Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]([OH:7])[CH3:6].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].C1C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]\[CH:5]([OH:7])[CH3:6]
Reactant: CC(O)C#C[Si](C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: c1ccccc1
Product: CC(O)/C=C\[Si](C)(C)C

Procedure:
A solution of 94.15 parts by weight of 4-(trimethylsilyl)-3-butyn-2-ol (II) in 940 parts by volume of benzene and 4.7 parts by volume of quinoline is hydrogenated at a constant pressure of 2 p.s.i. in the presence of 9.4 parts by weight of 5% palladium on barium sulfate until one equivalent of hydrogen is consumed. The catalyst is removed and the solution is washed twice with 100 parts per volume of 5% aqueous hydrochloric acid and then with water. After drying over sodium sulfate, the solvent is removed and the residue is distilled at 33°-39° C./0.3 mm to give cis-4-(trimethylsilyl)-3-buten-2-ol (III) which has the following structural formula: ##STR9##
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:34][C:35]1[C:36]([CH2:41]Br)=[CH:37][CH:38]=[CH:39][CH:40]=1>CN(C)C=O>[CH2:41]1[C:36]2[C:35](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][N:1]1[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1
Reactant: BrCc1ccccc1CBr
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2ccccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nc(CN4Cc5ccccc5C4)no3)ncn2-c2ccccc2C1=O
Yield: 23.1 %

Procedure:
1.28 g (4.1 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 25 ml of N,N-dimethylformamide, 2 ml (11.7 mmol) of N-ethyldiisopropylamine and 1.19 g (4.5 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 4 hours. After evaporating the solvent the residue was chromatographed on 180 g of silica gel while eluting with ethyl acetate. The uniform fractions were evaporated. There was obtained 0.39 g (23%) of 5,6-dihydro-3-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 155°-160°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(=O)C)[CH2:23][CH2:22]2)[N:3]=1.FC(F)(F)C(O)=O.[CH3:37][S:38](N1CCC(N)CC1)(=[O:40])=[O:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[O:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with 1-[4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone (Example 341) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone. MS (M+H)+, 436
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].CC([O-])(C)C.[K+:18]>CCOCC>[Cl:1]/[C:2](/[CH:8]=[O:9])=[C:3](\[O:5][CH2:6][CH3:7])/[O-:4].[K+:18]
Reactant: CCOC=O
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCO/C([O-])=C(\Cl)C=O

Procedure:
A cooled (0° C.) suspension of ethyl 2-chloroacetate (17.47 ml, 163 mmol) and ethyl formate (13.18 ml, 163 mmol) in ether (250 ml) was treated slowly (over 3 hrs) with potassium 2-methylpropan-2-olate (18.31 g, 163 mmol) keeping the temperature below 5° C. The mixture was concentrated in vacuo and the resulting solid was washed with ether and dried (47° C. in a vacuum oven) to afford the title compound;
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[NH:12]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38]>CN(C=O)C>[NH2:17][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN3C(=O)c4ccccc4C3=O)c2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine (7.5 g, 31.6 mmol) was dissolved in DMF (100 ml) and potassium carbonate (4.37 g, 31.6 mmol) was added. After the suspension had been stirred at room temperature for 15 min., 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (8.00 g, 29.8 mmol) was added and the suspension was vigorously stirred at room temperature for 10 hours. The reaction mixture was extracted with ethyl acetate, washed with water, brine and dried. The crude material was recrystallized from EtOAc/diethyl ether to give the title compound in three different batches (2.02 g), (2.44 g) and (1.60 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2].[C:13]1(=O)[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]1>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:6]=1[CH3:7])=[O:12])[CH3:2]
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCOC(=O)C=C(C)NC1CC1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(C2CC2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.1 %

Procedure:
Neat 3-cyclopropylamino-but-2-enoic acid ethyl ester (5.63 g, 33.2 mmol) is added to a mixture of p-benzoquinone (7.19 g, 66.5 mmol) and acetic acid (120 mL). The mixture is stirred at room temperature for 5 h and a dark solid is precipitated. The solid is washed with acetic acid and water, dried, adsorbed onto silica gel, and purified via flash chromatography eluting with dichloromethane. The product is triturated in dichloromethane-hexane to afford the title compound (440 mg, 21%). ES/MS m/e 260.0 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14].N1C=CC=CC=1.[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14])(=[O:31])=[O:32]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC1=C(c2cc(F)ccc2N)C(=O)CC1
Solvent: c1ccncc1
Product: CC1=C(c2cc(F)ccc2NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)CC1

Procedure:
0.700 g (3.14 mmol) of 2-(2-amino-5-fluorophenyl)-3-methyl-2-cyclopenten-1-one, 0.273 g (3.45 mmol) of pyridine, 0.754 g (3.45 mmol) of 2-mesitylenesulfonyl chloride, and 3 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (0.760 g, 60%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][S-:15].[Na+]>CN(C=O)C>[CH3:10][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([S:15][CH3:14])[CH:9]=1
Reactant: Cc1cc(Br)c(C#N)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(C)c([N+](=O)[O-])cc1C#N
Temperature: 60 °C

Procedure:
To a solution of 2-bromo-4-methyl-5-nitrobenzonitrile (3 g, 12.45 mmol) in DMF (124 mL), sodium thiomethoxide (1.31 g, 18.67 mmol) was added and the reaction heated to 60° C. for 1 h. The reaction was then cooled to room temperature, quenched with a sat. aq. solution of NaHCO3 and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated. The resulting residue was purified using FCC eluting with heptanes:EtOAc 1:1 to give the title compound. MS (ESI−) m/z 207.3 (M−H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([C:48]([F:51])([F:50])[F:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:61])=[C:36]([C:48]([F:51])([F:49])[F:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(2-pyridyl)methyl]-3-trifluoromethylphenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (355 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (205 mg), and the mixture was stirred overnight under nitrogen atmosphere. To the mixture was added water, and the mixture was extracted with ethyl acetate, washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (176 mg) as colorless amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[C:37]([NH2:41])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([NH:41][C:23](=[O:25])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CC(C)(C)N
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NC(C)(C)C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with tert-butylamine.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10](Cl)=[O:11])(=[O:6])=[O:5].[CH2:24]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1.[OH-].[Na+]>[CH2:32]([N:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:6])(=[O:5])[N:3]([CH3:23])[CH3:2])[CH:8]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C(=O)N(Cc3ccccc3)Cc3ccccc3)cc2S(=O)(=O)N(C)C)CC1

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were added portionwise at room temperature, while stirring, to a solution of 22 g of dibenzylamine and 20 g of triethylamine in 0.2 l of tetrahydrofurane. Subsequently the reaction mixture was heated for another hour under reflux, and then the tetrahydrofurane was eliminated in vacuo. The amorphous residue was dispersed in 0.5 l of acetic ester and 0.5 l of 1N NaOH. The acetic ester phase was separated and was dried over magnesium sulfate. The acetic ester solution was then concentrated to half its volume and was mixed with the same volume of petroleum ether under heat. Upon trituration the final product crystallized and was suction-filtered after having been cooled with ice water for 1 hour.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N(c1cc(Br)cnc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 51.6 %

Procedure:
To a solution of 5-bromo-2-chloropyridin-3-amine (1.00 g, 4.82 mmol) in pyridine (2.41 ml) was dropwise added benzenesulfonyl chloride (0.851 g, 4.82 mmol) at 0° C. The mixture was stirred for 40 min at room temperature and acidified with 1 N HCl. The residue was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give N-(5-bromo-2-chloropyridin-3-yl)-N-(phenylsulfonyl)benzenesulfonamide (0.606 g, 26% yield) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.02 (1H, s), 7.47-7.56 (2H, m), 7.59-7.66 (1H, m), 7.78-7.86 (2H, m), 8.16 (2H, dd, J=2.4, 7.2 Hz).
Reaction SMILES: NC(N)=O.[N:5]1([S:9]([C:12]2[C:13]([OH:20])=[C:14]([CH:16]=[CH:17][C:18]=2[Cl:19])[NH2:15])(=[O:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.[Cl:21][C:22]1[C:27](Cl)=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[N:5]1([S:9]([C:12]2[C:13]([OH:20])=[C:14]([NH:15][C:30]([NH:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[O:31])[CH:16]=[CH:17][C:18]=2[Cl:19])(=[O:11])=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Yield: 42.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-(azetidin-1-yl)sulfonyl-4-chloro-2-hydroxyaniline (235 mg, 0.9 mmol) and 2,3-dichlorophenylisocyanate (169 mg, 0.9 mmol) were coupled to form the desired urea (160 mg, 40%). LC-MS 450.0 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([S:15][CH3:16])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)C>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([S:15][CH3:16])[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCB(CC)c1cccnc1
Reactant: CSc1nncc(-c2ccc(F)c(Br)c2)n1
Product: CSc1nncc(-c2ccc(F)c(-c3cccnc3)c2)n1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-methylsulfanyl-[1,2,4]triazine was coupled to diethyl(3-pyridyl)borane by the method of Example 12 to give 5-[4-fluoro-3-(pyridin-3-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine as a yellow solid: δH (400 MHz, CDCl3) 2.74 (3H, s), 7.37-7.46 (2H, m), 7.91-7.95 (1H, m), 8.16-8.20 (1H, m), 8.30 (1H, dd, J 2.3, 7.4 Hz), 8.70 (1H, dd, J 1.4, 4.9 Hz), 8.86 (1H, s), 9.40 (1H, s); m/z (ES+) 299.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:12][CH2:13][CH2:14][Cl:15]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:7][CH2:6]1
Reactant: ClCCCBr
Reactant: COCCN1CCNCC1
Solvent: CCO
Product: COCCN1CCN(CCCCl)CC1

Procedure:
144 Grams of N-(2-methoxyethyl)-piperazine and 157.5 grams of 3-bromo-1-chloropropane were dissolved in 500 milliliters of ethanol and refluxed for 2 hours. The ethanol was evaporated, the residue dissolved in water, the aqueous solution made alkaline with sodium hydroxide solution, the solution extracted with ether, the ether solution separated, washed with water, dried and evaporated. 110 grams of 4-(2-methoxyethyl)-1-(3-chloropropyl)piperazine was thus obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([O:16][CH2:17][C:18](Cl)=[O:19])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH2:17][C:18]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:19])(=[O:15])[CH3:14]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc2nc(N)sc2c1
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)COC(C)=O)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-6-methoxybenzothiazole (12.0 g) is dissolved in pyridine (250 ml) and thereto is added dropwise acetoxyacetyl chloride (7.9 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water and then with diethyl ether, dried and recrystallized from ethanol to give the title compound (15.3 g) having the following physical properties.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]3[C:22]4[CH:21]=[C:20]([C:23]([O:25]C)=[O:24])[NH:19][C:18]=4[CH2:17][CH2:16]3)[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]3[C:22]4[CH:21]=[C:20]([C:23]([OH:25])=[O:24])[NH:19][C:18]=4[CH2:17][CH2:16]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(O)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(O)cc2)c1
Yield: 51 %

Procedure:
The title compound was synthesized from methyl 4-((4′-hydroxybiphenyl-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.044 g, 0.13 mmol) and lithium hydroxide (0.055 g, 1.31 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 21.7 mg, 51% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.13 (s, 1H), 2.48-2.62 (m, 3H), 2.80 (dd, J=7.05, 3.78 Hz, 2H), 3.25-3.29 (m, 1H), 6.39 (s, 1H), 6.81-6.86 (m, 2H), 7.09 (d, J=7.52 Hz, 1H), 7.25-7.30 (m, 2H), 7.33-7.37 (m, 1H), 7.38-7.42 (m, 2H); LCMS ESI− 332.2 (M−H); HPLC (UV=98.1%), (ELSD=100%).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH:5]([O:7][CH2:8][CH3:9])=[CH2:6].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>>[CH2:5]([O:7][CH:8]([O:4][CH2:1][CH:2]=[CH2:3])[CH3:9])[CH3:6]
Reactant: C=COCC
Reactant: C=CCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: C=CCOC(C)OCC
Reaction time: 3 h

Procedure:
Allyl alcohol (46.8 ml. 40 g., 0.69 mol) and ethyl vinyl ether (98.8 ml., 74.5 g., 1.033 mols) were stirred together at -12°. dl-Camphorsulfonic acid (150 mg.) was added acid and stirring continued for 3 hours at that temperature. The mixture was then washed 1×100 ml. saturated NaHCO3, 1×100 ml. brine, dried and stripped to yield title product as an oil (100 ml., essentially quantitative yield). 1H-nmr: 1.14 (t, 3H), 1.29 (d, 3H), 3.56 (dp, 2H), 4.06 (m, 2H), 4.75 (q, 1H), 5.26 (m, 2H), 5.99 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3]1.[C:29](OC(=O)C)(=[O:31])C>C(O)=O>[CH:29]([NH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3]1)=[O:31]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
3α-Aminocholestane (2.00 g, 5.15 mmol) was dissolved in 98-100% formic acid (10 ml) and acetic anhydride (3.6 ml) was added under ice cooling. After the mixture was stirred for 18 hours at room temperature, the precipitated solid was filtered off and recrystallized from methanol to obtain N-formyl-3α-aminocholestane (1.14 g, yield=53%). The N-formyl-3α-aminocholestane was dissolved in tetrahydrofuran (50 ml) and lithium aluminum hydride (415 mg) was added. The mixture was heated under reflux for 1.5 hours. After the completion of the reaction, saturated aqueous solution of sodium sulfate was added to the mixture to decompose an excess of lithium aluminum hydride. Ether (100 ml) was added, and the mixture was stirred and allowed to stand. After the organic layer was collected by decantation, ether (50 ml) was added to the aqueous layer. After the mixture was stirred and allowed to stand, the ether layer was collected again. The organic layers were combined, washed with saturated saline solution, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (50 ml) and 4N hydrochloric acid-ethyl acetate (0.7 ml) was added. The resulting precipitate was filtered off. The precipitate was suspended in ether (500 ml) and 40% aqueous solution of potassium hydroxide (100 ml) was added. The suspension was vigorously stirred until the precipitate was dissolved. The ether layer was washed with saturated saline solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.04 g, yield=94%).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17].O>CS(C)=O>[Br:1][C:2]1[O:3][C:4]([C:7]([O:9][CH2:16][CH3:17])=[O:8])=[CH:5][CH:6]=1
Reactant: CCI
Reactant: O=C(O)c1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Br)o1
Reaction time: 15 h

Procedure:
To absolution of 2-bromo-5-carboxyfuran (10 g) in dimethyl sulfoxide (100 ml), potassium carbonate (7.96 g) was added at 15 to 30° C. and ethyl iodide (16.8 ml) was added dropwise thereto. The mixture was stirred for 15 hours. The reaction solution was then poured into water and extracted with chloroform. The organic layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=2;l) to obtain 11.34 g of the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Yield: 85.2 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and tert-butylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-tert-butyl-2-(trifluoromethoxy)benzenesulfonamide (0.33 g, 85%) was provided after purification. MS (ESI) m/z 376. HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.