Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[O-:18][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Yield: 75.6 %

Procedure:
To a solution of 9-Ethyl-9H-carbazole-3-carbaldehyde (Aldrich, 5.0 g, 22.39 mmol) in acetone (100 ml) at 70° C. under nitrogen was added dropwise a solution of KMnO4 (4.74 g, 30.00 mmol) in H2O (100 ml) slowly over 1 hour. When the reaction was complete the reaction mixture was filtered through celite, the celite pad washed with H2O/acetone, and the filtrate washed with ether. The aqueous layer was then acidified to pH 2 with aqueous HCl, and the white precipitate filtered and dried under vacuum to afford the desired product (4.05 g, 76% yield). MS m/z @ 240 (m+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][C:19]([CH2:21][CH:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C(N(CC)CC)C.O.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:17][O:18][C:19]([CH2:21][CH:22]([NH:29][C:13](=[O:15])[C@@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20]
Reactant: COC(=O)CC(N)c1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC(NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
N-tert-butoxycarbonyl-D-valine (5.34 g, 24.6 mmols) and 5.31 g (24.6 mmols) of (RS)-α-methoxycarbonylmethylbenzylamine hydrochloride (S:R=2:1) were suspended in 100 ml of methylene chloride, and the suspension was maintained at 0° C. Triethylamine (3.78 ml, 27.1 mmols), 5.20 g (27.1 mmols) of water-soluble carbodiimide hydrochloride and 3.66 g (27.1 mmols) of HOBt were added thereto, and the mixture was stirred for 1 hour while being cooled and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and 150 ml of water were then added to the residue. The solution was extracted twice with 100 ml of ethyl acetate. The organic layer was washed twice with 100 ml of a 5% citric acid aqueous solution, with 100 ml of a saturated aqueous solution of sodium chloride, twice with a 5% sodium hydrogencarbonate aqueous solution and with 100 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and magnesium sulfate was then removed by filtration. The filtrate was concentrated under reduced pressure to obtain 9.27 g (24.5 mmols) of N-tert-butoxycarbonyl-D-valine (RS)-α-methoxycarbonylmethylbenzylamide as a solid.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.[CH3:7][C@@H:8]1[CH2:13][C:12](=O)[CH2:11][C@H:10]([CH3:15])[O:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:7][C@@H:8]1[CH2:13][CH:12]([NH:6][C:5]2[NH:1][N:2]=[CH:3][N:4]=2)[CH2:11][C@H:10]([CH3:15])[O:9]1
Reactant: Nc1ncn[nH]1
Reactant: C[C@@H]1CC(=O)C[C@H](C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1CC(Nc2ncn[nH]2)C[C@H](C)O1
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 1H-1,2,4-triazol-5-amine (1.6 g) in acetic acid (30 mL) was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (2.5 g) at room temperature, and the mixture was stirred for 30 min. After stirring, sodium triacetoxyborohydride (5.2 g) was added, and the mixture was stirred at room temperature for 20 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized from diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried by heating under reduced pressure to give the title compound as a pale-yellow solid (1.6 g, 49%).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:12]1[C:3]([CH2:1][CH3:2])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: CCc1nc2ncccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCc1nc2ncccc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
2-Ethyl-[1,8]naphthyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline (115 mg), and 4-dimethylaminopyridine (63 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (35 mg, yield 57%).
Reaction SMILES: CC1(C)CC(C2C=CC=C([C:18]([F:21])([F:20])[F:19])C=2)C2C(=CC(OC)=CC=2)N1.[CH3:25][C:26]1([CH3:45])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39](Cl)=[CH:38][CH:37]=2)[C:33]2[C:28](=[CH:29][C:30]([O:43][CH3:44])=[CH:31][CH:32]=2)[NH:27]1>>[CH3:25][C:26]1([CH3:45])[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:18]([F:21])([F:20])[F:19])=[CH:38][CH:37]=2)[C:33]2[C:28](=[CH:29][C:30]([O:43][CH3:44])=[CH:31][CH:32]=2)[NH:27]1
Reactant: COc1ccc2c(c1)NC(C)(C)CC2c1ccc(Cl)cc1
Reactant: COc1ccc2c(c1)NC(C)(C)CC2c1cccc(C(F)(F)F)c1
Product: COc1ccc2c(c1)NC(C)(C)CC2c1ccc(C(F)(F)F)cc1

Procedure:
2,2-dimethyl-7-methoxy-4-(3-trifluoromethylphenyl)dihydroquinoline; and 2,2-dimethyl-7-methoxy-4-(4-chlorophenyl)dihydroquinoline.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].[NH2:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>O1CCOCC1.C(OCC)(=O)C>[CH2:3]([O:7][C:11]1[N:10]=[C:9]([NH2:8])[CH:14]=[N:13][CH:12]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: Nc1cncc(Cl)n1
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCCOc1cncc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
A suspension of NaH (60%, 618 mg, 15.45 mmol) in dioxane (30 mL) at 0° C. was treated with 3-buten-1-ol (1.33 mL, 15.45 mmol), stirred for 2 hours, treated with 2-amino-6-chloropyrazine (1 g, 7.72 mmol), stirred at 100° C. for 2.5 days, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with hexanes/ethyl acetate (2:1) to provide the desired product (390 mg, 31%). MS (DCI/NH3) m/z 166.12 (M+H)+; 1H NMR (500 MHz, benzene-d6) δ 2.66 (m, 2H), 4.42 (t, J=6.87 Hz, 2H), 5.24 (dd, J=10.22, 1.98 Hz, 1H), 5.30 (m, 1H), 6.04 (m, 1H), 7.64 (s, 1H), 7.65 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10]2)=[CH:5][CH:4]=1.N.S(=O)(=O)(O)[OH:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:19])[CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2ncc(C#N)c2N)cc1
Reactant: O=S(=O)(O)O
Agent: N
Product: COc1ccc(-n2ncc(C(N)=O)c2N)cc1
Temperature: 0 °C

Procedure:
1.5 g of 1-(4-methoxyphenyl)-5-amino-4-pyrazolecarbonitrile were stirred at 10°-15° C. with 10 ml of concentrated sulphuric acid until all of the solid had dissolved. The mixture was poured on to 60 g of crushed ice and made basic with concentrated ammonia solution. The precipitated product was filtered off, washed with water and recrystallized from ethanol to give 900 mg of 1-(4-methoxyphenyl)-5-amino-4-pyrazolecarboxamide of melting point 213°-215° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:13][C:14](=[O:26])[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>C1COCC1>[CH:3]1([CH2:9][CH2:10][O:11][CH2:13][C:14](=[O:26])[CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(CCl)CC(=O)OCc1ccccc1
Reactant: OCCC1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCC1CCCCC1)CC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
0.68 g (17.0 mmol) of sodium hydride (60% oily) was suspended in 7 ml of THF. 1.36 g (10.6 mmol) of 2-cyclohexylethanol was added to the obtained suspension at 0° C., and they were stirred at 40° C. for 30 minutes. 2.00 g (8.82 mmol) of benzyl 4-chloroacetoacetate was added to the obtained mixture at room temperature, and they were refluxed at 100° C. for 3 hours. 1 N hydrochloric acid was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was washed with 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=4/1) to obtain the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:15]([NH:1][CH:2]1[CH:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Solvent: ClCCl
Product: CC(=O)NC1CN(C(=O)OC(C)(C)C)CC1O
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl trans-3-amino-4-hydroxypyrrolidine-1-carboxylate (500 mg, the compound of Step A, Intermediate 15), in dichloromethane (20 mL) at 0° C. was added acetic anhydride (0.24 mL) and stirring continued for 1 h. The reaction mixture was quenched with saturated sodium bicarbonate (40 mL), extracted with dichlomethane (4×20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound which was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][CH2:11][CH2:12]O)=[O:8])[CH:2]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:28]([OH:31])(=[S:30])[CH3:29]>O1CCCC1.O>[C:28]([S:30][CH2:12][CH2:11][CH2:10][CH2:9][C:7](=[O:8])[C:3]1[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=1)(=[O:31])[CH3:29]
Reactant: O=C(CCCCO)c1cccnc1
Reactant: CC(O)=S
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)SCCCCC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
A solution of 4-hydroxybutyl 3-pyridyl ketone (89.6 g) in tetrahydrofuran (750 ml) under nitrogen at room temperature is treated with N,N-diisopropylethylamine (155.1 g). The mixture is then cooled to 0° C. and treated with methanesulphonyl chloride (63.0 g) continually during 10 minutes, maintaining the temperature at between 5° C. and 10° C., and then the mixture is stirred for 10 minutes. It is then treated with thioacetic acid (45.7 g) during 10 minutes and allowed to warm to 35° C. It is stirred for 1 hour at 35° C. and then cooled to 20° C. It is then treated with water (750 ml) during 5 minutes and the mixture is extracted twice with toluene (750 ml and 350 ml). The combined extracts are washed with water and evaporated, to give S-(4-nicotinoylbutyl) thioacetate (113.4 g), in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH3:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:39][C:40]([OH:42])=O)[CH:25]=[CH:26][C:27]=1[N:28](C1C=CC=CC=1C)[C:29]([NH2:31])=[O:30]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:40](=[O:42])[CH2:39][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([NH:31][C:4]2[CH:3]=[CH:13][CH:12]=[CH:11][C:5]=2[CH3:6])=[O:30])=[C:22]([O:21][CH3:20])[CH:23]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCNCCOc1ccc(C(=O)OCC)cc1OC
Reactant: COc1cc(CC(=O)O)ccc1N(C(N)=O)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 8 h
Yield: 180.7 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (290 mg, 1.08 mmol) and pentafluorophenyl ester of 3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetic acid (502 mg, 1.05 mmol) in DMF (7 mL) was added Et3 N (250 μl, 1.79 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (40:1, v/v) as an eluent to give 550 mg (93%) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an amorphous solid. 1H-NMR (CDCl3) δ 1.11–1.18 (m, 3 H), 1.37–1.41 (m, 3 H), 2.30 (s, 3 H), 3.47–3.53 (m, 2 H), 3.61–3.75 (m, 7 H), 3.84 (s, 3 H), 4.03–4.27 (m, 2 H), 4.33–4.39 (m, 2 H), 6.34–8.07 (series of m, total 12 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([NH2:12])[CH2:7]2.[C:13](Cl)(=O)[CH2:14][CH3:15].[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCCl>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:7]2
Reactant: NC1COc2c(Br)cccc2C1
Reactant: CCC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCNC1COc2c(Br)cccc2C1
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a mixture of 8-bromo-3-aminochroman (200 mg; 0.9 mmol) in CH2Cl2 (25 ml) and 10% aqueous Na2CO3 (25 ml) was added propionyl chloride (400 mg; 2.2 mmol) and the mixture was stirred for 2 hours. The phases were separated and the organic layer was dried (MgSO4). The solvent was evaporated and the crude amide was reduced with tetrabutylammonium borohydride (400 mg, 1.6 mmol) in a boiling (1:1)-mixture (50 ml) of dichloromethane and 1,2-dichloroethane overnight. The solution was extracted with water, dried (Na2SO4) and the solvent was evaporated yielding 140 mg (58%) of 8-bromo-3-(n-propylamino)chroman.
Reaction SMILES: [CH2:1]([C:5]1([CH2:16][CH3:17])[NH:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[K]>C(O)(C)(C)C.O>[CH2:1]([C:5]1([CH2:16][CH3:17])[N:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC)CSc2ccccc2CN1
Agent: [K]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCC1(CC)CSc2ccccc2C=N1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of the product from step (b) (6.0 g) in tert-butyl alcohol (180 ml) was added a solution of potassium permangante (5.7 g) in water (90 ml). The mixture was heated to reflux for 10 minutes, cooled to room temperature, and filtered through celite. Solvent was evaporated to provide the title compound (5.9 g) as a colorless oil. 1H NMR consistent with the proposed structure.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([NH:19][C@H:20]([C:22]4[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH2:29](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[CH:29]=[N:16][C:15]4[C:10]3=[N:11][C:12]([NH:19][C@H:20]([C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH3:21])=[N:13][CH:14]=4)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Reactant: CCO
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncc2ncn(-c3cc(C4CC4)[nH]n3)c2n1)c1ncc(F)cn1
Temperature: 25 °C

Procedure:
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-5-nitropyrimidine-2,4-diamine (Intermediate 18, 0.25 g) was dissolved into ethanol (20 mL) with Pd—C (40 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 95° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.013 g of the title compound. MS (electrospray): 366 (M+1) for C17H17FN9. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.65 (s, 1H) 8.40 (s, 1H) 6.40 (d, 1H) 5.30 (dd, 1H) 2.00 (m, 1H) 1.65 (d, 3H) 1.10 (m, 2H) 0.90 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:36]3[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:35]=3[Cl:34])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: O=[N+]([O-])c1ccc(Cl)c(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCO
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc([N+](=O)[O-])ccc1Cl

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (1.0 g, 1.68 mmol), 2-chloro-5-nitro phenyl boronic acid (0.67 g, 3.3 mmol), tetrakis(triphenylphosphine) palladium (97 mg, 5% mol) and sodium carbonate (0.39 g, 3.68 mmol) in 50 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC(CH2Cl2:hexane/1:1) showed that the reaction was complete. The solvents were removed. Water (30 ml) was added. The organic was extracted with methylene chloride (3×40 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using CH2Cl2:hexane/6:4 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of roamers 8.16-8.31 (m, 1H), 8.21 (d, J=2.5 Hz, ½H), 8.16 (d, J=2.5 Hz, ½H), 7.90 (s, 1H), 7.71-7.78 (m, 5H), 7.42-7.46 (m, 1H), 5.66 (d, J=4.5 Hz, ½H), 5.64 (d, J=4.5 Hz, ½H), 4.93 (d, J=15.5 Hz, ½H), 4.79 (d, J=16 Hz, ½H), 4.03 (d, J=16 Hz, ½H), 3.94 (m, 1H), 3.91 (d, J=15.5 Hz, ½H), 0.70 (d, J=6.5 Hz, 1.5H), 0.64 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[C:12]#[N:13])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH2:26]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[C:12]([NH2:13])=[O:26])[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC(=C1Nc2ccc([N+](=O)[O-])cc2S1)c1nccc(C(F)(F)F)n1
Reactant: O
Agent: O=S(=O)(O)O
Product: NC(=O)C(=C1Nc2ccc([N+](=O)[O-])cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
2-(6-Nitrobenzothiazol-2(3H)-ylidene)-2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (296 mg, 0.81 mmol) was dissolved in concentrated sulfuric acid (3.0 mL). The reddish mixture was stirred at 50° C. for 8 hr, then poured into cold water (25 mL). The yellow precipitate was collected by filtration, washed with hexanes (30 mL), and dried under vacuum to give 2-[6-nitrobenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (280 mg, 89% yield) as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].N1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>CN(C)C=O>[N:12]1([C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
A mixture of 2,4-dinitrobenzonitrile 4.20 g (21.75 mmol) and morpholine 5.7 mL (66.0 mmol) in N,N-dimethylformamide 20 mL was stirred at room temperature for 20 hours. The reaction mixture was poured into water. The precipitate was collected and washed with water to give the title compound 4.20 g as orange solid. Yield 74.5%.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.FC(F)(F)S(O)(=O)=O>>[CH:14]1[C:15]2[C:7](=[O:8])[C:2]3[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To 1.0 grams of 2-biphenylcarboxylic acid was added 3 mL of trifluoromethanesulfonic acid. The sample was maintained at room temperature for 2.5 hours The mixture was poured over ice-water and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution until the aqueous phase was basic. The aqueous phase was separated. The organic phase was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give 9H-fluoren-9-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br.CCN(C(C)C)C(C)C>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([N:15]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[CH:13][CH:14]=2)[O:5]1
Reactant: BrCCOCCBr
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C

Procedure:
A solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (164 mg, 0.75 mmol), 1-bromo-2-(2-bromoethoxy)ethane (418 mg, 1.8 mmol), and DIPEA (0.64 mL, 3.6 mmol) in THF (2 mL) was stirred at reflux overnight. The mixture was concentrated, diluted with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography to give the title compound. MS (m/z): 290 (M+H)+.