Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:19][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[F:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C.C(OCC)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:1][CH2:2][C@@H:3]2[CH2:19][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[N:13]=[CH:14][C:15]([F:18])=[CH:16][N:17]=4)[CH2:11][C@@H:6]3[CH2:5][CH2:4]2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(F)cc1
Reactant: OC[C@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(OC[C@H]2CC[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.1 %

Procedure:
A solution of 0.82 g (3.08 mmol) of (7S,9aS)-7-hydroxymethyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 13), 0.52 g (4.62 mmol) of 4-fluorophenol, 0.97 g (3.70 mmol) of triphenylphosphine in dry THF was treated with 0.64 g (3.70 mmol) of diethyl azodicarboxylate and stirred at room temperature for 72 h. The solvent was evaportated, the residue dissolved in 50:50 ethyl acetate:ethyl ether, and treated with HCl(g) in ethyl ether until precipitation ceased. The solid was collected by filtration, dissolved in chloroform, 1M sodium hydroxide was added, and the layers were separated. The organic layer was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 hexane:ethyl acetate gave 0.49 g (44%) of the title compound. mp (—HCl) 225-228° C. 13C NMR (base, CDCl3): δ24.8, 25.2, 33.8, 44.3, 49.7, 54.8, 56.6, 61.0, 69.5, 115.48, 115.53, 115.59, 115.83, 144.97, 145.26, 149.85, 153.15, 155.42, 155.54, 158.69, 158.74. HRMS calcd for C19H22F2N4O: 360.1762, found: 360.1752.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][C:47]3[CH:48]=[C:49]([CH:54]=[CH:55][CH:56]=3)[C:50]([O:52][CH3:53])=[O:51])[C:38]2=[O:57])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1>>[OH:27][C:28]1[C:29]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][C:47]3[CH:48]=[C:49]([CH:54]=[CH:55][CH:56]=3)[C:50]([O:52][CH3:53])=[O:51])[C:38]2=[O:57])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1
Reactant: COC(=O)c1cccc(CN2C(=O)C(c3cc4c(cc3O)OCO4)c3ccccc32)c1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: COC(=O)c1cccc(CN2C(=O)C(CO)(c3cc4c(cc3O)OCO4)c3ccccc32)c1

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with methyl 3-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate, the title compound was obtained (81%) as a white powder: MS (ES+) m/z 470.3 (M+23), 448.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13](=O)[CH3:14])[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[CH2:1]([C:3]1[CH:12]=[C:11]([CH:13]([NH2:29])[CH3:14])[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCc1cc(C(C)=O)c(-c2cccc(F)c2)c2ncccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CCc1cc(C(C)N)c(-c2cccc(F)c2)c2ncccc12
Temperature: 65 °C

Procedure:
A mixture of 1-[5-ethyl-8-(3-fluorophenyl)quinolin-7-yl]ethanone (6.1 mg, 0.021 mmol) and ammonium acetate (0.017 g, 0.22 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.052 mL, 0.052 mmol) was added to the mixture. The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H20FN2 (M+H)+: m/z=295.2; Found: 295.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[NH:3]1.C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH3:1][CH:2]1[N:3]2[C:4]3[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=3[CH2:10][CH2:11]1)[C:16](=[O:15])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23]2
Reactant: Cc1ccc2c(c1)NC(C)CC2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cn2c3c(ccc(C)c3c1=O)CCC2C

Procedure:
Using the procedure of Example 25, 2,7-dimethyltetrahydroquinoline and diethyl ethoxymethylenemalonate are reacted to give solid ethyl 6,7-dihydro-5,10-dimethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate, m.p. 106°-108° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]([C:27]3([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28]3)(O)[O:17][N:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:33][O:32][C:30]([C:27]1([C:18]2[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:10][CH:11]=3)[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:28][CH2:29]1)=[O:31]
Reactant: COC(=O)C1(C2(O)ON=C(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 80 °C

Procedure:
Methyl 1-[3-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-hydroxy-4-phenyl-4,5-dihydroisoxazol-5-yl]cyclopropanecarboxylate (Compound C, 42 g) is dissolved in toluene (100 mL) and p-toluenesulfonic acid hydrate (1.7 g) is added with swirling. The mixture is heated over a steam bath until the internal mixture temperature, measured with a digital thermometer, is raised to 80° C. The mixture is then removed from the steam bath and is treated with water (50 mL.) The layers are shaken and separated and the toluene phase is dried over anhydrous magnesium sulfate and is concentrated under reduced pressure to afford an oil that is purified by flash silica gel column chromatography. Elution through a 400 g Analogix silica cartridge with a gradient (100% hexanes to 35% ethyl acetate over 1800 mL, or three column volumes) afforded an oily product. The product is dissolved in chloroform and is reconcentrated under reduced pressure to afford a residue that solidified overnight under high vacuum to the solid product (32 g.)
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH:15]1[CH2:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>C(O)C>[C:2]([NH:5][C:6]([CH:15]1[CH2:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: BrC1Cc2ccccc21
Reactant: CCOC(=O)C(C#N)NC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)(NC(C)=O)C1Cc2ccccc21
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
Sodium (464 mg, 20.2 mmol, 1.2 eq.) was allowed to react with absolute ethanol (40 mL, 0.42 M); to the resulting mixture was added ethyl 2-(acetylamino)-2-cyanoacetate (3.44 g, 20.2 mmol, 1.2 eq.). After 20 minutes at 60° C., 7-bromobicyclo[4.2.0]octa-1,3,5-triene (3.092 g, 16.89 mmol, 1 eq.) was added and the reaction mixture was heated at reflux overnight, then filtered and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a dark oil, which was purified by silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) to give #99 (4.38 g) as a yellow gum. LC-MS: m/z 273.2 [M+H+], retention time=2.36 minutes.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].B(O)(O)[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)O)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a stirred solution of 3-iodo-5-nitrobenzoic acid (15.48 g, 52.83 mmol) and Pd(Ph3P)4 (1.84 g, 1.69 mmol) in 300 ml of toluene and 50 ml of ethanol was added p-tolylboronic acid (7.87 g, 58.11 mmol) and a solution of Cs2CO3 (18.89 g, 58.11 mmol) in 20 ml water at room temperature. The reaction was brought to reflux for 18 hours and then cooled to room temperature. To the solution was added 2N NaOH, and the reaction mixture was stirred for 30 minutes. The organic phase was separated, and the aqueous phase was adjusted to PH<4 using 12N HCl. The resulting solid preciptate was filtered and washed with toluene to afford 13.2 g of 4′-Methyl-5-nitro-biphenyl-3-carboxylic acid as light yellow solid (97.2%). MS (M+H)=258.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[O:24][C:23]([C:25]([O:27]C)=[O:26])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[O:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)o1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)o1
Yield: 90.7 %

Procedure:
The title compound was prepared from methyl 5-(2-(7-phenylheptanoyl)oxazol-5-yl)furan-2-carboxylate (7 mg, 0.018 mmol) following General Procedure E. Preparative thin layer chromatography (10% MeOH/CH2Cl2) yielded the title compound as a white solid (6 mg, 85%): 1H NMR (THF-d8, 500 MHz) δ 7.68 (s, 1H), 7.27 (d, 1H, J=3.5 Hz), 7.22-7.07 (m, 5H), 7.04 (d, 1H, J=4.0 Hz), 3.05 (t, 2H, J=7.0 Hz), 2.60 (t, 2H, J=7.5 Hz), 1.73-1.71 (m, 2H), 1.65-1.61 (m, 2H), 1.42-1.40 (m, 4H); 13C NMR NMR (THF-d8, 125 MHz) δ 187.6, 164.6, 158.3, 146.2, 145.8, 143.5, 129.1, 128.9, 128.9, 126.3, 126.0, 119.7, 111.7, 39.6, 36.7, 32.4, 30.0, 30.0, 24.6; MALDI-FTMS m/z 368.1501 (M+H+, C21H22NO5, requires 368.1492).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].[H][H]>C(OCC)C>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19]
Reactant: COC(=O)c1cccc(-c2c(C)cccc2C)c1C
Reactant: [H][H]
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: Cc1cccc(C)c1-c1cccc(CO)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Step B (1 g, 3.93 mmol) in diethyl ether (20 ml) was carefully added lithium aluminum hydride (1.5 g, 3.93 mmol). The mixture was stirred at room temperature for 16 h. Saturated aqueous ammonium chloride solution was added dropwise until no hydrogen gas was being generated. A few more drops of saturated aqueous ammonium chloride solution was added and the mixture was stirred at room temperature for 30 min and filtered. The filtrate was dried on magnesium sulfate and concentrated to dryness to give the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[S:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C)C(=O)C.O.C(OCC)(=O)C.C(OCC)C.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:26]2[S:22][CH:23]=[N:24][CH:25]=2)[N:3]=1
Reactant: c1cscn1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: O
Product: Brc1cccc(-c2cncs2)n1
Temperature: 115 °C

Procedure:
A suspension of 2,6-dibromopyridine (11.13 g, 47.0 mmol), pivalic acid (0.545 mL, 4.70 mmol), potassium carbonate (6.49 g, 47.0 mmol) in N,N-dimethylacetamide (45 mL) was deoxygenated by bubbling argon through it for 20 minutes. Thiazole (1.681 mL, 23.49 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.086 g, 0.940 mmol) were added, the flask was sealed, and the reaction mixture was heated to 115° C. for 18 hours. The reaction mixture was cooled to room temperature and then diluted with water (50 mL), ethyl acetate (50 mL), and diethyl ether (50 mL). The layers were separated and then the organic layer was washed with water (2×50 mL), saturated aqueous sodium bicarbonate solution (25 mL), and brine (50 mL) The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-60% ethyl acetate/hexanes) to provide 2-bromo-6-(1,3-thiazol-5-yl)pyridine. MS ESI calc'd. for C8H5BrN2S [M+H]+ 241 and 243. found 241 and 243. 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.64 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=[O:17])(=[O:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>C1COCC1>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[C:14]([F:23])=[C:13]([NH:12][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 1.5 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
Methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (490 g, 1 equiv.), prepared generally in accordance with Step A, above, was dissolved in THF (2.45 L, 5 vols) and stirred and cooled to 0-3° C. 1M lithium bis(trimethylsilyl)amide in THF (5.25 L, 3.7 equiv.) solution was charged to the reaction mixture followed addition of 2-chloro-4-methylpyrimidine (238 g, 1.3 equiv.) in THF (2.45 L, 5 vols). The reaction was then stirred for 1 hr. The reaction was quenched with 4.5M HCl (3.92 L, 8 vols). The aqueous layer (bottom layer) was removed and discarded. The organic layer was concentrated under reduced pressure to ˜2 L. IPAC (isopropyl acetate) (2.45 L) was added to the reaction mixture which was then concentrated to ˜2 L. IPAC (0.5 L) and MTBE (2.45 L) was added and stirred overnight under N2. The solids were filtered. The solids and mother filtrate added back together and stirred for several hours. The solids were filtered and washed with MTBE (˜5 vol). The solids were placed in vacuum oven at 50° C. overnight. The solids were dried in vacuum oven at 30° C. over weekend to obtain N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (479 g, 72%).
Reaction SMILES: [CH:1]([C:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:5]#[N:6])([CH3:3])[CH3:2].C=O.[CH:34](O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([C:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)([CH2:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH3:34])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C#N)(CCCNCCOc2ccccc2OC)C(C)C)cc1OC
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C(C#N)(CCCN(C)CCOc2ccccc2OC)C(C)C)cc1OC
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 2.35 g of alpha-isopropyl-alpha-[3-[N-[2-(2-methoxyphenoxy)ethyl]amino]propyl]-3,4-dimethoxyphenylacetonitrile, 8 ml of 37% formalin, and 16 ml of 90% formic acid was stirred for 1 hour at 110° C. After cooling, to the mixture were added water and potassium carbonate to make it alkaline. The solution was extracted with chloroform and the extract was washed with water, dried, and evaporated. The residue was chromatographed on silica gel using chloroform as an eluent to give 1.30 g of the desired compound as a pale yellow oil.
Reaction SMILES: [N:1]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]=[O:3].[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH2:13]>C(OCC)C>[CH2:7]([O:6][C:4](=[O:5])[NH:1][C:2]([NH:13][CH2:12][CH2:11][N:10]([CH3:14])[CH3:9])=[O:3])[CH3:8]
Reactant: CCOC(=O)N=C=O
Reactant: CN(C)CCN
Solvent: CCOCC
Product: CCOC(=O)NC(=O)NCCN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl isocyanatoformate (500 mg, 4.2 mmol) in absolute diethyl ether (15 mL) was added dropwise to a solution of N1.N1-dimethylethane-1,2-diamine (440 mg, 550 μL, 5 mmol) in diethyl ether (25 mL) and stirred for 2 h at room temperature. The precipitate was filtered off and the filtrate was concentrated under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[C:6]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11]O)[CH:7]=1.CCN(CC)CC.CS(Cl)(=O)=O.[NH4+].[Cl-].[N-:32]=[N+:33]=[N-:34].[Na+]>C(Cl)Cl.O>[N:32]([CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: OC[C@H]1C[C@@H]1c1cc(Br)ccc1OCC1CC1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: [N-]=[N+]=NC[C@H]1C[C@@H]1c1cc(Br)ccc1OCC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To ((1S,2S)-2-(5-bromo-2-(cyclopropylmethoxy)phenyl)cyclopropyl)methanol (S8) (2.15 g, 7.23 mmol, 1.00 equiv) in CH2Cl2 (30 mL) in an oven-dried round-bottom flask under a N2 atmosphere at 0 ° C. was added Et3N (2.20 g, 3.03 mL, 21.7 mmol, 3.00 equiv) and MsCl (1.66 g, 1.13 mL, 14.5 mmol, 2.00 equiv). The reaction mixture was stirred at 0 ° C. for 2 hours. The reaction mixture turned yellow and a precipitate formed. The reaction mixture was poured into a separatory funnel with saturated NH4Cl solution (40 mL). The funnel was shaken and the organic phase collected. The aqueous phase was extracted from with diethyl ether (3×75 mL). The organic phases were combined and washed with saturated NaHCO3 (100 mL) and brine (100 mL), dried with MgSO4, and concentrated in vacuo. The residue was dissolved in DMF (30 mL) and NaN3 (1.88 g, 28.9 mmol, 4.00 equiv) was added. The reaction mixture was heated at 60 ° C. for 1 hour. The reaction mixture was cooled and poured into 60 mL of water. The reaction mixture was extracted from with diethyl ether (3×75 mL). The combined organic phases were washed with brine (100 mL), dried with MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of 5-10% EtOAc in hexanes (v/v) to afford 1.95 g of the title compound as a colorless oil (84% yield). Rf=0.60 (hexanes/EtOAc 19:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 7.21 (dd, J=8.7, 2.3 Hz, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 3.84-3.78 (m, 2H), 3.40 (dd, J=12.8, 6.4, 1H), 3.24 (dd, J=12.8, 7.1 Hz, 1H), 2.11 (ddd, J=8.7, 5.0, 5.0 Hz, 1H), 1.38-1.32 (m, 1H), 1.31-1.25 (m, 1H), 1.08-1.04 (m, 1H), 0.98-0.94 (m, 1H), 0.68-0.58 (m, 2H), 0.40-0.31 (m, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 156.9, 132.8, 129.5, 128.8, 113.4, 112.9, 73.3, 55.3, 20.8, 16.2, 12.8, 10.4, 3.3, 3.2. HRMS-FIA (m/z): calcd for C14H16BrN3NaO [M+Na]+, 344.0374; found, 344.0363.
Reaction SMILES: I[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.N1CCCCC1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>[Cu]I>[CH3:20][Si:21]([C:24]#[C:25][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1)([CH3:23])[CH3:22]
Reactant: Ic1ccc(CN2CCCC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(CN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A reaction mixture of 1 g (3.48 mmol) of 1-(4-iodobenzyl)pyrrolidine, 5 mL of piperidine, 105 mg (0.091 mmol) of tetrakistriphenylphosphine palladium, and 10 mg (0.053 mmol) of copper (I) iodide is cooled to 0° C. At this temperature, 0.59 mL (4.18 mmol) of trimethylsilylacetylene is added dropwise and then the cooling bath is removed. It is stirred for 3 hours at ambient temperature, then combined with a saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate (1:1)). Yield: 0.75 g (83.6% of theory); C16H23NSi (M=257.45); calc.: molecular ion peak (M+H)+: 258; found: molecular ion peak (M+H)+: 258.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][N:16](C)[CH2:15]2)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1C=CC=CC=1>[CH2:39]([O:38][C:36]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:28])[F:27])=[CH:10][CH:11]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:37])[CH3:40]
Reactant: CN1Cc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Reactant: CCOC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1Cc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Yield: 50.2 %

Procedure:
To a solution of 2 -methyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline of Example 4 (18.0 g, 0.06 mole) in 200 ml benzene, is added K2CO3 (20 g, 0.145 mole), and, with stirring, a solution of ethyl chloroformate (7.6 g, 0.07 mole) in 50 ml benzene. After refluxing for four hours, the mixture is cooled, washed twice with 100 ml portions of water, thrice with dilute HCl solution (100 ml), twice with water (100 ml), then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent is evaporated to an oil, which solidifies upon cooling, to a solid, 13.7 g (64%), m.p. 84° C. This material is recrystallized from hexanes twice, to yield 11.0 g, m.p. 107°-109° C. of 2-ethoxycarbonyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](I)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC2N=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=C(Br)C=3)[NH:29]C=2C=1)(=O)C>>[C:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:34]4[CH:33]=[N:29][CH:28]=[CH:30][CH:35]=4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(I)c1
Reactant: CC(=O)c1ccc2nc(-c3cccc(Br)c3)[nH]c2c1
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1

Procedure:
5-Acetyl-1-(3-iodophenyl)benzimidazole in mixture with 5-acetyl-(3-bromophenyl)benzimidazole (36) was prepared analogously from 35 (Example 4). Yield: ~91% (2 steps from 34).