Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C:12]([CH3:28])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[CH2:13][OH:14]>N1C=CC=CC=1>[C:2]([O:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]([CH3:28])([CH3:11])[CH2:13][O:14][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(CO)CCCCCCCCC(C)(C)CO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(CCCCCCCCC(C)(C)COC(=O)c1cccnc1)COC(=O)c1cccnc1
Yield: 50.5 %

Procedure:
53.10 Grams (0.3 mole) of nicotinoyl chloride hydrochloride in 150 ml of anhydrous pyridine were reacted with 12.90 grams (0.05 mole) of 2,2,11,11-tetramethyl-1,12-dodecanediol according to the procedure of the above example. 11.8 Grams of the title product, recrystallized from an 80/20 (v/v) mixture of ethanol/water, were obtained, having m.p. 66°-67° C. Yield: 50.5% of theoretical.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][C:15]3=[O:18])=[CH:11][CH:10]=2)O1.I[C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][N:28]=[CH:29][C:22]=12.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O>[NH:27]1[C:23]2=[N:24][CH:25]=[CH:26][C:21]([C:9]3[CH:17]=[C:16]4[C:12]([CH2:13][CH2:14][C:15]4=[O:18])=[CH:11][CH:10]=3)=[C:22]2[CH:29]=[N:28]1
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)CC3)OC1(C)C
Reactant: Ic1ccnc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCc2ccc(-c3ccnc4[nH]ncc34)cc21
Yield: 56 %

Procedure:
To a mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (3 g, 11.6 mmol) and 4-iodo-1H-pyrazolo[3,4-b]pyridine (3.13 g, 12.8 mmol) in DME (20 mL) was added aq. sodium carbonate (2M, 11.62 mL, 23.2 mmol) followed by tetrakistriphenylphosphine palladium (978 mg, 0.846 mmol). The mixture was microwaved for 90 min at 150° C. The reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic layer was filtered off since it contained a yellow precipitate (desired prod ca. 85% pure) and then it was washed with water and then dried (MgSO4), filtered and concentrated and added to the precipitate above. The solids were recrystallised from boiling MeOH-THF to provide the pure ketone (1.62 g, 56%) as a yellow solid.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:8][C:6](=[O:7])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].C([N:15](CC)CC)C.[OH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[OH:30])[CH2:24][CH2:25][NH2:26]>CO>[O:7]=[C:6]([NH2:15])[C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:8])[OH:11])[OH:10])[OH:9].[NH2:26][CH2:25][CH2:24][C:23]1[CH:27]=[CH:28][C:29]([OH:30])=[C:21]([OH:20])[CH:22]=1
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCN(CC)CC
Agent: NCCc1ccc(O)c(O)c1
Solvent: CO
Product: NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 48.6 %

Procedure:
Gluconolactone (1.9 gm, 10.5 mmol) and triethylamine (TEA; 1.1 gm, 10.5 mmol) were added to methanol (25 mL) in a 100 mL round bottom flask with stirring. The gluconolactone was allowed to dissolve. When the solid was dissolved, the solution was stirred for an additional 10 minutes and then 3-hydroxytyramine (2.0 gm, 10.5 mmol) was added slowly, i.e., allowing it to dissolve. The reaction mixture was stirred in the dark for about 2 hrs. during which time a white solid precipitant appeared. The white solid precipitant was collected by filtration, washed with methanol (5 mL) and dried in vacuo for 6 hrs. to give dopamine gluconamide (1.69 gm, 5.10 mmol, 48.6% yield). Melting point of the synthesis product was 154-155° C. Predicted: C14H21N1 (331.32): C, −50.75%; H, −6.39%; N, −4.23%; analysis results of synthetic product: C, 50.65; H, 6.63; N, 4.44.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:41]([NH2:43])=[O:42])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([NH:36][CH2:37]C(C)C)[CH3:35])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:44][CH:45](C)[CH2:46]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:41]([NH2:43])=[O:42])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([N:36]5[CH2:37][CH2:46][CH2:45][CH2:44]5)[CH3:35])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CC(C)CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C(C)NCC(C)C)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C(C)N5CCCC5)c4)cc23)CC1
Yield: 71 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl)-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (101 mg, 1.98 mmol) for (2-methylpropyl)amine to afford 29.2 mg of the title compound (71%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([CH:7]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)CCc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CCc2cccc(F)c2)C1
Yield: 48 %

Procedure:
tert-Butyl 3-(3-(3-fluorophenyl)propanoyl)-4-oxopiperidine-1-carboxylate (285 mg, 48%) was synthesised from tert-butyl 4-oxopiperidine-1-carboxylate and 3-(3-fluorophenyl)propanoyl chloride according to the general procedure for the preparation of diketones. MS (ES+) m/z 250 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[C:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([OH:11])[C:5]=2[CH:4]=1)[CH3:2].[CH:37](N(C(C)C)CC)(C)C.CO.C[Si](C=[N+]=[N-])(C)C>C(#N)C>[CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[C:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([O:11][CH3:37])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(O)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: CCc1cc2c(OC)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a mixture of 4′-{[2-ethyl-4-hydroxy-6-oxo-5-(2-phenylethyl)thieno[2,3-b]pyridin-7(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), diisopropylethylamine (0.72 mL), methanol (2 mL) and acetonitrile (18 mL) was added trimethylsilyldiazomethane (2M hexane solution, 0.72 mL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.28 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][CH:12]([N:15]3[C:19]([CH3:20])=[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[N:17]=[N:16]3)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:29][C:30]([O:32]CC)=[O:31].[Li+].[OH-]>C1COCC1.CO.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][CH:12]([N:15]3[C:19]([CH3:20])=[C:18]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[N:17]=[N:16]3)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)Cc1c2n(c3c(F)cccc13)CC(n1nnc(Cc3ccc(F)cc3)c1C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccc(F)cc2)nnn1C1CCc2c(CC(=O)O)c3cccc(F)c3n2C1
Reaction time: 8 h

Procedure:
The racemic ethyl {4-fluoro-7-[4-(4-fluorobenzyl)-5-methyl-1H-1,2,3-triazol-1-yl]-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl}acetate (as described in Example 36) was hydrolyzed to the final acid product by dissolving in 1:1:1 THF/MeOH/water (0.06 M), treating with LiOH (3.6 eq.) and stirring overnight. The reaction mixture was then diluted with EtOAc, extracted with 2 N HCl, water, dried (Na2SO4), and concentrated to provide the title compound: MS (EI) calc'd for C24H23F2N4O2 [M+1]+437.2, found 437.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7]2.[C:15](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc2cccc(Br)c2n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 8-bromoquinoline-2-carboxylic acid (Princeton Biomolecular Research, Monmouth Junction, N.J.; 2.65 g, 10.51 mmol) in DCM (25 mL) at 0° C. was treated with oxalyl chloride, 2.0 M solution in DCM (10.51 mL, 21.0 mmol), followed by 12 drops of DMF. The ice bath was removed, the mixture was stirred at RT for 1 h, becoming completely soluble during that time. The reaction mixture was then concentrated in vacuo and the residue was dissolved in DCM (50 mL) and cooled to 0° C. MeOH (1.7 mL, 42.1 mmol) and TEA (1.7 mL, 12.6 mmol) were added, the ice bath was removed, and the mixture was stirred at RT for 1 h. The reaction mixture was then diluted with DCM (50 mL), washed sequentially with 0.5 N HCl (25 mL), water (25 mL), 0.5 N NaOH (25 mL) and brine (25 mL), then dried over MgSO4, filtered, and concentrated to give methyl 8-bromoquinoline-2-carboxylate as a brown oil. This material was used without further purification, assuming the theoretical yield: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (d, J=8.4 Hz, 1H), 8.24 (d, J=7.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 3.98 (s, 3H). m/z (ESI, +ve ion) 266.0/268.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:54](#[N:56])C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N.CN(C=O)C>[C:54]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:24])[CH3:25])[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1)#[N:56]
Reactant: CC#N
Reactant: CC(C)[Si](OCCC(CN(C)C(=O)OC(C)(C)C)c1ccc(Br)cc1)(C(C)C)C(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCC(CN(C)C(=O)OC(C)(C)C)c1ccc(C#N)cc1)(C(C)C)C(C)C
Yield: 41 %

Procedure:
tert-Butyl {2-(4-bromophenyl)-4-[(triisopropylsilyl)oxy]butyl}methylcarbamate (1.16 g, 2.25 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.62 g, 0.68 mmol) and tri-o-tolylphosphine (1.03 g, 3.38 mmol) were mixed together with acetonitrile (3 mL) and DMF (3 mL) under argon. Zinc cyanide (0.16 g, 1.35 mmol) was added and the mixture was stirred at 81° C. for 24h and then concentrated. Ethyl acetate was added to the residue and the slurry was filtered through a micro filter. The solvent was removed by evaporation and the residue purified by flash chromatography (hexane-ether, 10:1). There was obtained 0.43 g, (41%) of tert-butyl {2-(4-cyanophenyl)-4-[(triisopropylsilyl)oxy]butyl}-methylcarbamate as a solid. 1H NMR (300 MHz, CDCl3): 0.9-1.1 (m, 21H), 1.4 (s, 9H), 1.7-1.9 (m, 2H), 2.7 (m, 3H), 3.2-3.6 (m, 5H), 7.3-7.4 (m, 2H), 7.5-7.6 (m, 2H); MS: m/z 361 (M+1)+.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc([N+](=O)[O-])c1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of (S)-[(3-nitro-benzyl)-tert-butoxycarbonyl-amino]-phenyl-acetic acid cyclopentyl ester (1.509 g, 3.32 mmol) in ethanol (10 ml) was added palladium on carbon (10%, 0.38 g, 0.36 mmol). The flask was evacuated and back-filled with hydrogen gas. The mixture was stirred overnight, then filtered through Celite, washed with ethanol (150 ml) and then concentrated to yield the desire product as a colourless oil (1.351 g, 96% yield). 1H NMR (300 MHz, CDCl3), δ: 7.19-7.42 (5H, m), 6.97 (1H, t, J=7.5 Hz), 6.46 (2H, dd, J=8.1, 16.5 Hz), 6.29 (1H, br s), 5.58 (1H, br s), 5.29 (1H, br s), 4.69 (1H, br s), 4.00 (1H, d, J=15.9 Hz), 3.74 (1H, q, J=6.9 Hz), 3.51 (2H, br s), 1.20-2.00 (17H, m)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH3:17][N:18]1[C:22]2[C:23]([CH3:38])=[CH:24][C:25]([C:27]([C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31](F)[CH:30]=3)=[O:28])=[CH:26][C:21]=2[O:20][C:19]1=[O:39]>CN(C=O)C>[CH3:17][N:18]1[C:22]2[C:23]([CH3:38])=[CH:24][C:25]([C:27]([C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:30]=3)=[O:28])=[CH:26][C:21]=2[O:20][C:19]1=[O:39]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2ccc(C#N)c(F)c2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2ccc(C#N)c(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12
Temperature: 300 °C

Procedure:
0.26 g (1.2 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 93 mg (0.30 mmol) 4-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-2-fluoro-benzonitrile were combined and heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[NH:10][C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](I)[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:22][CH3:23])[C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)OC(C)(C)C)CC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
A suspension of 3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3.645 g, 12.51 mmol), ethyl iodide (2.01 mL, 25.02 mmol) and Cs2CO3 (8.153 g, 25.02 mmol) in acetonitrile (35 mL) was stirred at room temperature for 6 hrs. The reaction mixture was evaporated to dryness, the residue dissolved in water and extracted with DCM. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The solid residue was washed with n-hexane and dried in vacuum. The desired compound (3.50 g, 88%) was obtained as white crystalline powder.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Cl)(OC(C)(C)C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:27](=[O:46])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][CH:36]2[C:45]3[N:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH2:39][CH2:38][CH2:37]2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([NH:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[O:46])=[CH:29][CH:30]=1)[CH:36]1[C:45]2[N:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:39][CH2:38][CH2:37]1
Reactant: O=C(NCc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NCc1ccccn1)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 28.4 %

Procedure:
N-BOC-chloromethyl benzimidazole (215 mg, 0.84 mmol), N-Pyridin-2-ylmethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzamide (AMD9363) (300 mg, 0.84 mmol), and K2CO3 (346 mg, 2.50 mmol) were heated to reflux in CH3CN (4 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, then brine, and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, followed by radial chromatography on silica gel (1 mm plate, 3:3:94 CH3OH—NH3 H2O—CH2Cl2,), afforded the free base of the title compound (120 mg, 28%) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reaction time: 0.33 h

Procedure:
A sample of crude 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (40.8 g, 0.14 mole) was dissolved in methylene chloride (300 mL). The solution was treated with oxalyl chloride (15.7 mL, 0.18 mole), followed by N,N-dimethylformamide (12 drops). Off-gassing began shortly after adding the N,N-dimethylformamide catalyst. The reaction mixture was stirred for about 20 minutes under ambient conditions, then was heated to reflux for a period of 35 minutes. Volatiles were removed by concentrating the reaction mixture on a rotary evaporator at a bath temperature of 55° C. The crude product, approximately 43 g of a light-yellow oil, was used directly in the next step.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:23][CH3:24])(=[O:22])[C@@H:19]([CH3:21])[OH:20].[CH:25]([O:27][CH2:28][CH3:29])=[CH2:26]>C(OCC)(=O)C>[CH2:25]([O:27][CH:28]([O:20][C@H:19]([CH3:21])[C:18]([O:23][CH3:24])=[O:22])[CH3:29])[CH3:26]
Reactant: COC(=O)[C@@H](C)O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 139 %

Procedure:
A catalytic amount of pyridinium para-toluenesulfonate was added to 20.8 g (0.2 mole) of methyl (R)-(-+)-lactate (98.9% e.e) and 18.7 g (0.26 mole) of ethyl vinyl ether. The resulting mixture was stirred at room temperature for 6 hours. After the reaction, thereto was added 100 ml of ethyl acetate, followed by washing with 70 ml of a saturated aqueous sodium hydrogen carbonate solution, 70 ml of water and 70 ml of a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 49.0 g (yield: 97.8%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][N:21]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH2:22]4)=[CH:17][CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39].[ClH:40]>O1CCOCC1>[ClH:40].[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][N:21]([CH2:25][C:26]([OH:28])=[O:27])[CH2:22]4)=[CH:17][CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39]
Reactant: COCc1cc(-c2nc(-c3ccc4c(c3)CN(CC(=O)OC(C)(C)C)CC4)no2)ccc1-c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3ccc4c(c3)CN(CC(=O)O)CC4)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
tert-butyl [7-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}-3,4-dihydroisoquinolin-2(1H)-yl]acetate obtained from step 1 was dissolved in HCl in dioxane (4M, 10 mL), stirred at rt for 30 hours. Solvents were removed under vacuum, Et2O added and the solid residue filtered after which solid was triturated in hot CH3CN and filtered to give the title compound as a light green powder. 1H NMR (DMSO-d6) δ 8.32 (m, 1H), 8.17-8.15 (m, 1H), 8.04-8 (m, 2H), 7.49 (d, J=8.1 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.36-7.27 (m, 3H), 7.15-7.13 (m, 1H), 4.60 (bs, 2H), 4.24-4.13 (m, 4H), 3.60 (bs, 2H), 3.25-3.22 (m, 5H), 2.03 (s, 3H). HPLC (Method A) Rt 4.47 min (Purity: 93.4%). LC/MS (method B): 470.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=4)[CH:11]=3)=[CH:7][C:6]=2[CH:22]=1.[C:23](Cl)(=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=4)[CH:11]=3)=[C:7]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C:6]=2[CH:22]=1
Reactant: COc1ccc2cc(-c3cc4cc(Cl)ccc4o3)ccc2c1
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccc(Cl)cc12
Yield: 89.1 %

Procedure:
Following the procedure described in Step 2 of Example 1, the title compound was prepared by the acylation of 5-chloro-2-(6-methoxy-naphth-2-yl)-1-benzofuran (6.6 g, 21.37 mmol), with valeryl chloride (2.3 mL, 16 mmol) in presence of tin (IV) chloride in chloroform. Purification by flash chromatography on silica gel using 2.5% ethyl acetate in hexane as the mobile phase yielded the title compound as a white solid (5.6 g), mp 119-120° C. Mass spectrum (+ESI, [M+NH4]+) m/z 410. 1HNMR (400 MHz, DMSO-d6): δ8.36 (d, 1H, J=1.6 Hz), 8.02 (dd, 2H, J=7.0, 2.2 Hz), 7.99 (s, 1H), 7.81 (dd, 1H, J=8.6, 1.7 Hz), 7.77 (d, 1H, J=8.8 Hz), 7.48-7.44 (m, 2H), 7.27 (dd, 1H, J=8.8, 2.3 Hz), 3.92 (s, 3H), 2.69 (t, 2H, J=7.3 Hz), 1.51 (m, 2H), 1.1 (m, 2H), and 0.68 ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C24H21 ClO3: Calculated: C, 73.37; H, 5.39; N, 0.00. Found: C, 73.34; H, 5.27; N, 0.03.