Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:15]3[CH2:16][CH2:17][O:18][CH:14]3[O:13][N:12]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].C(Cl)(=O)C(Cl)=O.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:10]([C:11]2[CH:15]3[CH2:16][CH2:17][O:18][CH:14]3[O:13][N:12]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:29]1[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH:30]=1)=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: CS(=O)(=O)c1ccc(C(=O)[O-])c(Cl)c1C1=NOC2OCCC12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1C1=NOC2OCCC12
Reaction time: 2 h

Procedure:
58.0 g (167.8 mmol) of 2-chloro-4-methylsulfonyl-3-(3a,4,5,6a-tetrahydrofuro[3,2-d]isoxazol-3-yl)-benzoate are dissolved in 600 ml of dichloromethane, and 31.94 g (251.6 mmol) of oxalyl chloride and three drops of dimethylformamide are added at room temperature. After the evolution of gas has ceased (approx. 2 hours), the mixture is refluxed for a further hour. It is subsequently concentrated, and redissolved in 300 ml of dichloromethane. At 0-5° C., a mixture of 19.5 g (173.9 mmol) of 1,3-cyclohexanedione and 17.6 g (173.9 mmol) of triethylamine in 200 ml of dichlormethane is added dropwise. The mixture is stirred for 2 hours and then washed in succession with sodium carbonate solution and sodium chloride solution, and the organic phase is then dried over magnesium sulfate. After removal of the solvent, 64.5 g (87% of theory) of crude 3-oxocyclohex-1-enyl 2-chloro-4-methyl-sulfonyl-3-(3a,4,5,6a-tetrahydrofuro[3,2-d]isoxazol-3-yl)benzoate are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1)(C)(C)C.[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1>>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:19])([F:20])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:38](=[O:39])[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][N:36]=3)[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: COc1ccc(C(=O)O)nc1
Product: COc1ccc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)nc1

Procedure:
Synthesized from tert-butyl[(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-methoxypyridine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.88 (dd, J=13.8, 3.7 Hz, 1 H), 3.23 (dd, J=13.8, 2.4 Hz, 1 H), 3.46 (d, J=7.3 Hz, 1 H), 3.89-4.02 (m, 4 H), 4.54-5.00 (m, 4 H), 7.11 (dd, J=11.9, 8.8 Hz, 1 H), 7.36 (dd, J=8.8, 2.8 Hz, 1 H), 7.61 (dd, J=7.1, 2.8 Hz, 1 H), 7.97 (dt, J=8.5, 3.6 Hz, 1 H), 8.23-8.30 (m, 2 H), 9.86 (s, 1 H)
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[OH:21])([CH3:10])([CH3:9])[CH3:8].C=O.[CH2:24](NCCCC)CCC>C(O)C>[C:17]([C:13]1[CH:14]=[C:15]([CH:16]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12]=1[OH:21])[CH2:24][C:5]1[NH:4][N:3]=[C:2]([SH:1])[N:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Sc1nc[nH]n1
Reactant: CCCCNCCCC
Agent: C=O
Solvent: CCO
Product: CC(C)(C)c1cc(Cc2nc(S)n[nH]2)cc(C(C)(C)C)c1O

Procedure:
3-Mercapto-1,2,4-triazole (20.2 g, 0.2 mol), 2,6-di-tertbutylphenol (41.2 g, 0.2 mol), paraformaldehyde (6.0 g, 0.2M) and di-n-butylamine (2 ml) are heated, under reflux, in ethanol (100 ml) for ten hours. The reaction mixture is cooled, and the product is crystallised as a white solid (43 g, 67% of theory) having a m.p. of 184°-185° C. (Found C=63.39; H=8.03; N=13.29; S=10.20 C17H25N3OS requires C=63.95; H=7.84; N=13.17 and S=10.03%).
Reaction SMILES: C1(C[NH:8][CH:9]([C@:18]2([CH2:33][OH:34])[O:22][C@@H:21]([N:23]3[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]3=[O:25])[CH2:20][C@@H:19]2[OH:32])NCC2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[NH2:8][CH2:9][C@:18]1([CH2:33][OH:34])[O:22][C@@H:21]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:20][C@@H:19]1[OH:32]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@](CO)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
4′-C-(1,1′-diphenylmethylaminomethyl)thymidine (3) (0.65 g, 1.5 mmol) was dissolved in absolute ethanol (50 mL). Cyctohexene (12 mL), glacial acetic acid (5 mL) and 5%-palladium on charcoal (0.6 g) were added and the mixture heated under reflux with stirring. The solution was heated for 5 hours and then allowed to cool to ambient temperature. Palladium catalyst was removed by filtration through celite and the filtrate was concentrated under vacuum to give the crude title compound (4), which was used in the following step without further purification. ES +ve m/z 272(M+H)+, 242(M—CH2NH2)+. For an alternative synthesis of this compound see: Wang et al; Tetrahedron Letters 1996, 37, 6515–6518.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[NH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH:13]([NH2:14])([CH3:18])[CH3:12].[N:23]1([NH:22][C:3]([C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Reactant: NN1CCOCC1
Product: CC(C)N
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN2CCOCC2)on1
Yield: 123.1 %

Procedure:
As described for example 28, 3-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (110 mg, 0.37 mmol), was converted using 4-aminomorpholine (153 mg, 1.5 mmol), instead of isopropyl amine, to the title compound (83 mg, 61%) which was obtained as a colourless oil after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=365.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([OH:21])=[O:20].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:9]=2)[C:5]([CH2:18][C:19]([OH:21])=[O:20])=[CH:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)Cc1cn(Cc2ccccc2)c2ccc(Br)cc12
Product: O=C(O)Cc1cn(Cc2ccccc2)c2ccc(-c3ccccc3)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo-1-benzyl-1H-indol-3-yl]acetic acid and phenylboronic acid were used.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8].Cl[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8])[C:17]([O:19][CH3:20])=[O:18])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCN(CC(=O)c1ccc(Cl)cc1)C(=O)OC
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To 25 g (454 mmole) of propargylamine in 200 ml of methylene chloride cooled to -40° C. was rapidly added 46 g (200 mmole) of 2-bromo-4'-chloroacetophenone dissolved in 200 ml of methylene chloride. The temperature rose to 0° C. and was maintained there for 15 minutes. The reaction mixture was washed with 250 ml of 1M sodium hydroxide and recooled to -20° C. whereon 22 g (233 mmole) of methyl chloroformate was added while maintaining an internal temperature of -20° C., then 20 g (253 mmole) of pyridine was added. After stirring for 1 hour the mixture was concentrated in vacuo, partitioned between diethyl ether and water, washed with dilute hydrochloric acid, washed with brine, dried over anhydrous magnesium sulfate, reconcentrated in vacuo, and chromatographed over silica gel using diethyl ether and hexanes to yield 34 g of the expected compound, an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[C:5]2[O:9][C:8]([F:11])([F:10])[O:7][C:6]=2[CH:12]=1.[C:20](=[O:22])=[O:21].[NH4+].[Cl-].Cl>C(OCC)C>[F:10][C:8]1([F:11])[O:9][C:5]2[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:3][C:2]([C:20]([OH:22])=[O:21])=[CH:12][C:6]=2[O:7]1
Reactant: O=C=O
Reactant: CC[Si](CC)(CC)c1cc(Br)cc2c1OC(F)(F)O2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC[Si](CC)(CC)c1cc(C(=O)O)cc2c1OC(F)(F)O2
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
200 ml of anhydrous diethyl ether were poured to 1.9 g of Mg turnings and 2.0 g of (6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane (Eur. J. Org. Chem. 2004, 1, 64) added. The mixture was then stirred at 35° C. for 30 minutes. Then, the heating was shut down and 23.4 g of (6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane was added dropwise to the stirred mixture at a rate that ensured gentle boiling. Stirring was continued at 35° C. for 2 h. Then, the mixture was intensely stirred at room temperature under an excess of anhydrous CO2 for 2 h. The reaction mixture was then poured into 300 ml of a saturated aqueous NH4Cl-solution, acidified to pH=3 using aqueous HCl-solution and the organic layer separated. The aqueous layer was then extracted using 200 ml of diethyl ether. The combined organic layer was dried using MgSO4 and evaporated to yield 22.0 g of the title compound that was used without further purification.
Reaction SMILES: [F:1][S:2]([F:16])([F:15])([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[N+:17]([O-:20])([OH:19])=[O:18]>>[N+:17]([C:8]1[CH:7]=[CH:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[S:2]([F:13])([F:14])([F:15])([F:16])[F:1])([O-:19])=[O:18].[N+:17]([C:6]1[CH:7]=[CH:8][C:3]([S:2]([F:16])([F:15])([F:1])([F:13])[F:14])=[CH:4][C:5]=1[NH:9][C:10](=[O:12])[CH3:11])([O-:20])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(S(F)(F)(F)(F)F)c1
Product: CC(=O)Nc1cc(S(F)(F)(F)(F)F)ccc1[N+](=O)[O-]
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(S(F)(F)(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
20.00 g of N-(3-pentafluorosulfanylphenyl)acetamide (preparation as in Tetrahedron 56, (2000) 3399) were dissolved in portions at from −35° C. to −40° C. in 100 ml of 90% HNO3. The mixture was stirred at −40° C. for 15 minutes, then poured onto 1 kg of ice and stirred at RT for 1 h. The product was then filtered, washed with water and dried under reduced pressure. Chromatography on silica gel using DIP afforded 3.61 g of N-(4-nitro-3-pentafluorosulfanylphenyl)acetamide as well as 17.00 g of N-(2-nitro-5-pentafluorosulfanylphenyl)acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH:20]([CH3:24])[C:21](Cl)=[O:22].O>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:12][CH:20]([CH3:24])[C:21](=[O:22])[NH:1][C:2]=2[CH:7]=1)=[O:9]
Reactant: CC(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Temperature: 50 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 2-amino-4-methoxycarbonylphenol [Acta Chimica Academiae Scientiarum Hungaricae, 99(1), 49-50 (1979)] (5.0 g) in dimethylformamide (30 ml) were added potassium carbonate (8.3 g) and 2-chloropropionyl chloride (4.0 g) and the mixture was stirred at 50° C. for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The extraction was concentrated and hexane was added thereto to give precipitates, which were taken by filtration and dried to give 6-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (4.7 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:28]=O.[BH4-].[Na+]>CO.O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH3:28])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: C=O
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.67 g, 0.207 mmole) in 10 mL of methanol was added 37% formalin solution (1 mL), and the resulting mixture was cooled in an ice bath under Argon. To this mixture was added sodium borohydride (0.69 g, 18.2 mmol) in small portions. The reaction mixture was allowed to warm to ambient temperature and was stirred for three days. The reaction mixture was diluted with water (25 mL), and the resulting solution was extracted three times with chloroform (25 mL). The organic extracts were combined, dried (Na2SO4), and concentrated to provide a pale yellow oil. This material was purified on a flash silica gel column (10% methanol-chloroform to 15% methanol-chloroform) to provide 0.54 g of N,N-diethyl-4-[benzyl(1-methylpiperidin-4-yl)amino]benzamide as a pale yellow semisolid. This material was dissolved in acetonitrile, and oxalic acid (0.13 g) was added. Upon addition of diethyl ether, a cream-colored precipitate came out of solution. Recrystallization from acetonitrile and diethyl ether afforded 0.18 g (18% yield) of a cream-colored solid, mp 101-105° C. MS (ES), m/z 380 (MH+). 300 MHz 1H NMR (DMSO-d6) δ0.85-1.15 (br m, 6H), 1.75-2.02 (br m, 2H), 2.72 (s, 3H), 2.95-3.15 (br m, 2H), 3.16-3.45 (m, 6H), 4.12-4.30 (br m, 1H), 4.49 (br s, 2H), 6.63-6.82 (br m, 2H), 7.10-7.40 (m, 7H). Elemental analysis: Calculated for C24H33N3O.C2H2O4.0.6H2O: C, 65.01; H, 7.60; N, 8.75; H2O, 2.25. Found C, 64.77; H, 7.25; N, 8.59; Karl Fischer H2O, 1.55.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].Cl[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(=O)(O)(O)O.C=CC1C=CC=CC=1>>[CH3:11][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=2)[CH2:5]1
Reactant: ClCCc1ccccc1
Reactant: C=Cc1ccccc1Cl
Agent: O=P(O)(O)O
Solvent: C=Cc1ccccc1
Product: CC1CC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 115 parts of o-chlorostyrene and 35 parts of o-chloroethylbenzene is added to 652 parts of 89 per cent strength by weight aqueous phosphoric acid at 40° to 45° C whilst stirring vigorously. A mixture of 90 parts of styrene, 115 parts of o-chlorostyrene and 35 parts of o-chloroethylbenzene is added to the resulting emulsion at a temperature of 40° to 45° C over 5 hours. After completion of the addition, the mixture is stirred for a further 2 hours at 40° to 45° C. The organic phase is separated off, washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution and fractionated. 24.9 parts of 1-methyl-3-phenylindan (b.p. 145° to 146° C (10 mm)), 63.1 parts of 1-methyl-3-(o-chloro)-phenylindan (b.p. 165° to 168° C (10 mm), nD25 : 1.5890) and 31 parts of 1-methyl-3-(o-chloro)-phenyl-7-chloroindan (b.p. 195° to 200° C (10 mm)) are isolated.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.[Li]C(CC)C.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1.O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][C:3]=1[B:27]([OH:32])[OH:28]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCC1CCC(C2CCc3ccc(F)c(F)c3O2)CC1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCc3cc(B(O)O)c(F)c(F)c3O2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7,8-difluoro-2-(4-propylcyclohexyl)chroman (3.82 g) obtained in Example 2 was dissolved in THF (38 mL). To the solution was added dropwise sec-BuLi (0.99 M solution, 15.5 mL) at −70 to −75° C. and stirred after the end of dropping at the same temperature for additional 1 hour. To the solution was added dropwise a THF solution (5 mL) of triisopropyl borate (2.15 g) at −70 to −75° C. After the end of dropping, it was stirred at the same temperature for additional 3 hours. Then temperature thereof was gradually raised to room temperature. The solution was left stirring overnight. While cooling on ice, to the reaction mixture was added 2 M hydrochloric acid and stirred at room temperature for additional 2 hours. The reaction mixture was poured to water, which was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated residue was further washed with heptane to obtain crude 7,8-difluoro-6-dihydroxyboryl-2-(4-propylcyclohexyl)chroman. The product was used in a second step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.C([OH:26])C.O.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>O>[C:28]1([CH3:38])[CH:29]=[CH:30][C:31]([S:34]([OH:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1.[C:28]1([CH3:38])[CH:29]=[CH:30][C:31]([S:34]([OH:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1.[NH2:9][CH2:10][C:11]1[N:12]([C:13]2[S:17][C:16]([CH2:18][CH3:19])=[CH:15][C:14]=2[C:8](=[O:26])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:20]([CH3:23])=[N:21][N:22]=1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (702 g) was suspended in a mixed solvent (4.9 l) of ethanol and water (9:1), and p-toluenesulfonic acid monohydrate (1165 g) was added. The mixture was stirred at 80° C. for 1.5 hours. The mixture was concentrated to about 2.5 l by evaporating the solvent under reduced pressure, and ethyl acetate (4 l) was added. The reaction mixture was filtered to give crystals, and the crystals were washed with ethyl acetate and ethanol and dried to give 1214 g of 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH2:46][CH2:47][NH:48][CH2:49][CH:50]=3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:57][S:58](Cl)(=[O:60])=[O:59].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:31][CH2:32]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH2:46][CH2:47][N:48]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:49][CH:50]=3)=[CH:41][C:40]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:35]([F:37])([F:36])[F:38])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5=CCNCC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C5=CCN(S(C)(=O)=O)CC5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (320 mg, 0.413 mmol) in CH2Cl2 (5.0 mL) was added methanesulfonyl chloride (47 mg, 0.41 mmol) and triethylamine (94 mg, 0.83 mmol), and the reaction was stirred for 1.5 h at RT and then concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2Cl2 to 90:9:1 CH2Cl2:MeOH:conc. NH4OH) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3.C(=O)([O-])[O-].[Na+].[Na+].[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[SH:42].CN(C=O)C>O>[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][C:2]1[C:3]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:4][C:5]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:19])[C:11]3[C:6]=2[C:7]=1[CH:8]=[CH:9][CH:10]=3
Reactant: Nc1ccccc1S
Reactant: CCCCC(CC)COc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1cc2c3c(cccc3c1Sc1ccccc1N)C(=O)c1ccccc1-2
Temperature: 125 °C
Reaction time: 3 h

Procedure:
A 250 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 27 g of 3-bromo-2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one, 5.0 g sodium carbonate, 8.5 g 2-aminothiophenol and 80 g DMF. The mixture was agitated well, heated to 120-130° C., and held at 120-130° C. for three hours. Sodium carbonate (1.0 g) and 1.2 g 2-aminothiophenol were added and the mixture heated for an additional one hour. The reaction mixture was cooled to 25° C. and 250 g of water were added. The reaction mixture was extracted twice with 200 g chloroform. The organic layers were combined and washed twice with 250 g water. The solvent was removed on a rotary evaporator, then the crude product was passed through a flash silica gel column using methylene chloride as the elutant. The product fractions were collected and the solvent removed using a rotary evaporator. The yield of semi-solid 3-[(2-aminophenyl)thio]-2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one was 27.5 g.