Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([O:9]C)[CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([OH:9])[CH:8]=1
Reactant: CCOC(=O)Cc1cc(OC)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(O)cc(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3,5-dimethoxyphenylacetate (11.0 g, 52,32 mmol) in 200 ml of CH2Cl2 is added 75 ml (25 mmol, 1.4 eq) of 1.0M BBr3 in CH2Cl2. This is then refluxed for 36 hours. The mixture is concentrated in vacuo, then partitioned between EtOAc and HCl. The organics are dried (MgSO4) and concentrated in vacuo. This is then redissolved in EtOH and HCl is bubbled in for 5 minutes and then stirred overnight at room temperature. The mixture is concentrated in vacuo, then partitioned between EtOAc and saturated NaHCO3 solution. The organics are dried (MgSO4) and concentrated in vacuo. This is then chromatographed using silica gel and eluted with Et2O. The filtrate is concentrated in vacuo to obtain ethyl 3,5-dihydroxyphenylacetate which is confirmed by NMR and used directly in the next step.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42]>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:42][CH2:41][C:40]4[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=4[CH3:38])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: Cc1ccccc1CN
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccccc4C)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-methylbenzylamine, m.p. 204° C. MS [(+)ESI), m/z]: 556 [M+H]+ Anal. Calcd for C36H33N3O3: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.73; H, 5.95; N, 7.55.
Reaction SMILES: COC1C(OCOC)=C(OC)C(OC)=C(OCOC)C=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[C:31]([O:32]COC)=[C:30]([O:36][CH3:37])[C:29]([CH2:38][CH2:39][O:40]COC)=[C:28]([O:44]COC)[C:27]=1[O:48][CH3:49].O1CCCC1.C(O)(C)C.Cl>O1CCCC1.C(O)(C)C>[CH3:49][O:48][C:27]1[C:28](=[O:44])[C:29]([CH2:38][CH2:39][OH:40])=[C:30]([O:36][CH3:37])[C:31](=[O:32])[C:26]=1[CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: COCOCCc1c(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(OC)c(OCOC)c2OC)c(OC)c1OCOC
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCCCCC1=C(OC)C(=O)C(CCO)=C(OC)C1=O
Reaction time: 12 h

Procedure:
503 Milligrams of 1-[2,4,5-trimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[ 2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(2-methoxymethyloxyethyl)phenyl]pentane was dissolved in a mixed solvent of 5 ml of tetrahydrofuran with 5 ml of isopropanol, to this solution was added 1 millilter of tetrahydrofuran-isopropanol (1:1) solution of 20%-hydrogen chloride, and the whole mixture was stirred for 12 hours. After concentrated the reaction mixture, the residue was treated by an azeotropic distillation with benzene, then dissolved in 8 ml of methanol, further a small amount of sodium hydrogen carbonate was added thereto, and oxygen gas was blown into the solution. 2 Hours later, the solution was concentrated, and 50 ml of dichloromethane was added, then washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After concentrated, the residue was recrystallized from diethyl ether to obtain 123 mg of 2-(2,5,6-trimethoxy)-1,4-benzoquinon-3-yl)-5-[2,5-dimethoxy-6(2-hydroxyethyl)-1,4-benzoquinon-3-yl]pentane. Yellow crystals.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
10.0 g of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 10 ml of triethylamine were dissolved in 50 ml of dioxane, and the resulting mixture was cooled with ice. To the mixture was added 7.0 g of 2-methylbenzoyl chloride, and the resulting mixture was allowed to stand at room temperature for 30 minutes and then at 45° C. for 60 minutes. The crystals formed were filtered off, and the filtrate was concentrated under reduced pressure. The thus obtained oily residue was dissolved in 50 ml of ethanol by application of heat. After being cooled, the solution was inoculated, and there was obtained 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)-uridine) as crystals. Recrystallization of the product from ethanol afforded 11.3% (yield: 84.0%) of colorless prismatic crystals having a melting point of 108° to 109° C. The structure of the product was supported by the absorption spectra and elemental analysis.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]([N:32]=1)=[N:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:24][N:25]=2)=[O:15])(C(C)(C)C)(C)C.Cl>ClCCl>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]([N:32]=1)=[N:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:24][N:25]=2)=[O:15]
Reactant: CC(C)(C)[Si](C)(C)OCCCCNC(=O)Nc1ccc2ncc(-c3ccccc3)nc2n1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCCCO)Nc1ccc2ncc(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
360 mg (0.22 mmol) of 1-[4-(tert-butyldimethylsilanyloxy)butyl]-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea were dissolved in 20 ml of dichloromethane and admixed with 5 ml of a 2 molar isopropanolic HCl solution. After stirring at room temperature for 12 h, the reaction mixture was washed with water and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a bright yellow solid.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([N+:19]([O-])=O)=[C:14]2[O:18][CH:17]=[CH:16][C:15]=12)=[O:9]>C(OCC)(=O)C.C(O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([NH2:19])=[C:14]2[O:18][CH:17]=[CH:16][C:15]=12)=[O:9]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2occc12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c2occc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.1 %

Procedure:
Tin (II) chloride dihydrate (15.0 g, 66.5 mmol) was added to a suspension of 7-nitro-benzofuran-4-carboxylic acid methyl ester (4.82 g, 21.8 mmol) in ethyl acetate (80 mL) and ethanol (80 mL). The reaction mixture was stirred at room temperature for four days then partitioned between ethyl acetate and saturated aqueous solution of potassium carbonate. The organic extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane give 7-amino-benzofuran-4-carboxylic acid methyl ester (3.67 g, 88%). 1H NMR (CDCl3) δ: 3.92 (s, 3H), 6.60 (d, 1H, J=8.2 Hz), 7.34 (d, 1H, J=2.1 Hz), 7.67 (d, 1H, J=2.1 Hz), 7.84 (d, 1H, J=8.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[C:10](=[O:25])[N:11]([C:16]1[CH:17]=[N:18][C:19]([N+:22]([O-])=O)=[CH:20][CH:21]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[C:10](=[O:25])[N:11]([C:16]1[CH:17]=[N:18][C:19]([NH2:22])=[CH:20][CH:21]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(=O)N(c1ccc([N+](=O)[O-])nc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1C(=O)N(c1ccc(N)nc1)C2
Reaction time: 16 h
Yield: 55.3 %

Procedure:
Following nitro group reduction procedure 1, 3-(6-Nitro-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (290 mg, 0.83 mmol) in methanol (10 mL) with nitrogen, then added 10% palladium on charcoal (200 mg, excess). Purged with hydrogen and allowed to stir under hydrogen atmosphere for 16 hours. Purged with nitrogen and filtered through a pad of celite, washing with methanol. Concentrated in vacuo which gave 3-(6-Amino-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (146 mg, 60%). Used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J=2.6 Hz, 1H), 7.21 (dd, J=9.1, 2.6 Hz 1H), 6.43 (d, J=9.1 Hz, 1H), 6.01 (s, 2H), 4.38 (br. s, 1H), 4.26 (m, 1H), 3.77 (m, 1H), 3.30 (m, 1H), 2.17-2.07 (m, 2H), 2.02-1.95 (m, 2H), 1.43 (s, 9H); MS m/z 319.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9]1.C(OC([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C>>[CH2:30]([C@@H:25]1[NH:24][CH2:29][CH2:28][N:27]([C:2]2[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([O:7][C@H:8]3[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9]3)[CH:14]=2)[CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(Br)cc1O[C@H]1CCN(C)C1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Product: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1O[C@H]1CCN(C)C1

Procedure:
The title compound was prepared by the method outlined for Example 1 using (3S)-3-(5-Bromo-2-methoxyphenoxy)-1-methylpyrrolidine as the aryl halide and 2(S)-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component. The title compound was isolated as an orange oil. 1H NMR (MeOH-d4) 7.33-7.30 (m, 2H), 7.26-7.22 (m, 3H), 6.83 (d, J=9.2, 1H), 6.44 (m, 2H), 4.81 (m, 1H), 3.73 (s, 3H), 3.36-3.28 (m, 2H), 3.04 (m, 2H), 2.93-2.66 (m, 8H), 2.52-2.46 (m, 1H), 2.36 (s, 3H), 2.19 (m, 1H), 1.95 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)[CH:19]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C.CCOC(C)=O>[I:26][C:23]1[CH:22]=[CH:21][C:20]([N:18]2[CH:19]=[C:15]([CH2:14][NH:13][C:10]([C:7]3[CH:8]=[C:9]4[C:4]([CH:3]=[CH:2][NH:1]4)=[CH:5][CH:6]=3)=[O:12])[N:16]=[CH:17]2)=[CH:25][CH:24]=1
Reactant: NCc1cn(-c2ccc(I)cc2)cn1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-6-carboxylic acid (85 mg, 0.528 mmol), 4-aminomethyl 1-(4-iodophenyl)imidazole 1-2 prepared in Example 1 (136 mg, 0.455 mmol) and TEA (0.150 mL, 1.08 mmol) in DMF (4 mL), BOP (280 mg, 0.633 mmol) was added. After the mixture was stirred at room temperature overnight, water and EtOAc were added. The organic layer was separated, washed with 5% aq. NaHCO3, dried over Na2SO4, concentrated in vacuo to give N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide as a crude sample, which was used in the next reaction without further purification. MS 443.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][CH:9]([CH3:11])[CH3:10].COC1C=CC(C(C)CN([CH2:49][CH2:50][CH2:51][O:52][C:53]2[CH2:54][C:55](=[CH:59][C:60]([O:62][CH3:63])=[O:61])[CH:56]=[CH:57][CH:58]=2)CC2C=CC=C(C(F)(F)F)C=2Cl)=CC=1>>[C:12]1([CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:6][N:5]([CH2:49][CH2:50][CH2:51][O:52][C:53]2[CH2:54][C:55](=[CH:59][C:60]([O:62][CH3:63])=[O:61])[CH:56]=[CH:57][CH:58]=2)[CH2:4][C:3]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:23])([F:24])[F:25])[C:2]=2[Cl:1])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccc(OC)cc2)C1
Reactant: CC(C)CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Product: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(CC(C)C)c2ccccc2)C1
Yield: 34 %

Procedure:
The titled compound was prepared from N-(2-chloro-3-trifluoromethylbenzyl)-2-phenyl-4-methylpentylamine in 34% yield in the same manner as the preparation of N-(2-[4-methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in Example 188e. MS (ESI) 576 (MH+)
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[CH2:26]([O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([N+:52]([O-])=O)[C:42]=1[C:43](=[O:51])[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:37]([OH:39])=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:52][C:41]1[C:42]([C:43](=[O:51])[C:44]2[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=2)=[C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: Nc1cc(C(=O)O)cc(OCc2ccccc2)c1C(=O)c1ccc(Cl)cc1

Procedure:
By replacing in Example 1, step C, 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid with 3-benzyloxy-4-(4'-chlorobenzoyl)-5-nitrobenzoic acid and following the procedure described, 5-amino-3-benzyloxy-4-(4'-chlorobenzoyl)benzoic acid is obtained with a melting point of 196°-197° C.
Reaction SMILES: [CH:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:15])(=O)=O>C(Cl)Cl>[Cl:15][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:1]=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCCCC=O
Solvent: ClCCl
Product: CCCCCCCCC(Cl)C=O
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A mixture of 59 g of caprinaldehyde, 15 ml of methylene chloride and 52 g of sulfuryl chloride was stirred for 2 hours, refluxed for 1 hour and was then rectified to obtain 34.5 g of α-chlorocaprinaldehyde with a boiling point of 115°C at 12 mm Hg and a refractive index of nD27 = 1.4460. A mixture of 11.6 g of the said product, 10 g of ethyl γ-propargyl-β -ethoxy-crotonate and 42.2 ml of butyl lithium were reacted as in Step A of Example 2 to obtain 4.75 g of ethyl 3-oxo-8-hydroxy-9-chloro-6-heptadecynoate with a refractive index of nD22 = 1.4780.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].N1C=CC=CC=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(Cl)Cl>[O:12]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:27])=[O:26])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: Nc1ccc2c(c1)C(=O)CCO2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CCOc2ccc(NS(=O)(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 6-amino-2,3-dihydro-4H-chromen-4-one (330 mg, 2.02 mmol) in CH2Cl2 is treated with pyridine (1 mL) and benzenesulfonyl chloride (0.28 mL, 2.2 mmol), stirred at ambient temperature for 1 hour, poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is washed sequentially with dilute hydrochloric acid until the pH of the wash is <2 and a saturated solution of sodium bicarbonate, dried over MgSO4 and concentrated in vacuo to afford the title compound as a beige solid, 460 mg (74% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([CH:11]([O:27][CH3:28])[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2OS(C(F)(F)F)(=O)=O)=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:31]([O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[C:32]#[CH:33]>CN(C=O)C>[C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9](=[O:10])[CH:11]([C:12]2[C:13]([C:33]#[C:32][CH2:31][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[CH:14][CH:15]=[CH:16][C:17]=2[F:18])[O:27][CH3:28])=[CH:5][CH:4]=1)#[N:2]
Reactant: C#CCOC1CCCCO1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1OS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1C#CCOC1CCCCO1
Temperature: 100 °C

Procedure:
A suspension of (RS)-trifluoro-methanesulfonic acid 2-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-3-fluoro-phenyl ester (520 mg, example 279.1) in DMF (10 ml) was heated to 100° C. and treated with TEA (0.49 ml), tetrahydro-2-(2-propynyloxy)-2H-pyrane (0.33 ml) and Cu(I)I (18 mg). The reaction mixture was degassed by passing a stream of Argon through the reaction mixture. Then bis(triphenylphosphine)palladium(II)chloride (32 mg) was added. The reaction was heated for 6 hrs at 100° C. After cooling to rt, the mixture was concentrated. The residue was taken up in EtOAc and H2O. After filtration through a glass microfibre filter, phases were separated. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (cyclohexane=>cyclohexane/EtOAc 3:2) to give (RS)-N-(4-cyano-benzyl)-2-{2-fluoro-6-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-acetamide as off-white solid. MS 454.3 ([M+NH4]+)
Reaction SMILES: CC1(C)C(C=CC2CCC/C(=C/[CH:17]=[C:18]3/[C:19](C)(C)[C:20]4[C:25](N/3CCCCS(O)(=O)=O)=[CH:24][CH:23]=[CH:22][CH:21]=4)/C=2OC2C=CC(OCCCCNCC3OC(O)C(N)C(O)C3O)=CC=2)=[N+](CCCCS([O-])(=O)=O)C2C1=CC=CC=2.[NH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1.C(=O)(OCC=CC1C=CC=CC=1)OC>C1COCC1>[C:20]1([CH:19]([N:73]2[CH2:77][CH2:76][CH2:75][CH2:74]2)[CH:18]=[CH2:17])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C1CCNC1
Reactant: CC1(C)C(C=CC2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Agent: CC1(C)C(/C=C/C2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Agent: COC(=O)OCC=Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC(c1ccccc1)N1CCCC1
Reaction time: 10 h
Yield: 81 %

Procedure:
A stock solution containing [(COD)Ir(η2-L1)(L1)] (Ir-2) (13.8 mg, 0.0100 mmol) and [(COD)IrCl]2 (3.4 mg, 0.0050 mmol) in 1.0 mL of THF was prepared. From this solution, 0.10 mL was added to 0.40 mL of THF in a screw-capped vial with a small magnetic stirbar. Pyrrolidine (87.5 mg, 1.23 mmol) and methyl cinnamyl carbonate (183 mg, 0.950 mmol) were added to the reaction mixture by syringe. The reaction was conducted at room temperature for 10 h. 1H NMR analysis of the crude mixture indicated that the ratio of the branched to linear products was 99/1. The mixture was purified by flash column chromatography on silica gel (5% ethyl acetate in hexane) to give 148 mg (81%) of the title compound. HPLC analysis indicated that the enantiomeric excess of product was 98% [Daicel Chiralcel® OD-H (0.46 cm×25 cm); hexane/diethylamine=99.75/0.25; flow rate=0.6 mL/min; detection wave length=220 nm; TR=7.60 (minor), 8.10 (major) min]; =11.2 (major), 12.5 (minor) min]: [α]DRT=+85 (c 3.2, CHCl3); 1H NMR (400.13 MHz, CDCl3) δ 7.28-7.37 (m, 4H), 7.20-7.25 (m, 1H), 6.04 (ddd, J=17.2, 10.0, 8.8 Hz,1H), 5.20 (dd, J=17.2, 1.2 Hz, 1H), 5.00 (dd, J=10.0, 1.2 Hz, 1H), 3.58 (d, J=8.8 Hz, 1H), 2.45-2.54 (m, 2H), 2.33-2.42 (m, 2H), 1.76 (m, 4H); 13C NMR (100.5 MHz, CDCl3) δ 142.7, 141.0, 128.5, 127.6, 127.1, 115.1, 75.2, 53.0, 23.3.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:21])C(=O)C1>CN(C=O)C>[CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:12])([F:13])[F:11])[C:6]=1[Cl:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(F)(F)F)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCCc1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 5-butyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in DMF to yield the title compound.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:33])[NH:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:29]([O:28][C:26](=[O:27])[NH:25][CH2:24][CH2:23][NH:22][C:21](=[O:33])[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCN)cc1
Yield: 62.9 %

Procedure:
A suspension of 32 (0.9 g, 1.92 mmol) with 10% palladium on carbon (0.30 g, wet) in methanol (50 mL) was stirred for 2 h at room temperature under atmospheric pressure of hydrogen. The mixture was then filtered through a silica gel pad. The solvent was evaporated and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 33 (0.405 g, 63%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.08 (m, 2H), 1.37 (s, 9H), 1.58 (m, 2H), 2.52 (m, 2H), 3.28 (m, 2H), 6.91 (m, 1H), 7.27 (d, 2H), 7.74 (d, 2H), 8.39 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])=[CH:27][CH:26]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: CN(C)c1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-dimethylaminophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][S:2][CH:3]([S:6][CH3:7])[S:4][CH3:5].[Li]CCCC.Br[CH:14]1[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[CH:19]=[CH:18][CH:17]=[C:16]3[CH2:15]1>C1COCC1.CCCCCC>[CH3:1][S:2][C:3]([S:6][CH3:7])([S:4][CH3:5])[CH:15]1[C:16]2=[C:25]3[C:20](=[CH:19][CH:18]=[CH:17]2)[CH:21]=[CH:22][CH:23]=[C:24]3[CH2:14]1
Reactant: BrC1Cc2cccc3cccc1c23
Reactant: CSC(SC)SC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSC(SC)(SC)C1Cc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tris(methylthio)methane (22 g) was dissolved in THF (100 ml) under N2 at -78° C. 1.6 M BuLi in hexane solution (95 ml) was added slowly to yield a dense white precipitate. 1-Bromoacenaphthene (31.4 g) was dissolved in 20 ml of dry THF and added slowly to the above suspension to yield, after 10 minutes, a colorless solution. This was allowed to warm to room temperature, with the development of a brown color, and stirred overnight.