Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCCNS(=O)(=O)c2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(2-amino-ethyl)-benzenesulfonamide hydrochloride and DBU in DME. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][OH:12].Cl.[OH-].[Na+].[CH:16](O)=O>>[Cl:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][OH:12])[CH:16]=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1NCCO
Reactant: O=CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: OCCn1cnc2cccc(Cl)c21
Yield: 93 %

Procedure:
The 2-[(2-chloro-6-aminophenyl)amino]ethanol (72.4 g, 0.388 mol), is dissolved in formic acid (350 ml) and stirred under reflux for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure to give a dark solid, then 500 ml of HCl 2N is added to the residue and the mixture is heated under reflux for 30 min. The solution is cooled on ice and 50% NaOH solution is added until alkaline and the obtained suspension is filtered under vacuum and the resulting solid dried to give the desired product (70.8 g 93%)
Reaction SMILES: [Na].[CH3:2][SH:3].CS(O[C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([C:26](=[O:28])[CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:29])[CH:21]=[CH:22]1)[CH2:17][CH2:16]3)(=O)=O>C(O)C>[CH3:2][S:3][C@@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([C:26](=[O:28])[CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18](=[CH:19][C:20](=[O:29])[CH:21]=[CH:22]1)[CH2:17][CH2:16]3
Reactant: CS
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Agent: [Na]
Solvent: CCO
Product: CS[C@@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 0 °C

Procedure:
To 6.9 gm. of sodium metal dissolved in 225 ml. of ethanol is added 30 ml. of methylmercaptan followed by 10 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat at reflux for 18 hours. Cool the solution to 0° C., filter solids and crystallize from chloroform/hexane to obtain the title compound; m.p. 180°-183° C.; [α]D26 +101.6° (DMF).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH2:19]2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=1.C(=O)([O-])[O-:23].[Na+].[Na+]>O>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH2:19]2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=1)=[O:23]
Reactant: c1ccc(CSc2nc3cccc4c3n2CCC4)nc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(Cc1ccccn1)c1nc2cccc3c2n1CCC3
Temperature: -50 °C
Reaction time: 16 h

Procedure:
A solution of 5,6-dihydro-2-(2-pyridylmethylthio)-4H-imidazo-[4,5,1-ij]quinoline hydrochloride (4.0 g) in water (10 ml) was basified with sodium carbonate solution and extracted into chloroform. The extracts were dried (MgSO)4 and evaporated and the residue was dissolved in methylene chloride (50 ml) and cooled to -50° C. 3-chloroperoxybenzoic acid (2 g) was added with stirring and the solution was allowed to warm to -20° C. when a further (0.5 g) of 3-chloroperoxybenzoic acid was added and the solution was kept at 6° C. for 16 hours. It was then washed (Na2CO3 solution and brine), dried (MgSO4) and evaporated to give an oil which was purified by chromatography on alumina with ethyl acetate as eluent and crystallised from di-isopropylether to give the title compound as a quarterhydrate(2.1 g) mp 100°-102° C. (Found: C, 63.9; H, 5.1; N,14.0. C16H15N3OS, 1/4H2O requires C, 63.7; H,5.2; N,13.9%).
Reaction SMILES: C(O[C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[N:11]=[CH:10]2)C.[NH2:30][CH2:31][CH:32]([OH:44])[CH2:33][N:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1>CCO>[CH2:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:42][CH2:43][N:34]1[CH2:33][CH:32]([OH:44])[CH2:31][NH:30][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1)[N:11]=[CH:10]2
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(OCC(=O)NCC(O)CN4CCc5ccccc5C4)ccc32)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
To a solution of tert-butyl 4-(5-(2-ethoxy-2-oxoethoxy)-1H-indazol-1-yl)piperidine-1-carboxylate (100 mg, 0.248 mmol) in EtOH (2 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (102.2 mg, 0.496 mmol) and the mixture was stirred at 120° C. for 2 h in microwave under N2. The mixture was allowed to cool, concentrated under reduced pressure, purified by TLC (Pet.Ether:EtOAc=1:1) to give tert-butyl 4-(5-(2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-2-oxoethoxy)-1H-indazol-1-yl)piperidine-1-carboxylate (70 mg, yield 50%) as a colorless oil. LCMS (m/z): 564.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[CH:15][CH:14]=1)[C:5]2=O.O.[NH2:27][NH2:28]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:13]3[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[CH:15][CH:14]=3)=[CH:7][NH:28][N:27]=2)[CH:3]=1
Reactant: N#CCCCOc1ccc(-c2coc3cc(O)c(Cl)cc3c2=O)cc1
Reactant: NN
Solvent: O
Product: N#CCCCOc1ccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)cc1
Yield: 71.6 %

Procedure:
This compounds was synthesised in the same manner as described above. 4-[4-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile (0.12 g, 0.34 mmol), Hydrazine hydrate (5 ml). The precipitate formed on quenching was filtered to give 4-{4-[3-(5-Chloro-2,4-dihydroxy-phenyl)-1H-pyrazol-4-yl]-phenoxy}-butyronitrile as a white solid (0.09 g, 71.6%); Rf 0.6 ethyl acetate/hexane (70/30)].
Reaction SMILES: C([O:5][C:6](=[O:35])[C@@H:7]([NH:31][C:32](=[O:34])[CH3:33])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:22])=[O:21])=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:32]([NH:31][C@@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:22])=[O:21])=[C:11]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:10]=1)[C:6]([OH:35])=[O:5])(=[O:34])[CH3:33]
Reactant: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)O

Procedure:
A solution of (S)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid tert-butyl ester (100 mg) in TFA/methylene chloride (1:1) is stirred at RT for 20 min. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: O([C:3](C)(C)C)[K].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])[CH:9]=1.CI.N1C2C(=CC=CC=2)C=C1>CN1C(=O)CCC1.O>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[N:14]([CH3:3])[C:16]([CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH3:24])=[CH:15]2
Reactant: CC(C)(C)O[K]
Reactant: C[C@@H]1CCCN1CCC#Cc1cc(Br)ccc1N
Agent: c1ccc2[nH]ccc2c1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CI
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a cooled (0° C.) suspension of KO-tBu (95%, 6.2 g, 52 mmol) in NMP (120 mL) was added a solution of 4-bromo-2-[4-(2-(R)-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine (8.0 g, 26 mmol) in NMP (50 mL) dropwise keeping the temperature below 5° C. The resulting mixture was then stirred at room temperature for 3 hours under nitrogen. HPLC indicated that all the starting material was consumed. MeI (1.95 mL, 31.3 mmol) was then added. The resulting mixture was stirred at room temperature for 2 hours. HPLC indicated that all the indole intermediate was methylated. H2O (300 mL) was added slowly to the reaction mixture followed by addition of IPAc (400 mL). The resulting mixture was stirred for 5 minutes and the organic layer was separated. The organic layer was washed with 20% brine (3×150 mL), dried over Na2SO4 and treated with activated carbon. After filtration, the filtrate was concentrated under vacuum to give the title compound as a thick oil (7.5 g), which was used in the next coupling reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=1.8 Hz, 1H), 7.36 (dd, J=1.8, 8.7 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 6.37 (s, 1H), 3.81 (s, 1H), 3.40-3.45 (m, 1H), 3.26-3.34 (m, 1H), 3.04-3.16 (m, 2H), 2.51-2.61 (m, 2H), 2.39 (q, J=8.78 Hz, 1H), 2.09-2.14 (m, 1H), 1.87-1.99 (m, 2H), 1.61-1.68 (m, 1H), 1.30 (d, J=6.2 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 140.30, 135.60, 129.18, 123.08, 121.92, 112.29, 109.95, 98035, 60.16, 54.22, 53.19, 32091, 29.86, 26.85, 22.00, 19.34. [M+H]+ at m/z 322.
Reaction SMILES: Cl[CH2:2][C:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:5][O:4]1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:3]([OH:4])([CH2:5][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:2][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:9][CH:10]=1
Reactant: ClCC1(COc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OC(COc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1

Procedure:
9.4 g (0.04 mole) of 2-chloromethyl-2-(4-chlorophenoxymethyl)oxirane are added dropwise to a mixture of 13.6 g (0.2 mole) of 1,2,4-triazole and 13.8 g (0.1 mole) of potassium carbonate in 200 ml of acetone with stirring. The mixture is allowed to stir at room temperature for 15 hours and then under reflux for 22 hours. The reaction mixture is then filtered cold and the filtrate is evaporated in vacuo. The oily residue is dissolved in chloroform, and the solution is washed with water, dried over sodium sulphate and purified by chromatography (silica gel 60, Merck, chloroform/methanol=20:1). 5.8 g (43%) of theory) of 2-(4-chlorophenoxymethyl)-1,3-di(1,2,4-triazol-1-yl)-2-hydroxypropane of melting point 99° C. are obtained.
Reaction SMILES: C1(COC2C=C(C3OC=C(C[NH:20][C:21](=[O:29])[C:22]4[C:27]([OH:28])=[CH:26][CH:25]=[CH:24][N:23]=4)N=3)C=CC=2OC)CC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH2:38][CH3:39].O>C(#N)C.C(OCC)(=O)C>[CH2:37]([O:28][C:27]1[C:22]([C:21]([NH2:20])=[O:29])=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:38][CH3:39]
Reactant: CCCBr
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3O)co2)cc1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCOc1cccnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.1 g of N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-hydroxypicolinamide obtained in Example 45 and 0.16 g of cesium carbonate were dissolved in 4 ml of acetonitrile, and 0.2 g of 1-bromopropane was added thereto and stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The extract was washed with water once, and further washed with saturated aqueous citric acid once. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, yielding 72 mg of white powdery N-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-propoxypicolinamide.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24]C2CCCCC2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:31]([CH2:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:32]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:38]4[CH:39]=[C:34]([CH2:33][C:31]#[N:32])[CH:35]=[CH:36][CH:37]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#CCc1cccc(B(O)O)c1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(CC#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 23.9 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(cyanomethyl)phenylboronic acid (16.7 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 2-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)phenyl)acetonitrile (5.25 mg, 24%). 1H-NMR (MeOD): 2.04 (m, 1H), 2.21 (m, 1H), 3.08 (d, 3H), 3.85 (s, 2H), 5.21 (d, 0.2H), 5.81 (d, 0.8H), 6.94 (d, 1H), 7.11 (m, 1H), 7.24 (m, 2H), 7.35 (m, 3H), 7.39 (m, 5H).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:4].CN(C)CCN(C)C.CC1(C)CCCC(C)(C)N1.C([Li])CCC.[I:43]I.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCCCCC.COC(C)(C)C>[I:43][C:11]1[CH:10]=[C:9]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1]
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1ccc(N2CCSCC2)nc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: CN(C)CCN(C)C
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)Nc1cnc(N2CCSCC2)cc1I
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Under argon) a solution of 75 g (268 mmol) 2,2-dimethyl-N-(6-thiomorpholin-4-yl-pyridin-3-yl)-propionamide, 187 g (1.61 mol) N,N,N′,N′-tetramethylethylenediamine and 85 g (604 mmol) 2,2,6,6,-tetramethylpiperidine in 750 ml tetrahydrofuran was cooled to −65° C. in a dry ice bath. Within 30 min, 805 ml (1.29 mol) of a 1.6 N n-butyllithium solution in hexane were added dropwise. The reaction mixture was allowed to warm up to −15° C. and was stirred for 3 h at this temperature. After cooling again to −70° C., 354 g (1.40 mol) iodine (dissolved in 1000 ml tetrahydrofuran) were added dropwise during 2 h and stirring was continued for 1 h. The suspension was warmed to −60° C. and was poured into 1000 ml of 30% sodium thiosulfate pentahydrate solution. Then, 750 ml tert-butyl methyl ether were added and the organic layer was separated. The aqueous layer was extracted three times with 750-ml portions of tert-butyl methyl ether and the combined organic layers were dried (sodium sulfate) and evaporated. Flash chromatography gave 68.9 g (63%) of the title compound as light brown crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])=[C:11](I)[CH:12]=2)[O:7][C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:4].CO[C:30]1C=CC=C(OC)[C:35]=1[C:36]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])=[C:11]([CH:36]3[CH2:35][CH2:30]3)[CH:12]=2)[O:7][C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 120 °C
Yield: 516.9 %

Procedure:
To 2-(4-Fluoro-phenyl)-5-iodo-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide (7 mg, 0.014 mmol), is added a premixed solution of SPhos (0.571 mg, 1.391 μmol), palladium acetate (0.125 mg, 0.556 μmol) in toluene (0.5 ml) andcyclopropylboronic acid (5.97 mg, 0.070 mmol) premixed with sodium carbonate (0.035 ml, 0.070 mmol). The reaction mixture is heated under microwave irradiation at 120° C. for 10 min. LCMS indicates predominant conversion to product. The toluene layer is transferred to a vial, and the aqueous layer is extracted with toluene and added to the vial. The toluene is removed in vacuo, and the residue is dissolved in DMF, filtered and purified by HPLC to afford 5-Cyclopropyl-2-(4-fluoro-phenyl)-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide (3 mg, 7.19 μmol, 51.7% yield). MS (ESI) m/z 503.9 (M+1). 1H NMR (400 MHz, CD3CN) δ ppm 8.05-8.01 (m, 2H), 7.73 (s, 1H), 7.32-7.27 (m, 2H), 6.82 (br s, 1H), 3.30 (s, 3H), 3.23 (s, 3H), 2.92-2.90 (d, 3H), 2.43-2.38 (m, 1H), 1.12-1.07 (m, 2H), 0.84-0.80 (m, 2H)
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl[C:38]1[CH:47]=[CH:46][C:45]2[CH2:44][CH2:43][N:42]3[C:48]4[CH:49]=[CH:50][CH:51]=[C:52]([F:55])[C:53]=4[CH:54]=[C:41]3[C:40]=2[N:39]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:55][C:52]1[C:53]2[CH:54]=[C:41]3[C:40]4[N:39]=[C:38]([C:19]5[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:11]6[O:10][C:9]([C:8]7[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=7)=[C:13]([C:14]([NH:16][CH3:17])=[O:15])[C:12]=6[CH:18]=5)[CH:47]=[CH:46][C:45]=4[CH2:44][CH2:43][N:42]3[C:48]=2[CH:49]=[CH:50][CH:51]=1
Reactant: CNC(=O)c1c(-c2ccnn2C(C)C)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccnn2C(C)C)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 120 °C
Yield: 36.8 %

Procedure:
To a solution of 2-(1-isopropyl-1H-pyrazol-5-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (78 mg, 0.14 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (35 mg, 0.13 mmol) and K2CO3 (27 mg, 0.19 mmol) in 1,4-dioxane (0.8 mL) and water (0.05 mL) were added X-Phos (10 mg) and Pd2(dba)3 (20 mg) under nitrogen. The mixture was heated at 120° C. for 2 hours and filtered through the Celite pad. The filtrate was extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by the prep-HPLC to give the desired compound (30 mg, yield: 42%). 1H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 7.72 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.28 (s, 1H), 7.17˜7.19 (m, 2H), 6.79˜6.83 (m, 1H), 6.69 (s, 1H), 5.85 (s, 1H), 4.61˜4.64 (m, 1H), 4.35˜4.38 (m, 2H), 3.44 (s, 3H), 3.32˜3.56 (m, 2H), 2.90 (d, J=5.2 Hz, 3H), 2.64 (s, 3H). MS (M+H)+: 627.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH:6]([C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1)=O.C(N)C1C=CC=CC=1>C(O)C>[C:3]([C:2]([C:1]#[N:5])=[CH:6][C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])#[N:4]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Solvent: CCO
Solvent: NCc1ccccc1
Product: N#CC(C#N)=Cc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
Malononitrile (132 mg, 2 mmol) was dissolved in ethanol (6 mL), and 5-formylsalicylic acid (332 mg, 2 mmol) was added. After cooling with ice bath, benzylamine (0.1 mL) was added and the mixture was stirred at room temperature for 2 hours. The separated yellow crystal was filtered and recrystallized (ethanol) to give the title compound (139.9 mg, 32.7%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:47](=[O:57])[N:48]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:49][CH2:50][CH2:51][CH3:52])=[N:4][N:5]([C:8]2[CH:34]=[CH:33][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28]([O:30]CC)=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:6]=1[CH3:7].[Li+].[OH-]>CCO.C1COCC1>[Cl:1][C:2]1[C:3]([C:47](=[O:57])[N:48]([CH2:53][CH2:54][CH2:55][CH3:56])[CH2:49][CH2:50][CH2:51][CH3:52])=[N:4][N:5]([C:8]2[CH:34]=[CH:33][C:11]([C:12]([NH:14][S:15]([C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][C:24]([C:28]([OH:30])=[O:29])=[CH:25]4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[O:13])=[CH:10][C:9]=2[C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)OCC)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccc(C(=O)O)cc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of ethyl 7-(N-(4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoyl)sulfamoyl)-2-naphthoate (Example 16, 84 mg, 0.10 mmol) in EtOH (0.5 mL) and THF (0.5 mL) was added 2N LiOH (0.5 mL, 1.03 mmol). The reaction mixture was stirred for 2 h at 40° C., concentrated to remove volatiles, diluted with water and quenched with 1N HCl. The solution was concentrated in vacuo and purified by preparative HPLC to afford the title compound (57 mg, 68%) as a white solid. 1H NMR (DMSO-d6, 2:1 mixture of amide rotamers) δ 8.41 (s, 1H), 8.36 (s, 1H), 8.07 (t, J=7.3 Hz, 2H), 7.99 (d, J=1.3 Hz, 1H), 7.88 (s, 2H), 7.79 (d, J=8.8 Hz, 1H), 7.55-7.51 (m, 1H), 7.20-7.07 (m, 3.5H), 6.97 (d, J=7.5 Hz, 0.5H), 4.10 (br s, 6H), 2.97 (br s, 1.5H), 2.74 (br s, 1.5H), 2.19 (s, 2H), 2.14 (s, 1H), 1.38 (br s, 1H), 1.29-1.12 (m, 6H), 1.01-0.91 (m, 2H), 0.88-0.82 (m, 3H), 0.68-0.61 (m, 3H); MS(ESI+) m/z 784.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([S:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)(=[O:27])=[O:26])[CH2:13][CH2:14]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)c(C)c1
Yield: 92 %

Procedure:
Sulfonylation of 1-(2,4-dimethylphenyl)piperazine (293 mg, 1.54 mmol) with naphthalene-2-sulfonyl chloride (350 mg, 1.54 mmol) was carried out according to a similar procedure described for example 3A using anhydrous dichloromethane (5 mL) as solvent and diisopropylethylamine (0.670 mL, 3.85 mmol) as base. 1-(2,4-dimethylphenyl)-4-(2-naphthylsulfonyl)piperazine was obtained in 92% yield (539 mg) as white solid.