Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnccn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cnccn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A mixture of 162b (110 mg, 0.20 mmol) and lithium hydroxide (84 mg, 2.0 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water and ethyl acetate. The water phase was separated and extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 162 (85 mg, 85%) as pale yellow solid. MS-ESI: [M+H]+ 498.3. 1H NMR (500 MHz, CHCl3) δ 8.73 (d, J=2.5 Hz, 1H), 8.54 (d, J=5 Hz, 1H), 8.29 (s, 1H), 8.15-8.14 (m, 2H), 8.01 (d, J=2.5 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.37 (d, J=5 Hz, 1H), 6.91 (s, 1H), 4.66-4.65 (m, 1H), 4.52-4.51 (m, 1H), 4.32-4.31 (m, 1H), 4.18-4.17 (m, 1H), 4.14-4.12 (m, 1H), 3.90-3.88 (m, 1H), 3.75 (s, 3H), 2.62-2.57 (m, 4H), 1.92-1.88 (m, 3H), 1.80-1.79 (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH:19]=[C:18]3[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:7]([CH3:9])[CH3:8])[CH3:6].N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37].CO>ClCCl>[C:36]([O:27][CH:25]1[CH2:24][CH2:23][C@@:22]2([CH3:28])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:17]2[CH2:16][CH2:15][C@@:14]2([CH3:29])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:2]([CH3:1])[CH:3]=[CH:4][C@H:5]([CH3:6])[CH:7]([CH3:8])[CH3:9])[CH2:26]1)(=[O:38])[CH3:37]
Reactant: CC(C)[C@@H](C)/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)OC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
Ergosterol (5.00 g, 12.6 mmol) was dissolved in dichloromethane (100 mL), and pyridine (4 mL) and acetyl chloride (2 mL) were sequentially added at 0° C. thereto, followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated to yield a residue and then methanol was added to the obtained residue for trituration to obtain the title compound (5.21 g, 94%).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH2:45][CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.Cl>C1COCC1.C(Cl)Cl>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:45][CH:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[O:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Stir a solution of 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid (19.0 g, 51.43 mmol) in anhydrous THF (250 mL), cool to 5° C., add N-methylmorpholine (5.8 mL, 52.72 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.0 g, 51.34 mmol). Stir the mixture at 0-5° C. for 1 h, add a solution of 4-aminotetrahydro-pyran (5.8 g, 57.36 mmol) in dry THF (75 mL) via dropping funnel. Bring the mixture to room temperature, stir for 3 h, and cool back down to 5° C. Stir the mixture and add 1N HCl (250 mL), add the resulting solution to a separatory funnel, and extract with ethyl acetate (250 mL). Separate the layers, wash the organic layer with brine (250 mL), and combine the aqueous layers and extract with ethyl acetate (250 mL). Combine the organics and wash with saturated aqueous sodium bicarbonate (400 mL) and dry the organic layer over sodium sulfate. Concentrate to give a foam, dissolve in minimum methylene chloride, and add to a biotage flash 65M cartridge. Elute with 3:2 hexanes/ethyl acetate to provide the major product as a foam, and dry (20 mm Hg, 40° C.) to give a white powder of pure product (20.3 g, 87%); MS (ESI) m/z 453 (m+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]([F:35])([F:34])[S:18][C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=[CH:23][CH:24]=1.S(Cl)(Cl)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([N:25]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:18][C:17]([F:35])([F:16])[F:34])[CH:20]=2)=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CNc1cccc(SC(F)(F)F)c1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(SC(F)(F)F)c2)c1
Yield: 16.1 %

Procedure:
Using a procedure similar to that described in Example 17, but starting with 2-[(3-methylphenyl)ureido]acetic acid (2.08 g), tert-butyl 2-[(3-trifluoromethylthiophenyl)amino]acetate (3.07 g) and sulphinyl chloride (1.3 g), and after recrystallisation in diisopropyl ether, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-(3-trifluoromethylthiophenyl)acetamido}acetate (0.8 g), m.p. 112° C., is obtained.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
3-Acetylthio-2-benzylpropanoyl chloride and (L)-tyrosine, methyl ester, hydrochloride are reacted in the presence of diisopropylethylamine according to the procedure of Example 26 to give (±)-N-[2-(acetyl-thiomethyl) -1-oxo-3-phenylpropyl]-L-tyrosine, methyl ester.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C(=O)([O-])[O-].[K+].[K+].[C:19]([CH2:21]P(=O)(OCC)OCC)#[N:20].O>O1CCCC1>[C:19](/[CH:21]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:20]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COC(=O)c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/C#N)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of methyl 3-formylbenzoate (1.00 g, 6.09 mmol) in tetrahydrofuran (10 mL) were added potassium carbonate (1.02 g, 7.31 mmol), diethyl (cyanomethyl)phosphonate (1.29 g, 7.31 mmol) and water (0.2 mL), and the mixture was stirred at 70° C. for 1 hr. To the reaction mixture was added water (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (5 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 recrystallized from ethyl acetate and hexane to give the title compound (730 mg, 64%) as colorless needle crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[C:9]([N+:13]([O-])=O)[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:21].[H][H]>C(O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[C:9]([NH2:13])[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:21]
Reactant: [H][H]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2C(N2CCCC2)C1O
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2cc(N)c(N)cc2C(N2CCCC2)C1O
Yield: 94.3 %

Procedure:
0.20 g (0.65 mmol) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-pyrrolidinyl)-6-amino-7-nitro-2H-benzo[b]pyran were dissolved in 34.9 g of ethanol and hydrogen gas was blown in the presence of 0.15 g of 5% palladium-carbon, as a catalyst, at room temperature for 3 hours under one atmospheric pressure while stirring. The reaction liquid was filtered under suction to remove the catalyst therefrom, and the solvent was distilled off to obtain 170 mg (yield: 94%) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-pyrrolidinyl)-6,7-diamino-2H-benzo[b]pyran as a dark red oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:17][C:18](=[O:35])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH2:31][CH:32](O)[CH3:33])[CH2:27][CH:28]([OH:30])[CH3:29])[CH:20]=1)C.[OH2:37].[NH2:38][NH2:39]>C(O)C>[OH:37][CH:32]([CH3:33])[CH2:31][N:26]([CH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:6]1[CH:7]=[CH:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:10][C:5]=1[C:4]([NH:38][NH2:39])=[O:3])=[O:35])[CH2:27][CH:28]([OH:30])[CH3:29]
Reactant: O
Reactant: NN
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1NC(=O)c1cccc(CN(CC(C)O)CC(C)O)c1
Solvent: CCO
Product: CC(O)CN(Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)NN)c1)CC(C)O
Reaction time: 12 h

Procedure:
Subsequently, 2-(3-{[bis-(2-hydroxy-propyl)amino]-methyl}-benzoylamino)-5-piperidin-1-yl-benzoic acid ethyl ester (200 mg) was dissolved in ethanol (2 ml). Hydrazine monohydrate (200 μl) was added dropwise to the solution at room temperature, and the mixture was then stirred at that temperature for 12 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 3-{[bis-(2-hydroxy-propyl)-amino]-methyl}-N-(2-hydrazinocarbonyl-4-piperidin-1-yl-phenyl)benzamide as a useful intermediate (200 mg, yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Cl>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: ClCCNCCCl
Reactant: Nc1ccc(F)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Fc1ccc(N2CCNCC2)cc1F
Temperature: 120 °C
Reaction time: 1 h

Procedure:
3,4-Difluoro-aniline (1 g, 7.7 mmol) was dissolved in dry n-butanol (10 mL) and dry sodium carbonate (3.2 g, 30 mmol) was added to it and the reaction mixture stirred for 1 hour under nitrogen. Bis(2-chloroethyl) amine hydrochloride (1.38 g, 7.7 mmol) in nBuOH (10 mL) were then added to the mixture via a syringe. The reaction was then heated at 120° C. for 48 h. The nBuOH was evaporated in vacuo and the residue was extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded the crude product. Purification using flash column chromatography (chloroform/methanol) afforded 1-(3,4-Difluoro-phenyl)-piperazine as an off white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]#N)=[N:23][CH:24]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([OH:29])[CH3:28].Cl.[O:31]1CCOCC1>>[CH2:27]([O:29][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:16]=[N:15][C:10]3[NH:11][CH2:12][C:13](=[O:14])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9]=3[CH:18]=2)=[CH:24][N:23]=1)=[O:31])[CH3:28]
Reactant: N#Cc1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cn1
Reactant: CCO
Reactant: C1COCCO1
Agent: Cl
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cn1
Temperature: 150 °C

Procedure:
5-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)pyridine-2-carbonitrile (32 mg) was mixed with ethanol (1.5 mL) and 4 N HCl (2.0 mL) in dioxane and then heated in a microwave oven at 150° C. for 80 minutes. The reaction mixture was concentrated and purified with preparative reversed-phase HPLC to give the title compound as an orange solid. LCMS: m/z=389.22 (M+H+), 1H-NMR (CD3OD, 400 MHz) δ 1.42 (3H, t, J=7.1 Hz), 4.44 (4H, m), 5.35 (2H, s), 7.28 (1H, m), 7.37 (5H, m), 7.55 (1H, d, J=1.8 Hz), 8.00 (1H, d, J=1.8 Hz), 8.03 (1H, dd, J=8.1, 2.3 Hz), 8.17 (1H, d, J=8.3 Hz), 8.69 (1H, d, J=2.0 Hz).
Reaction SMILES: C([C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)=[CH:5][S:6]([N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])(=[O:8])=[O:7])(=O)C.[CH2:24]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:36])/[CH:32]=[C:33](\[NH2:35])/[CH3:34])[CH2:25][CH3:26].[CH:37](O)(C)[CH3:38]>>[CH2:24]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:36])[C:32]1[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:5]([S:6](=[O:7])(=[O:8])[N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])=[C:37]([CH3:38])[NH:35][C:33]=1[CH3:34])[CH2:25][CH3:26]
Reactant: COCCN(C)S(=O)(=O)C=C(C(C)=O)c1cccc([N+](=O)[O-])c1
Reactant: CCCOCCOC(=O)/C=C(/C)N
Reactant: CC(C)O
Product: CCCOCCOC(=O)C1=C(C)NC(C)=C(S(=O)(=O)N(C)CCOC)C1c1cccc([N+](=O)[O-])c1
Yield: 47 %

Procedure:
A solution of 3.42 g (0.01 mol) of α-acetyl-N-(2- -methoxyethyl)-N-methyl-3-nitrostyrenesulfonamide and 1.87 g (0.01 mol) of 3-aminocrotonic acid 2-propoxyethyl ester in 15 ml of isopropanol is heated to reflux for 2 hours, thereupon treated with 1.0 g of Amberlyst® 15 as the catalyst and then heated to reflux for an additional 30 minutes. After concentration under reduced pressure 0 the oily residue is dissolved in methylene chloride, the catalyst remaining behind is removed by filtration under suction, and the filtrate is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to dryness. The residual oil is chromatographed on 300 g of silica gel with methylene chloride/ethyl acetate (4:1) as the elution agent. The uniform fractions yield an oil which crystallizes upon trituration and leaving to stand under hexane. After recrystallization from ether, there are obtained 2.4 g (47%) of 1,4-dihydro-2 6-dimethyl-5-[(2-methoxyethyl)methylsulfamoyl]-4-(3-nitrophenyl)nicotinic acid 2-propoxyethyl ester. m.p. 67°-70°, as an almost colorless crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5](C#N)=[CH:4][N:3]=1.[C:31]([O-:34])(O)=[O:32].[Na+]>O1CCOCC1.S(=O)(=O)(O)O.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5]([C:31]([OH:34])=[O:32])=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1nc(N)ncc1C(=O)O)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 90 °C
Reaction time: 60 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile (53) (495 mg, 1.19 mmol) in anhydrous 1,4-dioxane (20 mL), sulfuric acid/water (1:1, 7 mL) was added dropwise. The reaction mixture was stirred at 90° C. for 60 h. The mixture was allowed to cool to RT and basified with NaHCO3. The precipitate was collected by filtration and then dissolved in water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 117, (S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxylic acid. The material was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[C:12]1([C:7]2[C:6]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][C:10]=3[OH:9])=[N:20][NH:21][CH:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Solvent: CCO
Solvent: O
Product: Oc1ccc(-c2n[nH]cc2-c2ccccc2)c(O)c1
Temperature: 60 °C
Yield: 80.3 %

Procedure:
7-Hydroxy-3-phenyl-chromen-4-one (0.2 g, 0.84 mmol) was dissolved in ethanol (5 ml) and heated to ˜60° C. Hydrazine hydrate (5 ml) was added, and the solution refluxed until no starting material was visible by TLC (45 mins). After this time the majority of the ethanol was remove under vacuum and the residue quenched with cold water. The residue was extracted into ethyl acetate, washed (water), and the solvent removed under vacuum to give 4-(4-Phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as a white solid (0.17 g, 80.3%); Rf 0.65 ethyl acetate/hexane (70/30)].
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([CH3:34])[CH:23]=1)[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:32][CH2:33]2)=[C:24]([CH3:34])[CH:23]=1)[CH3:19]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(C)c1
Temperature: 105 °C
Yield: 62.7 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (129 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)—N-ethyl-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (128.5 mg, 0.286 mmol, 62.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.03 (m, 3 H) 2.09-2.25 (m, 1 H) 2.50 (m, 4 H) 2.75 (d, J=4.29 Hz, 3 H) 2.96-3.14 (m, 4 H) 3.35-3.45 (m, 3 H) 3.53-3.65 (m, 1 H) 3.93-4.05 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.04 (t, J=8.59 Hz, 1 H) 7.51-7.67 (m, 3 H) 8.27-8.38 (m, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: Cl.N[C:3]([CH3:9])([CH2:6]NC)[CH2:4][OH:5].[NH2:10][C:11]([NH2:13])=[O:12].N.Cl[CH2:16]Cl>>[OH:5][CH2:4][C:3]1([CH3:9])[CH2:6][N:13]([CH3:16])[C:11](=[O:12])[NH:10]1
Reactant: NC(N)=O
Reactant: ClCCl
Reactant: CNCC(C)(N)CO
Agent: Cl
Agent: N
Product: CN1CC(C)(CO)NC1=O
Yield: 45 %

Procedure:
In a round bottom flask, a mixture of 2-amino-2-methyl-3-(methylamino)propan-1-ol hydrochloride (3.3 g, 21 mmol) and urea (1.26 g, 21 mmol) were heated in a 200° C. sand bath for 1 hour until ammonia gas ceased to evolve. The resultant mixture was suspended in dichloromethane and filtered to remove insoluble material. The organic solution was concentrated to 3.3 g of black solid and purified by column chromatography, eluting from silica gel with a gradient of 1-12% methanol in dichloromethane to give 1.3 g of desired product as a tan oil (45% yield). 1H NMR (400 MHz, CDCl3) δ1.26 (s, 3H), 2.76 (s, 3H), 3.07-3.9 (d, J=8.8 Hz, 1H), 3.36-3.36 (d, J=8.8 Hz, 1H), 3.43-3.44 (d, J=2.1 Hz, 2H), 3.46 (s, 1H). 13C NMR (100 MHz, CDCl3/MeOD) δ 23.5, 30.1, 50.0, 55.7, 67.7, 161.9. LRMS (ESI/APCI): 145 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2([CH:29]([F:31])[F:30])[N:13](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:12](=[O:26])[C:11]([CH3:28])([CH3:27])[O:10][CH2:9]2)[CH:7]=1.C(O)(=O)CS.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2([CH:29]([F:31])[F:30])[NH:13][C:12](=[O:26])[C:11]([CH3:28])([CH3:27])[O:10][CH2:9]2)[CH:7]=1
Reactant: CC1(C)OCC(c2cc(Br)ccc2F)(C(F)F)N(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1=O
Agent: O=C(O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(c2cc(Br)ccc2F)(C(F)F)NC1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-2,2-dimethyl-4-(2-nitro-benzenesulfonyl)-morpholin-3-one (6.29 g, 11.71 mmol) and thioglycolic acid (1.83 g, 19.90 mmol) in 63 mL DMF was added potassium carbonate (6.47 g, 46.8 mmol). The reaction mixture was heated to 60° C. After 120 minutes, additional thioglycolic acid (324 mg, 3.51 mmol) was added. 30 minutes later on, the reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated, washed with saturated aqueous NaHCO3, brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was crystallized from TBME/hexane to give 3.14 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:10]([NH2:13])[NH:11][N:12]=1.C([O:23][C:24](=O)[CH:25]([CH3:29])[C:26](=O)[CH3:27])C.C(OCC)C>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:12][N:11]3[C:24]([OH:23])=[C:25]([CH3:29])[C:26]([CH3:27])=[N:13][C:10]=23)=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1[nH]nc(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c(O)c1C
Temperature: 100 °C

Procedure:
To a mixture of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-1b; 0.642 g, 2.11 mmol) in acetic acid (2.6 ml) was added 2-methyl-3-oxobutyric acid ethyl ester (366 mg, 2.53 mmol). The reaction was heated at 100° C. for 5 hours. After cooling to room temperature, the precipitated solid was isolated by vacuum filtration and then repulped from diethyl ether to afford I-4A-1a (292 mg, 36%) as a colorless solid: +ESI MS (M+1) 384.1; 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.45–7.33 (m, 6H), 7.11 (d, J=8.7 Hz, 2H), 2.33 (s, 3H), 1.99 (s, 3H).