Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:30])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].[ClH:31].O1CCOC[CH2:33]1>>[ClH:31].[CH3:1][N:2]([CH3:33])[C:3](=[O:30])[C@H:4]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Reactant: C1COCCO1
Agent: Cl
Product: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CN)CC1
Reaction time: 0.5 h

Procedure:
To the compound (III) (34.30 g) was added 4N hydrogen chloride/1,4-dioxane solution (400 ml) under room temperature, and the mixture was stirred for 30 minutes. The mixture was concentrated under a reduced pressure, and the residue was washed with diethyl ether, followed by filtration to give N-(trans-4-aminomethyl-cyclohexylcarbonyl)-L-phenylalanine dimethylamide hydrochloride (28.50 g).
Reaction SMILES: [CH3:1][CH2:2][CH3:3].C=CC.[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([CH:2]([CH3:3])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC
Reactant: c1ccccc1
Solvent: C=CC
Product: CC(C)c1ccccc1

Procedure:
An integrated process is disclosed for (i) catalytically cracking (FCC) a heavy hydrocarbon feedstock, (ii) obtaining a combined propane/propylene stream, and (iii) reacting the propylene of the combined propane/propylene stream with benzene to produce a cumene product stream. The integrated process comprises contacting a heavy hydrocarbon feedstock with a hydrocarbon cracking catalyst in a fluidized reactor zone to produce a hydrocarbon effluent stream that includes propane and propylene. The process then further comprises separating the combined propane/propylene stream from the hydrocarbon effluent stream, passing the combined propane/propylene stream to an alkylation reactor; and reacting at least some of the propylene of the combined propane/propylene stream with benzene in the alkylation reactor to produce cumene.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH:8]=1)(=O)=O.[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38]C)=[O:37])[CH2:32][CH2:31]1.[Li+].[OH-]>CN(C=O)C.C1COCC1.CO.O>[F:29][CH:27]([F:28])[O:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[N:19][C:14]([NH:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[CH2:6][N:30]3[CH2:31][CH2:32][CH:33]([C:36]([OH:38])=[O:37])[CH2:34][CH2:35]3)=[N:15][CH:16]=2)=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)OCc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Reactant: COC(=O)C1CCNCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(Cc2cccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)c2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl methanesulfonate 37 (0.050 mmol) in anhydrous DMF (1 mL) is added methyl piperidine-4-carboxylate (0.10 mmol) and the solution is heated at 100° C. for 8 h. After the reaction is complete, the mixture is diluted with THF:MeOH:H2O (3:2:1, 5 mL). To the reaction mixture is added 6N LiOH (0.30 mmol). The reaction is stirred at rt for 1 h. Purification by preparative LC/MS affords 1-(3-(5 (4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid E3. 1H NMR (400 MHz, d4-MeOH) δ 8.64 (s, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.78 (t, J=74.0 Hz, 1H), 4.11 (s, 2H), 3.31 (m, 2H), 2.92 (m, 2H), 2.36 (m, 1H), 2.02 (m, 2H), 1.81 (m, 2H). MS (m/z) (M+1)+: 455.2.
Reaction SMILES: [CH3:1][O-].[Na+].C=O.[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[BH4-].[Na+].[OH-].[K+]>CO>[CH3:1][NH:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH3:6])[CH2:12][CH2:11]2)[N:19]=1
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Reactant: C[O-]
Agent: C=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CNc1cccc(OC2CCN(C)CC2)n1
Yield: 83.1 %

Procedure:
Combine sodium methoxide (290 mg, 5.38 mmol), paraformaldehyde (94 mg, 3.13 mmol), 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60, 260 mg, 1.25 mmol) and methanol (5 mL), heat at 50° C. for 20 hr. Add NaBH4 (85 mg, 2.25 mmol), beat at reflux for 1.5 hr. Then add 1.0N KOH solution (2 mL), beat at reflux for 2 hr. Partition between water and CH2Cl2, extract aqueous phase with CH2Cl2. Combine organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 5% 2M NH3-methanol in methylene dichloride provides 230 mg of methyl-[6-(1-methyl-piperidin-4-yloxy)-pyridin-2-yl]-amine with a small amount (5-10%) of inseparable starting amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17]([OH:19])=O)[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:27]([F:29])([F:28])[F:30])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[O:19])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)N2CCN(C)CC2)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid (0.11 mmol, 1.0 equiv), 14 μL of 1-methylpiperazine (0.13 mmol, 1.2 equiv), 60 μL TEA (0.43 mmol, 4.00 equiv), 71 mg BOP (0.16 mmol, 1.5 equiv), and 500 μL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-4-(4-methyl-piperazine-1-carbonyl)-piperidin-1-yl]-ethanone: MS (ES) M+H expected=546.4, found=546.1.
Reaction SMILES: [Na].[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4]1.CCCCCCC.[CH:17]1([C:22]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([OH:28])[C:23](OCC)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>CCOCC>[CH:17]1([C:22]([C:29]#[C:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([OH:28])[C:23]([O:9][CH:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]2)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCC1
Reactant: CN1CCCC(O)C1
Agent: [Na]
Solvent: CCCCCCC
Solvent: CCOCC
Product: CN1CCCC(OC(=O)C(O)(C#Cc2ccccc2)C2CCCC2)C1
Reaction time: 8 h

Procedure:
Sodium (~0.05 g.) and 1-methyl-3-piperidinol (4.0 g., 0.035 mole) were refluxed in 250 ml. of dry n-heptane in a reaction flask equipped with a Dean-Stark trap until all of the sodium reacted. Then 6.5 g. (0.024 mole) of ethyl α-cyclopentyl-α-phenylethynylglycolate, undiluted, was added dropwise over a 0.25 hour period. The reaction mixture was subsequently refluxed for 20 hours, and about 30 ml. of solvent was collected toward the end of that period. The reaction mixture was kept overnight. No crystallization occurred during that time, but some tarry material was present and was filtered. Ether (acidic) and chloroform (basic) extracts were made of the filtrate as described previously. The chloroform extract yielded, after the solvent was stripped, 6.2 g. of a red-brown oil. The oil was dissolved in ether and petroleum ether (20°-40°) was added until turbidity was produced. The material was then placed in a freezer for four days and the product precipitated. It weighed 3.2 g., (39%) and melted at about 85° after being filtered and dried. The solid was recrystallized from 20°-40° petroleum ether. The first batch yielded off white crystals melting at 112°-113°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[CH2:18][C:19](=O)[CH3:20]>C(O)(=O)C.S(=O)(=O)(O)O>[F:15][C:16]([F:24])([F:23])[C:17]([C:18]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:19]=1[CH3:20])=[O:22]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sccc1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sccc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 16.9 %

Procedure:
To a stirred solution of 50 mg (0.24 mmol) (2-amino-thiophen-3-yl)-phenyl-methanone in 2 ml acetic acid was added 0.031 ml (0.24 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 13 mg (17%) 2,2,2-trifluoro-1-(6-methyl-4-phenyl-thieno[2,3-b]pyridin-5-yl)-ethanone as a yellow oil. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])=[N:5]1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=3)[C:54](O)=[O:55])=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[C:53]([C:54]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:55])[CH:57]=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191 mg; compound B78) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C8) and HBTU (304 mg) in DCM/DMF (14 ml/1 ml) in the presence of DIPEA (377 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and preparative HPLC as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:6]([OH:7])[C:5]=1[OH:14])([O-:3])=[O:2].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([O:7][C:6]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:14])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cc(O)c(O)c([N+](=O)[O-])c1
Product: O=C(Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O)c1ccccc1
Reaction time: 4 h

Procedure:
A mixture containing 2.0 g of 3,5-dinitrocatechol in 5 ml of benzoylchloride was cooked for 4 hours in 100° C. When cooled petroleum ether (b.p. 40° C.) was added and the product was filtered and washed with petroleum ether. The raw product was crystallizedfrom ethanol. Yield 2.5 g (82%), m.p. 150°-152° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:32])[N:14]([CH3:33])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:34]1[N:43]=[CH:42][C:41]2[C:36](=[C:37]([F:48])[CH:38]=[C:39]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:40]=2)[C:35]1=[O:49])(=O)C.[OH-].[Na+]>C1COCC1>[C:44]([C:39]1[CH:40]=[C:41]2[C:36](=[C:37]([F:48])[CH:38]=1)[C:35](=[O:49])[N:34]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][C:22]([CH:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:23][CH:24]=4)[C:15](=[O:32])[N:14]([CH3:33])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:43]=[CH:42]2)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (1.6 g) was dissolved in 20 mL THF. To the reaction solution was added 12 mL of 2 N NaOH. The reaction mixture was stirred at room temperature overnight. Reaction was not complete. An additional 10 equiv. of 2 N NaOH was added and the reaction mixture was stirred at room temperature for an additional 2 hours. THF was added until the reaction mixture was homogeneous and the reaction was heated to 40° C. for 30 min. The reaction was allowed to cool to room temperature and stirred overnight. The reaction had gone to completion as indicated by LC/MS. The reaction was concentrated to a reduced volume to remove most of the THF. A solid formed which was collected by filtration. The solid was redissolved in DCM, filtered through pack of celite, washed with water, dried over Na2SO4, filtered and conc in vacuo. to afford the desired product as a white solid (1.27 g). (M+H)+=624 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 1.80-1.92 (m, 5H) 2.31-2.58 (m, 3H) 3.03 (d, J=8.28 Hz, 1H) 3.92 (s and overlapping multiplet, 4H) 4.45 (d, J=6.53 Hz, 2H) 6.93 (d, J=8.28 Hz, 1H) 7.45-7.63 (m, 5H) 7.65-7.71 (m, 1H) 8.22-8.32 (m, 3H) 8.61 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19]([C:21]4([NH:25]C(=O)OC(C)(C)C)[CH2:24]C[CH2:22]4)=[O:20])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.CC(N(C1(C(NC2C=NC(OC3C4C(C)(C)COC=4C=CC=3)=CC=2)=O)CC1)C(=O)[O-])(C)C>>[NH2:25][C:21]1([C:19]([NH:18][C:15]2[CH:16]=[N:17][C:12]([O:11][C:7]3[C:6]4[C:2]([CH3:1])([CH3:33])[CH2:3][O:4][C:5]=4[CH:10]=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)=[O:20])[CH2:22][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)Nc2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)CCC1
Agent: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N(C(=O)[O-])C(C)(C)C)CC4)cn3)c21
Product: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CC4)cn3)c21

Procedure:
The title compound (10 mg) was made in a similar fashion to the preparation of Intermediate 70 replacing 1,1-dimethylethyl {1-[({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]cyclobutyl}carbamate with 1,1-dimethylethyl{1-[({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]cyclopropyl}carbamate (Intermediate 72, 13 mg).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:21])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:52]([CH3:53])=[N:51][N:50]=[N:49]2)=[C:44]([C:54]([F:57])([F:56])[F:55])[CH:43]=1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:21])/[C:13](/[C:42]1[CH:47]=[CH:46][C:45]([N:48]2[C:52]([CH3:53])=[N:51][N:50]=[N:49]2)=[C:44]([C:54]([F:57])([F:56])[F:55])[CH:43]=1)=[CH:14]/[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCC1
Reactant: Cc1nnnn1-c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
A mixture of zinc dust (710 mg, 11 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (108 mg, 1 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (1.54 g, 5.5 mmol) in dry tetrahydrofuran (2 mL) over 3 min. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (4 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (81 mg, 0.15 mmol) and triphenylphosphine (156 mg, 0.6 mmol) in dry tetrahydrofuran (6 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.05 g, 3.5 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 40-45° C. over the weekend. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (50 mL), and the organic compound was extracted into ethyl acetate (3×35 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylic acid methyl ester (1.03 g, 77.6%) as a light yellow solid: EI-HRMS m/e calcd for C18H19F3N4O2 (M+) 380.1460, found 380.1453.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[CH3:14]>CO>[CH3:14][N:13]([CH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:7]2[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=2)[N:20]=1)[CH3:12]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
To a cooled (6° ) suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (0.74 g; 4.17 mmoles) in 80 ml of methanol was added dropwise over a period of 45 minutes a solution of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine (0.96 g; 4.17 mmoles) [prepared in Step E] to give 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide, Rf=0.64 [Silica/CH2Cl2 : CH3OH (9:1)]. The temperature was maintained at 6° and anhydrous methylamine was bubbled into the solution for 8 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 80 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined and the residue was rechromatographed on 25 g of aluminum oxide using a gradient elution of methylene chloride-methanol to give 0.52 g of product. Recrystallization from isopropyl alcohol/ether yielded the title compound, mp 144°-148° (foaming).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8](/[CH:16]=[CH:17]/[C:18]#[N:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C>Cl.CO>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH:16]=[CH:17]/[C:18]#[N:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](/C=C/C#N)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: N#C/C=C/[C@H](N)Cc1ccccc1

Procedure:
Compound 31e (4.0 g, 14.7 mmol) was treated with 2M HCl/MeOH (300 mL). After the reaction was over, the solvents were removed under reduced pressure to give a white solid. The product was directly used in the next reaction step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:10](=[O:29])[C:11]3[N:12]=[CH:13][N:14]([C:17]4[CH:18]=[C:19]([S:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:20]=[CH:21][CH:22]=4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[OH2:41].[OH2:42].O.O.O.O.C1(=O)OOOOC(=O)C2=CC=CC=C12.[Mg]>CO.ClCCl>[C:26]([O:25][CH2:24][S:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:14]2[CH:13]=[N:12][C:11]3[C:10](=[O:29])[N:9]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=4)=[N:16][C:15]2=3)[CH:18]=1)(=[O:42])=[O:41])(=[O:28])[CH3:27]
Reactant: O
Reactant: CC(=O)OCSc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Agent: O=c1ooooc(=O)c2ccccc12
Agent: [Mg]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)OCS(=O)(=O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of acetic acid (3-(2-(4-bromophenyl)-1-(4-chlorophenyl)-6-oxo-1H-purin-9(6H)-yl)phenylthio)methyl acetate (3, 2.1 g, 3.6 mmol) in methanol (12 mL), dichloromethane (36 mL), magnesium monoperoxy phthalate hexahydrate (1.9 g, 3.97 mmol) is added at 0° C. The resulting solution is stirred at rt for 12 h. The reaction is quenched with the addition of saturated solution of sodium bicarbonate, and extracted with dichloromethane. The organic layer is dried over Na2SO4, concentrated. The crude product is purified by column chromatography to afford (3-(2-(4-bromophenyl)-1-(4-chlorophenyl)-6-oxo-1H-purin-9(6H)-yl)phenylsulfonyl)methyl acetate (4).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.ClNC(=O)CCC(N)=O.[CH3:20][CH:21]([OH:24])[C:22]#[CH:23]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:23]=[C:22]([CH:21]([OH:24])[CH3:20])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(F)cc1
Reactant: C#CC(C)O
Agent: NC(=O)CCC(=O)NCl
Solvent: ClCCl
Product: CC(O)c1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a stirred solution of 4-fluorobenzaldehyde oxime (0.2 g, 1.4 mmol) in DCM (10 mL) was added N-chlorosuccinamide (0.1 g, 1.4 mmol) and the reaction stirred for 1 hour at room temperature. But-3-yn-2-ol (0.23 g, 1.68 mmol) was added and the reaction mixture stirred at reflux for 3 h. After completion of the reaction (as monitored by TLC), the mixture was extracted with DCM (3×100 mL), the organic layer washed with water (100 mL) followed by brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (60-120 mesh; using 50% ethyl acetate in hexanes) to obtain 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanol as liquid (0.15 g, 50% yield). 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, 2H), 7.05 (t, 2H), 6.48 (s, 1H), 5.04 (q, 1H), 1.63 (d, 3H).