Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)NC=3)=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[S:22]1C2C=CC=CC=2C(C(Cl)=O)=[N:23]1>>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][C:11]([C:13]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:22][N:23]=3)=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=C(Cl)c1nsc2ccccc12
Reactant: O=C(NCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: O=C(NCC12CCN(CC1)CC2)c1nsc2ccccc12

Procedure:
N-(quinuclidin-4-ylmethyl)benzo[d]isothiazole-3-carboxamide was prepared in a similar manner to N-((quinuclidin-4-yl)methyl)-1H-indole-3-carboxamide, substituting benzo[d]isothiazole-3-carbonyl chloride as the electrophile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 73 %

Procedure:
A solution of 4-benzyloxyphenol (6.01 g, 30 mmol) in anhydrous dimethylformamide (50 ml) under a nitrogen cover was treated with sodium hydride (1.2 g of 60% oil dispersion, 30 mmol) in one portion at room temperature. A moderate gas evolution ensued, and the reaction temperature rose to 41° C. After stirring an additional 35 minutes, 4-Fluoronitrobenzene was added rapidly dropwise, neat via syringe. A mild exotherm brought the reaction temperature to 32° C., after which the reaction was stirred for 18 hours at room temperature. The reaction mixture was poured over ice/water (250 ml), stirred for thirty minutes and the yellow solid collected by suction filtration. Silica gel chromatography (Waters® LC2000; two Pre-Pak® columns, P eluting with 3/1 hexanes/methylene chloride) afforded 4-(4-benzyloxyphenoxy)-1-nitrobenzene (5.9 g, 73%) as a white solid. 1H NMR(400 MHZ): 5.08(2H,s), 6.94-6.99(2H,m), 7.02(4H,s), 7.32-7.47(5H,m), 8.15-8.20(2H,m); MS(ESI)m/z 320.2([M−H]−,100).
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([CH2:30][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 25 mg of 2-bromoacetophenone was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 33 mg of white crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:18])[N:9]2[CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:4][CH:3]=1.[CH3:19][O-:20].[Na+].CO.O>CO>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:20][CH3:19])[N:11]=2)[CH:6]=[CH:7][C:8]1=[O:18]
Reactant: O=c1ccc2ccc(Cl)nc2n1CC1OCCO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2ccc(=O)n(CC3OCCO3)c2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2.5 g of 7-chloro-1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one in 30 mL of methanol, 5.4 g of a 28% sodium methoxide/methanol solution was added, and the mixture was heated under reflux while stirring for 3 hours 40 minutes. The reaction mixture was cooled to room temperature, then water was added thereto, and the solvent was then distilled off under reduced pressure. To the resultant residue, water, a saturated aqueous ammonium chloride solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.9 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#N)=[C:7]([Cl:13])[CH:6]=1.C(O)=[O:16]>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:16])=[C:7]([Cl:13])[CH:6]=1
Reactant: O=CO
Reactant: COC(=O)Cc1ccc(C#N)c(Cl)c1
Product: COC(=O)Cc1ccc(C=O)c(Cl)c1
Temperature: 110 °C

Procedure:
A solution of (3-chloro-4-cyano-phenyl)acetic acid methyl ester 13 (7.4 g, 35.3 mmol) in 88% formic acid (100 mL) is combined with Raney-alloy (9.0 g) and heated to reflux for 10 hours at 110° C. After cooling to room temperature, the alloy is removed by filtration over Celite. The filtrate is concentrated to ˜10% of the original volume and diluted with EtOAc (250 mL) and washed three times with water (80 mL). The organic layer is dried (MgSO4), filtered and concentrated to afford crude product, which is purified by silica gel chromatography using an EtOAc/hexane gradient to give (3-Chloro-4-formyl-phenyl)-acetic acid methyl ester 14 as a wax-like solid. Another amount of product 14 is collected by reesterification of saponified byproduct (3-Chloro-4-formyl-phenyl)-acetic acid: 1H-NMR (400 MHz, CDCl3) δ=10.31 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 3.86 (s, 3H), 3.64 (s, 2H). MS calculated for C10H10ClO3 (M+H+) 213.0, found 213.3.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[NH2:8][CH2:9][CH:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)[OH:11]
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NCC(O)c1ccc(O)c(C(N)=O)c1
Reaction time: 16 h

Procedure:
To 5-[2-(dibenzylamino)acetyl]salicylamide (75.0 g, 0.200 mmol) and acetic acid (24.0 g, 0.40 mmol) in 1.0 liter methanol, add 5% palladium/carbon (40.0 g). Hydrogenate at 3 atmospheres for 16 hours. Filter the catalyst, concentrate slightly and adjust the volume to give a solution of the title compound of the desired molarity.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.[Br:23][C:24]1[S:25][C:26](Br)=[N:27][N:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[Br:23][C:24]1[S:25][C:26]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)=[N:27][N:28]=1
Reactant: Brc1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nnc(Br)s2)CC1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
To a 5 mL microwave vial was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (247 mg, 0.8 mmol), 2,5-dibromo-1,3,4-thiadiazole (98 mg, 0.4 mmol), K3PO4 (212 mg, 1.0 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), 1,4-dioxane (2 mL), and water (0.4 mL). The mixture was purged with N2 for 10 min, then heated to 100° C. in the microwave for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to afford 64 mg (46%) of tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate: MS (M+2)=348.1; 1H NMR (400 MHz, CHLOROFORM-d) δ 6.46 (td, J=3.0, 1.9 Hz, 1H), 4.15 (d, J=3.0 Hz, 2H), 3.64 (t, J=5.6 Hz, 2H), 2.73 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19]C)=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1.O>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:2]3[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([OH:19])=[O:18])[CH:8]=4)[N:3]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (60 mg, 0.20 mmol, 1.00 equiv), 1H-indol-5-ylboronic acid (100 mg, 0.62 mmol, 3.05 equiv), Pd(PPh3)4 (23.6 mg, 0.02 mmol, 0.10 equiv), K3PO4 (174 mg, 0.82 mmol, 4.01 equiv), 1,4-dioxane/H2O (4/1 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 55% in 8 min, hold 55% in 3 min, up to 100% in 0.1 min, hold 100% in 0.9 min); Detector, UV 220&254 nm. This resulted in 25 mg (33%) of 2-(1H-indol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a red solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4]>[Ni].O>[CH3:1][CH:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4]
Reactant: CC(CO)Cc1ccccc1
Agent: [Ni]
Solvent: O
Product: CC(CO)CC1CCCCC1
Yield: 80 %

Procedure:
2-Methyl-3-phenylpropanol (219 g., 1.46 mol.) and 10.30 g. of 50% Ni on silica catalyst (4.7 wt %, G-49-C, United Catalyst) were stirred at 700 rpm in a Parr reactor at 150° C. and 200-600 psi of hydrogen until hydrogen absorption stopped (12 hours). Utilizing 2 wt. % of the catalyst requires that the reaction be run at 180° C. The reaction mixture was filtered through a filter bed (Celite™) using toluene as a rinse solvent and concentrated to a clear, colorless liquid. The odor grade product was isolated by fractional distillation, 174 g., 80% yield; bp 80° C. at 4 mm. Odor: very pleasant green, fruity, rosy. Mass Spectrum from 5508-36. MS (El) m/z (relative intensity) 138 (M+−H2O, 15), 123 (M+−Me and H2O, 15).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH2:6][CH2:7][PH:8](=[O:12])[O:9]CC>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH2:6][CH2:7][PH:8](=[O:9])[OH:12]
Reactant: CCO[PH](=O)CCc1ccc([N+](=O)[O-])c(OC)c1
Agent: Cl
Product: COc1cc(CC[PH](=O)O)ccc1[N+](=O)[O-]
Yield: 102 %

Procedure:
A solution of ethyl (3-methoxy-4-nitrobenzyl)methylphosphinate (Compound 216D, 0.500 g, 1.83 mmol) in 37% HCl (5.00 mL) was stirred at 100° C. for 6 hours. The reaction mixture was concentrated under reduced pressure to yield the desired product as a yellow foam, 457.2 mg (102% yield). This material was used in successive reactions without any further purification. 1H NMR (CDCl3, 400 MHz): δ=1.41 (d, J=13.89 Hz, 3 H), 3.13 (d, J=16.42 Hz, 2 H), 3.97 (s, 3 H), 6.89 (d, J=8.08 Hz, 1 H), 7.02 (s, 1 H), 7.82 (d, J=8.34 Hz, 1 H). MS (ES+): m/z 246.05 [MH+] (TOF, polar).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCNC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A solution of tert-butyl 4-aminobutylcarbamate (8.50 g, 45.2 mmol) in DMF (20 mL) in an addition funnel was added over 1 hour to a stirred solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (10.0 g, 45.2 mmol) and triethylamine (9.30 mL, 67.8 mmol) in DMF (100 mL). The addition funnel was rinsed with DMF (17 mL) and the solution was added to the reaction vessel. After the reaction solution was stirred overnight at room temperature, additional tert-butyl 4-aminobutylcarbamate (0.1 equivalent) was added. The solution was allowed to stir an additional 2 hours, then was concentrated under reduced pressure. The resulting oil was partitioned between ethyl acetate (400 mL) and water (100 mL). The organic phase was washed with water (4×50 mL), then was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 33% ethyl acetate in hexanes followed by 66% ethyl acetate in hexanes) to afford 9.2 g of tert-butyl 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:28]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:29]=2[S:30][C:31]=1[C:32](Cl)=[O:33]>CN(C=O)C>[Cl:26][C:27]1[C:28]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:29]=2[S:30][C:31]=1[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:11][N:10]=2)=[CH:6][CH:7]=1)=[O:33]
Reactant: O=C(Cl)c1sc2cc(F)ccc2c1Cl
Reactant: NC(=O)c1c(Nc2ccc(N)cc2)n[nH]c1NCc1ccc(O)cc1
Solvent: CN(C)C=O
Product: NC(=O)c1c(Nc2ccc(NC(=O)c3sc4cc(F)ccc4c3Cl)cc2)n[nH]c1NCc1ccc(O)cc1
Reaction time: 0.25 h
Yield: 4.9 %

Procedure:
3-((4-aminophenyl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was dissolved in 3.0 mL of DMF and TEA (125 μL, 3.0 eq.) was then added to the reaction vessel. Reaction was then stirred on an ice bath for 15 min and 3-Chloro-6-fluorobenzo[b]thiophene-2-carbonyl chloride (75 mg, 1.00 eq.) dissolved in DMF (2.0 mL) was slowly added into the reaction. The reaction continued stirring for 18 hrs and allowed to reach room temperature. The reaction was tracked via HPLC, once completed and no traces of starting material is present, the solvent was then removed via vacuo and column chromatography was used to purify the compound. A gradient of 0 to 20% MeOH in dichloromethane was used and the desired fractions were combined, evaporated and triturated with diisoproyl ether then filtered to yield product as an off white powder (0.008 g, 6.0% yield).
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.[ClH:14]>C(O)(C)C>[Cl:14][CH2:3][CH2:2]/[CH:1]=[C:4](/[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)\[CH3:5]
Reactant: CC(O)(c1ccc(F)cc1)C1CC1
Reactant: Cl
Solvent: CC(C)O
Product: C/C(=C\CCCl)c1ccc(F)cc1
Yield: 84 %

Procedure:
1-Cyclopropyl-1-(4-fluorophenyl)ethanol (307 mg, 1.70 mmol) in a solution of 1 N HCl in isopropyl alcohol (3.6 mL) was heated at 60° C. for 1 h. The reaction mixture was then concentrated in vacuo, and column chromatography purification yielded 1-[(1E)-4-chloro-1-methyl-1-butenyl]-4-fluorobenzene (282 mg, 84%) as a colorless oil. The title compound was isolated as a yellow oil (36 mg, 70%) according to the method of Example 286, Step C from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-[(1E)-4-chloro-1-methyl-1-butenyl]-4-fluorobenzene (48 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.62 (br-s, 1H), 1.90-2.20 (m, 9H), 2.31-2.44 (m, 5H), 2.71-2.80 (m, 1H), 2.81-2.89 (m, 1H), 2.92-3.00 (m, 1H), 3.04-3.13 (m, 1H), 3.17-3.24 (m, 2H), 3.27-3.31 (m, 1H), 3.51-3.63 (m, 1H), 3.80-3.91 (m, 1H), 5.64-5.73 (m, 1H), 6.62 (t, 1H, J=7.5 Hz), 6.87 (d, 1H, J=6.6 Hz), 6.91-7.00 (m, 3H), 7.29-7.34 (m, 2H) ppm)
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18](=[O:23])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]#[C:9][CH2:8][NH:7][C:6](=[O:24])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:12]([C:18](=[O:23])[C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:13]=1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1C#CCNC(=O)OC(C)(C)C
Reactant: Fc1cccnc1Br
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1C(=O)c1ncccc1F
Yield: 45 %

Procedure:
In a manner similar to that described above for compound 3al, 3-(4-chloro-2-(methoxy(methyl)carbamoyl)phenyl)prop-2-ynylcarbamic acid tert-butyl ester and 2-bromo-3-fluoropyridine were converted to 3am (45% yield): MS m/z=389 (M+H).
Reaction SMILES: O[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.O=P(Cl)(Cl)Cl.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(N(CC)CC)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: COc1ccc2c(O)noc2c1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(N3CCNCC3)noc2c1
Temperature: 30 °C

Procedure:
Prepare 4-(6-methoxybenzo[d]isoxzaol-3-yl)piperazine by slowly adding a solution of hydroxylamine hydrochloride (57.2 g, 0.823 mol) and water (600 mL) to a solution of sodium hydroxide (76.9 g, 1.92 mol) and water (300 mL). Then add a solution of methyl 4-methoxysalicylate (100 g, 0.55 mol, Aldrich Chemical Co.) and ether (800 mL), stir overnight, evaporate the ether, acidify with dilute hydrochloric acid, cool to 0° C., and filter. Recrystallize the filter cake from methanol to afford the 2-hydroxy-p-anisohydroxamic acid (78 g). Treat a warm (50° C.) solution of the hydroxamic acid (78 g) and tetrahydrofuran (500 mL) under nitrogen with a solution of carbonyldiimidazole (138.1 g, 0.85 mol) and tetrahydrofuran (500 mL), reflux for 3.5 hours, quench by addition of water (1000 mL), acidify to pH 3, add water (1000 mL) and refrigerate overnight. Collect the solid, wash with water and recrystallize from methanol to afford 54 g of 3-hydroxy-6-methoxy-1,2-benzisoxazole. Heat a stirred mixture of 3-hydroxy-6-methoxy-1,2-benzisoxazole (54 g) and POCl3 (100.3 g, d 1.645) at 95° C. under nitrogen, cool to 30° C., add triethylamine (33 g), heat at 140° C. overnight, quench with stirring into ice water and filter. Dissolve the filter cake in cyclohexane (2000 mL), filter, concentrate and recrystallize the residue from petroleum ether to give 3-chloro-6-methoxy-1,2-benzisoxzole (33 g). Treat this product with piperazine as described in U.S. Pat. No. 5,852,022, the contents of which are herein incorporated by reference, to afford 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>O>[C:15]([O:13][C:1](=[O:14])[C:2]1[CH:3]=[C:4]([O:5][CH3:6])[C:7]([OH:8])=[C:9]([O:10][CH3:11])[CH:12]=1)(=[O:17])[CH3:16]
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(C(=O)OC(C)=O)cc(OC)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A suspension of syringic acid 81 (10.0 g, 50.5 mmol) in acetic anhydride (30.0 g, 27.7 mL, 294.1 mmol) was warmed gently until a clear solution was obtained. Fused sodium acetate (0.5 g, 6.10 mmol) was added to the solution which was allowed to stir for 16 hours at room temperature. The solution was poured into water (100 mL) and stirred thoroughly to ensure hydrolysis of any excess anhydride. Crude O-Acetyl-syringic acid was recrystallized from water to afford the product as an off-white powder (11.2 g, 46.7 mmol). H1 NMR (270 MHz, CDCl3) δ 7.36 (s, 2H), 5.94 (br s, 1H), 3.87 (s, 6H), 2.35 (s, 3H). HRMS calcd for 240.0634, found 240.0637.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].N>CN(C)C=O>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:18]
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: N#C[Cu]
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 180 °C
Yield: 73.7 %

Procedure:
10.0 g of 4'-bromo-4-biphenylcarboxaldehyde and 5.31 g of copper(I) cyanide were dissolved in 80 ml of dimethylformamide while gassing with argon and the solution was heated to reflux for 15 hours at 180° C. bath temperature. Thereafter, the reaction mixture was poured cautiously into 200 ml of 25 percent ammonia and extracted three times with 200 ml of methylene chloride each time. The organic phases were washed once with 200 ml of 25 percent ammonia and twice with 200 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the yellowish, crystalline residue (8.7 g) on silica gel gave 5.85 g (74%) of 4'-cyano-4-biphenylcarboxaldehyde as slightly yellowish crystals; Rf-value (toluene/ethyl acetate vol. 90:10) 0.27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][OH:15])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:17]1[NH:21][C:20]2[CH:22]=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:24]=[C:25]([C:26]3[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=3)[C:19]=2[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][OH:15])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:17]2[NH:18][C:19]3[C:25]([C:26]4[CH:27]=[C:28]([F:34])[C:29]([F:33])=[C:30]([F:32])[CH:31]=4)=[CH:24][C:23]([C:35]([F:38])([F:36])[F:37])=[CH:22][C:20]=3[N:21]=2)[CH2:10][CH2:9]1
Reactant: OCc1cnc(N2CCNCC2)c(Cl)c1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: OCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)CC2)c(Cl)c1

Procedure:
The piperazine from step (a) above (114 mg, 0.5 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (140 mg, 0.4 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 542 (M+1).