Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C@@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[OH:8].C(N(CC)CC)C.[Cl:28][C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[OH:8][C@@:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:29]([Cl:28])=[O:31])[CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 159.1 %

Procedure:
A solution of (S)-5-methoxy-1-phenyl-1-((R)-piperidin-3-yl)pentan-1-ol (455.6 mg, 1.8 mmol) and triethylamine (1.50 mL, 10.7 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. A solution of triphosgene (278.6 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added with fast dropwise addition. The solution was stirred for 30 min at 0° C. and then for 2 h at rt. The reaction mixture was cooled to 0° C., washed with ice-cold satd aq NaHCO3 (3×10 mL) and ice-cold brine (3×10 mL), dried (Na2SO4), decanted, and stripped to afford (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride (540.8 mg, 99%) as a yellow oil. This material was carried on directly to the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[H][H]>FC(F)(F)C(O)=O.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Yield: 56 %

Procedure:
A solution of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoyl)-L-glutamate in 30 mL of trifluoroacetic acid was hydrogenated at 55 psi of hydrogen in the presence of 1.0 g of 5% Pd/C at room temperature for 14 hours. The catalyst was removed by filtration, the filtrate evaporated under reduced pressure, and the residual solid partitioned between 100 mL of chloroform and 50 ml of 2N aqueous sodium carbonate. The organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent removed by evaporation to give a gum which was chromatographed on silica gel. Elution with chloroform:methanol (97:3) gave 0.25 g (56%) of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate; mp 215°-217° C.; NMR (CDCl3) delta 1.25, 1.35 (2t, 6H, J=6 Hz), 2.1-2.5 (m, 4H), 2.55 (s, 3H), 3.1 (s, 4H), 4.15, 4.25 (2q, 4H, J=6 Hz), 4.6-4.96 (m, 1H), 7.05 (s, 1H), 7.25, 7.75 (AB q, 4H, J= 9 Hz), 8.35 (d, 1H, J=3 Hz), 8.77 (d, 1H, J=3 Hz); IR (Nujol) 3200, 3150, 1725, 1675, 1630, 1605 cm-1. Anal.: Calc'd for C27H31N5O7 : C, 60.32; H, 5.81; N, 13.03. Found: C, 59.98; H, 6.03; N, 12.92).
Reaction SMILES: Cl.Cl[CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[Cl:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([S:26][CH:3]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: ClC(CCc1ccccc1)Cn1ccnc1
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(SC(CCc2ccccc2)Cn2ccnc2)cc1Cl

Procedure:
A mixture of 600 mg. of 1-(2-chloro-4-phenylbutyl)imidazole hydrochloride, 1.2 g. of 3,4-dichlorothiophenol and 800 mg. of potassium carbonate in 40 ml. of acetone was stirred and refluxed for 4 hours. The solvent was evaporated under vacuum and 50 ml. of water was added. The resulting mixture was extracted with ether and the ether extract was washed with saturated sodium chloride solution, dried and evaporated to afford 1-[2-(3,4-dichlorophenylthio)-4-phenylbutyl]imidazole as an oil. This material was converted to the oxalate salt by treatment with oxalic acid in ether, which salt was recrystallized from acetone/ethyl acetate as colorless flakes (850 mg.), m.p. 145°-147° C.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[N-:25]=[N+:26]=[N-:27].[Na+].O>CS(C)=O.S(=O)(=O)(O)O>[N:25]([C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N=[N+]=[N-])C[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 51.3 %

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (500 mg) was dissolved in dimethylsulphoxide (25 ml) and sodium azide (1.5 g) added to the solution. Concentrated sulphuric acid (10 drops) was added and the mixture heated on a steam bath for 48 hours. The solution was poured into iced water (600 ml) and the precipitate extracted into ether (100 ml). The ether extract was washed with water (4 + 250 ml) and then saturated sodium bicarbonate solution (250 ml) and finally water (250 ml.). The organic solution was dried over anhydrous sodium sulphate and evaporated to a white foam which was purified by preparative T.L.C. using ethyl acetate/petrol (1/1) run twice. The main band gave title compound (290 mg;) as a foam, [α]D + 95° (c, 0.98).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[CH3:23][O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][O:21][C:19]1[CH:18]=[CH:17][C:9]2[C:10]([CH3:16])([CH3:15])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[C:7](=[O:22])[C:8]=2[CH:20]=1)=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=4
Reactant: COC(=O)CCCBr
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCOc1ccc2c(c1)C(=O)c1c([nH]c3cc(Br)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ2, 20 mg, 0.056 mmol), 4-bromo-butyric acid methyl ester (7.0 μl, 0.056 mmol) and cesium carbonate (36.6 mg, 0.112 mmol) were dissolved in DMA (0.09 ml), and then stirred at room temperature for 1 hr. Thereafter, 4-bromo-butyric acid methyl ester (7.0 μl, 0.056 mmol) was added thereto and the mixture was stirred at room temperature for 3 hr, followed by further stirring at 45° C. for 30 min. The reaction solution was added with water, extracted with diethyl ether and dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the resulting residues were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain 4-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-butyric acid methyl ester. This compound was dissolved in MeOH (0.50 ml), added with aqueous solution of sodium hydroxide (6 mol/1), and then stirred at room temperature for 10 min. The reaction solution was added with hydrochloric acid (3 mol/1), extracted with diethyl ether, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain white solid. This white solid was washed with methylene chloride to obtain the title compound (6.1 mg, 25%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][CH2:29][NH:28][C:27](=[O:32])[C:26]=2[CH:33]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][CH2:30][CH2:29][NH:28][C:27](=[O:32])[C:26]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)C(=O)NCCC2
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)C(=O)NCCC3)ncc1Cl
Yield: 17.3 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (100 mg, 0.321 mmol), 8-Amino-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (69 mg, 0.392 mmol), DL-10-Camphorsulfonic acid (93 mg, 0.400 mmol) and isopropanol (4 mL) in a microwave tube. Microwaved reaction at 120° C. for 30 minutes. Evaporated off solvent and purified with normal phase chromatography to yield an off-white solid, 2-[5-Chloro-2-(1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylamino)-pyrimidin-4-ylamino]-3,N-dimethyl-benzamide (25 mg, 17%). mp 259° C.; LCMS: m/z=451.36 (M+H+), 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.69 (m, 1H), 7.58 (s, 1H), 7.42 (m, 2H), 7.37 (m, 1H), 7.30 (m, 1H), 6.97 (d, 1H, J=8.3 Hz), 4.24 (m, 1H), 3.50 (m, 1H), 3.15 (m, 1H), 3.02 (m, 2H), 2.82 (s, 3H), 2.73 (m, 2H), 2.24 (s, 3H), 1.97 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].[Cl:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])=[O:13].N1C=CC=CC=1>O1CCCC1>[C:1]([O:5][CH2:6][CH2:7][O:8][C:17](=[O:18])[CH2:16][CH2:15][S:12]([CH2:11][CH2:10][Cl:9])(=[O:14])=[O:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCS(=O)(=O)CCCl
Reactant: C=CC(=O)OCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)OCCOC(=O)CCS(=O)(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Into a mixture of 600 ml. of tetrahydrofuran, 45.8 g. of hydroxyethyl acrylate, and 72 g. of 3-(2-chloroethylsulfonyl)propionyl chloride placed in a reaction vessel chilled with ice-water to maintain the temperature below 5° C., a solution of 31.2 g. of pyridine in 100 ml. of tetrahydrofuran was poured dropwise for 1.75 hours. The resulting mixture was stirred at room temperature for 2 hours, and poured into 2.5 l. of ice-water. The aqueous mixture was then extracted with 4 portions of 300 ml. of chloroform. The organic extract was dried over sodium sulfate, and concentrated to give 87 g. of 2-[3-(2-chloroethylsulfonyl)propionyloxy]ethyl acrylate (yield 88%).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[CH2:21][C:22]([OH:24])=[O:23]>C(O)(=O)C>[N+:8]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH2:12][CH:13]([CH2:21][C:22]([OH:24])=[O:23])[CH2:14]2)([O-:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CC1Cc2ccccc2C1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.2 %

Procedure:
Acetic anhydride (3.5 mL) was added slowly to a stirred solution of nitric acid (2.1 g, S.G.1.42) in glacial acetic acid (4.2 mL) cooled in an ice-water bath. This nitrating solution was then added dropwise over 5 minutes to a rapidly stirred solution of indan-2-acetic acid (1.65 g) in a mixture of glacial acetic acid (4.2 mL) and acetic anhydride (3.5 mL), whilst keeping the reaction temperature below 5° C. After stirring for a further 20 minutes at room temperature the reaction mixture was poured onto ice-water (60 mL). This mixture was extracted three times with dichloromethane. The combined extracts were washed twice with a little water, then dried over magnesium sulfate and then evaporated to give the title compound (2.22 g) as a red oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
Into a solution of 4,5-difluoro-2-nitroaniline (3.7 g) in acetic acid (27 ml) was added bromine (6.8 g) dropwise at 50° l to 56° C. and stirred for 2.5 hours. The reaction mixture was poured into ice water (60 ml) and the resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (4.7 g) as yellow prisms, mp 105° C.
Reaction SMILES: C(OC(=O)[C:5]([C:13]#[N:14])=[C:6]([OH:12])[C:7]([O:9]CC)=[O:8])C.[OH-:16].[Na+]>>[NH2:14][C:13](=[O:16])[CH2:5][C:6](=[O:12])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(O)=C(C#N)C(=O)OCC
Reactant: [OH-]
Agent: [Na+]
Product: NC(=O)CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
The 4-amino-2,4-dioxobutanoic acid was synthesized using the diethyl-2-cyano-3-hydroxy-butenedioate prepared as described above. A 5-liter Morton flask was equipped with an air condenser. Diethyl-2-cyano3-hydroxy-butenedioate (214.2.grams, 1.00 mole, 1.0 equivalent) was dissolved in aqueous sodium hydroxide (1.0 M, 1000 milliliters, 4.0 equivalents) at room temperature in the flask while stirring the contents of the flask. After about one minute, a heating mantle was placed underneath the flask. Using the heating mantle, the flask was heated sufficiently for reflux while the reaction mixture was stirred. After about 4½ hours at reflux, the heat was removed and the reaction mixture was allowed to cool to room temperature and was stirred overnight at room temperature. The reaction solution was placed into an ice-water bath and acidified using 6M HCl until the pH of was equal to about 1. Solids formed after about 5 minutes. The solids were filtered. The colorless solids (27 grams) were analyzed by NMR and were found to include carbonate (13C-NMR δ=162 ppm). The bulk of the water was evaporated using a rotary evaporator at about 40° C. The solids were stirred in acetone (1000 milliliters) and then filtered. The acetone was then removed under a vacuum using a rotary evaporator followed by a vacuum pump to yield the 4-amino-2,4-dioxobutanoic acid in 56% yield (74 grams) as a light yellow solid that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].F[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C#N)cc3)ccc2C1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Combine in a round bottom flask equipped with a Dean Stark Trap 6-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.59 g, 6.36 mmol), toluene, dimethylacetamide (10 ml and 30 ml respectively), K2CO3 (1.25 g, 9.04 mmol), and 4-Fluorobenzonitrile (0.72 g, 6.04 mmol). Reflux the reaction under a Nitrogen atmosphere for 4 hours then cool to room temperature. Add water to the reaction mixture and extract the product from the water layer using ethyl acetate. The product, a white solid, precipitates out from the ethyl acetate to afford 1.93 g, 5.5 mmol (87% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5 (9H, s), 2.75-2.85 (2H, m), 3.6-3.7 (2H, m), 4.5 (2H, s), 6.8-6.9 (2H, m), 6.9-7.0 (2H, m), 7.1-7.2 (1H, m), 7.5-7.6 (2H, m); MS m/z 249 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.C1(C([N:16]2[CH2:20][CH2:19][CH:18]3[CH2:21][N:22]([C:24]4[C:25]5[S:33][C:32]6[CH2:34][CH2:35][CH2:36][CH2:37][C:31]=6[C:26]=5[N:27]=[C:28]([NH2:30])[N:29]=4)[CH2:23][CH:17]23)C)C=CC=CC=1>[OH-].[OH-].[Pd+2].CCO>[NH:16]1[CH2:20][CH2:19][C@@H:18]2[CH2:21][N:22]([C:24]3[C:25]4[S:33][C:32]5[CH2:34][CH2:35][CH2:36][CH2:37][C:31]=5[C:26]=4[N:27]=[C:28]([NH2:30])[N:29]=3)[CH2:23][C@H:17]12
Reactant: CC(c1ccccc1)N1CCC2CN(c3nc(N)nc4c5c(sc34)CCCC5)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N2C[C@H]3CCN[C@H]3C2)c2sc3c(c2n1)CCCC3
Reaction time: 36 h
Yield: 95.1 %

Procedure:
A 90 mL parr shaker was charged with 4-[1-(1-phenyl-ethyl)-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl]-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine trifluoroacetate (synthesized by route described in Example 2, Steps A-E; 0.20 g, 0.4 mmol), Pd(OH)2/C (30% by weight, 0.06 g) and EtOH (3.7 mL). The mixture was submitted to 60 psi H2 with shaking for 36 h. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated to afford the desired compound (0.12 g). MS: 316.1. 1H NMR (400 MHz, CD3OD) δ ppm 4.47-4.29 (m, 2H), 4.25-4.07 (m, 2H), 3.91-3.80 (m, 1H), 3.54-3.38 (m, 3H), 2.97-2.84 (m, 2H), 2.69-2.61 (m, 2H), 2.41-2.29 (m, 1H), 2.14-2.02 (m, 1H), 2.02-1.86 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Br)(Br)([Br:17])=O.[OH-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Br)nc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
4-Nitroquinoline 1-oxide (940 mg, 4.9 mmol) in chloroform (12 mL) was cooled to 0° C. To this solution, POBr3 (1.77 g, 6.2 mmol) was added in small portions. The mixture was stirred at 0° C. for 2 h and diluted with DCM (50 mL), and poured on ice (50 g). To this suspension, 1 M NaOH was added to adjust pH to about 9. Layers were separated and the organic layer was washed with water (2×50 mL) and dried over MgSO4 and concentrated. The crude product was purified by silica chromatography to afford 2-bromo-4-nitroquinoline as a yellow solid (620 mg, 50%). 1H NMR (400 MHz, CDCl3): δ 7.63-7.94 (m, 2H), 8.06 (s, 1H), 8.17 (t, J=7.16, 6.84 Hz, 1H), 8.38 (d, J=8.76 Hz, 1H).
Reaction SMILES: [C:1]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[C:14]=2[C:15]=1[NH2:16])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CC(O)=O.OP(O)(O)=O>[Cl:23][C:17]1[C:14]2[C:15]3[NH:16][CH:3]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:2][C:1](=[O:10])[C:11]=3[O:12][C:13]=2[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc2oc(C(=O)C=Cc3ccccc3)c(N)c2c1Cl
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2oc3c(c2c1Cl)NC(c1ccccc1)CC3=O
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A mixture of 8A (1.9 g, 5.8 mmol) in AcOH (10 mL) and H3PO4 (10 mL) was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (20 mL) The yellow solids were precipitated out, collected by filtration and dried to give product 8B (1.78 g, 93.68% yield).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:14]#[N:15])(=[O:3])[CH3:2].[CH2:16]([OH:18])[CH3:17].[ClH:19].C(OCC)C>>[ClH:19].[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:14](=[NH:15])[O:18][CH2:16][CH3:17])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)N1c2ccc(F)cc2CC1C#N
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)C1Cc2cc(F)ccc2N1C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of intermediate (19) (0.004 mole) and HCl/diethylether (60 mL) was cooled in an ice bath under argon. Ethanol (0.0075 mole) was added. HCl was bubbled into the solution for 50 minutes until the mixture became homogeneous. The mixture was allowed to slowly warm to room temperature and stir for 4 hours. The ether was decanted off and dissolved in methanol. The methanol solution was concentrated in vacuum and the residue was used as is for the next step, yielding ethyl 1-acetyl-5-fluoro-2,3-dihydro-1H-indole-2-carboximidate monohydrochloride (intermediate 20).
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[C:9]([CH:11]([NH:19][CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][N:7]=1)=[O:5])C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:21]([NH:28][C:4]([C:6]1[N:10]=[C:9]([CH:11]([NH:19][CH3:20])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:8][N:7]=1)=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1noc(C(Cc2ccccc2)NC)n1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CNC(Cc1ccccc1)c1nc(C(=O)NCc2ccccc2)no1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
5-(1-Methylamino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethylester (3.3 g, 9.0 mmol) was dissolved in ethanol (30 ml). Benzylamine (3 ml) was added and the reaction mixture was stirred for 18 h at 20° C. The reaction mixture was concentrated in vacuo and the residue was crystallised from ethanol to give 2.07 g of (R) 5-(1-methylamino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid benzylamide.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH:20]1([C:23]([C:29]2[S:33][C:32]([SH:34])=[N:31][CH:30]=2)([OH:28])[C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:21]1>>[CH:20]1([C:23]([C:29]2[S:33][C:32]([S:34][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)=[N:31][CH:30]=2)([OH:28])[C:24]([F:26])([F:25])[F:27])[CH2:22][CH2:21]1
Reactant: OC(c1cnc(S)s1)(C1CC1)C(F)(F)F
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(Sc3ncc(C(O)(C4CC4)C(F)(F)F)s3)cc2o1

Procedure:
Employing the procedure described in Example 1, Step 3, using 7-bromo-4-(4-fluorophenyl)-2H-chromen-2-one and (−)-1-cyclopropyl-2,2,2-trifluoro-1-(2-mercapto-1,3-thiazol-5-yl)ethanol, the titled compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 8.00 (s, 1H), 7.68 (m, 2H), 7.56-7.60 (m, 2H), 7.48 (dd, 1H), 7.39 (t, 2H), 6.43 (s, 1H), 5.88 (s, 1H), 1.65 (m, 1H), 0.82 (m, 1H), 0.54-0.71 (m, 3H); [α]D=−29.6° (c=1, EtOH).
Reaction SMILES: Cl/[C:2](/[N+]([O-])=O)=[CH:3]\[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[N:19]=[CH:18][N:17]=1.N12CCCN=C1CCCCC2>C(O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[C:21]3[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=3[O:15][CH:2]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(/C=C(\Cl)[N+](=O)[O-])cc1
Reactant: Oc1cc(O)ncn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: COc1ccc(-c2coc3nc[nH]c(=O)c23)cc1

Procedure:
As in the procedure described in the literature [D. Dauzonne, Tetrahedron, 1992, 3069-3080], stir a suspension of 10.1 g (47.4 mmol) 1-[(Z)-2-chloro-2-nitrovinyl]-4-methoxybenzene and 5.8 g (52.2 mmol) 4,6-dihydroxypyrimidine in 200 ml ethanol for ten minutes at 85° C. Next, slowly add 15.6 ml (15.9 g, 104.3 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene. Stir for 15 h at this temperature and then concentrate by vacuum evaporation. Take up the residue in dichloromethane and chromatograph on silica gel (solvent: dichloromethane/methanol 95:5). Mix the solid obtained with acetonitrile and then filter. 2.3 g (20% of theor.) of the target product is obtained.