Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>CN(C=O)C.O>[CH2:21]([S:1][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][S:7][N:8]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: S
Reactant: Clc1nsnc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSc1nsnc1-c1cccnc1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Sodium hydrogen sulfide (0.5 g, 6.8 mmol) was added to a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.5 g, 2.5 mmol) in DMF (20 ml) at room temperature and the reaction mixture was stirred for 30 min. Potassium carbonate (2 g, 14.5 mmol) and butyliodide (1 ml, 8.8 mmol) were added and the reaction mixture was stirred for additionally 10 min. Water (50 ml) was added and extracted with ether. The combined ether phases were dried and evaporated to give the title compound Yield: 0.6 g.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:20]([O:22][C:23](=O)[O:24]CC)[CH3:21].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.C(O)(=O)C>O1CCCC1>[CH2:20]([O:22][C:23]([CH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:24])[CH3:21]
Reactant: Cc1cc(OCCN2CCOCC2)ccc1C(=O)O
Reactant: CCOC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(OCCN2CCOCC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-methyl-4-(2-morpholin-4-yl-ethoxy)-benzoic acid (3.58 g, 13.5 mmole) and diethylcarbonate (2.40 g, 20.4 mmole) in tetrahydrofuran (30 mL) is added dropwise to a solution of lithium diisopropylamide (30.0 mmole) at −78° C. (freshly prepared from diisopropylamine (3.04 g, 30.0 mmole) and n-butyllithium (18.8 mL of 1.6M in hexanes, 30.1 mmole) in tetrahydrofuran (20 mL)) over 15 minutes. This mixture is allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture is cooled with an ice bath then glacial acetic acid (3.1 mL, 54.0 mmole) is added dropwise. The tetrahydrofuran evaporated in vacuo and the mixture is then extracted with ethyl acetate (3×25 mL). The ethyl acetate layer is dried over sodium sulfate, filtered and evaporated. This is purified by HPLC (acetonitrile-water without trifluoroacetic acid and dried to give, 2.81 g, (61%), MS (ESI): m/z 338.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)[CH:14]=1)#[N:2].[BH4-].[Na+].C[OH:33]>C(=O)([O-])O.[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]([CH2:15][C:17]2([OH:33])[CH:22]=[CH:21][CH:20]=[CH:19][NH:18]2)[CH:14]=1)#[N:2]
Reactant: CO
Reactant: N#Cc1ccccc1-c1cc(C(=O)c2ccccn2)cn(-c2ccccc2)c1=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1ccccc1-c1cc(CC2(O)C=CC=CN2)cn(-c2ccccc2)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 25 mg of 3-(2-cyanophenyl)-5-(2-pyridinecarbonyl)-1-phenyl-1,2-dihydropyridin-2-one in 5 ml of methanol was added 2 mg of sodium borohydride under ice-cooling. After 30 minutes, the mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate), to give 15 mg of the title compound as a pale yellow powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[C:34](Cl)(=[O:36])[CH3:35].Cl>C1COCC1>[C:34]([N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:18]([F:20])([F:21])[F:19])[C:14]([F:17])([F:16])[F:15])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COC(c1ccc(NC(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(N(C(C)=O)C(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
Sodium hydride (32 mg, 60% by weight, 0.8 mmol) was suspended in THF (10 ml) and a THF (5 ml) solution of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pheny}-3-methylpyrazine-2-carboxamide (300 mg, 0.67 mmol) was added dropwise thereto. The reaction solution was stirred at room temperature for 30 minutes, and was added with a THF (2 ml) solution of acetyl chloride (63 mg, 0.8 mmol) and stirred overnight. The reaction solution was poured into a diluted HCl solution, followed by extracting with ethyl acetate, and washing with water. The solution was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 0.10 g of the desired compound.
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:9][N:10]=[N+:11]=[N-:12])([CH3:8])[CH2:6][OH:7])=[N+:2]=[N-:3].[CH3:13]I>O1CCOCC1>[CH3:13][O:7][CH2:6][C:5]([CH2:4][N:1]=[N+:2]=[N-:3])([CH2:9][N:10]=[N+:11]=[N-:12])[CH3:8]
Reactant: CI
Reactant: CC(CO)(CN=[N+]=[N-])CN=[N+]=[N-]
Solvent: C1COCCO1
Product: COCC(C)(CN=[N+]=[N-])CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.3 g (43 mmol) of compound 1 were dissolved in 50 ml of dioxane, and 7.2 g of potassium tert.-butylate were added. 6.71 g (47 mmol) of methyl iodide, dissolved in 20 ml of dioxane, were added dropwise to the mixture. After stirring at room temperature for 3 hours, the reaction batch was concentrated in vacuo. The resultant syrup was purified by chromatography over 70 g of silica gel (eluent: hexane/diisopropyl ether 5:1).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([NH2:13])=[N:9][NH:10]2)=[C:6]([O:14][CH3:15])[CH:5]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].Cl>CS(C)=O.O>[NH2:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([F:3])=[CH:5][C:6]=2[O:14][CH3:15])[N:10]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[N:9]=1
Reactant: COc1cc(F)cc2[nH]nc(N)c12
Reactant: N#Cc1cccc(CCl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(F)cc2c1c(N)nn2Cc1cccc(C#N)c1
Reaction time: 0.08 h

Procedure:
Potassium hydroxide (85% pure, 0.84 g, 12.7 mmol) was powdered and added to DMSO (25 mL) and the mixture was stirred for 5 min. A solution of 1:1 mixture of 6-fluoro-4-(methyloxy)-1H-indazol-3-amine and 4-fluoro-6-(methyloxy)regioisomer) (1.085 g, 6 mmol) in DMSO (5 mL) was added and the mixture was stirred for 5 min. The colour of the reaction mixture turned to dark red. Solid 3-(chloromethyl)benzonitrile (1.0 g, 7.1 mmol) was added and the mixture stirred for 1 h. The mixture was diluted with water, treated with 2M HCl (3 mL) and extracted with ethyl acetate. The organic solution was washed with water (4 times) and once with brine, dried (MgSO4) and evaporated. The residue was dissolved in DCM and MeOH and pre-absorbed on florisil (5 g). The pre-absorbed compound was placed on two 100 g Silica cartridges and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-cyclohexane over 60 min. The appropriate fractions (RT=48 min) were evaporated under reduced pressure to give impure title compound as an orange solid. This required further purification and was pre-absorbed on florisil and purified by chromatography on Flashmaster silica 100 g using a 0-100% ethyl acetate-cyclohexane over 100 min. The appropriate fractions (RT=46-70 min) were combined and evaporated in vacuo to give the title compound (362 mg, 20%) as a yellow solid: LCMS (System A) RT=0.96 min, ES+ve m/z 297 (M+H)+, NMR δ (CDCl3) 7.57-7.53 (1H, m), 7.43-7.38 (3H, m), 6.37 (1H, dd, J 10, 2 Hz), 6.15 (1H, dd, J 12, 2 Hz), 5.23 (2H, s), 4.45 (2H, br), 3.94 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)[C:8]2[C:23](=[O:24])[N:22]3[CH2:25][CH2:26][CH2:27][N:21]3[C:9]=2[NH:10][C:11]=1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:5])[CH3:2].C(Cl)Cl>C(#N)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)=[C:8]2[C:23](=[O:24])[N:22]3[CH2:25][CH2:26][CH2:27][N:21]3[C:9]2=[N:10][C:11]=1[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(CCc2ccc(F)cc2)Nc2c(c(=O)n3n2CCC3)C1c1ccc(C(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)c(=O)n1n2CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ceric ammonium nitrate (228 mg, 0.42 mmol) in acetonitrile (1 mL) and water (0.2 mL) was added dropwise to a solution of the product from Step D (102 mg, 0.21 mmol) in acetonitrile (1 mL). The resulting solution was stirred at rt for 2 h and then concentrated at reduced pressure. Trituration of the remaining material with a mixture of CH2Cl2 and water provided E as a light yellow solid (75 mg, 0.15 mmol, 73%): 1H NMR (400 MHz, DMSO-d6) δ 13.05 (br, 1H), 7.95 (d, 2H, J=8), 7.41 (d, 2H, J=8), 7.22 (dd, 2H, J=8, 6), 7.07 (t, 2H, J˜9), 3.87 (m, 4H), 3.77 (t, 2H, J=7), 3.07 (m, 2H), 2.99 (m, 2H), 2.54 (quint., 2H, J=7), 0.75 (t, 3H, J=7) ppm; ESI-MS m/z 490 (M+H)+.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:14]O>>[CH3:14][O:12][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1)=[O:13]
Reactant: O=C(O)c1nccc2ccccc12
Reactant: CO
Product: COC(=O)c1nccc2ccccc12
Yield: 50 %

Procedure:
A mixture of 1-isoquinolinecarboxylic acid (25 g.0.14 mol), 25 g of AMBERLYST®-15 (H+), and 300 ml of methanol was refluxed for 3 days. The reaction mixture was cooled, filtered, and the filtrate was concentrated in vacuo to afford 13.6 g (50%) of 1-isoquinolinecarboxylic acid methyl ester.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]([CH3:25])[CH2:11][CH2:12][CH2:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:15]#[N:16].[C:26](=[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:28])[CH3:27].[ClH:40]>C1COCC1.CCCCCCC.O1CCCC1.O>[ClH:40].[C:15]([C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)([CH2:13][CH2:12][CH2:11][N:10]([CH3:9])[CH3:25])[C:26]([CH:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:27])[CH3:28])#[N:16]
Reactant: COc1cccc(C(C#N)CCCN(C)C)c1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)C(C#N)(CCCN(C)C)c1cccc(OC)c1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A nitrogen atmosphere was applied to a reaction vessel and 50 ml of dry tetrahydrofuran is added. The solvent was cooled to less than −40° C. and 32 mmoles of lithium diisopropylamide in tetrahydrofuranne-heptane was added (16 ml of a 2 M solution). A solution of 6.97 g (30 mmoles) of α-[3-(dimethylamino)propyl]-3-methoxybenzeneacetonitrile in 30 ml of tetrahydrofuran was added at less than −20° C. and left at this temperature for 30 min. The mixture was then cooled to −50° C. and a solution of 6.62 g (33 mmoles) of diethyl isopropylidenemalonate in 30 ml of tetrahydrofuran was added to the reaction mixture at a rate such that the temperature did not exceed −50° C. The mixture was stirred at −50° C. for 30 min and the cold reaction mixture added to a stirred solution of 30 ml of aqueous hydrochloric acid (36% w/w) in 100 ml of water cooled to 10° C. The mixture was extracted twice with toluene and the toluene phase is back extracted with a solution of 2 ml of hydrochloric acid (36% w/w) in 8 ml of water. The aqueous acidic extract was combined with the aqueous acidic phase from above and extracted twice with 50 ml portions of methylene chloride. The combined methylene chloride extracts were washed with water and the methylene chloride phase filtered and concentrated to low volume by distillation at atmospheric pressure. A 100 ml portion of ethyl acetate was added and the resulting slurry cooled to 5–10° C. The resulting solid was collected by filtration, washed with ethyl acetate and dried at 50° C. to give 10.1 g of white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:18]#[N:19].[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:27])[C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:18]#[N:19]
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)cnn(-c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)c1=O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 4 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile, 1.4 parts of potassium carbonate and 22.5 parts of N,N-dimethylformamide were added 2.84 parts of iodomethane at room temperature. The reaction mixture was stirred for 1.5 hours at 40° C. After evaporation in vacuo, the residue was taken up in water. The precipitated product was filtered off and washed with water. After crystallization from acetonitrile, the product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.5 parts (59.2%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-4-methyl-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile; mp. 159.7° C. (intermediate 46).
Reaction SMILES: O([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH2:18][CH:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=1)C1C=CC=CC=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.[BH-](O[C:46]([CH3:48])=[O:47])(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][CH:17]3[O:16][N:15]=[C:14]([C:9]4[CH:8]=[CH:13][CH:12]=[C:11]([O:47][C:46]5[CH:48]=[CH:10][CH:9]=[CH:8][CH:13]=5)[CH:10]=4)[CH2:18]3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: O=CCCC1CC(c2ccccc2Oc2ccccc2)=NO1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(N2CCN(CCCC3CC(c4cccc(Oc5ccccc5)c4)=NO3)CC2)cc1
Yield: 102.4 %

Procedure:
3-(3-(2-Phenoxyphenyl)-4,5-dihydroisoxazol-5-yl)propanal (38.0 mg, 0.122 mmol), 1-(4-fluorophenyl)piperazine (20.0 mg, 0.111 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (70.5 mg, 0.333mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 28.7 mg (56.3%) of the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([N:12]2C(=O)C3=CC=CC=C3C2=O)=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.O.NN>CS(C)=O>[NH2:12][C:5]1[C:4]([F:23])=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][O:10]2
Reactant: O=C1c2ccccc2C(=O)N1c1c(F)cc(Cl)c2c1CCCO2
Agent: NN
Solvent: CS(C)=O
Solvent: O
Product: Nc1c(F)cc(Cl)c2c1CCCO2
Temperature: 0 °C

Procedure:
To a solution of 10.05 g of 41D in 60 mL of DMSO was added 7.58 g of hydrazine hydrate. The mixture was heated to 65°-75° C. for 3 hours, cooled, and poured into ice-water. The mixture was extracted with 3 portions of ether. The ether layer was extracted with water, brine, and dried over MgSO4 to afford 5-amino-8-chloro-6-fluorochromane (41E) as a yellow oil which solidified on standing. m.p.: 47°-50° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:31]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:28]([C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[N:3]=3)[CH:6]=2)[CH:12]=1)=[O:30])([CH3:27])[CH3:26])#[N:29]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.486 mmol) in N,N-dimethylacetamide (2.0 mL) was added cyclopropanecarbonyl chloride (46 μL, 0.510 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), fractions containing the object product was concentrated under reduced pressure, and the residue was triturated with ethyl acetate and diisopropyl ether to give the title compound (100 mg, 43%) as a colorless solid.
Reaction SMILES: C(OC(=O)C)(=O)C.C(OC1C=CC=CC=1NC=[C:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][C:24](S(N)(=O)=O)=[CH:23][CH:22]=2)[N:17]=[C:16]1[CH3:31])C.C[N:37](C1C=CC=CN=1)C>N1C=CC=CC=1>[NH2:37][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[C:19](=[O:20])[CH2:15][C:16]([CH3:31])=[N:17]2)=[CH:22][CH:23]=1
Reactant: CN(C)c1ccccn1
Reactant: CCOc1ccccc1NC=C1C(=O)N(c2ccc(S(N)(=O)=O)cc2)N=C1C
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC1=NN(c2ccc(N)cc2)C(=O)C1
Reaction time: 10 h

Procedure:
0.17 ml of acetic anhydride is added dropwise to a solution of 1.0 g of 4-(4-(2-ethoxyanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzenesulfonamide and 0.9 g of dimethylaminopyridine in 30 ml of pyridine while cooling in ice, and the mixture is then stirred for 10 hours. The residue obtained after concentration in vacuo is mixed with dilute hydrochloric acid, and the crystals which have separated out are filtered off with suction and triturated with ethanol.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:14]=2[CH:30]=1.CN1CCOCC1>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:14]=2[CH:30]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1cccc(CN2CCOc3ccc(N)cc32)c1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCC(=O)Nc1ccc2c(c1)N(Cc1cccc(C(=O)OC)c1)CCO2
Reaction time: 0.5 h

Procedure:
Hexanoyl chloride (0.135 g.) was added dropwise to a stirred solution of methyl 3-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (X) (0.3 g.), and N-methylmorpholine (0.101 g.) in dichloromethane (30 ml.). After 0.5 hours, the mixture was diluted with dichloromethane, washed with water, dried (MgSO4) and evaporated to give an oil which was filtered through a short column of silica gel using 35:65 v/v ethyl acetate:hexane to give the title compound as a syrup: partial NMR (80 MHz, CDCl3): 0.8-1.9 [complex m,9 H, CH3 (CH2)3 ]; 2.2 (m,2 H, CH2CONH); 3.3 (m,2 H, N.CH2.CH2.O; 3.9 (s,3 H, OMe); 4.2 (m,2 H, N.CH2.CH2O); 4.5 (s,2 H, N.CH2Ar).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=4)[C:26]([O:28]CC)=[O:27])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CO.[Li+].[OH-]>C1COCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=4)[C:26]([OH:28])=[O:27])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Reaction time: 0.25 h

Procedure:
Ethyl3-[2-[[2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetyl]amino]thiazol-5-yl]oxybenzoate (Example A2; 16 g, 27 mmol) was taken in THF (200 mL) and Methanol (100 mL) in a 1 L single necked round bottom flask at 20-25° C. To it was added solution of LiOH (11.44 g in 200 mL water, 272 mmol) slowly under vigorous stirring for 15 minutes and further continued to stir for 16 hours. Completion of reaction was confirmed by TLC. Organic solvent was removed under reduced pressure. The obtained residue was diluted with water (200 mL) and washed with ethyl acetate (2×150 mL). The aqueous layer was acidified with 1N HCl to pH 1-2 and extracted with Ethyl acetate (3×150 mL). The combined organic layer was washed with brine (150 mL) dried over anhydrous sodium sulphate and the solvent was removed under vacuum to get the pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[F:27])[C:21](O)=[O:22])=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:61][N:62]1[CH2:68][CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]([C:21]([N:65]3[CH2:66][CH2:67][CH2:68][N:62]([CH3:61])[CH2:63][CH2:64]3)=[O:22])[CH:24]=[CH:25][C:26]=2[F:27])=[CH:15][CH:14]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2cc(C(=O)O)ccc2F)o1
Reactant: CN1CCCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[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: CN1CCCN(C(=O)c2ccc(F)c(-c3ccc(C=C4C(=O)Nc5ccc(Cl)cc54)o3)c2)CC1
Temperature: 25 °C

Procedure:
To 3-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-4-fluorobenzoic acid (39 mg, 0.102 mmol) in DMF was added HBTU (58 mg, 0.153 mmol) and DIEA (53 μL, 0.306 mmol). The mixture was stirred at room temperature then was added 1-methylhomopiperazine (16 μL, 0.122 mmol) and allowed to stir at room temperature. The solid formed was isolated by filtration and purified by HPLC to yield 5-chloro-3-((5-(2-fluoro-5-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=480).