Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:53][C:54]([F:66])([F:65])[C:55]1[CH:56]=[C:57]([CH2:61][C:62](O)=[O:63])[CH:58]=[CH:59][CH:60]=1>CN(C=O)C.C(Cl)Cl.CO>[F:53][C:54]([F:65])([F:66])[C:55]1[CH:56]=[C:57]([CH2:61][C:62]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:18]5[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=5[O:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:63])[CH:58]=[CH:59][CH:60]=1
Reactant: Nc1ncnc2occ(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred dark greenish solution of 5-(2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (400 mg, 1.59 mmol) and HATU (663 mg, 1.74 mmol, 1.1 equiv) in 4 mL of DMF was added DIEA (305 uL, 1.74 mmol, 1.1 equiv). To this mixture was added [3-(trifluoromethyl)phenyl]acetic acid portionwise (324 mg total, 1.59 mmol, 1 equiv), about 80 mg at 30 min intervals. After a total of 3 h, LCMS showed there was still 16% starting material left by UV. The mixture was diluted with ice cold water (40 mL) to give a dark greenish suspension, which was filtered. The cake was washed with water (2×8 mL), and sucked under house vacuum for 18 h to afford crude product (900 mg), which was dissolved in 10% DCM in MeOH and absorbed onto a dryload cartridge. Purification was done on an SF25-60 g silica gel cartridge using gradient elution of 1% A to 50% A in DCM (A was a mixture of 3200 mL DCM, 800 mL of MeOH and 80 mL of conc NH4OH). The product eluted around 25-30% A. The fractions with product were combined and concentrated in vacuo. This material contained an impurity, and the residue underwent another silica gel purification on an SF25-80 g silica gel cartridge using gradient elution of 1% B in EtOAc to 50% B (B was a mixture of 10% MeOH in EtOAc). The desired product eluted from 10-13% B. Pure fractions were combined and evaporated. The residue (200 mg) was taken up in CHCl3 (0.45 mL), MTBE (3 mL) and hexane (3 mL) to give a suspension, which was filtered. The solids were washed with hexane (2×3 mL) and dried under vacuum at 65° C. for 18 h to afford 5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (170 mg) as light cream-colored solids. LC-MS (ES) m/z=439 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.27 (t, J=8.3 Hz, 2H), 4.05 (s, 2H), 4.28 (t, J=8.6 Hz, 2H), 7.30 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 7.56-7.66 (m, 3H), 7.68 (s, 1H), 7.93 (s, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.25 (s, 1H), NH2 protons not visible or existed as broad hump.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].[Cl:13][C:14]1[C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24]Cl)=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>O>[Cl:13][C:14]1[C:19]([C:20]2[O:21][CH2:24][C:23]([CH3:27])([CH3:26])[N:22]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(CCl)NC(=O)c1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2cccnc2Cl)=N1

Procedure:
2 l of toluene and 155 g (1.84 mole) of sodium bicarbonate are then added to the solution of 2-chloro 3-(1,1-dimethyl 2-chloro-ethyl)aminocarbonylpyridine thus formed and the mixture is refluxed with vigorous stirring until the starting material has completely disappeared (10 to 15 H). The water formed by the reaction of the hydrochloric acid liberated with the sodium bicarbonate is collected in a separator, and the sodium chloride formed is filtered off and washed with toluene. The filtrate is then concentrated under reduced pressure to give 2-chloro 3-(4,4-dimethyl 2-oxazolinyl)pyridine in the form of a yellow oil which can be purified by distillation under reduced pressure.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[Br:16]Br.O>O1CCOCC1>[Br:16][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc(Cl)cc(NS(C)(=O)=O)c1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(Cl)cc(C(=O)CBr)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
N-(3-acetyl-5-chlorophenyl)methanesulfonamide (500 mg) was dissolved in dioxane (10 mL). The temperature was maintained at 50° C. and bromine (0.11 mL) was added. After stirring for 30 minutes, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with water (50 mL) twice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (1:2 ethyl acetate/hexane) to yield N-(3-bromoacetyl-5-chlorophenyl)methanesulfonamide (600 mg) as a colorless crystal.
Reaction SMILES: [CH2:1]1[C:21]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]([NH2:19])=O)[CH:15]=[CH:16][C:10]=4[CH:9]=[CH:8][C:7]=3[CH:20]=2)[CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>N1C=CC=CC=1>[CH2:1]1[C:21]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]#[N:19])[CH:15]=[CH:16][C:10]=4[CH:9]=[CH:8][C:7]=3[CH:20]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc2c(c1)Sc1cc3c(cc1C=C2)CCC3
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1ccc2c(c1)Sc1cc3c(cc1C=C2)CCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
The crude amide from Step A (4.34 g, 14.8 mmole) in pyridine (43.5 ml) was treated slowly under cooling (ice-bath) with trifluoroacetic anhydride (8.7 ml). The mixture was stirred for 1 hour at ambient temperature and then poured into a mixture of ice (400 g) and concentrated hydrochloric acid (50 ml). The product was extracted into ether and the ethereal extract was washed with water, then with 10% sodium carbonate solution and finally with saturated sodium chloride solution. After drying (MgSO4) the solution was evaporated to a tan colored solid (3.22 g). The product was purified by chromatography on Merck silica gel using toluene as solvent to give 2.45 g of the title compound. Melting point 142°-143° C. (from acetonitrile).
Reaction SMILES: O.[CH2:2]([O:9][NH:10][C@H:11]1[CH2:16][N:15](C(=O)C(F)(F)F)[C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C(O)(=O)C>O1CCOCC1>[CH2:2]([O:9][NH:10][C@H:11]1[CH2:16][NH:15][C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Yield: 90.1 %

Procedure:
Water (9.2 mL) was added to a solution of 6.91 g (17.17 mmol) of (2S,5R)-tert-butyl 5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate in 1,4-dioxane (34 mL), and, under ice cooling, 2.5M NaOH (13.7 mL) was added dropwise, followed by allowing to react at the same temperature for 0.5 hours. Acetic acid (ca. 1 mL) was added to the reaction mixture, followed by concentration under reduced pressure, and subsequently the resulting concentrated residue was extracted with ethyl acetate (58 mL, 29 mL). After the organic layers were washed respectively with 50% aqueous potassium carbonate solution, they were combined, followed by drying with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=19/1) to afford 4.74 g of the title compound as a colorless oil (yield 90%). Enantiomeric excess: 98.9% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, diethylamine/hexane/ethanol=0.1/80/20, flow rate 1 mL/min., retention time 5.5 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:38])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][NH:22]C(OCC2C=CC=CC=2)=O)=[N:19][C:18]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[N:17]1.[BrH:39].C(O)(=O)C>CCOCC>[BrH:39].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:38])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][NH2:22])=[N:19][C:18]([C:33](=[O:37])[N:34]([CH3:35])[CH3:36])=[N:17]1
Reactant: CN(C)C(=O)c1nc(CNC(=O)OCc2ccccc2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN(C)C(=O)c1nc(CN)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2',5-dichloro-2-(3-dimethylcarbamoyl-5-carbobenzoxyaminomethyl-1,2,4-triazol- 1-yl)benzophenone (3.6 g) and 30% hydrogen bromide-acetic acid (9 ml) is stirred at room temperature for 2 hours. The reaction mixture is mixed with ether, and the precipitate is isolated by decantation and washed thrice with ether, whereby 2',5-dichloro-2-(3-dimethylcarbamoyl-5-aminomethyl-1,2,4-triazol- 1-yl)-benzophenone hydrobromide is obtained. This hydrobromide (1.2 g) is added to a solution of chloroacetyl chloride (1.2 g) in benzene (40 ml) to give a solution, which is mixed with dimethylformamide (20 ml). The resultant mixture is stirred at room temperature for 3 hours. The reaction mixture is mixed with ethyl acetate and neutralized with aqueous sodium bicarbonate. The organic layer is separated, washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is treated with ethanol/n-hexane to give 2',5-dichloro-2-[3-dimethylcarbamoyl-5-(2-chloroacetylamino)methyl-1,2,4-triazol- 1-yl]-benzophenone (12.9 g), which is recrystallized from ethyl acetate to give colorless needles melting at 80°-82° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH:8]([CH3:10])[CH3:9]>C(OCC)C>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:17][CH:16]=1)=[O:6]
Reactant: CC(C)COc1ccc(N)cc1
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: CC(C)COc1ccc(NC(=O)NCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloroethyl isocyanate (15 g, 142 mmols) is added dropwise to a solution of 4-isobutoxy phenylamine (20 g, 121 mmols) in diethyl ether (100 mL) and stirred at RT for 1 h. The solid formed is collected by filtration and recrystallisation from ethanol affords the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([N:10]2[CH:14]=[CH:13][NH:12][C:11]2=[O:15])=[O:9])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([N:10]2[CH:14]=[CH:13][NH:12][C:11]2=[O:15])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)n1cc[nH]c1=O
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)n2cc[nH]c2=O)cc1
Yield: 96.1 %

Procedure:
1b (200 mg, 0.86 mmol) in 20 mL MeOH was hydrogenated over 10% Pd/C (40 mg) at 50 psi H2. The reaction mixture was filtered through a plug of Celite®, washed with MeOH and concentrated on a rotary evaporator to give 168 mg (98% yield) of 4-aminobenzoyl-1,3-dihydroimidazol-2-one 1c. MS found: (M+H)+=204.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH2:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:22]([O:29][C:3]([C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][CH:9]=1)=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cccc(-n2cccc2C(=O)C(Cl)(Cl)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2cccc2C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The mixture of methyl 3-(2-trichloroacetylpyrrol-1-yl)benzoate (10.0 g), benzyl alcohol (3.3 ml) and potassium carbonate (4.4 g) in N,N-dimethylformamide (30 ml) was stirred for 6 hours at ambient temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with toluene. The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(2-benzyloxycarbonylpyrrol-1-yl)benzoate (8.35 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(C(C)C)C(C)C)C.C(#N)CC.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C.CN(C=O)C>[NH2:8][C:5]1[C:4](/[CH:12]=[CH:11]/[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ncc(Br)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cc(Br)cnc1N
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
A reaction vessel was charged with 5-bromo-3-iodopyridin-2-amine (1 g, 3.35 mmol), tert-butyl acrylate (0.97 mL, 6.69 mmol), and (i-Pr)2EtN (1.75 mL, 10.01 mmol) followed by propionitrile (20 mL) and then DMF (5 mL). The solution was de-oxygenated with argon for 15 minutes. The mixture was treated with Pd(OAc)2 (75 mg, 0.34 mmol) and P(o-tol)3 (204 mg, 0.67 mmol) then heated to 90° C. for 16 h (overnight) then filtered through a pad of silica gel. The filtrate was concentrated and dried under reduced pressure to give a dark brown residue which was subjected to flash chromatography on silica gel using 20% ethyl acetate:hexanes to 40% ethyl acetate:hexanes. The appropriate fractions were collected and concentrated to give a yellow solid. Yield: 700 mg (70%); 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, 1H, J=2.3 Hz), 8.03 (d, 1H, J=2.3 Hz), 7.61 (d, 1H, J=15.0 Hz), 6.58 (s, 2H), 6.50 (d, 1H, J=15.0 Hz), 1.50 (s, 9H); ESI MS m/z 299 (100%); 301 (100%) [C12H15N2O2Br+H]+
Reaction SMILES: C1([O:6][C:7](=[O:39])[C@@H:8]([NH:15][C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:37])[NH:35][OH:36])[CH:21]=2)=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)CCCC1.[OH-].[Na+]>C1COCC1>[OH:36][NH:35][C:34]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([NH:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][NH:18][C:16](=[O:17])[NH:15][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]([OH:39])=[O:6])=[O:38])=[O:37]
Reactant: O=C(CCCCCCC(=O)Nc1cccc(CNC(=O)N[C@H](C(=O)OC2CCCC2)c2ccccc2)c1)NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCCCC(=O)Nc1cccc(CNC(=O)N[C@H](C(=O)O)c2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound (79) (75 mg) was dissolved in THF (1 ml) and 2M NaOH (aq, 1 ml) added. The reaction was stirred at room temperature for 2 h. THF was removed under a stream of N2 and the aqueous layer (˜1 ml) was purified by preparative HPLC to yield compound (80). LCMS purity 99%, m/z 471 [M++H]+, 1H NMR (400 MHz, MeOD), δ: 1.20-1.35 (4H, m, 2×CH2), 1.45-1.65 (4H, m, 2×CH2), 2.00 (2H, t, CH2), 2.25 (2 H, t, CH2), 4.20 (2H, s CH2NH), 5.25 (1H, s CHPh), 6.90 (1H, d, Ar), 7.10 (1H, t, Ar), 7.15-7.40 (7H, m, Ar).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[O:18][CH2:19][CH2:20][O:21][CH:22]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)OCCO1
Agent: O=C[O-]
Agent: [NH4+]
Product: c1cc2c(cc1C1COCCO1)CNC2

Procedure:
Prepared in analogy to Example A49(b) from 2-benzyl-5-(5,6-dihydro-[1,4]dioxin-2-yl)-2,3-dihydro-1H-isoindole and ammonium formate. Purple solid. MS (m/e): 206.3 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)[CH2:13][CH2:14][CH3:15])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.[Cl-].[Ca+2].[Cl-]>O.[Fe]>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[NH2:22])[CH2:13][CH2:14][CH3:15])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(CCC)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCCCCCN1CC2C(C1)C2(CCC)c1cccc(N)c1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a stirred suspension of 3-hexyl-6-(3-nitrophenyl)-6-propyl-3-azabicyclo[3.1.0]hexane (Preparation 65, 2.60 g, 7.2 mmol), ethanol (150 ml) and iron powder (0.41 g, 73.2 mmol) was added calcium chloride (1.5 g 13.0 mmol) in water (50 ml). The reaction mixture was heated under reflux for 16 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite®, and the mother liquors were concentrated in vacuo. The residue was dissolved in dichloromethane and filtered through a pad of sodium sulphate to give upon concentration the title compound as a yellow oil (2.17 g, 100%).
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCc1nc(C(O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
14 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 0.86 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1hydroxybutyl)imidazole-5-carbonitrile [prepared as described in step (b) above] in 14 ml of ethanol, and the resulting mixture was heated under reflux for 10 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c) to afford 0.58 g of the title compound as an amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:15].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1
Reactant: OB(O)c1cccnc1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (120 mg, 0.29 mmol) and pyridine-3-boronic acid (58 mg, 0.47 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-20%EtOAc in hexane), the title product as a yellow solid. MP 196-197° C. MS (ESI, pos. ion) m/z: 408 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH:3]=1.CC1(C)C(C)(C)OB(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:8](=[O:9])[C:4]2[CH:3]=[C:2](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:14]=1
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Reactant: COc1ccc(CNC(=O)c2cc(Br)ccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNC(=O)c2cc(/C=C/c3ccccc3)ccn2)cc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
To a flask containing 4-bromo-N-(4-methoxybenzyl)picolinamide (0.3 g) in 1,4-dioxane (1.1 mL) was added (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.22 g), Pd(dppf)—chloroform adduct (0.04 g) and 2M aqueous cesium carbonate (1.9 mL). The mixture was stirred at about 95° C. for about 12 h. The reaction was diluted with water and washed three times with CH2Cl2. The organic solution was filtered over Celite®, and concentrated under reduced pressure yielding (E)-N-(4-methoxybenzyl)-4-styrylpicolinamide as a deep yellow oil (0.25 g, 80%). LC/MS (Table-1, Method f) Rt=2.03 min; MS m/z 345 (M+H)+. This intermediate was then dissolved in 4.3 mL of 1,4-dioxane and treated with 0.87 mL of water and sodium periodate (0.75 g). After stirring for approximately 30 min at RT, osmium tetroxide (0.30 mL of a 0.1 M solution in t-butanol) was added to the reaction which was then stirred for about an additional 4 h at RT. The layers were separated and the organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was isolated by flash chromatography to give 4-formyl-N-(4-methoxybenzyl)picolinamide (0.25 g, 80%): LC/MS (Table 1, method-f) Rt=1.01 min; MS m/z 271 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:26])[CH3:25]
Reactant: CCOC(=O)Nc1c(F)cc(F)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)Nc1c(F)cc(F)cc1C#C[Si](C)(C)C
Yield: 67.3 %

Procedure:
In a 2 L flask, 2-bromo-4,6-difluoro-N-carbethoxy aniline (42 g, 150 mmol) in CH3CN (500 mL) is degassed with vacuum and purged with N2. Dichlorobis(triphenylphosphine)palladium(II) (10.5 g, 15 mmol, 10 mol %), followed by CuI (710 mg, 4 mmol, 2.5 mol %) and triethyl amine (41 mL) are added and rinsed in with 100 mL of CH3CN. Trimethylsilyl acetylene (31.8 ml, 225 mmol) is added and reaction is refluxed under N2. Approximately 2 hours later, the starting material is consumed, indicated by TLC (20% ethyl acetate/hexane, UV). The reaction is cooled, filtered, concentrated, and the residue is dissolved in ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, concentrated, and is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 30 g of 2-(trimethylsilylethynyl)-4,6-difluoro-N-carbethoxyaniline (71%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]=[CH:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: CCCC1CCC(C2CCC(C=Cc3c(C)cc(OCC)c(F)c3F)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(CCc3c(C)cc(OCC)c(F)c3F)CC2)CC1
Yield: 80.7 %

Procedure:
0.31 g of Pd/C was added to 6.20 g of the compound 1-3-3-9 having been dissolved in 50 mL of toluene and 50 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 5.03 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethane (Compound 1-3-3-1) as colorless crystals.