Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[CH3:40][NH2:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.CC(O)=O>[Cl:1][C:2]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:41][CH3:40])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNCc1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 16.9 %

Procedure:
A solution of 4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzaldehyde, (0.0443 g, 0.080 mmol) in dichloromethane (1 ml) and AcOH (00.1 mL), was treated with CH3NH2 (40% solution in H2O, 0.073 mmol) at ambient temperature. To the mixture was added NaBH(OAc)3 (0.017 g, 0.080 mmol), and the reaction was stirred overnight. The reaction mixture was then concentrated, in vacuo, to an oil, which was then dissolved in DMSO and purified via reverse-phase HPLC to afford the title compound (0.007 g, 15%); MS (ES+) m/e 568 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[C:4]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])[C:5](=O)[NH:6][N:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:5]1[N:6]=[N:7][C:2]([CH3:1])=[C:3]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:4]=1[C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(C(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
2.43 g of 6-methyl-5-(4-trifluoromethylphenyl)-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.50 g of 3-chloro-6-methyl-5-(4-trifluoromethylphenyl)-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xxiv) of the present invention).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[C:8]([NH2:19])=[N:7][C:6]=1[CH3:20])[CH3:2]>[Zn].C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([NH2:16])[C:8]([NH2:19])=[N:7][C:6]=1[CH3:20])[CH3:2]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(N)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCNc1c(N)c(N)nc(C)c1C(=O)OCC
Reaction time: 0.17 h

Procedure:
29.6 g. of 6-amino-4-butylamino-2-methyl-5-nitronicotinic acid ethyl ester (0.1 mol.) are dissolved in 150 ml. of acetic acid. The solution is heated at reflux temperature. Zinc is added carefully until the mixture is colorless (about 20 g.). Heating is continued for an additional 10 minutes. The mixture is then evaporated to dryness and about 100 ml. of water are added. The solution is neutralized with dilute aqueous ammonia and extracted three times with 100 ml. portions of ether. The ether extracts are combined, dried with calcium chloride and the solvent evaporated. The oily residue. 5,6-diamino-4-butylamino-2-methylnicotinic acid ethyl ester, crystallizes from methanol, yield 21 g. (79%), m.p. 82°-83° methanol/H2O).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:15]1[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:17][C:16]=1[O:30]C(=O)C(C)(C)C)([CH3:14])([CH3:13])[CH3:12]>CCCCCC>[C:11]([C:15]1[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:17][C:16]=1[OH:30])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(C)Cc2c(c(C(C)(C)C)cc(OC(=O)C(C)(C)C)c2C(C)(C)C)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CC1(C)Cc2c(c(C(C)(C)C)cc(O)c2C(C)(C)C)O1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Under a nitrogen stream, 3.60 ml of diisobutylaluminium hydride (IM in n-hexane) was added dropwise into a solution of 0.43 g of 4,7-di-t-butyl-2,2-dimethyl-5-trimethylacetoxy-2,3-dihydrobenzofuran in 5 ml of n-hexane at room temperature, and the mixture was stirred overnight. After the reaction was quenched with 5% hydrochloric acid, the reaction solution was extracted with water and ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified on a short column of silica gel (in n-hexane containing 0.2%-1% ethyl acetate) to give 0.22 g of 4,7-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran as a white solid (yield 67%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][CH2:23][CH2:24][OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:22][CH2:23][CH2:24][OH:25])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCCO
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NCCO)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 3 (100 mg, 0.35 mmol) was reacted with 2-aminoethanol (CAS 141-43-5) (43 mg, 0.7 mmol), HATU (276 mg, 0.7 mmol) and DIPEA (0.30 mL, 1.8 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(2-hydroxyethyl)benzamide 7. LC/MS (ESI+): m/z 328 (M+H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.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]>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CS)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(SCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 1, 1.41 g, 4.15 mmol), tert-butyl 4-(mercaptomethyl)piperidine-1-carboxylate (prepared in STEP B of Example 5, 1.20 g, 5.19 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (120 mg, 0.208 mmol), tris(dibenzylideneacetone)dipalladium(0) (95.2 mg, 0.104 mmol) and N,N-diisopropylethylamine (1.09 mL, 6.23 mmol) in 1,4-dioxane (8.5 mL) was stirred at 130° C. for 18 h. The mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue (2.40 g) was used for the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[O:27][CH2:26]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:51]>>[ClH:51].[CH2:1]([O:3][C:4]([C@H:6]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([OH:36])=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[O:27][CH2:26]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
In 5 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.12 g of tert-butyl 3(S)-[1(R)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 64, and the solution is allowed to stand at room temperature for 3 hours. Petroleum ether (100 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.08 g of 3(S)-[1(R)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[N:6][CH:5]=[N:4]1)[CH3:2].[H-].[Na+].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:21][N:22]2[C:27]=1[CH:26]=[N:25][N:24]=[C:23]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34].O>CN(C)C=O>[CH2:1]([N:3]1[C:7]([CH2:8][O:9][C:20]2[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])=[C:27]3[N:22]([C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[N:24][N:25]=[CH:26]3)[N:21]=2)=[N:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nncc3c2-c2ccccc2F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccc1F
Reaction time: 0.5 h

Procedure:
The title compound was prepared as part of a rapid analogue library using the following methodology. To a solution of (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (32 mg, 0.25 mmol) in dry N,N-dimethylformamide (5 ml) in a RADLEYS reaction carousel under nitrogen was added sodium hydride (60% wt in oil) (10 mg, 0.25 mmol) and the suspension was stirred for 30 min. A solution of 3,7-bis(2-fluorophenyl)-2-(p-toluenesulfonyloxy)pyrazolo[1,5-d][1,2,4]triazine (100 mg, 0.21 mmol) in dry N,N-dimethylformamide (2 ml) was then added and the solution was stirred under nitrogen for 1 h. A further amount (4 mg, 0.10 mmol) of sodium hydride (60% wt in oil) was added and the solution was stirred for 18 h. Water (25 ml) was added to quench the reaction and the solid which was precipitated was collected by filtration and washed with water. The solid was dissolved in dichloromethane, filtered and the filtrate was concentrated in vacuo to give a white solid (40 mg). Data for the title compound: mp=164° C.; 1H NMR (360 MHz, CDCl3) δ 1.31 (3H, t), 4.09-4.16 (2H, m), 5.56 (2H, s), 7.21-7.33, (3H, m), 7.37-7.43 (2H, m), 7.58-7.68 (2H, m), 7.82 (1H, m), 7.87 (1H, s), 9.28 (1H, s); MS (ES+) m/e 434 [MH]+; HPLC>97% purity (run on an HP1100, using a Hichrom KR100-5C18, 25 cm column, flow rate of 1 ml/min and 50% acetonitrile/pH 3 phosphate buffer as the mobile phase).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]=[N+:14]=[N-:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]#[CH:17]>CC(C)=O.C(=O)=O.CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#C
Reactant: [N-]=[N+]=NC1CCN(Cc2ccccc2)C1
Agent: O=C=O
Solvent: CC(C)=O
Product: c1ccc(CN2CCC(n3ccnn3)C2)cc1

Procedure:
A solution of N-benzyl-3-azido-pyrrolidine (1.5 g, 0.0074 mol) in acetone was taken in a steel bomb and cooled in dry ice/acetone bath. To this cold solution acetylene (2.5 mg, 0.096 mol) was added under N2 atmosphere. The sealed steel bomb was then heated in an oil bath at 75° C. for 20 h. The vessel was cooled again in dry ice/acetone bath and excess of acetylene released slowly, while the temperature rose to the room temperature (r.t.). The reaction mixture was concentrated to yellow-brown oil. Crude yield: 2.02 g. Crude compound was purified on silica gel column to obtain the title compound as a light yellow-brown oil. Yield: 1.02 g (60%). 1H NMR (CDCl3) δ: 2.0-3.3 (m, 6H), 3.7 (S, 2H), 5.3 (m, 1H), 7.45 (s, 5H), 7.8 (s, 1H), 7.95 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([Cl:12])[N:8]=[C:7]([NH:13][NH2:14])[C:6]1=[O:15])([OH:3])=[O:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O.O1CCOCC1>[CH2:25]([O:24][C:22]([NH:14][NH:13][C:7]1[C:6](=[O:15])[N:5]([CH2:4][C:1]([OH:3])=[O:2])[C:10]([CH3:11])=[C:9]([Cl:12])[N:8]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1c(Cl)nc(NN)c(=O)n1CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(Cl)nc(NNC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
To a solution of the compound of Example 14 (1.9 g, 8.26 mmol) and NaHCO3 (2.08 g, 24.75 mmol) in water, (60 mL) was added drop-wise a solution of benzyl chloroformate (1.9 mL, 13.21 mmol) in dioxane (100 mL). The resulting mixture was stirred at room temperature for 4 hours, then was diluted with water (60 mL) and washed with ether (100 mL). The aqueous solution was acidified with 2 M KHSO4 and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (1:1 EtOAc/hexane, then 9:1 DCM/MeOH) to afford the title compound (1.6 g, 53%) as a pale yellow solid. 1H NMR (DMSO-d4) δ 2.24 (s, 2H), 4.64 (s, 2H), 5.13 (s, 2H), 7.20-7.45 (m, 5H), 9.22 (s, 1H), 9.29 (s, 1H). HPLC Rt 11.4 minutes (water/ACN/TFA, 5 to 75%, 0.1% TFA, 20 minutes).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:12]=[C:11](F)[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:14])[CH:5]=1.[CH3:15][S-:16].[Na+]>CN(C)C=O>[F:14][C:6]1[C:7]([C:8]([OH:10])=[O:9])=[C:11]([S:16][CH3:15])[CH:12]=[C:4]([Br:3])[CH:5]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: C[S-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1cc(Br)cc(F)c1C(=O)O
Temperature: -12.5 °C
Reaction time: 0.21 h

Procedure:
To a 20 L flask was charged dimethyl formamide (14.5 L, 10.0 vol), followed by sodium hydroxide (293.7 g, 1.2 eq) and the reaction mass cooled to −15 to −10° C. 4-bromo-2,6-difluorobenzoic acid (1450 g, 1.0 equiv) was added over a period of 10-15 min at −15 to −10° C. and stirred for an additional 10-15 min. Sodium thiomethoxide (514.6 g, 1.2 equiv) was added over a period of 5-10 min at −10 to −5° C. On completion of the addition the temperature of the reaction was raised to 25-28° C. over a period of 45 to 60 min and maintained at that temperature 1.5-2 h. The temperature of the reaction was then raised to 60-65° C. over a period of 30-60 min and maintained at 60-65° C. for 5 h until the reaction was deemed complete. The reaction mixture was then cooled to 20-25° C. and quenched with a cooled (5-10° C.) solution of 2N HCl (5.045 L of 12N HCl in 30.3 L water). Following the quench, ethyl acetate (14.5 L, 10 vol) was added and the mixture stirred for 10-15 min. The phases were separated and the aqueous layer was extracted with ethyl acetate (7.25 L, 5 vol). The two phases were separated and the combined organic layer was washed with a brine solution (725 g of NaCl in 3.625 L of water). The phases were separated and the organic layer was washed with water (5.0 vol, 7.25 L). The phases were separated and the organic layer was dried over sodium sulfate (1450 g). The organic layer was filtered to remove the sodium sulfate, which was then washed with ethyl acetate (2.9 L, 2 vol). The organic layer was concentrated under reduced pressure at 45-50° C./30-40 mm Hg to ˜1 to 1.2 volumes and petroleum ether (7.25 L, 5 vol) was added at 40-45° C. over a period of 15-20 min. The solution was cooled to 20-25° C. over a period of 20-25 min. The solid was filtered and washed with petroleum ether (2.9 L, 2.0 vol) and the product dried under vacuum at 25-28° C., 0.4 to 0.7 mbar to afford 1410 g (87%, 99.40 Area %) of the intermediate 6-fluoro-4-bromo-2-methylsulfanyl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][C:8](=O)[CH2:7][CH2:6][C:5]=2[N:4]=1.C([O-])(=O)C.[Na+].Cl.[NH2:20][OH:21]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][C:8](=[N:20][OH:21])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: NO
Reactant: COc1ccc2c(n1)CCC(=O)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(n1)CCC(=NO)C2

Procedure:
2-Methoxy-7,8-dihydro-5H-quinolin-6-one (246 mg, synthesized according to J. Org. Chem. 1991, 56 (15), 4636) was dissolved in ethanol/water 1:1 (14 ml) and sodium acetate (600 mg) and hydroxylamine hydrochloride (482 mg) was added. The resulting suspension was heated to reflux for 4 hours until TLC analysis confirmed complete consumption of the starting tetrahydroquinolinone. The reaction mixture was poured into a mixture of ice, water and 1N NaOH (pH>10) and the aqueous layer was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried and evaporated to give a crude product. This was purified by flash chromatography (gradient of ethyl acetate in hexanes, 20% to 50%) to give the desired product as a mixture of (E/Z)-isomers (232 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].OS(O)(=O)=O.[CH3:21][CH2:22]O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: CCO
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (6.04 g, 21.7 mmol) and cone. H2SO4 (1.2 mL) were combined in EtOH (100 mL) and stirred with heating at 85° C. After 1.5 h, the completed reaction was cooled to RT and concentrated as completely as possible. The residue was dissolved in MTBE (50 mL) and washed with H2O (2×), and brine (2×), dried (MgSO4), filtered and evaporated to afford a dark orange oil. The crude was purified by silica gel column chromatography to obtain ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (5.8 g, 87% yield).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][O:15][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(Nc2ccccc2)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Temperature: 0 °C
Yield: 49.7 %

Procedure:
To a mixture of (3-anilinophenyl)methanol (1.12 g, 5.62 mmol), methyl 3-(4-hydroxyphenyl)propanoate (1.22 g, 6.75 mmol), triphenylphosphine (1.92 g, 7.31 mmol) and tetrahydrofuran (20 mL) was added diethyl azodicarboxylate toluene solution (40%, 3.32 mL) with stirring at 0° C. and the mixture was stirred at room temperature for 14 hrs. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (1.01 g, yield 50%) as beige crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].[Cl-].[NH4+]>C(OCC)C>[CH2:1]([O:8][C:9]1[S:10][C:11]([CH:21]=[O:22])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(COc2cccs2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: O=Cc1ccc(OCc2ccccc2)s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a solution of 2-benzyloxy-thiophene (184 mg, 0.967 mmol) in diethyl ether (4 mL) was added n-butyl lithium (2.47M hexane solution, 0.47 mL, 1.16 mmol) at −78° C. under nitrogen atmosphere, then, the solution was stirred for 1.5 hours on an ice bath. The solution was cooled again to −78° C., N,N-dimethylformamide (487 μl, 4.84 mmol) was added, and the solution was stirred for 45 minutes while warming to room temperature. An aqueous solution of saturated ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, then, filtered with silica gel, the filtrate was concentrated in vacuo, and 5-benzyloxy-thiophene-2-carbaldehyde (171 mg) was obtained.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH2:15]([NH:17][C:18]([C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=O)=[O:19])[CH3:16].N1CCCCC1>ClCCl>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[C:18]([NH:17][CH2:15][CH3:16])=[O:19])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCNC(=O)C(=O)c1ccc[nH]1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCNC(=O)C(=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21)c1ccc[nH]1

Procedure:
Alternatively, a mixture of 5-aminosulfonylindolin-2-one (0.22 g, 1.0 mmol), 2-(ethylamino)carbonylcarbonylpyrrole (0.33 g, 2.0 mmol) and piperidine (0.2 mL, 2.0 mmol) was irradiated in a microwave at 160° C. for 5 minutes. The reaction mixture was dissolved in dichloromethane (25 mL). The resulting mixture was washed with 0.2 N HCl (25 mL) and saturated sodium bicarbonate (25 mL), dried (magnesium sulfate) and concentrated. Chromatography on SiO2 (10 g) using hexane/ethyl acetate afforded 5-aminosulfonyl-3-[(pyrrol-2-yl)(ethylaminocarbonyl)methylene]indolin-2-one; (45 mg), 1H NMR (400 MHz, DMSO-d6) δ 1.16 (t, 3H), 3.36 (q, 2H), 6.40 (s, 1H), 6.64 (s, 1H), 7.02 (d, 1H), 7.20 (brs, 2H), 7.42 (s, 1H), 7.64 (d, 1H), 7.75 (s, 1H), 8.85 (t, 1H), 11.40 (s, 1H) ppm.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[N:20]2[CH3:23])=[C:16]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:15]=1>CN(C=O)C>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:15]=2)[N:5]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Ic1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3nc(I)c4ccccc43)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.5 eq) was added to 3-iodoindazole (0.5 g) in DMF (5 mL) and the reaction was stirred for 30 minutes at 0° C. 2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol was subsequently added to the reaction mixture and heated in a Biotage microwave for 10 minutes at 180° C. The reaction was purified by flash column chromatography to afford 2-(1-((2-(3-iodo-1H-indazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.4 g) as a brown solid.