Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH2:7][CH2:8][CH3:9].[C:19](=[O:21])=[O:20].CCOCC>C1COCC1>[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([F:18])[C:14]([C:19]([OH:21])=[O:20])=[C:15]([F:17])[CH:16]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1cc(F)cc(F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOc1cc(F)c(C(=O)O)c(F)c1

Procedure:
A solution of n-butyllithium (10.5M in hexane; 3.60 ml, 0.038 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 16 (7.00 g, 0.038 mol) in dry THF (35 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and then poured onto a slurry of solid carbon dioxide and dry ether. The product was extracted into 10% sodium hydroxide which was then acidified with 36% hydrochloric acid. The product was filtered off and dried (CaCl2) in vacuo to give a colourless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)=[O:34])=[CH:22][CH:21]=1
Reactant: COc1ccc(N(C)C(=O)CN(C(=O)CN)c2ccccc2)cc1
Reactant: Cc1cccc(N=C=O)c1
Product: COc1ccc(N(C)C(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)cc1
Yield: 37.5 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.9 g of 2-(2-amino-N-phenylacetamido)-N-(4-methoxyphenyl)-N-methylacetamide and 0.77 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: ethyl acetate/cyclohexane (80-20 by volume)], collecting 20 cm3 fractions. Fractions 14 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from acetonitrile, 1.0 g of N-(4-methoxyphenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 202° C. is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:20])=[CH:9][C:10]=2[Cl:19])[N:5]=1)([OH:3])=[O:2].[H][H]>C(O)C.[Pt]=O>[C:1]([C@H:4]1[CH2:13][C@@H:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:20])=[CH:9][C:10]=2[Cl:19])[NH:5]1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(C(=O)O)nc2cc(Cl)cc(Cl)c12
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Yield: 55.5 %

Procedure:
2-Carboxy-5,7-dichloro-4-ethoxycarbonylquinoline (1.6 g) was dissolved in ethanol (100 ml) and platinum oxide (0.16 g) was suspended in the solution. The reaction mixture was stirred under one atmosphere pressure of hydrogen for 1 h at ambient temperature, then filtered and concentrated in vacuo. Chromatography on SiO2 with 2.5% methanol, 0.5% acetic acid and 97% dichloromethane gave, as a colourless solid, cis-2-carboxy-5,7-dichloro-4-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.9 g, m.p. 160°-162° C.); δ (360 MHz, DMSO), 1.15 (3H, t, J=7.1 Hz, CH3CH2), 2.17 (1H, m, CHACHBHCCHD), 2.52 (1H, m, CHACHBHCCHD), 3.85 (1H, dd, J=7.1 and 3.1 Hz, CHACHBHCCHD), 3.98 (3H, m, CH3CH2 and CHACHBHCCHD), 6.65 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.70 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.87 (1H, br, s, NH); m/e 317 (M+), 198 (100%, M-CO2H, CO2Et and H); Found: C, 49.12; H, 4.18; N, 4.27. C13H13Cl2NO4 requires C, 49.08; H, 4.22; N. 4.40%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2cccc(Cl)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cccc(Cl)c2s1

Procedure:
Methyl 7-chlorobenzo[b]thiophene-2-carboxylate (3 g, 13 mmol) was dissolved is ethanol (15 mL) and treated 5 N sodium hydroxide (5 mL). The reaction was heated at reflux overnight. The volatiles were removed in vacuo and the aqueous residue was acidified to pH 2 using 5 N HCl. The resulting white solid was filtered off, washed well with water and dried in a vacuum oven at 60° C. Yield=2.6 g. MS (M−H)-210.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33]CN(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:33][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH:24]=2)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2c1c(CCN(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Yield: 68 %

Procedure:
To a solution of (S)-3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (700 mg, 2.5 mmol) in DMF (50 mL) were added (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-amine iodide salt (1.3 g, 3.8 mmol) and K2CO3 (700 mg, 5.1 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 4 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product (S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (737 mg, 67%) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:26]3[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]3)=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1CCNCC1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: CC1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)CC1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (200 mg) and 4-methylpiperidine (2 ml) was heated at 120° C. for 8 h to obtain 40 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(4-methylpiperidin-1-yl)ethanone after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COCCCN
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Solvent: C1COCCO1
Product: COCCCNc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A mixture of 2,4-dichloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (60 mg, 0.2 mmol) and 3-methoxypropylamine (89 mg, 1.0 mmol) in dioxane (5 ml) was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol/dichloromethane in a volume ratio of 1:80, affording the pure title compound (69 mg, yield 99%) as a white solid which was characterised as follows: MS (m/z): 347 ([M+H]+, 100).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>C1(C)C=CC=CC=1>[C:1]([NH:26][CH2:25][CH2:24][N:23]([CH2:27][CH3:28])[CH2:21][CH3:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCN(CC)CCN
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)NCCN(CC)CC

Procedure:
142.24 (0.5 mole) stearic acid and 58.09 g (0.5 mole) 2-diethylaminoethylamine are heated in toluene to produce 0.5 mole stearamidoethyl diethylamine. 76.53 g (0.2 mole) of the stearamidoethyl diethylamine are then reacted with 49.60 g (0.1 mole) 1,12-dibromoheptaethylene glycol to yield compound FF, N,N'di(stearamidoethyl)-N,N,N',N'-tetraethyl-1,12(3,6,9,12,15-pentaoxadodecylene)diammonium dibromide of the formula: ##STR15##
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10])[OH:8].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:15]([O:8][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[OH:10])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Oc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium carbonate (63.6 g) was added to a solution of pyrocatechol (55 g) in water (230 mL), and to the resulting mixture was added dropwise benzoyl chloride (58 mL) over a period of 2 hours with vigorous stirring. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was acidified carefully by dropwise addition of 2N hydrochloroic acid (350 mL) and then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate (100 mL) and n-hexane (400 mL) to give the title compound (64.6 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34]C)=[O:33]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)[C:11]([F:13])([F:14])[F:12])[O:8][C:28]1[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:26]([F:25])[CH:27]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(c1ccc(Oc2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 151, step 7) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine. The product of this reaction was hydrolyzed in analogy to Example 141 to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=498.1 [M−H+].
Reaction SMILES: [I:1][C:2]1[C:19](O)=[N:18][C:5]2[CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:23]>CN(C=O)C>[Cl:23][C:19]1[C:2]([I:1])=[CH:3][C:4]2[CH:10]([CH3:11])[CH2:9][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:7][CH2:6][C:5]=2[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(I)cc21
Solvent: CN(C)C=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2nc(Cl)c(I)cc21
Temperature: 100 °C
Yield: 40 %

Procedure:
A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (137 mg, 342 μmol), DMF (100 μl) and POCl3 (5 ml) was heated at 100° C. for 16 h. The reaction mixture was concentrated in vacuo and purified by column chromatography to furnish 57.0 mg (40%) of 2-chloro-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 419.1/421.1. A mixture of 2-chloro-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (58.0 mg, 139 μmol), K2CO3 (50 mg) and MeOH (10 ml) was heated for 1 h at 60° C. The reaction mixture was concentrated in vacuo and purified by column chromatography furnishing 37.7 mg (84%) of 2-chloro-3-iodo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 3.13 (m, 2H), 3.07-2.92 (m, 4H), 2.75 (dd, 1H), 1.33 (d, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:18][C:15]1[CH:14]=[C:3]2[C:2](=[CH:17][CH:16]=1)[N:1]=[C:21]([CH2:20][Cl:19])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:4]2=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2cc(Cl)ccc2nc(CCl)n1-c1ccccc1Cl
Yield: 91.8 %

Procedure:
Prepared according to Procedure B with 1d (500 mg, 1.78 mmol) and chloroacetyl chloride (0.42 mL, 5.33 mmol) in acetic acid (10 mL). Purified by recrystallization from isopropanol to afford 555 mg of a yellow solid (92%). 1H NMR (CDCl3) δ: 8.27 (d, J=1.9 Hz, 1H); 7.74-7.78 (m, 2H); 7.60-7.66 (m, 1H); 7.48-7.57 (m, 3H); 4.37 (d, J=12 Hz, 1H), 4.07 (d, J=12 Hz, 1H). MS (ES): m/z 339.0 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(OC)c2)cc1

Procedure:
The colourless oil (E)-ethyl 3-(3′-methoxy-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (example 50a) and 3-methoxyphenyl boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=[CH:12]2)[C@@H:6]1[O:22][C:23](=[O:25])[CH3:24])(=[O:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=[C:12]2[Br:26])[C@@H:6]1[O:22][C:23](=[O:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](n2cnc3cc(Cl)c(Cl)cc32)CCC[C@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)CCC[C@H]1OC(C)=O

Procedure:
(±)-(1R*,2S*,3R*)-3-(5,6-Dichloro-1H-benzimidazol-1-yl)-1,2-cyclohexanediyl diacetate (part b of this example, 1.58 g, 4.10 mmol) was dissolved in dry N,N-dimethylformamide (6.4 ml) and maintained at 65° C. under nitrogen while N-bromosuccinimide (1.46 g, 8.2 mmol) was added in 2 portions over 1 h. Volatiles were evaporated in vacuo and the residue was chromatographed on silica gel. Title compound was eluted with ethyl acetate as an off-white powder (0.95 g, 49%), m.p. 71-79° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[N:4][C:3]=1[C:10]1[N:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.C(OC(=O)[NH:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C:28]([F:33])([F:32])[C@@H:27]1[NH2:34])(C)(C)C>ClCCl>[NH2:25][C@@H:26]1[C@@H:27]([NH:34][C:7]([C:5]2[S:6][C:2]([Cl:1])=[C:3]([C:10]3[N:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:13]4=[N:12][CH:11]=3)[N:4]=2)=[O:8])[C:28]([F:33])([F:32])[CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC(F)(F)[C@@H]1N
Reactant: O=C(Cl)c1nc(-c2cnc3cccnn23)c(Cl)s1
Solvent: ClCCl
Product: N[C@H]1CCCC(F)(F)[C@@H]1NC(=O)c1nc(-c2cnc3cccnn23)c(Cl)s1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
5-Chloro-4-(imidazo[1,2-b]pyridazin-3-yl)-1,3-thiazole-2-carbonyl chloride (59.5 mg, 0.199 mmol) and tert-butyl[(1S,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (54.8 mg, 0.219 mmol) were dissolved in dry dichloromethane (3 mL). The reaction mixture was left to stir at room temperature for 42 h. After consumption of the starting material, trifluoroacetic acid (2 mL) was added to the reaction mixture and left to stir at room temperature for 2 h. The solution was then concentrated and the residue purified by prep HPLC. The compound was neutralized by taking the fractions and adding an aqueous saturated sodium bicarbonate solution and extracting three times with ethyl acetate. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.73 (d, 1H); 8.66 (s, 1H); 8.24 (d, 1H); 7.45 (dd, 1H); 4.05 (m, 1H); 2.85 (m, 1H); 2.08 (m, 1H); 1.22-2.08 (m, 6H). LRMS (APCI) calc'd for (C16H15ClF2N6OS) [M+H]+, 413.1. found 413.0.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:27])[F:26])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[CH2:28]([C:30]1[CH:34]=[N:33][N:32]([CH3:35])[C:31]=1[NH2:36])[CH3:29]>>[CH2:28]([C:30]1[CH:34]=[N:33][N:32]([CH3:35])[C:31]=1[NH:36][C:11]([C:13]1[C:21]2[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=2[C:16]([O:24][CH:25]([F:26])[F:27])=[CH:15][CH:14]=1)=[O:12])[CH3:29]
Reactant: CCc1cnn(C)c1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(CC)cnn3C)c2o1

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (100 mg) and 4-ethyl-2-methyl-2H-pyrazol-3-ylamine (64 mg). Purification by column chromatography on silica eluting with 5% methanol in dichloromethane afforded the title compound as an off white solid (55 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1.[CH3:31][C:32]1([CH3:39])[CH2:37][CH2:36][CH:35](O)[CH:34]=[CH:33]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:31][C:32]1([CH3:39])[CH2:37][CH2:36][CH:35]([N:21]2[C:22](=[O:29])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20]2=[O:30])[CH:34]=[CH:33]1
Reactant: CC1(C)C=CC(O)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)C=CC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C
Yield: 42.8 %

Procedure:
Resin supported triphenylphosphine (32.7 g, 106 mmol), isoindoline-1,3-dione (17.19 g, 117 mmol), and 4,4-dimethylcyclohex-2-enol (13.4 g, 106 mmol) were combined and THF (197 mL) was added. The mixture was stirred and cooled to 0° C., then diisopropyl azodicarboxylate (21.09 mL, 107 mmol) was added drop-wise over 2 min. The reaction was stirred and allowed to warm slowly to ambient temperature overnight. The reaction mixture was filtered and then concentrated to a yellow solid under reduced pressure. Ethyl acetate (200 mL) was added and the resulting solids were filtered off again. The ethyl acetate filtrate was washed with water (100 mL), the aqueous layer extracted with ethyl acetate (100 mL), the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil that was purified by silica gel chromatography (0-20% ethyl acetate/hexane) to afford 2-(4,4-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (11.59 g, 45.4 mmol, 42.8% yield) as an oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (s, 4H), 5.51-5.62 (m, 1H), 5.43 (d, J=10.15 Hz, 1H), 4.59-4.74 (m, 1H), 2.14-2.30 (m, 1H), 1.67-1.81 (m, 1H), 1.44-1.68 (m, 2H), 1.09 (s, 3H), 1.01 (s, 3H); MS (ESI) m/z 256.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCC>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.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](=[O:19])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)Cl)CC1)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=C(N[C@H]1CC[C@H](C(=O)c2ccccc2)CC1)OCc1ccccc1

Procedure:
Under argon atmosphere, a mixture comprising 1.0 g trans-4-(benzyloxycarbonylamino)cyclohexanecarbonyl chloride, 1.92 g of tributylphenyltin, 61 mg of dichlorobis-(triphenylphosphine)palladium and 10 mL of dioxane was stirred at 110° C. for 12 hours. After cooling, the reaction mixture was concentrated by a centrifugal concentrator, and then, the residue was dissolved in tetrahydrofuran and evaporated to dryness with 5 g of silica gel. The resulting residue was purified by silica gel flash chromatography (solvent: ethyl acetate-hexane (1:2) to (1:1) to obtain 883 mg of N-benzyloxycarbonyl-trans-4-benzoylcylohexylamine.
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5]Br.CN1CCCC1=[O:17]>O>[Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5][OH:17]
Reactant: CN1CCCC1=O
Reactant: FC(F)(Br)C(F)(Cl)CCBr
Solvent: O
Product: OCCC(F)(Cl)C(F)(F)Br
Temperature: 130 °C
Yield: 49 %

Procedure:
A mixture of 1,4-dibromo-2-chloro-1,1,2-trifluorobutane (XVI) (7.5 g, 24.6 mmol), 1-methyl-2-pyrrolidinone (14 mL) and water (2.5 mL) was heated at 130° C. for 16 hours. The mixture was cooled to room temperature, diluted with water (80 mL) and extracted with ether (2×75 mL). The ether extract was washed with water (31×40 mL), brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was chromatographed over silica gel to give 2.9 g (49%) of the desired alcohol as a clear oil.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11](C4C=CC=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28]([O:30][C:31]1[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH3:29]>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11]([C:33]4[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH2:28][CH3:29])[CH:32]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Reactant: C[C@@H](Oc1cc(-c2ccccc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: CCOc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)ccc1OC
Yield: 42.7 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-phenyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (106.3 mg, 0.411 mmol) as a starting material to afford 51.0 mg (42.7%) of (R)-4-((R)-1-((1-cyclopropyl-5-(3-ethoxy-4-methoxyphenyl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.058 (s, 1H), 7.576 (s, 1H), 7.367 (d, J=1.2 Hz 1H), 7.184 (s, 1H), 7.155 (d, J=1.8 Hz, 1H). 6.99 (t, J=4.4 Hz 2H), 4.84 (t J=5.9 Hz, 1H), 4.11 (dd, J=7.2, 6.6 Hz, 2H), 3.768 (s, 3H), 3.709-3.637 (m, 1H), 3.38 (t, J=9 Hz, 1H) 3.18 (dd, J=6.9, 9.3 Hz, 1H), 2.83-2.75 (m, 1H), 2.379-2.207 (m, 2H), 1.358-1.282 (m, 6H), 1.125-1.00 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H29N3O4:435.22; found 436.18.