Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])(F)[F:14])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([NH2:34])[CH2:31][CH2:32][NH2:33]>>[F:16][CH:13]([F:14])[O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:17]1[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:28])(=[O:29])[CH2:19][CH2:18]1)[CH:3]=[C:2]2[NH:33][CH2:32][CH2:31][CH2:30][NH2:34]
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: NCCCN
Product: NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(OC(F)F)cc12

Procedure:
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro-6-(difluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-(difluoromethoxy)quinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 463, 1H NMR (400 MHz, CD3OD) δ ppm 8.02-8.00 (d, J=7.6 Hz, 1 H), 7.98-7.90 (d, J=2 Hz, 1 H), 7.84-7.82 (d, J=8.4 Hz, 2 H), 7.68-7.64 (t, J=7.6 Hz, 1 H), 7.54-7.50 (m, 1 H), 7.05-6.68 (d, J=73.6 Hz, 2 H), 5.95 (s, 1 H), 5.28 (s, 2 H), 4.48 (s, 2 H), 3.68 (s, 2 H), 3.57-3.54 (t, J=6.8 Hz, 2 H), 3.08-3.04 (t, J=7.6 Hz, 2 H), 2.11-2.04 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Cl.O1CCOCC1>CC(O)=O.[Ni]>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1cc(CN2CCOCC2)c(C#N)c(=O)[nH]1
Agent: [Ni]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(CN2CCOCC2)c(CN)c(=O)[nH]1
Yield: 95.3 %

Procedure:
A clear solution of 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.60 g, 2.57 mmol) in HOAc (20 mL) was treated on an H-Cube apparatus (50 psi, 60° C., 1 mL/min., Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete. The reaction was evaporated to dryness, taken up in a small volume of MeOH and treated with 4 N HCl in dioxane (5 mL, 20.00 mmol). The mixture was evaporated to dryness under vacuum (began to ppt. out during evaporation), triturated with Et2O, filtered and dried under vacuum to give the product 3-(aminomethyl)-6-methyl-4-(4-morpholinylmethyl)-2(1H)-pyridinone (0.76 g, 2.450 mmol, 95% yield) as a light grey solid. 1H NMR (400 MHz, DMSO-d6) δ 6.39 (s, 1 H), 4.28 (s, 2 H), 3.99 (s, 2 H), 3.87 (br. s., 4 H), 3.27 (br. s., 4 H), 2.22 (s, 3 H). MS(ES)+m/e 238.0 [M+H]+ (weak), 221.3 [M+H]+—NH3 (strong).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.S(Cl)([Cl:26])=O>CN(C=O)C.C(Cl)Cl>[Cl:26][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2N2CCCCC2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.4 %

Procedure:
To a solution of 67.20D (0.2318 g, 0.73 mmol) in dry DMF (0.03 mL) and dry DCM (3 mL) was added thionyl chloride (0.13 mL, 1.8 mmol) at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was diluted with DCM and then washed once with saturated aqueous sodium bicarbonate and once with brine. After drying over anhydrous magnesium sulfate, filtering, and removing the solvent under reduced pressure, the residue was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 67.20E (86.3 mg, 35% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.16 (1H, m), 7.00 (4H, m), 6.72 (1H, dt, J=9.0, 3.5 Hz), 4.50 (2H, s), 3.71 (3H, s), 2.71 (4H, m), 1.34 (6H, m).
Reaction SMILES: [C:1]([CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])#[N:2].C([Sn]([N:29]=[N+:30]=[N-:31])(CCCC)CCCC)CCC>O1CCCC1>[NH:29]1[C:1]([CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])=[N:2][N:31]=[N:30]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(CC#N)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1nnn[nH]1)C(=O)O
Reaction time: 72 h
Yield: 84.9 %

Procedure:
17.5 g (82 mmol, 1 equiv. ) of 3-cyano-2- (1,1-dimethylethoxy) methanamido-propionic acid 26 was dissolved in 125 mL of tetrahydrofuran and 40.5 g (129 mmol, 1.5 equiv. ) tributyltin azide was added. The reaction mixture was brought to reflux and held there for 3 days. The reaction mixture was cooled and the volatiles removed in vacuo on a rotary evaporator. The residue was dissolved in 300 mL of 0.5M sodium hydroxide and this aqueous solution was washed with ethyl acetate (4×100 mL). The aqueous layer was passed through a 125 mL bed of Dowex 50X8-400 ion exchange resin and the resin washed with four column volumes of 1:1 methanol:water. The volatiles were removed in vacuo on the rotary evaporator to yield 17.9 g of the product as a white solid (85% yield). 1H-NMR (CD3OD): 4.55 p.p.m (m, 1H); 3.40 p.p.m. (m, 2H); 1.40 p.p.m. (s, 9H). This material is suitable for use in solid-phase peptide synthesis.
Reaction SMILES: [Na].CS(C)=O.[OH:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[CH2:27]([O:26][C:24]([CH:23]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[N:8]=1)[CH3:29])=[O:25])[CH3:28]
Reactant: Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 0.54 g portion of sodium was dissolved in 15 ml of absolute ethanol, and was added to 50 ml of dimethylsulfoxide containing 5.4 g of 3-hydroxy-1-(4-trifluoromethylphenyl)-1,2,4-1H-triazole. An additional 25 ml of dimethylsulfoxide was added, and the mixture was heated on the steam bath for 15 minutes. Then 4.3 g of ethyl 2-bromopropionate was added and heating was continued for 1 hour. The mixture was then cooled and poured over ice-water, and the product was collected, dried, and purified by high-performance liquid chromatography, eluting with 1:1 hexane:ethyl acetate. The product-containing fractions were combined and evaporated under vacuum to obtain 3.5 g of the desired product.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:21]([CH2:32][O:33][CH3:34])[CH:20]=3)[O:16][N:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].Cl>CO.O>[F:3][C:4]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:21]([CH2:32][O:33][CH3:34])[CH:20]=3)[O:16][N:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1N1CCCCC1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1N1CCCCC1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 5N aqueous solution of NaOH (0.52 mL, 2.62 mmol) was added to a suspension of methyl 2-fluoro-4-{5-[3-(methoxymethyl)-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}benzoate (230 mg, 0.52 mmol, obtained in Example 113) in MeOH (5 mL). The resulting mixture was stirred at RT for 30 minutes. The reaction mixture was acidified with a 1N aqueous solution of HCl until pH=4 and diluted with water. The precipitate was filtered off, washed with water (3×) and dried under reduced pressure to give the title compound as a white powder. HPLC (Method A), Rt: 3.79 min (purity: 99.5%). LC/MS, M+(ESI): 426.2, M−(ESI): 424.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]=O)[CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]([O:22][CH3:23])=[N:20][C:19]2[C:14]1=[N:15][C:16]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:17][C:18]=2[NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:26]([O:25][C:16]1[N:15]=[C:14]2[C:19]([N:20]=[C:21]([O:22][CH3:23])[N:13]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][O:1][CH2:2]2)=[C:18]([NH2:24])[N:17]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Reactant: O=CC1CCCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCOC3)c2n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 70.4 %

Procedure:
Tetrahydro-2H-pyran-3-carbaldehyde (19.39 mg, 0.17 mmol) was added to 9-(3-aminopropyl)-2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine (50 mg, 0.17 mmol) in DCM (1 ml). Sodium triacetoxyborohydride (72.0 mg, 0.34 mmol) and DCM (1 ml) was added followed by acetic acid (0.024 ml, 0.425 mmol). The mixture was stirred at 20° C. under nitrogen for 5 hours. The mixture was quenched with NaHCO3 (5 ml) and diluted with DCM (2 ml). The organic layer was separated using a hydrophobic frit and the solvent removed in vacuo. The sample was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen to give the title compound as white solid (47 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[Na].[CH3:13][OH:14]>>[CH3:13][O:14][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: CO
Agent: [Na]
Product: COC(=O)c1cc(OC)ccn1

Procedure:
A mixture of methyl 4-chloropyridine-2-carboxylate (3.7 g), sodium metal (0.5 g) and methanol (100 ml) was stirred and heated to reflux for 8 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated to give methyl 4-methoxypyridine-2-carboxylate (3 g).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[C:12](/[CH3:28])=[CH:13]/[CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:31]=1>>[C:22]1([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[C:12](\[CH3:28])/[C:11]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[O:10])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCCCc1cccnc1
Reactant: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Product: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)NCCCCc1cccnc1
Yield: 86.3 %

Procedure:
As in Example 134, (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid 4-nitrophenyl ester (1.6 g) was reacted with 3-pyridinebutanamine (0.63 g) for 18 hours at 25° C. The crude amide obtained from the usual work up was purified by HPLC (ethyl acetate) and then crystallized from ether to provide 1.42 g of (E)-5,5-diphenyl-2-methyl-N-[4-(3-pyridinyl)butyl]2,4-pentadienamide mp 93°-94° C. Anal. Calculated for C27H28N2O: C, 81.78; H, 7.12; N, 7.06 Found: C, 81.74; H, 7.02; N, 7.01.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[Cl:25][C:26]1[C:31]([NH:32][CH2:33][CH3:34])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:25][C:26]1[N:27]=[CH:28][C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)=[CH:30][C:31]=1[NH:32][CH2:33][CH3:34]
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1Cl
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(C)c2C)c(=O)n4C)cnc1Cl

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.101 mmol) and [2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-ethyl-amine (stage 153.1.1) to give the title compound as a yellow solid. (HPLC: tR 2.74 min (Method A); M+H=462 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.13-8.08 (m, 1H), 7.98-7.93 (m, 1H), 7.76-7.73 (m, 1H), 7.58-7.54 (m, 1H), 6.97-6.93 (m, 1H), 5.72 (t, 1H), 3.79 (s, 3H), 3.59 (s, 3H), 3.26 (qt, 2H), 2.07 (s, 3H), 1.91 (s, 3H), 1.22 (t, 3H))
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.Cl>CN(C)C=O.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:21])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(OCc2ccccc2)c1

Procedure:
A stirred mixture of 3-benzyloxybenzoic acid (22.0 g; 0.096 mol) and dry dimethylformamide (2 drops) in dry dichloromethane (100 cm3) was treated with oxalyl chloride (19 g; 0.15 mol) which was added in 4 approximately equal portions over ˜30 minutes. The mixture was stirred at room temperature until evolution of hydrogen chloride had ceased (˜6 hrs). The resulting colourless solution was evaporated in vacuo at 40° to constant weight to give a very pale tan oil that solidified rapidly to give the title compound as off-white needles.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11]([C@@H:17]3[C@@H:22]4[CH2:23][C@@H:19]([CH2:20][CH2:21]4)[N:18]3C(OC(C)(C)C)=O)=[N:10][C:9]=2[CH:8]=1.Cl.C(OCC)(=O)C>CO>[C@H:19]12[CH2:23][C@H:22]([CH2:21][CH2:20]1)[C@@H:17]([C:11]1[NH:12][C:13](=[O:16])[C:14]3[S:15][C:7]([C:3]4[CH:4]=[N:5][NH:6][C:2]=4[CH3:1])=[CH:8][C:9]=3[N:10]=1)[NH:18]2
Reactant: Cc1[nH]ncc1-c1cc2nc([C@@H]3[C@H]4CC[C@H](C4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]ncc1-c1cc2nc([C@H]3N[C@@H]4CC[C@H]3C4)[nH]c(=O)c2s1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
To a solution of tert-butyl(1R,3S,4S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate (690 mg) in methanol (10 mL) was added 4M hydrochloric acid/ethyl acetate solution (2.0 mL) with stirring at room temperature. The reaction system was stirred with heating at 50° C. for 30 min, and the mixture was concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate. Insoluble material was removed by filtration. The mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate), and the obtained colorless solid was crystallized from methanol/ethyl acetate to give the title compound (220 mg) as a colorless solid. The optical purity was 86% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK OD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: methanol, flow rate: 0.5 mL/min, column temperature: 30° C., detection 254 nm).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:19]2)C=CC=CC=1.O>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH:20]2[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:21]2)=[CH:24][CH:25]=1
Reactant: O=C(Cl)Cl
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reaction time: 18 h

Procedure:
A solution of 52.09 g (0.527 mole) of phosgene in 500 ml of methylene chloride was stirred with 73 g (0.53 mole) of potassium carbonate under nitrogen atmosphere for 30 min, then treated with 146.3 g (0.439 mole) of 1-diphenylmethyl-3-(4-fluorophenoxy)azetidine in 300 ml of methylene chloride added dropwise. After stirring for 18 hr, the reaction mixture was treated with 200 ml of water added slowly. The aqueous phase was separated and the organic solution dried by filtration through Whatman phase separating filter paper then concentrated in vacuo to a pale amber oil. Trituration of the oil with 30/60 petroleum ether yield a crude tacky solid, 89.3 g (88.6%). A portion of this solid was recrystallized from 30/60 petroleum ether yielding a fine white crystalline product, m.p. 44°-52° C. A second recrystallization from isopropyl ether yielded fine white crystals, m.p. 57°-58.5° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([CH:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:13]=2[CH:21]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1nc2ccc(F)cc2n1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of [1-(6-fluoro-1-pyridin-4-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (210 mg, 0.59 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound (120 mg, 79%) as a yellow solid. LCMS (Method C): RT 1.63 min [M+H]+ 257.15.
Reaction SMILES: [Cl-].O[NH3+].CC[O:6]CC.[CH2:9]([O:11][C:12](=[NH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:10]>O>[C:12](=[N:24][OH:6])([O:11][CH2:9][CH3:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOCC
Reactant: CCCCCCCCCCCC(=N)OCC
Agent: [Cl-]
Agent: [NH3+]O
Solvent: O
Product: CCCCCCCCCCCC(=NO)OCC
Temperature: 2 °C
Yield: 77 %

Procedure:
A mixture containing fourteen grams of hydroxylammonium chloride dissolved in 100 ml of water was added to 100 ml of ether in a 250 ml flask. The resulting mixture was cooled to 2° C. and 45.4 g of ethyldodecaneimidate were added to the mixture with stirring. The reaction mixture was stirred for an additional 30 minutes at 2° C. The layers were separated and the aqueous layer was extracted three times with 75 ml of ether. The ether layer and washings were combined and then dried over sodium sulfate and concentrated to yield 37.3 g (77% yield) of ethyl dodecane hydroximate as a white, solid substance. IR and NMR analyses confirmed the structure.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH3:5].C(Cl)[C:7](=[CH2:9])[CH3:8]>>[CH3:5]/[CH:4]=[CH:3]/[CH2:2][C:2]#[C:3][CH2:4][CH2:5][CH2:8][CH2:7][CH3:9]
Reactant: C=C(C)CCl
Reactant: CC=CCBr
Product: C/C=C/CC#CCCCCC

Procedure:
Obtained in 74% yield (as a 92:8 E/Z mixture) from 1-heptyn using 1-bromo-but-2-en and using methallylchloride according to the procedure described under a).
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[CH3:17][O-:18].[Na+].[C-]#N.[Na+].C(Cl)Cl>CO>[Cl:7][C:5]1[N:6]=[C:2]([O:18][CH3:17])[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Cl:8]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Cl)c1Cl
Reactant: C[O-]
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Yield: 67 %

Procedure:
A solution of 2-bromo-4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.12 g, 0.35 mmol), sodium methoxide (0.12 mL of a 25% solution in methanol, 0.53 mmol) and CuBr (0.010 g, 0.07 mmol) in methanol (0.5 mL) was heated at 100° C. for 6 h. Dilute aqueous NaCN and CH2Cl2 were added and the solution was stirred for a few minutes. The solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-40% EtOAc/hex) to afford the title compound (0.070 g, 67%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.11 (s, 2H) 4.02 (s, 3H) 3.51-3.63 (m, 2H) 0.88-0.97 (m, 2H) −0.01 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[C:16](Cl)(=[O:18])[CH3:17].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:11][C:10]1[C:2]([NH:1][C:16](=[O:18])[CH3:17])=[C:3]2[C:7](=[CH:8][C:9]=1[O:13][CH3:14])[C:6](=[O:15])[CH2:5][CH2:4]2
Reactant: COc1cc2c(c(N)c1OC)CCC2=O
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(c(NC(C)=O)c1OC)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
4-Amino-5,6-dimethoxy-indan-1-one (Intermediate U) (0.214 g, 1.0 mmol) was taken up into 5 mL of DMF and acetyl chloride(0.071 mL, 1.0 mmol) and DIEA (0.18 mL, 1.0 mmol) were added. The reaction stirred overnight at room temperature. The reaction was quenched with sat. sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and removed in vacuo. 0.25 g of the crude material was produced (Intermediate V); MS m/z 250.1 (M+H)+.
Reaction SMILES: N1C2=CC=C(N)CC2NC1.C([BH3-])#N.[Na+].[CH2:15]([O:22][C:23]1[CH:44]=[C:43]([Cl:45])[C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][N:30]([N:33]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:36]=4[N:35]=[CH:34]3)[C:29]2=[O:42])=[C:25]([Cl:46])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO.C(OCC)(=O)C>[CH2:15]([O:22][C:23]1[CH:44]=[C:43]([Cl:45])[C:26]([CH2:27][C@@H:28]2[CH2:32][CH2:31][N:30]([N:33]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:36]=4[N:35]=[CH:34]3)[C:29]2=[O:42])=[C:25]([Cl:46])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C(Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1n1cnc2c1CCCC2
Agent: NC1=CC=C2NCNC2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1n1cnc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add Preparation 10 (5.25 g) to a suspension of imidazolocyclohexy-3-amine hydrochloride (2 gm) (Preparation 8) in methanol (30 mL). Stir the mixture at room temperature for 30 min. Add sodium cyanoborohydride (1 g) and stir the mixture for 2 h. Heat the reaction mixture at 50° C. for 2 h. Dilute the reaction mixture with ethyl acetate (50 mL) and wash the mixture with water (50 mL). Dry ethyl acetate layer over sodium sulfate and concentrate on rotary evaporator to give a crude. Purify the crude by silica flash chromatography eluting with a gradient of 0-5% methanol in DCM to give the product as a mixture of diastereomers, 3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one (4.5 gm). MS: m/z=470 (M+1).