Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[N:10]([CH2:14][CH2:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(OCC)C.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[C:1]([C:9]1[N:10]2[C:11](=[CH:12][CH:13]=1)[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCn1cccc1C(=O)c1ccccc1)C(=O)OCC
Agent: [Mn+3]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of 2-benzoyl-1-[3,3-di(ethoxycarbonyl)propyl]pyrrole (1.00 g, 2.80 mmol) and anhydrous sodium acetate (4.60 mg, 5.6 mmol) in acetic acid (20 mL) is added manganese(III) acetate dihydrate (2.25 g, 8.4 mmol) The mixture was stirred for two hours at 80° C. The reaction mixture was diluted with diethyl ether (100 mL), and filtered. The resulting solution was washed with water (2×25 mL), 10% sodium hydroxide (2×30 mL), and water (2×25 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude oil was purified by flash chromatography on silica eluting with hexane/ethyl acetate (90:10-80:20) to yield 800 mg (80%) of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][O:24][CH2:25][Mg]Cl.[Cl-].[NH4+].Cl.C(OC(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:20])[CH2:25][O:24][CH2:23][CH2:22][Cl:21])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2cc(OCc3ccccc3)ccc2c1
Reactant: ClCCOC[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(COCCCl)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
6.0 g of 6-benzyloxy-2-naphthaldehyde was dissolved in 60 ml of tetrahydrofuran. The solution was cooled to -30° C. Thereto was dropwise added, in 10 minutes, 30 ml of a tetrahydrofuran solution containing 1.6M of 2-chloroethoxymethylmagnesium chloride. The resulting mixture was stirred for 1 hour with ice cooling. The reaction mixture was added to a mixture of 100 ml of ice water, 100 ml of ethyl acetate and 3.6 g of ammonium chloride. The mixture was adjsuted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium chloride. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=20/1) to obtain a solid. To the solid was added 10 ml of diisopropyl ether. The resulting mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration and dried to obtain 4.7 g of 1-(6-benzyloxy-2-naphthyl)-2-(2-chloroethoxy)ethanol.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12](=[O:43])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[C:30]([C:41]#[N:42])[CH:29]=3)[CH:20]=2)=[CH:15][CH:14]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:41]([C:30]1[CH:29]=[C:28]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]3[CH:20]=[C:19]([C:16]4[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])=[O:43])=[CH:18][CH:17]=4)[O:27][C:26]=23)[CH:33]=[CH:32][C:31]=1[O:34][CH:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)#[N:42]
Reactant: CN(CCNC(=O)c1ccc(-c2cc3nccc(-c4ccc(OC5CCOCC5)c(C#N)c4)c3o2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCNC(=O)c1ccc(-c2cc3nccc(-c4ccc(OC5CCOCC5)c(C#N)c4)c3o2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[2-(4-{7-[3-Cyano-4-(tetrahydro-pyran-4-yloxy)-phenyl]-furo[3,2-b]pyridin-2-yl}benzoyl-amino)-ethyl]-methyl-carbamic acid tert-butyl ester (59.0 mg, 0.1 mmol) is dissolved in dichloromethane (1 ml). Trifluoro-acetic acid (1 ml, 12.98 mmol) is added to the solution. The mixture is stirred for 16 h at room temperature. The solvent is removed in vacuum; yield: 20 mg 4-{7-[3-cyano-4-(tetrahydro-pyran-4-yloxy)-phenyl]-furo[3,2-b]pyridin-2-yl}-N-(2-methyl-amino-ethyl)-benzamide trifluoroacetate; HPLC/MS: 1.61 min, [M+H]=497;
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:14][CH3:15])[CH2:10][CH2:9][CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[K+]>CCO>[CH2:14]([C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:10]1)[CH3:15]
Reactant: CCC1(C(=O)OC)CCC(C(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(C(=O)O)CCC(C(C)C)CC1
Yield: 86 %

Procedure:
4-Isopropyl-cyclohexanecarboxylic acid methyl ester (1.1 g, 6 mmol) was alkylated using a method analogous to General Procedure F using LDA (9 mmol) and iodoethane (1.4 g, 9 mmol) in THF (20 mL) at −78° C. to RT to produce 1-ethyl-4-isopropyl-cyclohexanecarboxylic acid methyl ester (1.0 g, 78% yield) as a mixture of isomers. Hydrolysis of this ester using KOH (12.5 mmol) in aqueous EtOH (1:1; 5 mL) at 150° C. for 2 hr in a pressurized vessel following a microwave method analogous to General Procedure G2 gave 1-ethyl-4-isopropyl-cyclohexanecarboxylic acid (800 mg, 86% yield) as a mixture of isomers after workup by evaporation of the solvent, treatment with aq 2 N HCl, extractive workup, and evaporation of the solvent.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[CH3:19][C:20]1[O:24][C:23]([C:25](Cl)=[O:26])=[CH:22][CH:21]=1>>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:25]([C:23]3[O:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[O:26])[S:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)Cl)o1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(C)o3)nc12

Procedure:
Using 2-amino-4-methoxy-7-phenyl-benzothiazole and freshly prepared 5-methyl-furan-2-carboxylic acid chloride the title compound was obtained crude, which-was chromatographed over SiO2 (Merck 230-400 mesh) eluting with nHexane/EtOAc (4:1), to afford the pure title compound as a pale yellow solid (67% yield), MS: m/e=364.0 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.N.[Li].C(O)C>CCOCC.O>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[C:19]2[CH2:18][CH:17]=[CH:16][CH2:15][C:14]=2[CH2:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CN(C)CCCC1c2ccccc2Cc2ccccc21
Agent: N
Agent: [Li]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCCC1C2=C(CC=CC2)Cc2ccccc21
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A solution of 21.55 g of 9,10-dihydro-N,N-dimethyl-9-anthracenepropanamine in 100 ml of ether is added to 1 liter of liquid ammonia. Lithium ribbon (1.125 g) is added in several portions over a period of 5 minutes. After stirring for 15 minutes, absolute ethanol is added dropwise until the color is discharged (25 ml added in 30 minutes). More ether is added and the ammonia is boiled off. The mixture is then cooled in an ice bath and 500 ml of water is added. The layers are separated and the aqueous layer is reextracted with ether. The combined ether layers are dried over potassium carbonate, filtered, and the solvent is removed in vacuo leaving 21.2 g of crude product.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][C:11]([C:14](OC)=[O:15])=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C(=O)OC)ccc2[nH]1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cc(CO)ccc2[nH]1
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A solution of 2.1 g of 2-butyl-6-carbomethoxybenzimidazole in 50 mL of tetrahydrofuran was cooled with ice. To this solution was added dropwise 18 mL of 25% diisobutylaluminum hydride (DiBAl-H) in toluene. After the addition, the reacted mixture was stirred for 30 minutes with ice cooling and then for an additional 1 hour at room temperature. The reaction mixture was cooled back down to 0° and the reaction quenched by adding 15 mL of saturated ammonium chloride (NH4Cl) solution. The mixture was then filtered through celite and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (100% EtOAc elution) to give 1.23 g of the desired product as a thick colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:39]([CH3:40])[C:33]=3[F:32])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cccc(N)c1F
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3F)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 83.9 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.2 g, 0.45 mmol) obtained in Example 128, step 2 and 2-fluoro-3-methylaniline (0.085 g, 0.68 mmol), the title compound (0.2 g, 85%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].Br[CH2:16][CH2:17][O:18][CH3:19]>>[CH3:19][O:18][CH2:17][CH2:16][O:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: COCCBr
Product: COCCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 46.2 %

Procedure:
3-nitro-5-(trifluoromethyl)phenol (770 mg, 3.72 mmol) and 1-bromo-2-methoxyethane (1.75 mL, 19 mmol) were reacted using the procedure described in Example 40A Step 3 to give 1-(2-methoxyethoxy)-3-nitro-5-(trifluoromethyl)benzene (456 mg, 1.72 mmol, 46%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 4.36 (dd, 2H), 3.71 (dd, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 266 (M+H)+.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]>C(O)C.C(O)(=O)C>[Br:1][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:3]
Reactant: O=C(O)c1cccc(O)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc(Br)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
Bromine (0.37 mL, 7.2 mmol) was added to 3-hydroxybenzoic acid (500 mg, 3.6 mmol) in ethanol (2 mL) and acetic acid (1 mL). The mixture was stirred at room temperature for 30 min and then concentrated and purified by column chromatography to give the product (314 mg, 40%). MS (DCI) m/z 234 (M+NH4)+.
Reaction SMILES: [C:1]1([C@@:11]23[CH2:16][CH:15]2[CH2:14][O:13][C:12]3=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClCCl>O1CCCC1>[C:1]1([C@@:11]2([CH2:12][OH:17])[CH2:16][CH:15]2[CH2:14][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCC2C[C@@]12c1cccc2ccccc12
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC1C[C@]1(CO)c1cccc2ccccc12
Yield: 167 %

Procedure:
BMS (8.10 mL, 107 mmol) was added to (1R)-1-(1-naphthyl)-3-oxabicyclo[3.1.0]hexan-2-one (12 g, 53.5 mmol) in dry tetrahydrofuran (100 mL) under nitrogen atmosphere. The reaction mass was refluxed for 5 hours and monitored by TLC (dichloromethane (100%)). The reaction was quenched with 10% potassium carbonate solution. The aqueous layer was extracted with dichloromethane (2×150 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 20.4 g (92%) of desired product. 1H NMR δ(300 MHz,CDCl3): 0.87 (1H,m), 1.01-1.25 (2H,m,), 1.78-1.83 (2H,m,) 3.4-3.7 (2H,m), 4.12-4.18 (2H,m), 7.36-7.52 (4H,m), 7.57-7.75 (1H,m) 7.83-7.86 (1H,m) 8.25 (1H,brs).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[C:36]=1[F:53])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:53][C:36]1[C:37]([O:43][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=1[C:21](=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCOC2CCCCO2)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCCOC2CCCCO2)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
After adding 13 mg of 2-hydrazinopyrimidine and 0.016 ml of triethylamine to a solution of 69 mg of (2-{2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated to give a crude product of 5-({2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]methyl)-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH2:40])(=[O:39])=[O:38])([O-:30])=[O:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N+:28]([O-:30])=[O:29])(=[O:38])=[O:39])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-nitrobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (22%); 1H NMR (d6-DMSO) δ 8.18 (d, J=5.2 Hz, 1H), 7.99 (d, J=5.9 Hz, 1H), 7.94–7.84 (m, 2H), 7.44–7.08 (m, 13H), 6.86 (d, J=8.1 Hz, 2H), 6.50 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 539 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CO
Reaction time: 18 h
Yield: 88.9 %

Procedure:
Add borane-tetrahydrofuran complex (0.2 mol, 200 mL, 1.0 M solution) to a solution of 4-bromo-2-methylbenzoic acid (39 g, 0.18 mol) in tetrahydrofuran (200 mL). After 18 hours at room temperature, remove the solvent under reduced pressure to provide a solid. Purify by flash chromatography to yield the title compound as a white solid (32.9 g, 0.16 mol). 1H NMR (CDCl3): δ 1.55 (s, 1H), 2.28 (s, 3H), 4.61 (s, 2H), 7.18-7.29 (m, 3H).
Reaction SMILES: [C:1]1([S:7][CH2:8][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([Li])[CH2:14][CH2:15]C.CC(C)C=O>C1COCC1.CCCCCC.[Cl-].[Na+].O>[C:1]1([S:7][CH:8]=[C:14]([CH3:15])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CSc1ccccc1
Reactant: [Li]CCCC
Agent: CC(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CSc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 3.92 g (20 mmol) of phenylthiomethyltrimethylsilane in 10 ml THF at 0° is added 20 ml n-butyllithium in hexane. The resulting yellow solution is stirred for 15 min at 0°, and a solution of 1.44 g (20 mmol) of 2-methyl-1-propanal in 5 ml THF is added. The reaction mixture is stirred for 15 min at 0°, then for 2 hr at 25°. Brine (15 ml) is added and the product extracted with ether. The organic layer is dried over calcium sulfate, filtered and the solvent is removed under vacuum to give 2-methyl-1-propenyl phenyl sulfide, which is purified by distillation under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:23]([N:27]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[S:53](=[O:56])(=[O:55])[NH2:54])=[CH:43][CH:42]=1)[C:28]([N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1)=[O:29])[CH2:24][CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1>>[CH2:23]([N:27]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[S:53](=[O:55])(=[O:56])[NH:54][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])=[CH:45][CH:46]=1)[C:28]([N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCCc2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1)C(=O)N1CCCc2ccccc21

Procedure:
The title compound was prepared from 2-chlorobenzoic acid (2.5 equivalents), CDI (2.5 equiv), 1-[N-butyl-N-[(2'-sulfamoylbiphenyl-4-yl)methyl]carbamoyl]-1,2,3,4-tetrahydroquinoline (from Step B) (1.0 equiv), and DBU (2.5 equiv), according to the procedure of Example 3, Step C, to give an 83% of the desired material after flash chromatography as an off-white solid, mp 80°-82° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; FAB-MS m/e 616 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Br)[N:5]=[C:4]([NH2:11])[CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC.O.C1COCC1.CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1c(N)cc(N)nc1-c1ccccc1
Temperature: 130 °C

Procedure:
A 5 mL sealable heavy walled glass tube suitable for microwave heating was charged with 213 mg (1.00 mmol) of 4,6-diamino-2-bromo-nicotinonitrile, 183 mg (1.5 mmol) of phenylboronic acid, 11 mg (0.050 mmol) of palladium(II)acetate, 60 mg (0.020 mmol) of tri(o-tolyl)phosphine, and 220 mg (2.05 mmol) of sodium carbonate. To this mixture was added 2 mL of DMF, 2 mL of THF, and 1 mL of water. The tube was sealed, then heated with a microwave apparatus at 130° C. for 20 min. The mixture was poured into 20 mL of water, extracted with ethyl acetate (3×10 mL). The combined ethyl acetate layers were back extracted with 1M NaOH(aq.) (2×10 mL) and brine (1×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The product was partially purified via silica gel chromatography, eluting with 60:40 ethyl acetate:hexanes to provide an off-white solid. This was taken up in ethyl acetate, then hexane was added (until about 50:50 hexanes:ethyl acetate) to precipitate 63 mg (30%) of white crystals. 1H NMR (300 MHz, d6-DMSO) δ 7.66 (m, 2H), 7.45 (m, 3H), 6.35 (s, 2H), 6.25 (s, 2H), 5.69 (s, 1H); MS (ESI) m/e 211 (M+H)+, 209 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:62]([C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[O:55][CH3:54])(=[O:64])=[O:63])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccccc1OC)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (40 mg) was treated with 2-methoxy-benzenesulfonyl chloride according to General Procedure E to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2-methoxy-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester. This (26 mg) was hydrolyzed according to General Procedure B to give the title compound (23 mg). LCMS (m/z): 906.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:30]O.[NH4+].[OH-].CCOC(C)=O>CC(O)=O.O.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:30]=[C:15]([CH:16]([CH3:18])[CH3:17])[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)C(C(=O)C(C)C)C(CC(=O)c1ccccc1)c1ccc(F)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Temperature: 25 °C
Yield: 65.2 %

Procedure:
A mixture of β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-δ-oxobenzenepentanoic acid, ethyl ester (7.92 gm, 20.6 mmol) and hydroxylamine hydrochloride (4.32 gm, 62.2 mmol) in glacial HOAc (100 ml) was refluxed for 2.5 hours. The reaction was cooled to room temperature and poured into an ice cold solution of concentrated NH4OH (140 ml) in H2O (400 ml). The resulting mixture was extracted twice with Et2O and the combined ethereal layers were washed with brine, dried (Na2 SO4), filtered and stripped to yield a gummy orange-red oil. Flash chromatography of the oil (Merck SiO2, 7% EtOAc in hexane) gave 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylic acid, ethyl ester (4.88 gm, 65%) as a near colorless gum.