Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
A solution (20 ml.) of thionyl chloride containing 3.0 g of 4-acetoxybenzoic acid (Preparation 5) is refluxed for 3 hours. After evaporation of excess thionyl chloride, 4-acetoxybenzoyl chloride is obtained and dissolved in 15 ml. THF and 15 ml. acetone at 5°. This solution is added over 30 minutes to 2 g. of sodium azide in 10 ml. of water. The mixture is extracted with 2×75 ml. of toluene and the toluene solution washed several times with water. After drying the toluene solution containing the 4 acetoxybenzoyl azide with anhydrous magnesium sulfate, the mixture is filtered and the filtrate refluxed for one hour. The resulting 4-acetoxyphenyl isocyanate, in toluene, is cooled to 5° and reacted with 2.2 g. of 2-(endobicyclo[3.1.0]hex-6-yl)ethylamine. The product is a mixture of 4-acetoxy-[2-(endobicyclo[3.1.0]hex-6-yl)-ethyl]phenylurea and 4-hydroxy-[2-(endobicyclo[3.1.0]hex-6-yl)phenylurea in a ratio of 1:1. This mixture, in a solution of 50 ml. of methanol, is reacted with 10 ml. of a solution of 10% aqueous sodium hydroxide at 60° for 15 minutes. The resulting solution is then acidified with 6N hydrochloric acid. This mixture is extracted into 150 ml. of methylene chloride (CH2Cl2) and this extract washed with water, dried over magnesium sulfate and filtered. After chromatographing over silica gel, 1.7 g. of 4-hydroxy[2-(endobicyclo[3.1.0]hex-6-yl)ethyl]phenylurea are isolated.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([CH3:38])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:35]1[CH:36]=[C:31]([C:27]2[CH:26]=[C:25]([C:23]3[CH2:22][C:21](=[O:39])[NH:20][C:9]4[CH:10]=[C:11]([C:16]([F:18])([F:19])[F:17])[C:12]([CH:14]=[CH2:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[CH:32]=[C:33]([CH3:38])[N:34]=1
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example M221) (175 mg, 0.316 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (104 mg, 76%).
Reaction SMILES: BrC1C(=O)C(C(O)=O)=CN(C(C)C)C=1C.[Br:16][C:17]1[C:18](=[O:31])[C:19]([C:28]([OH:30])=O)=[CH:20][N:21]([C@@H:24]([CH2:26][CH3:27])[CH3:25])[C:22]=1[CH3:23].Cl.CS(C1C=CC(CN)=CC=1)(=O)=O.[CH3:45][C:46]1[O:50][C:49]([CH2:51][NH2:52])=[N:48][N:47]=1.BrBr>>[CH3:45][C:46]1[O:50][C:49]([CH2:51][NH:52][C:28]([C:19]2[C:18](=[O:31])[C:17]([Br:16])=[C:22]([CH3:23])[N:21]([C@@H:24]([CH2:26][CH3:27])[CH3:25])[CH:20]=2)=[O:30])=[N:48][N:47]=1
Reactant: CC[C@@H](C)n1cc(C(=O)O)c(=O)c(Br)c1C
Reactant: Cc1nnc(CN)o1
Agent: BrBr
Agent: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Product: CC[C@@H](C)n1cc(C(=O)NCc2nnc(C)o2)c(=O)c(Br)c1C

Procedure:
Preparation 25 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 11b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine. ESI mass spectrum: [M+H]+=383 (bromine isotope pattern); Retention time HPLC: 0.83 min (Z018_S04).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@H](O)CN
Reactant: O=CCC1Cc2ccc(F)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](O)Cn1ccc2c1-c1cc(F)ccc1C2
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A solution of 1.92 g of (RS)-2-(2-oxoethyl)-6-fluoro-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.51 g (65%) of (S)-1-(7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCI
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCNCC(OC)OC
Yield: 78.1 %

Procedure:
Hexyl iodide (50 mmol, 7.38 ml) was added to a mixture of 2-amino acetaldehyde dimethyl acetal (100 mmol, 11 ml) and potassium carbonate (50 mmol, 6.9 g) in DMF (10 ml) at 0° C. Stirring was continued for 16h before diluting with ethyl acetate (200 ml), and ffitering the solution through a plug of celite. Concentration in vacuo was follwed by column chromatography (eluant ethyl acetate) to give N-hexyl 2-amino acetaldehyde dimethyl acetal (7.39 g, 78%) as a colourless oil.
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]1([OH:10])[CH2:9][CH2:8]1>C(O)(C)C>[Br:1][CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5][CH2:4][Cl:3]
Reactant: BrBr
Reactant: OC1(CCCCl)CC1
Solvent: CC(C)O
Product: O=C(CCBr)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (2.0 mL, 39 mmol) was added slowly to a solution of 1-(3-chloropropyl)cyclopropanol (5.0 g, 34 mmol) in isopropanol (80% solution in water, 30 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 1 hour and then was quenched with water (15 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 1-bromo-6-chlorohexan-3-one, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[N:13](O)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:21]>[Zn]>[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CN(O)C3CCCCC23)cc1OC
Agent: Cl
Agent: [Zn]
Product: COc1ccc(C2CNC3CCCCC32)cc1OC
Reaction time: 2 h

Procedure:
A mixture of 10.0 g (0.036 mole) of 3-(3,4-dimethoxyphenyl)hexahydro-1-hydroxyindoline base, 400 ml of 1N hydrochloride acid (0.4 mole) and 20 g of zinc dust was heated with stirring on the steam bath for 11/2 hours. The cooled mixture was decanted (still acid to congo red) and 10M KOH (150 ml) was added. The separated oil was ether extracted (800 ml) and the ether solution was dried (K2CO3), filtered and treated with HCl gas to precipitate solid salt; wt. 9.5 g (84.2%), mp 188°-198° C. Recrystallization from 2-propanol-ether gave pure material melting at 190°-192° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[F:19][C:20]1([F:39])[CH2:25][N:24]([C:26]([C:28]2[S:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[O:27])[CH2:23][C:22]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[O:21]1.C(N(CC)CC)C>C(#N)C>[F:39][C:20]1([F:19])[CH2:25][N:24]([C:26]([C:28]2[S:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[O:27])[CH2:23][C:22]2([CH2:34][CH2:35][N:36]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][OH:11])[CH:4]=3)[CH2:37][CH2:38]2)[O:21]1
Reactant: Cc1ccc(C(=O)N2CC(F)(F)OC3(CCNCC3)C2)s1
Reactant: OCCc1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1ccc(C(=O)N2CC(F)(F)OC3(CCN(Cc4cccc(CCO)c4)CC3)C2)s1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.095 g) was added to a solution of (2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone trifluoroacetate (example 37, step e) (0.19 g) and triethylamine (0.185 mL) in acetonitrile (10 mL) and the reaction mixture stirred at 20° C. for 3 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.188 g.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([Br:27])[CH:20]=3)(=[O:18])=[O:17])[CH:11]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Br:27][C:21]1[CH:20]=[C:19]([S:16]([N:12]2[CH:11]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]3[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]2=3)(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2c2ccccc2)cc1Br
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)c(Br)c1)N1c2ccc(Br)cc2-c2ccccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A stirred suspension of 2-bromo-5-[(3-bromo-4-methoxyphenyl)sulfonyl]-6-phenyl-5,6-dihydrophenanthridine (0.527 g, 0.9 mmol) and cyclohexene (2.05 g, 25 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (6 mL, 6 mmol). After stirring for approximately two hours at room temperature, the reaction was quenched with methanol (10 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous, sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude orange residue (0.5 g,). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 30% methyl t-butyl ether in hexane at a flow rate of 50 mL/min; and afforded, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of ethyl acetate-diethyl ether-hexane yielded the title compound (0.322 g, 0.56 mmol, 63%) as a homogeneous, colorless, crystalline solid, m.p. 237-239° C.;
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5].C(N(CC)CC)C>C(OCC)C>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[CH:3]=[CH2:2]
Reactant: O=C(CCCl)c1cccs1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)c1cccs1
Reaction time: 60 h
Yield: 99 %

Procedure:
12 g of 3-chloro-1-(thiophen-2-yl)propan-1-one) prepared in Example 1a are solubilized in ethyl ether (180 mL). Triethylamine (10.2 g; 100 mmoles) is added at room temperature. The mixture is left under stirring for 60 hours, then washed with a HCl 10% solution and extracted with ethyl ether (2×20 mL). The organic phase is anhydrified with sodium sulphate, filtered and the solvent removed under vacuum. 9.4 g of 1-(thiophen-2-yl)-prop-2-en-1-one are obtained (yellow oil, yield 99%). Rf=0.74 (ligroin/ethyl acetate 8/2 volume/volume); 1H NMR (CDCl3) δ (ppm): 7.76 (m, 1H, ArH), 7.68 (m, 1H, ArH), 7.10 (m, 2H, ArH), 6.49 (m, 1H, CH2), 5.87 (m, 1H, CH2); 13C NMR (CDCl3) δ (ppm): 182.4, 144.6, 134.4, 132.5, 131.9, 129.4, 128.3; FT-IR (film) νmax: 3094.5, 1645.1, 1409.7, 1240.2, 850.4, 716 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13](O)=[O:14])=[C:6]2[O:16][CH:17]([CH3:19])[CH3:18].C(N1C=CN=C1)([N:22]1C=CN=C1)=O.[OH-].[NH4+].O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13]([NH2:22])=[O:14])=[C:6]2[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(c1)c(OC(C)C)c(C(=O)O)n2C
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)c(OC(C)C)c(C(N)=O)n2C
Temperature: 0 °C
Yield: 53.4 %

Procedure:
A mixture of 5-methoxy-1-methyl-3-(1-methylethoxy)-1H-indole-2-carboxylic acid (4.0 g, 15 mmol; Unangst PC, et al., J. Med. Chem. 1989;32:1360) and 1,1'-carbonyldiimidazole (2.6 g, 16 mmol) in 75 mL of acetonitrile is stirred at reflux for 2 hours. The mixture is cooled slightly and 75 mL of concentrated ammonium hydroxide is added. After stirring for 15 minutes, the mixture is added to 600 g of ice and water. The precipitated solid is filtered, washed with water, and recrystallized from aqueous acetonitrile to give 2.1 g (53%) of product; mp 147°-149° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:27]4[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:33]#[N:34])[CH2:24][C:23](=[O:35])[NH:22][C:9]=3[CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-3′-methoxy-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K21) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (118 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([O:24][C:25]([N:27]([CH2:29][C:30](O)=[O:31])[CH3:28])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])[CH2:29][N:27]([C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:26])[CH3:28])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)CN(C)C(=O)OC(C)(C)C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (750 mg), (tert-butoxycarbonyl-methyl-amino)-acetic acid (589 mg) and HBTU (1.37 g) in dry DMF (40 ml) containing N-methylmorpholine (0.79 ml) was stirred at room temp for 18 h. The mixture was then evaporated and the residue was purified by chromatography. Elution with 4:1 petrol:ethyl acetate gave a pale brown oil (494 mg)
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:18])C=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:7][C:6]([OH:8])([CH3:9])[CH2:5][O:4][CH2:1][CH:2]1[CH2:3][O:18]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOCC(C)(C)O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)COCC1CO1
Temperature: 0 °C
Reaction time: 6.5 h
Yield: 36.9 %

Procedure:
1-(Allyloxy)-2-methylpropan-2-ol (1.50 g, 11.5 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. mCPBA (77%> max, 9.94 g) was added. The suspension was stirred at 0° C. for 6.5 hr. and then saturated NaHCO3 solution (˜20 ml) and Na2S2O3 solution (˜20 ml) were added. The resulting mixture was stirred at 0° C. for 15 min and the two layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 1:0 to 1:2) to give the product as a colorless oil (620 mg, 37%). 1H NMR (400 MHz, CDCl3) δ ppm 3.64 (1H, ddd, J= 12.0, 5.2, 2.8 Hz), 3.24-3.29 (1H, m), 3.17-3.21 (1H, m), 3.11-3.14 (1H, m), 2.97-3.00 (1H, m), 2.88 (1H, br s), 2.60-2.64 (1H, m), 2.44-2.47 (1H, m), 1.02 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[CH:14]1.[Br:24]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Br:24]
Reactant: BrBr
Reactant: Nc1c(SC(F)(F)F)ncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: ClC(Cl)Cl
Product: Nc1c(SC(F)(F)F)nc(Br)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
To a solution of 1.35 g (3.40 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-amino-4-trifluoromethylsulfenylimidazole in 20 ml of chloroform was added 0.5 ml (9.76 mmole) of bromine. The resulting mixture was stirred at RT under a nitrogen atmosphere for 2 hr. The mixture was then evaporated to remove the excess of bromine and the residue was partioned between water and methylene chloride. The organic layer was dried over anhydrous sodium sulfate and solvent was removed. The residue was purified by flash column chromatography on silica gel using 7% ethyl acetate in hexane to give 200 mg (13.62% yield) of the desired product, mp 154° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34](=O)[CH2:35][CH3:36]>>[CH2:1]([O:8][C:9]1[C:10]([N:22]([CH2:34][CH2:35][CH3:36])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:19])([CH3:20])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2OCc2ccccc2)C(C)(C)CC=C3C)cc1
Reactant: CCC=O
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1OCc1ccccc1)C(C)(C)CC=C2C
Yield: 65 %

Procedure:
Following General Procedure P ethyl 4-(3-benzyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 114, 0.030 g, 0.07 mmol) was reacted with propionaldehyde to afford 0.021 g (65%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=1[F:29])[CH2:10][C:11]([O:13]C1CCCCC1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=1[F:29])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OC1CCCCC1)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 107.6 %

Procedure:
To a clean flask, 34.73 g (R)-cyclohexyl 3-(tert-butoxycarbonyl amino)-4-(2,4,5-trifluorophenyl)butyrate, 300 ml water and 5.2 g potassium carbonate were added. The mixture was warmed to 60° C. and kept at this temperature for 3 hours. 4.73 g hydrochloric acid was added dropwisely. After completion, the resulting mixture was kept at 20-30° C. for 2 hours and filtrated to obtain 29.99 g (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)n-butyric acid (yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:29]3[CH2:34][CH2:33][C@H:32]([C:35]([O:37][CH2:38]C)=[O:36])[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.C[O-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:29]3[CH2:34][CH2:33][C@H:32]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: CCOC(=O)[C@H]1CC[C@@H](n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@H](n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)CC1
Temperature: 75 °C
Yield: 35.1 %

Procedure:
cis-Ethyl 4-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-cyclohexanecarboxylate (0.030 g, 0.057 mmol), sodium methoxide (0.0033 g, 0.063 mmol) and methanol (2 mL) were combined and heated in a resealable Schlenk tube for 48 h at 75° C. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 15.6-16.5 min) afforded cis-methyl 4-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-cyclohexanecarboxylate as a white powder (0.010 g, 0.020 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 11.82 min; 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.23 (s, 1H), 7.92 (d, 2H), 7.65 (d, 2H), 7.12 (s, 1H), 6.80 (s, 1H), 4.67 (m, 1H), 3.63 (s, 3H), 3.27 (m, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 2.07 (m, 6H), 1.61 (m, 2H).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:8]=1[C:9]#[N:10].[C:18](C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH3:18][O:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:8]=1[C:9]#[N:10]
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Reactant: N#Cc1c(OC/C=C/CO)cccc1[N+](=O)[O-]
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC/C=C/COc1cccc([N+](=O)[O-])c1C#N
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of (E)-2-(4-hydroxybut-2-enyloxy)-6-nitrobenzonitrile (Example 199d) (0.50 g, 2.13 mmol) and 2,6-di-tert-butyl-4-methylpyridine (2.18 g, 10.65 mmol) in CH2Cl2 (15.0 mL) at rt, was added trimethyloxonium tetrafluoroborate (1.58 g, 10.65 mmol) under a nitrogen atmosphere. After 1 h at rt, the reaction was quenched with water (50 mL) and extracted with EtOAc (4×50 mL). The combined extract was washed with water, 1.5M HCl, saturated aqueous NaHCO3 and brine, and was dried over anhydrous MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using the solvent gradient hexanes→hexanes/EtOAc (3:7), to give 0.25 g (72%) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.84-7.92 (m, 2H), 7.68-7.73 (m, 1H), 5.82-6.03 (m, 2H), 4.82-4.88 (m, 2H), 3.87-3.93 (m, 2H), 3.21 (s, 3H).