Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=3[F:24])[C:17]([O:19]C)=O)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][NH2:39])[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:19])[NH:39][CH2:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:21]=[CH:22][C:23]=3[F:24])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CN1CCN(c2ccccc2CN)CC1
Reactant: COC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(Br)ccn34)c2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoate (Intermediate 1A)(1.08 g, 2.75 mmol), TBD (0.383 g, 2.75 mmol) and (2-(4-methylpiperazin-1-yl)phenyl)methanamine (0.565 g, 2.75 mmol) in toluene (35 ml) were heated to 80° C. for 6 hrs. A further portion of TBD (0.06 g, 0.431 mmol) and (2-(4-methylpiperazin-1-yl)phenyl)methanamine (0.100 g, 0.487 mmol) were added and the mixture was heated at 80° C. overnight. TBD (0.06 g, 0.431 mmol) was added and heating continued at 110° C. overnight. Toluene was removed in vacuo and the resulting solid was partitioned between aqueous sodium bicarbonate solution and EtOAc. The organic portion was washed with sodium bicarbonate solution (2×50 ml) and concentrated in vacuo. The resulting oil was dissolved in MeOH and purified by chromatography on silica eluting with 0-10% MeOH in DCM. The fractions were combined and the solvent removed in vacuo. The resulting solid was recrystallised from EtOAc (50 ml) to afford the title compound;
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[C:9]([CH:11]1[CH2:13][NH:12]1)#[N:10]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([NH:6][C:7]([N:12]1[CH2:13][CH:11]1[C:9]#[N:10])=[S:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C=S
Reactant: N#CC1CN1
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=S)N1CC1C#N
Temperature: 25 °C

Procedure:
3.94 g. Ethoxycarbonyl isothiocyanate are dissolved in 75 ml. anhydrous toluene and to this there is added dropwise, at a temperature between 20° and 30° C., a solution of 2.04 g. 2-cyanoaziridine in 50 ml. toluene. The reaction mixture is stirred at ambient temperature for a further hour and the crystals obtained are filtered off with suction, washed with toluene and then triturated with diethyl ether. There are thus obtained 4 g. 1-(N-ethoxycarbonyl-thiocarbamoyl)-2-cyanoaziridine; m.p. 152°-155° C. (foaming up).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:11]3)[CH2:9][N:8]([C:23](=[O:31])[NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)[C:5]2=[CH:6][CH:7]=1.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][OH:18])[CH2:11]3)[CH2:9][N:8]([C:23]([NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)=[O:31])[C:5]2=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCO)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Reaction time: 2 h
Yield: 49.9 %

Procedure:
Ethyl 3-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-3-oxopropanoate (62.1 mg, 0.128 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). Thereafter, sodium borohydride (150 mg, 3.97 mmol) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred for 2 hours while heating under reflux. Thereafter, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (28.2 mg, 49%) in the form of a white amorphous product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]([CH:24]=1)[C:22]#[N:23].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([CH3:16])[CH:18]=[CH:19][C:20]=1[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)#[N:23]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2C#N)c1
Temperature: 90 °C

Procedure:
A Parr pressure reactor was charged with dimethyl 5-bromoisophthalate (1.3 g, 4.8 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (2.0 g, 5.9 mmol), toluene (25 mL), ethanol (5 mL), cesium carbonate (1.7 g, 5.2 mmol), and water (2.5 mL). The mixture was degassed and purged with nitrogen several times before tetrakis(triphenylphosphine)-palladium(0) (280 mg, 0.24 mmol) was added. The tube was sealed and the mixture was heated at 90° C. overnight. After cooling, the mixture was diluted with EtOAc (200 mL), washed with brine, dried over Na2SO4, and concentrated. The residue was purified via flash chromatography to afford the desired product as a white solid. LC-MS: 310.5 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.75 (s, 1H), 8.39 (d, J=1.6 Hz, 2H), 7.61 (s, 1H), 7.49 (dd, J=1.1, 8.5 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 3.98 (s, 6H), 2.46 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCN(C(=O)[C@H](C)O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide hydrochloride (example A168) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:11].[Na].[CH3:13]I>CO>[CH3:1][C:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[S:11][CH3:13]
Reactant: CI
Reactant: Cc1ncn2c(=S)[nH]ncc12
Agent: [Na]
Solvent: CO
Product: CSc1nncc2c(C)ncn12
Reaction time: 0.5 h

Procedure:
A 1.66 gm. portion of 8-methyl-imidazo[1,5-d]-as-triazine-4(3H)-thione is added to a solution of 0.23 gm. of sodium in 10 ml. of methanol. A 0.75 ml. portion of methyl iodide is added, the mixture is allowed to stand for 30 minutes and then evaporated to dryness. The product is chromatographed on a silica gel column. The appropriate fractions are recrystallized from acetone giving the desired product, m.p. 128°-129° C.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(OCC)=O>O>[C:25]1(=[O:34])[N:1]([CH:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([OH:12])=[O:11])[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a stirred solution of d,l-phenylalanine (4.17 g, 25.0 mmol) and sodium carbonate (2.78 g, 26.25 mmol) in 50 mL of water is added N-carboethoxyphthalimide (5.65 g, 25.0 mmol). The resulting slurry is stirred for 1.5 hour and filtered. The pH of the filtrate is adjusted to 1-2 with 4 N hydrochloric acid with stirring. After 20 minutes, the slurry is refiltered and the solid washed with water. The solid is dried in vacuo (60° C., <1 mm) to afford 5.44 g (74%) of 2-phthalimido-3-phenylpropionic acid as a white powder: mp 165°-169° C.; 1H NMR (dmso-d6, 250 M Hz) δ 12.5(br s, 1H), 7.84(s, 4H), 7.23-7.06 (m, 5H), 5.13 (dd, 1H, J=5.0), 3.26-3.05 (m, 2H); 13C NMR (250 MHz, dmso-d6) δ 170.0, 167.0, 137.2, 134.8, 130.6, 128.6, 128.2, 126.5, 123.3, 52.8, 33.8. Anal. Calculated for C17H13NO4. Theoretical: C, 69.15; H, 4.44; N, 4.74. Found: C, 69.07; H, 4.34; N, 4.78.
Reaction SMILES: C(N)(C)C.C([Li])CCC.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>C1COCC1.O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=2)([C:23]#[N:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of isopropylamine (1.53 ml, 10.94 mmol) in THF (30 ml) at −78° C. was added n-butyllithium (4.38 ml of a 2.5M solution in hexanes, 10.938 mmol). After 10 minutes, a solution of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester in THF (12 ml) was added. After a further 1 hour, a solution of 4-chlorobenzyl chloride (1.84 g, 11.4 mmol) in THF (5 ml) was added and the solution warmed to room temperature over 15 hours. Water (150 ml) was added and the aqueous phase extracted with diethyl ether (150 ml). The organic phase was dried over magnesium sulphate and concentrated to give a crude solid that was purified by recrystallisation from diethyl ether/hexane in two batches to give the product as a white solid (2.650 g, 83%). LC-MS (LCT2) m/z 357 [M+Na+], 235 [M-Boc]+, Rt 8.02 min.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][NH2:8])#[CH:3].CN1CCOCC1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35](O)=[O:36])=[C:29]([C:38]([F:41])([F:40])[F:39])[CH:28]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[C:2]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][NH:8][C:35](=[O:36])[CH:34]=[CH:33][C:30]1[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][C:29]=1[C:38]([F:40])([F:39])[F:41])#[CH:3]
Reactant: COc1cc(C(F)(F)F)c(C=CC(=O)O)cn1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: C#Cc1cc(CNC(=O)C=Cc2cnc(OC)cc2C(F)(F)F)cc(F)c1NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 79.5 %

Procedure:
To a suspension of 3-ethynyl-5-fluoro-4-methansulfonylaminobenzylamine hydrochloride (67 mg, 0.24 mmol) m THF (2 mL) was added N-methylmorpholine (40 μL, 0.36 mmol). After stirring for 5 minutes, 3-(6-methoxy-4-trifluoromethylpyridin-3-yl)acrylic acid (50 mg, 0.20 mmol) dissolved in THF (3 mL) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 67 mg, 0.24 mmol) were added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexane to give N-(3-ethynyl-5-fluoro-4-methanesulfonylaminobenzyl)-3-(6-methoxy-4-trifluoromethylpyridin-3-yl)acrylamide (75 mg, 66.2%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl[O-].[Na+].S(=O)(=O)(O)[OH:16]>O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:16])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 15 °C
Yield: 99 %

Procedure:
p-Cyanobenzamide (146 g) which had been synthesized separately and water (584 g) were placed in a four-neck flask, and the mixture was cooled to 15° C. with stirring. Subsequently, an aqueous solution (1775 g) of sodium hypochlorite (effective chlorine 12%) was added to the reaction mixture over six hours while a 50% aqueous solution of sulfuric acid was added so as to maintain the pH of the mixture at 5-6. Liquid chromatographic analysis revealed that the reaction mixture contained 145.5 g of crude p-cyanobenzoic acid (yield 99%). To the reaction mixture, concentrated sulfuric acid was added so as to adjust the pH to 3.0 and precipitate p-cyanobenzoic acid from its salt. The precipitate was dissolved by adding methanol (820 g) with heat, and the solution was cooled for crystallization, to thereby obtain 138.9 g of p-cyanobenzoic acid having a purity of 99.5% (yield 94%).
Reaction SMILES: [CH2:1]([C:3]1[C:24]([CH2:25][CH3:26])=[CH:23][C:22]2[C:5](=[CH:6][C:7]3[C:8](=[O:28])[C:9]4[C:18]([C:19](=[O:27])[C:20]=3[CH:21]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=4)[CH:4]=1)[CH3:2].C([BH-](CC)CC)C.[Li+].Cl>C1COCC1>[CH2:25]([C:24]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]2[C:22](=[CH:21][C:20]3[CH:19]([OH:27])[C:18]4[C:9]([CH:8]([OH:28])[C:7]=3[CH:6]=2)=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=4)[CH:23]=1)[CH3:26]
Reactant: CCc1cc2cc3c(cc2cc1CC)C(=O)c1cc2ccccc2cc1C3=O
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc2cc3c(cc2cc1CC)C(O)c1cc2ccccc2cc1C3O

Procedure:
A solution of 150 mg of 2,3-diethyl-6,13-pentacenequinone dissolved in 30 mL of THF was added to 3.2 mL of a 1 mol/1000 mL THF solution of lithium triethylborohydride, and they were allowed to react with each other at room temperature for 2 hours in a nitrogen atmosphere. The resulting solution was neutralized with diluted aqueous hydrochloric acid, and the organic phase was separated, concentrated and dried under a vacuum to produce 2,3-di ethyl-6,13-dihydro-6,13-dihydroxypentacene almost stoichiometrically.
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:11](=[O:28])[NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29]I>>[ClH:1].[CH3:29][N:10]1[C:11](=[O:28])[C:12]2([CH2:17][CH2:16][N:15]([CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1
Reactant: CI
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCc3ccccc31)CC2
Agent: Cl
Product: CN1CN(c2ccccc2)C2(CCN(C3CCCc4ccccc43)CC2)C1=O

Procedure:
The title compound, m.p. 232-234° C. was prepared in accordance with the general method of example 4 from 1-phenyl-8-(1,2,3,4-tetrahydro-1-naphthyl)-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (1:1) and methyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[C:11]([C:16]([O:18]CC)=[O:17])=[CH:10][NH:9][C:8]=3[C:7](=[O:21])[C:6]=2[CH:22]=1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10][NH:9][C:8]=3[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Agent: Cl
Product: O=C(O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Yield: 87.5 %

Procedure:
A suspension of ethyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate (3.0 g, 0.0094 mole) in 6N hydrochloric acid (100 ml ) was refluxed under nitrogen for 15 hrs., cooled and filtered. The residue was washed with water and with acetone. Recrystallization from DMF gave white crystals (2.4 g, 87%), m.p. 325°-327°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:10]([NH:20][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)C=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c1

Procedure:
A solution of 20.0 g. of bis(4-chlorophenyl)acryloyl chloride in 150 ml. of dichloromethane is added to a stirred solution of 10.3 g. of methyl 3-aminobenzoate and 12.2 ml. of triethylamine in 150 ml. of dichloromethane. This solution is stirred under reflux for 3 hours and then at room temperature overnight and evaporated. The residue is stirred with 300 ml. of boiling acetone, filtered white hot, and the filtrate is chilled. The resulting solid is collected and dried in vacuo, giving 13.8 g. of the desired product as a white solid, m.p. 155°-159° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([O:11][C:12](=[O:31])[NH:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][C:26]=2[CH:27]=[C:28](Br)[CH:29]=1)(=[O:19])=[O:18])([CH3:10])([CH3:9])[CH3:8].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Na+].[Cl-]>O1CCOCC1.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.C(Cl)Cl.CCOC(C)=O>[C:7]([O:11][C:12](=[O:31])[NH:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][C:26]=2[CH:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=1)(=[O:19])=[O:18])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(Br)cc2cnccc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Yield: 94 %

Procedure:
An aqueous Na2CO3 solution (2M, 7.22 mL) is added to a stirred solution of [2-(7-bromo-isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (3.03 g, 7.04 mmol), phenylboronic acid (0.876 g, 7.18 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.407 g, 0.352 mmol) in 1,4-dioxane (36 mL) at ambient temperature under argon. The resultant mixture is heated at 95° C. for 24 hours. At ambient temperature, EtOAc (200 mL)/CH2Cl2 (50 mL) and half-saturated aqueous NaCl solution (200 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. After chromatography on silica gel (gradient 0-3% CH3OH in CH2Cl2), 2.83 g (6.62 mmol, 94% yield) of the title compound is obtained as a white solid. ESIMS: m/z 428 (M+H)+.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.Cl.Cl[CH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.O>CO>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:17][S:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH:23]=1
Reactant: Sc1ncnc2ccccc12
Reactant: Cc1ccnc(CCl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccnc(CSc2ncnc3ccccc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.3 %

Procedure:
13 ml of 28% methanolic solution of sodium methoxide were added to a solution of 5.0 g of 4-mercaptoquinazoline and 5.5 g of 2-chloromethyl-4-methylpyridine hydrochloride in 50 ml of methanol and stirred at room temperature for 5 hours. A reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with an aqueous sodium carbonate solution, dried over sodium sulfate and distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The fraction eluted with 10% ethyl acetate/chloroform was crystallized from isopropyl ether to obtain 1.84 g (22.3%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F-].C([N+:47]([CH2:56][CH2:57][CH2:58][CH3:59])([CH2:52][CH2:53][CH2:54][CH3:55])CCCC)CCC>O1CCOCC1.O>[CH3:33][C@H:28]1[O:29][C@@H:30]([CH3:32])[CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:59]4[CH:55]=[CH:54][CH:53]=[C:52]5[C:58]=4[CH:57]=[CH:56][NH:47]5)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][CH:23]=2)[CH2:27]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)o2)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
To a solution of 6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.103 mmol) in 1,4-dioxane (1.5 ml) and water (0.15 ml) was added {1-[1,1-dimethylethyl)(dimethyl)silyl]1-Hindol-4-yl}boronic acid (37 mg, 0.133 mmol), chloro[Z-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (5.75 mg, 10.27 μmol) and potassium phosphate tribasic (65 mg, 0.308 mmol). The reaction mixture was heated under microwave irradiation at 100° C. for 40 min. The solvent was removed and the residue dissolved in 10% methanol in dichloromethane (2 ml) and purified by silica gel chromatography, eluting with a gradient of cyclohexane and ethyl acetate. The appropriate fractions were concentrated to give a brown gum which was treated directly with tetra-n-butylammonium fluoride (0.2 ml, 0.2 mmol, 1M in tetrahydrofuran) and allowed to stand at 20° C. for 18 h. The solvent was removed and the residue dissolved in 1,4-dioxane (1 ml) and treated with 2M sodium hydroxide (1 ml) and allowed to stand at 20° C. for 48 h. The solvent was removed and the residue triturated with 10% methanol in dichloromethane then purified by silica gel chromatography, eluting with a gradient of dichloromethane and methanol to give a pale brown solid which was further purified by SCX SPE (1 g), eluting with 0.5M ammonia in 1,4-dioxane. The solvent was removed and the residue further purified by MDAP to give the title compound as a white solid (14 mg).