washed with saturated aqueous sodium chloride (1×10 mL), dried over sodium sulfate, filtered, and concentrated. Purification by ISCO chromatography (10 to 40% ethyl acetate:heptane) afforded 858 mg (56%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1 H), 8.28 (d, J=1.8 Hz, 1 H), 7.92 (d, J=8.3 Hz, 1 H), 7.80-7.61 (m, 1 H), 6.08 (dd, J=2.5, 9.3 Hz, 1 H), 3.99-3.69 (m, 2 H), 2.46-2.26 (m, 1 H), 2.17-1.92 (m, 2 H), 1.87-1.67 (m, 1 H), 1.68-1.53 (m, 2 H); MS (ESI): 309.03, 311.05 [M+H]+; HPLC tR=3.38 min (ZQ3, nonpolar—4 min).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[CH:30][C:29]=2[CH:40]=1>CCOCC>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH:33]([CH:37]([CH3:38])[CH3:39])[C:34]([O:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:4]=3)=[O:35])=[CH:30][C:29]=2[CH:40]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)OCc1ccc(F)c(Oc2ccccc2)c1)c1cc2cc(Cl)ccc2s1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-fluoro-3-phenoxybenzyl alcohol (0.22 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (1.5 mmol) in ether. The mixture is stirred for about 1 hour and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography, gives 4-fluoro-3-phenoxybenzyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: C(OC([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=O)C1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:40][CH2:41][CH2:42][OH:43]>ClCCl.O>[NH2:11][C:12]([CH3:16])([CH3:17])[C:13]([NH:40][CH2:41][CH2:42][OH:43])=[O:15]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(N)C(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (0.5 g) in dichloromethane (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g), 1-hydroxybenzotriazole (0.43 g) and 2-aminoethanol (1.16 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (0.10 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 2-(2-amino-2-methylpropionyl-amino)ethanol (0.11 g). To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (70 mg) in N,N-dimethylformamide (0.5 mL) were added 1-ethyl-3-(3-di-methylaminopropyl)carbodiimide hydrochloride (32 mg), 1-hydroxybenzotriazole (23 mg) and 2-(2-amino-2-methyl-propionylamino)ethanol (0.11 g), and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, 5 mol/L aqueous sodium hydroxide solution (0.25 mL) was added to the filtrate, and the resulting mixture was stirred at room temperature for 1 hour. To the mixture was added acetic acid (0.09 mL), and the mixture was diluted with water (1 mL). The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μL, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol=90/10-10/90) to give 3-(β-D-glucopyranosyloxy)-4-(4-{(1E)-3-[1-(2-hydroxyethylcarbamoyl)-1-methylethylcarbamoyl]prop-1-enyl}phenyl)methyl)-5-isopropyl-1H-pyrazole (14 mg). This material was dissolved in methanol (0.5 mL). To the solution was added 10% palladium-carbon powder (7 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (11 mg).
Reaction SMILES: [C:1]([N:3]([CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)#[N:2].[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl>>[C:12]1([NH:22][C:1]([N:3]([C:4]2[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2)[CH3:11])=[NH:2])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc2ccccc12
Reactant: Cc1cccc(N(C)C#N)c1
Agent: Cl
Product: Cc1cccc(N(C)C(=N)Nc2cccc3ccccc23)c1
Temperature: 25 °C

Procedure:
A mixture of N-cyano-N-methyl-3-toluidine (0.47 g, 3.22 mmol) and 1-naphthylamine.HCl (0.54 g, 3 mmol) in a 5 ml round bottom flask was heated in a preheated oil bath at 170-190° C. for 3 h under N2. The dark brown solution was allowed to cool to room temperature, and it became a rocky solid. The crude product was flash chromatographed on silica gel to yield N-(1-naphthyl)-N′-(m-tolyl)-N′-methylguanidine.HCl (40% yield) as a white powder. Elemental analysis: IR (CH2Cl2): 1625, 1600, 1560 cm−1. 1NMR (CDCl3): δ 2.135 (s, 3H), 3.536 (s, 3H), 6.847-7.972 (m, 11H). 13C-NMR (CDCl3): 20.9, 41.0, 122.6-141.6, 155.8. C19H20N3OCl.1/256 H2O. (Cacl.) C: 70.02%, H: 6.19%, N: 12.89%; (Found) C: 70.33%, H: 6.20%, N: 12.90%
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=2)(=[O:10])=[O:9])[CH:2]=1.Br[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24]>>[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([S:8]([N:7]([CH2:22][C:23]([OH:25])=[O:24])[C:3]2[CH:2]=[C:1]([CH3:20])[CH:6]=[CH:5][CH:4]=2)(=[O:10])=[O:9])=[N:12][CH:13]=1)([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cccc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Product: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)c1

Procedure:
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid m-tolylamide with tert-butyl bromoacetate
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[C:24]([C:27]#[CH:28])[CH:25]=2)[NH:20][C:19](=[O:30])[C:18]=1[C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)CC.Cl[C:44]1[CH:49]=[N:48][CH:47]=[CH:46][N:45]=1>C(OCC)C.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[C:24]([C:27]#[C:28][C:44]3[CH:49]=[N:48][CH:47]=[CH:46][N:45]=3)[CH:25]=2)[NH:20][C:19](=[O:30])[C:18]=1[C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Clc1cnccn1
Reactant: C#Cc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCN
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C#Cc4cnccn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-ethynyl-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (123 mg in 1.5 mL N,N-dimethylformamide) was added tetrakis(triphenylphosphine)palladium (13 mg) followed by copper(I) iodide (22 mg), n-propylamine (0.19 mL) and chloropyrazine (0.026 mL) and the mixture heated to 90° C. on an oil bath. After 10 minutes, the mixture was cooled to room temperature, diluted with diethyl ether and washed successively with water and brine then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 30:70; then 40:60; then 50:50) gave the title compound (69 mg).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:41]1[C:53]2[CH:52]([CH2:54][O:55][C:56]([N:58]3[CH2:63][CH2:62][CH2:61][CH:60]([NH:64][C:65]4[C:70]([NH2:71])=[CH:69][N:68]=[C:67]5[N:72]([S:75]([C:78]6[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=6)(=[O:77])=[O:76])[CH:73]=[CH:74][C:66]=45)[CH2:59]3)=[O:57])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH:41]1[C:53]2[CH:52]([CH2:54][O:55][C:56]([N:58]3[CH2:63][CH2:62][CH2:61][CH:60]([NH:64][C:65]4[C:70]([NH:71][C:5](=[O:7])[CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:69][N:68]=[C:67]5[N:72]([S:75]([C:78]6[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=6)(=[O:77])=[O:76])[CH:73]=[CH:74][C:66]=45)[CH2:59]3)=[O:57])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: O=C(O)CC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC1CC1)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Cyclopropylacetic acid (0.300 g, 3.00 mmol), HATU (1.14 g, 3.00 mmol), and diisopropylethylamine (0.627 ml, 3.60 mmol) were added sequentially to a solution of 3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.78 g, 3.00 mmol) in DMF (50 ml) at 25° C. The reaction mixture was stirred for 1.5 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (125 ml) and EtOAc (2×150 ml). The combined organic layers were dried over Mg2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude 3-[1-benzenesulfonyl-5-(2-cyclopropyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester as a brown foam. LCMS (Method G, ESI): RT=1.24 min, m+H=676.4. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:24])=[CH:4][C:5]([OH:23])=[C:6]([C:8](=[O:22])[CH2:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:12][CH:11]=2)[CH:7]=1.[C:25](OC(=O)C)(=O)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:24])[O:23][C:25]([CH3:26])=[C:9]([C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:12][CH:11]=1)[C:8]2=[O:22]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCCCOc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(OCCCC#N)cc1

Procedure:
This compounds was synthesised in the same manner as described above. 4-{4-[2-(5-Chloro-2,4-dihydroxy-phenyl)-2-oxo-ethyl]-phenoxy}-butyronitrile (0.62 g, 1.8 mmol), acetic anhydride (1.0 ml), potassium carbonate (1 g, 7.2 mmol). 4-[4-(6-Chloro-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile was obtained as a white solid (0.55 g, 82.7%) Rf 0.6 ethyl acetate/hexane (70/30).