Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:17][CH2:16][CH2:15][CH:13]3[O:12][N:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH2:14]3)[CH2:31][CH2:32]2)=[CH:38][CH:37]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)C2)c1
Yield: 65.3 %

Procedure:
3-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]propanal (19.3 mg, 0.077 mmol), 1-[bis(4-fluorophenyl)methyl]piperazine (20.4 mg, 0.070 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (45.0 mg, 0.212 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 23.8 mg (64.7%) of the target compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH:12]3[CH:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=1.[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18]>CO.C(OC(=O)C)(C)C>[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=1
Reactant: c1cncc(N2CC3CNCC32)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(=O)OC(C)C
Solvent: CO
Product: c1cncc(N2C[C@H]3CNC[C@H]32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
The product of Example 40C (65 mg, 0.37 mmol) was treated with fumaric acid (46.4 mg, 0.4 mmol) in methanol/isopropylacetate (1:10 v/v, 20 mL). The mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried under reduced pressure at 40-50° C. to provide the title compound (47 mg, 44% yield). 1H NMR (MeOH-d4, 300 MHz) δ3.18 (dd, J=12.6, 3.4 Hz, 1H), 3.35 (m, 1H), 3.46 (m, 1H), 3.75 (m, 3H), 4.04 (t, J=7.5 Hz, 1H), 4.90 (m, 1H), 6.58 (s, 2H), 7.04 (ddd, J=8.2, 2.7, 1.3 Hz, 1H), 7.27 (dd, J=8.2, 4.8 Hz, 1H), 7.87 (d, 2.7 Hz, 1H), 7.95 (dd, J=4.8, 1.1 Hz, 1H); m/z 176 (M+H)+; Anal. calculated for C10H13N3.1.25C4H4O4.0.6 H2O: C, 54.41; H, 5.84; N, 12.69. Found: C, 54.96; H, 5.50; N, 12.10.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:53][C:54]([F:64])([F:63])[C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58][NH2:59]>CN(C=O)C>[F:53][C:54]([F:63])([F:64])[C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][CH:62]=1)[CH2:58][NH:59][C:10]([C:5]1[C:4]2[CH:3]=[N:2][NH:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:12]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc2[nH]ncc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cccc2[nH]ncc12
Reaction time: 0.25 h

Procedure:
To a stirred room temperature solution of indazole-4-carboxylic acid (1.0 g, 6.1 mmol) in DMF (15 mL) was added PyBOP (3.5 g, 6.5 mmol) and triethylamine (0.90 g, 7.5 mmol). After 15 minutes, 3-trifluoromethyl-benzylamine (1.2 g, 7.0 mmol) was added. After 4 hours, the mixture was quenched with water (30 mL) and diluted with ethyl acetate (20 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20-60% ethyl acetate in hexanes to afford 1H-indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][N:19]=1.O>C1COCC1>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][O:13][C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][N:19]=1)[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CCCN(CCO)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCOc1ncc([N+](=O)[O-])c(OC)n1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-hydroxy-ethyl)-propyl-carbamic acid tert-butyl ester (1.07 g, 5.28 mmol) in THF (40 ml) at 0° C. was added NaH (0.25 g, 5.80 mmol). After stirring the suspension at 0° C. for 30 minutes a solution of 2-chloro-4-methoxy-5-nitropyrimidine (1 g, 5.28 mmol) in THF (10 ml) was added and the mixture was stirred at room temperature for 16 h. The mixture was added to water, which was extracted three times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6](Cl)=[N:5][S:4][N:3]=1.[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O.Cl>[Cl:1][C:2]1[C:6]([O:15][CH2:14][C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[N:5][S:4][N:3]=1
Reactant: OCc1ccncc1
Reactant: Clc1nsnc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Clc1nsnc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
3,4-Dichloro-1,2,5-thiadiazole (2.00 mL, 21.3 mmol) was dissolved in 70 mL of t-butanol along with 4-pyridine methanol (1.05 g, 9.62 mmol). 30 mL of 1.0 M potassium t-butoxide (30 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with 100 mL of water and neutralized with 1.0 M HCl. The product was extracted 3 times with 100 mL portions of ethyl acetate. The combined organic fractions were dried with magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography with a 2:1 solution of hexanes in ethyl acetate, affording 4-(4-chloro-[1,2,5]thiadiazol-3-yloxymethyl)-pyridine (821 mg) as an off-white solid.
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)(=O)C>[F:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)NCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
Add sodium cyanoborohydride (5.57 g, 88.78 mmol) to a solution of 6-fluoro-indole (10 g, 73.99 mmol) in acetic acid (100 ml). Stir at room temperature for 30 minutes. Pour the reaction mixture into 5N sodium hydroxide and extract with ethyl acetate. Wash the combined organic phases with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Concentrated under reduced pressure and subject the residue to silica gel chromatography to provide the desired compound as a colorless oil (7.69 g, 76%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[Br:6][C:7]([C:29]([OH:31])=[O:30])=[CH:8][C:9]1[CH:10]=[C:11]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])[CH:12]=[CH:13][C:14]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:6][C:7]([C:29]([O:31][CH2:4][CH2:3][O:2][CH3:1])=[O:30])=[CH:8][C:9]1[CH:10]=[C:11]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[N:18]([CH3:27])[C:17]2=[O:28])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)O)c2)c1=O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOC(=O)C(Br)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 17 h

Procedure:
0.52 ml of methoxyethyl bromide was added to a solution of 2.27 g of 3-[3-(2-bromo-2-carboxyethenyl)-4-chlorophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine and 0.76 g of potassium carbonate in dimethylformamide, and the resulting solution was stirred for 17 hours. Thereafter, 100 ml of water were added and the aqueous phase was extracted with twice 100 ml of dichloromethane. The combined organic phases were washed with three times 50 ml of water, dried over sodium sulfate and evaporated down. After flash chromatography (dichloromethane→9:1 dichloromethane/ethyl acetate), the title compound was obtained as an oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29](=[O:36])[CH2:28][CH2:27][C:26]1=[O:37]>>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:29](=[O:36])[CH2:28][CH2:27][C:26]3=[O:37])[CH2:18][CH2:19]2)[CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Reactant: CC(C)c1cc(N2CCNCC2)nc(C(C)(C)C)n1
Product: CC(C)c1cc(N2CCN(CCCCN3C(=O)CCC(=O)c4ccccc43)CC2)nc(C(C)(C)C)n1

Procedure:
Analogously to Example 3b, reaction of 2-tert-butyl-4-isopropyl-6-piperazin-1-ylpyrimidine (0.95 mmol, 0.25 g) with 1-(4-chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione afforded 0.04 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33]I>>[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(CCCCCl)C(=O)O)cc1
Yield: 36.6 %

Procedure:
Step AAN (1): 2-(4-Ethoxyphenyl)acetic acid (2.00 g, 11.1 mmol) was deprotonated with NaHMDS 2.0 M in THF (12.5 mL, 25.0 mmol) and reacted with 1-chloro-4-iodobutane (1.49 mL, 12.2 mmol) using a procedure analogous to Step AC (1) and after silica gel column chromatography (30-80% EtOAc/hexanes) afforded 6-chloro-2-(4-ethoxyphenyl)hexanoic acid (1.10 g, 4.06 mmol, 37% yield) as a pale-yellow oil. LC-MS (M+Na)+ 293.1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].[OH-].[K+].CCCCCC.CC(C)=[O:24]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:10])=[O:24])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: NC(=O)c1cnccc1C(F)(F)F
Yield: 52.6 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in methanol (15 ml), and potassium hydroxide (990 mg, 15 mmol) was added. The mixture was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/acetone=1/1) to obtain 1.03 g (yield 52.6%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
4-Nitrophenol (13.9 g, 100 mmol) was dissolved in N,N-dimethylformamide (20 ml), and t-butyl bromoacetate (29.3 g, 150 mmol) and potassium carbonate (27.6 g, 200 mmol) were added, which was followed by stirring at 70° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water, and the aqueous layer was extracted with ethyl acetate. The extract and the previously-obtained organic layer were combined. The mixture was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography. (n-hexane/ethyl acetate=5/1) and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 21.8 g of t-butyl 4-nitrophenoxyacetate as pale-yellow crystals (86%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:25])[C@H:17]([NH2:24])[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:14][O:15][C:16](=[O:25])[C@@H:17]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:24][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)[C@H](N)C1CCCCC1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)c1ccccc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a mixture of 2-nitrobenzoyl chloride (0.5 mL, 3.69 mmol) and (R)-amino-cyclohexyl-acetic acid methyl ester hydrochloride (1.0 g, 4.82 mmol), (prepared according to example A), in dichloromethane (10 mL) is added diisopropyl ethylamine (DIPEA) (1.5 mL, 8.61 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated and the resulting residue is purified by flash chromatography with 40% EtOAc in Hexane as the eluent to afford (R)-cyclohexyl-(2-nitro-benzoylamino)-acetic acid methyl ester (1.16 g, 98%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([CH:28]3[CH2:31][CH:30]([C:32]([O:34]CC)=O)[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:38])[CH:10]=1)#[N:2].[OH-].[Na+].Cl.[CH3:42][Mg]Br>O1CCCC1.C(O)C>[C:32]([CH:30]1[CH2:29][CH:28]([N:18]2[C:17](=[O:37])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:38])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:31]1)(=[O:34])[CH3:42]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CC(C(=O)OCC)C2)c2ncnn12
Reactant: C[Mg]Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CC(C(C)=O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of ethyl 3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate (4.0 g), tetrahydrofuran (40 mL), ethanol (40 mL) and 1 M aqueous sodium hydroxide solution (40 mL) was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was mixed with N,O-dimethylhydroxyamine hydrochloride (1.1 g), 1-ethyl-3-3-dimethylaminopropyl)carbodiimide hydrochloride (2.2 g), 1-hydroxybenzotriazole (1.6 g), triethylamine (3.3 mL) and N,N-dimethylformaldehyde (40 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in tetrahydrofuran (40 mL), methylmagnesium bromide (23 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 2 hr. Methylmagnesium bromide (11 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.8 g, 73%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([F:14])[CH:13]=1.[CH3:16][O:17][C:18](=[O:27])/[CH:19]=[C:20](\[NH:22][C:23](=[O:26])[CH2:24]Br)/[CH3:21]>CC(C)=O>[CH3:16][O:17][C:18](=[O:27])/[CH:19]=[C:20](\[NH:22][C:23](=[O:26])[CH2:24][O:15][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[C:12]([F:14])[CH:11]=1)/[CH3:21]
Reactant: COC(=O)/C=C(/C)NC(=O)CBr
Reactant: Oc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C(/C)NC(=O)COc1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a suspension of K2CO3 (1.38 g, 10.0 mmol) in acetone (50 mL) were added 3,5-difluorophenol (0.78 g, 6.00 mmol) and (Z)-methyl-3-(2-bromoacetamido)but-2-enoate (1.18 g, 5.00 mmol) and the mixture was refluxed for 5 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. To the residue was added DCM (100 mL) and the mixture was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=5:1) to give the title compound as a white solid (1.18 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[C:4]([Br:14])[C:3]=1[O:15][CH3:16].[N+:17]([O-])([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[C:5]([N+:17]([O-:19])=[O:18])=[C:4]([Br:14])[C:3]=1[O:15][CH3:16]
Reactant: COc1c(Br)cc(S(F)(F)(F)(F)F)cc1Br
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1c(Br)cc(S(F)(F)(F)(F)F)c([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
630 mg of 1,3-dibromo-2-methoxy-5-pentafluorosulfanylbenzene were stirred in 2 ml of a 90% aqueous HNO3 solution at 0° C. for 1 hour. Subsequently, the mixture was stirred at RT for 20 minutes and then poured onto 50 g of ice. An aqueous Na2CO3 solution was used to adjust to pH=6 and extraction was effected three times with 50 ml each of EA. Drying was effected over Na2SO4 and the solvent was removed under reduced pressure. Chromatography on silica gel using 1:3 DIP/HEP afforded 260 mg of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2.[CH3:16][O:17]C(Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:16]=[O:17])=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2
Reactant: CCC1(C)Cc2c(Cl)cc(C)c(C)c2C1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1(C)Cc2c(C)c(C)c(C=O)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 9.98 g of the 7-chloro-2-ethyl-2,4,5-trimethylindane in 100 ml of dry dichloromethane was continuously added 6.2 ml of α,α-dichloromethyl methyl ether and 7.5 ml of TiCl4 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 100 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 9.23 g of the title compound as yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([NH2:33])[C:21]([NH2:32])=[CH:22][C:23]=1[N:24]1[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]1>CN(C=O)C>[F:17][C:18]1[C:23]([N:24]2[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]2)=[CH:22][C:21]2[NH:32][C:15]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:6]=3)=[N:33][C:20]=2[CH:19]=1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: CN1CCCN(c2cc(N)c(N)cc2F)CC1
Solvent: CN(C)C=O
Product: CN1CCCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])nc3cc2F)CC1
Temperature: 22 °C
Reaction time: 4 h
Yield: 33.9 %

Procedure:
18 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde and 664 mg of ferric chloride are added to a solution of 19.1 g of 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)benzene-1,2-diamine in 406 mL of DMF. The reaction medium is stirred at 22° C. for 4 hours. After evaporation, the reaction crude is purified on a column 8 cm in diameter, with 3 kg of silica having a porosity of 0.063-0.2 mm. The elution is carried out with 2 L of pure dichloromethane and then 4 L of dichloromethane containing 10% of methanol, and then with dichloromethane containing 15% of methanol. 12 g of 5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzimidazole are isolated. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.41 to 2.31 (m, 8H); 2.91 (s, 3H); from 3.22 to 3.67 (m, 8H); 3.72 (m, 1H); 3.99 (m, 1H); 5.69 (dd, J=2.5 and 9.5 Hz, 1H); 7.32 (d, J=8.0 Hz, 1H); 7.75 (d, J=12.0 Hz, 1H); 9.40 (s, 1H). EI mass spectrum: m/z=443: M+. —m/z=373: (M−C4H8N)+—m/z=289: (m/z=373—C5H8O)+—m/z=84: C5H8O+. (base peak)—m/z=57: C3H7N+.
Reaction SMILES: [C:1]1([PH:7](=[O:15])[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[C:1]1([P:7](/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:15])[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCCCCCC
Reactant: O=[PH](OC1CCCCC1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCC/C=C/P(=O)(OC1CCCCC1)c1ccccc1
Yield: 98 %

Procedure:
In toluene (2 ml)under a nitrogen atmosphere at 100° C. for 20 hours, 1 mmol of cyclohexyl phenylphosphinate and 1 mmol of 1-octene were allowed to react using 3 molar % of Rh(PPh3)3Br as a catalyst to give cyclohexyl phenyl[(E)-1-octen-1-yl]phosphinate in a yield of 98%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(O)(C)C>[C:12]([NH:16][C:6]1[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Solvent: CC(C)O
Product: CC(C)(C)Nc1nc(Cl)nc2c1CCC2
Yield: 63.8 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (0.47 g, 2.5 mmol), tert-butylamine (1.25 ml, 11.8 mmol) and isopropanol (5 ml) was heated at reflux for 8 to 18 hours. After evaporation of volatiles the mixture was purified by flash chromatography over silica gel to afford the title compound as a white solid (0.36 g, 64% yield).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[C:6]([CH3:13])([CH3:12])[C:7](OCC)=[O:8]>C(O)C>[CH3:12][C:6]1([CH3:13])[S:3][C:2](=[NH:4])[NH:1][C:7]1=[O:8]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCO
Product: CC1(C)SC(=N)NC1=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A suspension of thiourea (19.0 g, 0.25 mole) in 150 ml of ethanol was heated under reflux until all of the thiourea had dissolved. Ethyl 2-bromo-isobutyrate (49.0 g, 0.25 mole) was then added over 10 minutes to the refluxing solution, after which time the solution was heated under reflux for six hours then allowed to stir at ambient temperature 36 hours. The solution was concentrated to dryness and the residue treated with water, then with aqueous NaHCO3 to adjust the pH to 7.0. The precipitated solid was collected by filtration, washed with water and dried to yield 5,5-dimethyl-2-iminothiazolidin-4-one: mp 252°-254° C.; 15.0 g (0.12 mole, 47%). Structure was confirmed by IR and NMR.