Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH2:24][S:25][CH:26]([CH3:28])[CH3:27])[CH:7]=1)[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([Cl:30])=[CH:32][CH:33]=3)=[CH:17][C:16]=2[CH2:24][S:25][CH:26]([CH3:28])[CH3:27])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSC(C)C)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSC(C)C)c1

Procedure:
[3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester was reduced to the amine according to the procedure described in Example 11, Step 2. The amine was treated with 4-chlorobenzoyl chloride to provide {3-[4-(4-Chloro-benzoylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester as outlined in Example 11, Step 4 provided the acid.
Reaction SMILES: [C:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([O:20]C)=[O:19])=[C:10]([CH2:22][NH2:23])[CH:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=[O:19])=[C:10]([CH2:22][NH2:23])[CH:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1c(CN)cc(C(=O)OC(C)(C)C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(CN)c(C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
The compound obtained in Example 25-1 (266.6 mg) was dissolved in THF (2.7 ml) and methanol (2.7 ml). After the addition of 1 mol/l aqueous solution of sodium hydroxide (2.7 ml), the mixture was stirred for 5 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in distilled water and 1 mol/l aqueous solution of hydrochloric acid was added to produce a precipitate. The precipitate was collected by filtration and dried to obtain the title compound (233.5 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.O>[CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(C)c2[nH]c(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2[nH]c(=O)n(CC(=O)OC(C)(C)C)c2c1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4,6-dimethyl-1,3-dihydro-2H-benzimidazol-2-one from Step A (7.15 g, 44.1 mmol) in DMF (200 mL) was added sodium hydride (1.76 g of a 60% dispersion in mineral oil, 44.1 mmol) over 2 min. The mixture was stirred for 20 min, then tert-butyl bromoacetate (8.17 g, 41.9 mmol) in DMF (40 mL) was added and stirring was continued for 1 h. The reaction mixture was diluted with H2O (400 mL) carefully and a solid precipitated. The mixture was aged for 5 min, then filtered to give a crude solid, which was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc-100:0 to 40:60, to provide the title compound. MS: m/z=277 (M+1).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][NH:46][CH2:45]2)[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][N:46]([C:3]3[N:8]4[N:9]=[C:10]([CH:12]5[CH2:17][CH2:16][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:14][CH2:13]5)[N:11]=[C:7]4[CH:6]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[Cl:28])[N:4]=3)[CH2:45]2)[N:32]=1
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(N4CCCC(Nc5ccc(C(=O)C(F)(F)F)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.17 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidine hydrochloride, 64.9 mg (0.2 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 22A) and 0.17 ml (0.99 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 32 mg (28% of theory) of the product as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][C:23]([C:25]1[CH:26]=[CH:27][C:28](O)=[CH:29][CH:30]=1)=[O:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:29][CH:30]=1)(=[O:24])[CH3:22]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: CC(=O)c1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-hydroxyacetophenone: MS (APCI) m/z 431 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:15][C:16]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:22][CH:23]=1)([F:27])[F:28]
Reactant: Clc1cccc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: FC(F)(F)Oc1ccc(-c2cccc(Cl)c2)cc1

Procedure:
A solution of DME (40 mL) and 2M K2CO3 (40 mL) containing 1-bromo-3-chlorobenzene (2.53 g, 13.21 mol), 4-(trifluoromethoxy)phenyl boronic acid (4 g, 19.4 mmol) and Pd(PPh3)4 (0.76 g, 0.66 mmol) was refluxed under an argon atmosphere until no starting material remained by HPLC analysis. The solution was concentrated (to remove excess DME) and partitioned between water and ethyl acetate. The organic phase was washed with 1N NaOH, water (2×) and brine. The solution was then dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS1 4.23 min.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([NH:42][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:1])([F:26])[F:25])=[CH:4][C:5]([C:15]5[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=5)=[N:6][C:7]=34)=[O:13])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 600.3 [(M+H)+]; mp 233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH2:7][S:8][CH3:9].[Br:17]Br>CO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[CH2:4][NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH2:7][S:8][CH3:9]
Reactant: CSC[C@H](NCc1ccccc1N)C(=O)O
Reactant: BrBr
Solvent: CO
Product: CSC[C@H](NCc1cc(Br)ccc1N)C(=O)O
Reaction time: 2 h

Procedure:
To a stirred suspension of 2.40 gm of N-(2-amino-benzyl)-S-methyl-cysteine in 50 cm3 anhydrous methanol a solution of 0.52 cc of bromine in 20 cc of methanol was added dropwise. After the addition of bromine was finished, stirring was continued for 2 hours. The solvent was evaporated in vacuo on a water bath, and residue was dissolved in 50 cc of distilled water. The aqueous solution was decolored by refluxing for 1 hour in the presence of a small quantity of charcoal. The coal was removed by filtration, and the pH of the filtrate was adjusted to 5 by addition of dilute ammonia. The desired product precipitated out. The mixture was allowed to stand for several hours, whereupon the precipitate was centrifuged off, washed with water and dried in a drying chamber. Melting point: 228° C.
Reaction SMILES: [CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH:17]=[CH:18][C:13]3=[CH:12][C:11]=2[C:19]([OH:21])=[O:20])=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)C.[H][H]>[Pd].O>[CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH2:17][CH2:18][C:13]3=[CH:12][C:11]=2[C:19]([OH:21])=[O:20])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)C1(C)N=C(c2nc3c(cc2C(=O)O)CCO3)NC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 5.9 %

Procedure:
A solution of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3-b]pyridine-5-carboxylic acid (1.7 g 0.056 mol) and 1.0 g (0.0072 mol) potassium carbonate in 200 mL 9:1 ethanol:water is added to 100 mg 5% palladium on carbon catalyst in a 500 mL pressure bottle. The bottle is fitted to a Parr hydrogenation apparatus, pressurized to 30 psi, with hydrogen, then shaken at room temperature for 10 hours. The catalyst is removed by filtration through a sintered glass funnel, and the filtrate concentrated in vacuo to 10 mL. Acidification of the residue to pH 2 gives a white precipitate which is removed by filtration, washed with water and air dried to give 1.0 g (63%) of 2,3-dihydro-6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3-b]pyridine-5-carboxylic acid as an off-white solid, mp 189°-192° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.[CH3:12][NH2:13]>CCO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:13][CH3:12])[C:5]2=[N:4][CH:3]=1
Reactant: CN
Reactant: Clc1nccn2c(Br)cnc12
Solvent: CCO
Product: CNc1nccn2c(Br)cnc12

Procedure:
(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine was prepared by a process analogous to that described in Example 2 starting from 3-bromo-8-chloro-imidazo[1,2-a]pyrazine and excess methylamine (33% weight in EtOH) at room temperature in EtOH.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][N:7]=1.[OH-].[Na+].[C:11]1([N:17]=[C:18]=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:8][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[NH:2][C:18]([NH:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:19]
Reactant: Cn1ccnc1N
Reactant: S=C=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1ccnc1NC(=S)Nc1ccccc1

Procedure:
A 4.8 g (0.036 mole) sample of 2-amino-1-methylimidazole hydrochloride is suspended in 20 ml of methylene chloride and stirred with 10 ml of 50% NaOH. The organic layer is separated and the aqueous layer is extracted twice with 20 ml portions of fresh methylene chloride. The combined organic extracts are dried over K2CO3 and filtered. The filtrate is treated with 4.86 g (0.036 mole) of phenyl isothiocyanate. The solution is heated under reflux for 4 hr. Evaporation of the solvent in vacuo followed by recrystallization of the residue from acetone-ether (1:1) and MeOH-ether (1:1) gives the product, N-(1-methylimidazol-2-yl)-N'-phenylthiourea; m.p. 170°-172° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.[CH2:19](S)[CH2:20][CH2:21]C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:15][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCCCS
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCSc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, butylmercaptan and DBU in DME. ES-MS m/e (%): 275 (M+H+, 100).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[C:30]2[C:29]3[CH2:28][CH2:27][CH2:26][C:25]=3[S:24][C:23]=2[N:22]=[CH:21][N:20]=1>O1CCCC1>[C:30]12[C:19]([O:1][CH:2]3[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]3)=[N:20][CH:21]=[N:22][C:23]=1[S:24][C:25]1[CH2:26][CH2:27][CH2:28][C:29]2=1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: Clc1ncnc2sc3c(c12)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (194 mg, 0.90 mmol, 1.40 equiv) in anhydrous tetrahydrofuran (5 mL) was added sodium hydride (60% dispersion in mineral oil, 77 mg, 1.92 mmol, 3.00 equiv) at 0° C. under nitrogen. After stirred at room temperature for 1 h, 12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraene (200 mg, 0.95 mmol, 1.00 equiv) was added and the resulting solution was stirred overnight at ambient temperature for additional 5 h. The reaction was then quenched with water and extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give the resulted ter t-butyl N-(4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexyl)carbamate (308 mg, 83%) as a yellow solid. MS (ES, m/z): 390 (M+H+).
Reaction SMILES: [CH:1](/[P:4](=[O:15])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:2]\[CH3:3].[O-2].[Al+3].[O-2].[O-2].[Al+3].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:3]/[CH:2]=[CH:1]/[P:4](=[O:15])([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C/P(=O)(OC(C)(C)C)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OP(=O)(/C=C/CBr)OC(C)(C)C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
(1)-2 To a solution of di-tert.-butyl trans-1-propenylphosphonate (12.0 g.) in carbon tetrachloride (120 ml.) were added basic aluminum oxide (24.0 g.), N-bromosuccinimide (10.95 g.) and then dibenzoylperoxide (1.4 g.). The mixture was heated to reflux for an hour and then stirred for 30 minutes under ice-cooling. The resultant mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give oily di-tert.-butyl 3-bromo-trans-1-propenylphosphonate (17.2 g.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][Br:17])[CH:3]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(Br)cc(CBr)c1
Yield: 84.2 %

Procedure:
A solution of 1-bromo-3,5-dimethyl-benzene (1.0 g, 5.4 mmol, 1.0 eq), NBS (1.06 g, 5.94 mmol, 1.1 mmol) and AIBN (180 mg, 1.08 mmol, 0.2 eq) in CCl4 (20 mL) was stirred at reflux overnight. The reaction was then diluted with water and extracted with CH2Cl2. The organic extracts were combined and washed with aqueous NaHCO3, dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (Petroleum ether:EtOAc, 1:0 to 10:1) to give the title compound as a light yellow oil (1.2 g, 84%).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH2:8]([C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:13]1)[CH2:9][CH2:10][CH3:11].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:8]([C@H:12]1[CH2:13][N:14]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:15][CH2:16][N:17]1[S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH2:9][CH2:10][CH3:11]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCCC
Reaction time: 8 h

Procedure:
Chloroethylsulfonylchloride (0.038 mL, 0.314 mmol) was added to a solution of 3(S)-butyl-1-(1-naphthoyl)piperazine (0.095 g, 0.285 mmol) and diisopropylethylamine (0.119 mL, 0.685 mmol) in dichloromethane (3 mL). The reaction was stirred overnight under nitrogen, quenched with saturated sodium bicarbonate and extracted into ethyl acetate. After drying with magnesium sulfate, the title compound was isolated.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:44])[S:40](Cl)(=[O:42])=[O:41].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[CH:29][CH:30]=2)=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([S:40]([N:39]([CH3:44])[CH3:38])(=[O:42])=[O:41])[CH2:17][CH2:18][CH2:19][OH:20])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2cccc(NCCCO)c2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)N(CCCO)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A solution of 1-{5-tert-butyl-2-[3-(3-hydroxy-propylamino)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea (100 mg, 0.21 mmol) in THF (1 mL) was treated with dimethylsulfamoyl chloride (90 mg, 0.62 mmol, 3 eq) followed by DIEA (30 mg, 0.21 mmol, 1 eq). The reaction mixture was stirred at 40° C. overnight. The mixture was evaporated at reduced pressure, and the product was isolated by MPLC (eluting with 1% to 4% MeOH in DCM) to afford 57 mg (46%) of desired product. 1H-NMR (DMSO-d6) δ 9.08 (s, 1H), 8.40-8.38 (m, 3H), 7.54-7.36 (m, 6H), 7.05 (d, J=8.9 Hz, 2H), 6.84 (d, J=5.6 Hz, 2H), 6.32 (s, 1H), 4.45 (t, J=4.6 Hz, 1H), 3.64 (t, J=7.0 Hz, 2H), 3.33-3.28 (m, 2H), 2.70 (s, 6H), 1.49-1.45 (m, 2H), 1.29 (s, 9H); MS LC-MS [M+H]+=608.2, RT=2.45 min.
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[CH2:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28]
Reactant: CC(C)(C)S(=O)NCCCBr
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)CCO4)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)NCCCn1c(Sc2cc3c(cc2I)CCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-6-amine (26 mg, 0.06 mmol) in DMF (1.5 mL) was added N-(3-bromopropyl)-2-methlpropane-2-sulfinamide (49 mg, 0.18 mmol) and Cs2CO3 (41 mg, 0.12 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS62 as a white solid (11 mg, 30%). 1H NMR (600 MHz, CDCl3): δ 8.33 (s, 1H), 7.66 (s, 1H), 6.61 (s, 1H), 5.85 (br s, 2H), 4.84 (t, J=6.7 Hz, 1H), 4.59 (t, J=8.7 Hz, 2H), 4.37-4.44 (m, 1H), 4.29-4.35 (m, 1H), 3.22 (t, J=8.5 Hz, 2H), 3.09-3.16 (m, 1H), 2.95-3.02 (m, 1H), 2.06-2.15 (m, 1H), 1.93-2.05 (m, 1H), 1.29 (s, 9H); HRMS (ESI) m/z [M+H]+ calcd. for C20H26IN6O2S2, 573.0603. found 573.0620.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O1CCC[CH2:14]1.CO.C[Si](C=[N+]=[N-])(C)C>C(O)(=O)C>[CH3:14][O:8][C:7]([CH:4]1[CH2:3][CH2:2][CH:1]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)=[O:9]
Reactant: C1CCOC1
Reactant: O=C(O)C1CCC(C(=O)O)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cold, stirred solution of cyclohexane-1,4-dicarboxylic acid (3.0 g, 17 mmol) in a mixture of 2:1 tetrahydrofuran/methanol (24 mL) was added trimethylsilyl diazomethane (9 mL of a 2.0 M in hexanes, 18 mmol). The reaction mixture was stirred at room temperature for 2 h. Acetic acid (5 mL) was added and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 10:1:0.01 hexanes/ethyl acetate/acetic acid) provided 4-(methoxycarbonyl)cyclohexanecarboxylic acid (1.00 g): 1H NMR (300 MHz, CDCl3) δ 3.68 (s, 3H), 2.53-2.47 (m, 2H), 1.97-1.89 (m, 4H), 1.74-1.66 (m, 4H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[C:37]#[N:38])=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[C:37]#[N:38])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])([O-:16])=[O:15]
Reactant: OC1CCOC1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)OC2CCOC2)c1
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoate.