Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[N:59]1([CH2:65][CH2:66]O)[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][CH2:65][N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCCN1CCOCC1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CCN2CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), 2-morpholin-4-ylethanol (0.51 mL) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.34 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH:35][C:12](=[O:14])[C:11]2[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[N:32][CH:31]=1)[CH3:25]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-benzyloxy-5-((S)-2-methoxy-1-methylethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17].C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>ClCCl>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:5]2[CH2:4][CH2:3][NH:2][C:29](=[O:32])[CH2:30][CH3:31]
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCN
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NCCc1c(C(=O)NC)[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(2-aminoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide hydrochloride (80.0 mg) and dichloromethane (4.44 mL) were added diisopropylethylamine (0.145 mL) and propionyl chloride (0.0296 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:0 to 10:1). The obtained residue was solidified with a mixed solvent of hexane:ethyl acetate=2:1 to obtain 5-methoxy-N-methyl-3-[2-(propionylamino)ethyl]-1H-indole-2-carboxamide (56.0 mg) as a white solid.
Reaction SMILES: [F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16](O)=[O:17].C(OC(=O)C)(=O)C>>[F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH:15][CH:16]=[O:17])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=CO
Reactant: COC(=O)C(=NOCF)c1nsc(N)n1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=NOCF)c1nsc(NC=O)n1
Yield: 75.6 %

Procedure:
To a suspension of methyl 2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetate (anti-isomer) (1.17 g, 5 mmol) in formic acid (1.38 g, 30 mmol), acetic anhydride (1.12 g, 10 mmol) was added. The mixture was treated in the same procedure as described in Example 9 to give methyl 2-fluoromethoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (991 mg, yield: 73.8%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]([C:17]3[NH:25][C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[CH:18]=3)=[CH:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>O1CCCC1.CO.[Pd]>[N:1]1([C:6]2[CH:7]=[C:8]([CH:12]([C:17]3[NH:25][C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[CH:18]=3)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)C=C(c1cccc(-n2cccn2)c1)c1cc2cccnc2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(c1cccc(-n2cccn2)c1)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.5 %

Procedure:
A solution of 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbut-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.4 g, 4.3 mmol) in tetrahydrofuran (20 mL) and methanol (40 mL) was treated with 10% palladium on carbon (285 mg). The reaction was stirred at 25° C. under hydrogen atmosphere for 3 d. At this time, the reaction mixture was filtered and was washed with tetrahydrofuran (2×15 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 25% ethyl acetate/petroleum ether) afforded 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbutyl)-1H-pyrrolo[2,3-b]pyridine (1.03 g, 71.8%) as a white solid: 1H NMR (300 MHz, d6-DMSO) δ ppm 11.62 (s, 1H), 8.48 (d, 1H, J=1.8 Hz), 8.10 (d, 1H, J=4.5 Hz), 7.89 (s, 1H), 7.81 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.65 (d, 1H, J=8.4 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.31 (d, 1H, J=7.5 Hz), 6.97 (dd, 1H, J1=7.8 Hz, J2=4.8 Hz), 6.54 (s, 1H), 6.33 (s, 1H), 4.28 (t, 1H, J=8.1 Hz), 2.17-2.10 (m, 1H), 1.97-1.90 (m, 1H), 1.45-1.36 (m, 1H), 0.93 (d, 3H, J=2.4 Hz), 0.91 (d, 3H, J=2.7 Hz).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([CH3:29])[CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f54) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[Cl:9][C:10]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:2].[Cl:9][C:10]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:11]=1[N:12]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: ClCCNCCCl
Reactant: Nc1cc(Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Clc1ccc(Cl)c(N2CCNCC2)c1
Yield: 13.2 %

Procedure:
7.14 g of bis(2-chloroethyl)amine hydrochloride was suspended in 70 ml of butanol and 6.48 g of 2,5-dichloroaniline was added thereto at room temperature. After heating under reflux for 48 hours, the reaction mixture was cooled and 5.52 g of potassium carbonate was added. After heating under reflux for additional 24 hours, the insoluble matters were filtered off and the filtrate was concentrated. Then the obtained residue was extracted with chloroform and a saturated aqueous solution of sodium hydrogencarbonate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (100 g, chloroform:methanol=50:1-30:1). The product was converted into hydrochloride by adding a 1N hydrochloric acid/ethanol solution to thereby give 1.41 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:40])[CH2:26][N:25]([C:27]2[CH:28]=[C:29]([NH2:39])[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:24][CH2:23][O:22]1.Cl.O1CCOCC1.CN1C(=O)CCC1>>[CH3:20][C:21]1([CH3:40])[O:22][CH2:23][CH2:24][N:25]([C:27]2[CH:28]=[C:29]([NH:39][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:3]=3[CH3:19])[C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH2:26]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCOC(C)(C)C2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
Prepared according to Procedure K, method 2 using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (66.3 mg, 0.24 mmol; described herein), 5-(2,2-dimethylmorpholino)-2-morpholinopyridin-3-amine (71.0 mL, 0.243 mmol, described herein), 4.0M hydrochloric acid in 1,4-dioxane (60 μL, 0.24 mmol), and NMP (350 μL, 3.6 mmol), and heating in a microwave at 160° C. for 3 h. Purification afforded N-(5-(2,2-dimethyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=3.5, 1.2 Hz), 7.86-7.95 (2H, m), 7.78-7.86 (2H, m), 7.58 (1H, d, J=2.7 Hz), 7.40 (1H, ddd, J=6.9, 5.0, 1.8 Hz), 7.28-7.33 (1H, m), 6.83 (1H, s), 6.22 (1H, d, J=2.7 Hz), 3.93 (4H, t, J=4.7 Hz), 3.72-3.84 (3H, m), 3.65 (1H, t, J=5.9 Hz), 3.09-3.33 (4H, m), 2.80-2.93 (2H, m), 2.74 (2H, s), 2.37 (3H, s), 1.25-1.31 (4H, m). Mass Spectrum (ESI) m/e=529.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([O:25][CH2:26][CH:27]=[CH2:28])[C@@H:20]([O:29][CH2:30][CH:31]=[CH2:32])[C@H:19]([CH3:33])[O:18][C:17]1=[O:34])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([O:25][CH2:26][CH2:27][CH3:28])[C@@H:20]([O:29][CH2:30][CH2:31][CH3:32])[C@H:19]([CH3:33])[O:18][C:17]1=[O:34])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCO[C@H]1[C@H](C)OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@@H]1OCC=C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCO[C@H]1[C@H](C)OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@@H]1OCCC
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7,8-diallyloxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]carbamate (170 mg, 0.350 mmol) in EtOAc (3 mL) in a 50 mL high pressure reactor with a stir bar was added 5% Pd/C (20.0 mg, 9.40 μmol). After the reactor was sealed, it was purged with H2 (4×), and charged to ˜600 psi with H2 at room temperature. The reaction mixture was warmed to 40° C. and stirred for 2 h. The reaction mixture was filtered through a pad of Celite® and the filtrate concentrated to provide the title compound as a colorless oil (170 mg, 99%): 1H NMR (400 MHz, CDCl3) δ 5.21 (dd, J=8.9, 4.2 Hz, 1H), 4.77 (dq, J=9.3, 6.2 Hz, 1H), 4.26 (dd, J=12.1, 4.2 Hz, 1H), 3.92 (dd, J=12.1, 8.9 Hz, 1H), 3.86-3.77 (m, 2H), 3.60-3.41 (m, 4H), 3.29-3.12 (m, 2H), 1.67-1.52 (m, 2H), 1.49 (s, 19H), 1.42 (d, J=6.4 Hz, 3H), 0.92 (td, J=7.4, 2.8 Hz, 7H); 13C NMR (101 MHz, CDCl3) δ 169.04, 152.59, 84.88, 83.40, 82.95, 75.71, 75.41, 72.78, 72.65, 72.55, 57.88, 27.91, 23.48, 23.27, 18.62, 10.59, 10.57; ESIMS m/z 513.3 ([M+Na]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C@H:10]2[C:31]([OH:33])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1.[CH2:38]1[CH2:48]CN2C(=NCCC2)C[CH2:39]1.C(Br)C=C>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C@H:10]2[C:31]([O:33][CH2:48][CH:38]=[CH2:39])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCOC)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2OCOC)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
(1S,2R,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (4.8 g, 9.5 mmol) was dissolved in dry acetonitrile (30 ml) and DBU (1.7 ml, 11.4 mmol) was added followed by allyl bromide (3,4 g, 28. mmol). After stirring for 0.5 h. the product was partitioned between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound as a pale yellow oil (5.7 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1cccc(S(=O)(=O)N2c3cc(Cl)ccc3-c3ccccc3C2C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2ccc(Cl)cc2N1S(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred suspension of 3-chloro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.38 g, 0.95 mmol) and cyclohexene (1.73 mL, 17.1 mmol) was treated dropwise at room temperature under nitrogen with a solution of 1.0 M boron tribromide (5.7 mL, 5.7 mmol) in dichloromethane. After stirring for 20 hours at room temperature, the reaction was quenched with a saturated, aqueous sodium bicarbonate solution (50 mL), and extracted with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude residue. The crude residue was triturated with hexane and purified by flash column chromatography, eluting with a mixture of ethyl acetate-hexane (30:70), to afford the title compound as a homogeneous, white, crystalline solid (0.17 g, 73%), m.p. 215° C.;
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2([CH3:18])[CH2:17][CH2:16]2)=[C:9]([CH:19]([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.CN(C=O)C.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>[CH:19]([C:9]1[CH:8]=[C:7]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:12]=[CH:11][C:10]=1[CH2:13][O:14][C:15]1([CH3:18])[CH2:17][CH2:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1COC1(C)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C#C[Si](C)(C)C)ccc1COC1(C)CC1
Temperature: 95 °C
Yield: 107.7 %

Procedure:
Using General Procedure D; 3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenyl 1,1,1-trifluoromethanesulfonate (Intermediate 164, 120.0 mg, 0.34 mmol) in triethylamine (2 mL) and anhydrous DMF (5 mL) was sparged with argon for 5 minutes. Trimethylsilyl acetylene (700.0 mg, 0.71 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (24.0 mg, 0.03 mmol). The resulting reaction mixture was heated to 95° C. for 60 hours. The title compound 110.0 mg, (99%) was isolated by chromatography (0-1% EtOAc-hexanes).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O>C(OCC)(=O)C>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(-c2ccc3[nH]ccc3c2)cc1
Yield: 57.9 %

Procedure:
A stirred slurry of 6.56 g (62 mmol) Na2CO3, 3.03 g (15.5 mmol) 5-bromoindole, 3.415 g (16.5 mmol) 4-(trifluoromethoxy)phenylboronic acid, and 0.50 g (0.43 mmol) tetrakistriphenylphosphine palladium was heated to reflux for 3 hr. The reaction mixture was allowed to cool and was then poured into 300 mL water and shaken with ethyl acetate. The combined aqueous and organic phases were filtered and the organic layer was separated, dried over MgSO4, and concentrated. The residue was chromatographed on silica (eluting with 20–33% EtOAc-hexane) to afford 2.49 g (58%) 5-[4-(trifluoromethoxy)phenyl]indole as a solid.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)=[O:17]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Cl)cc1
Reaction time: 0.21 h

Procedure:
After dissolving 14.2 g. (0.1445 mole) of 2-imino-1 -methylpyrrolidine in anhydrous benzene, 22.2 g. (0.1445 mole) of p-chlorophenylisocyanate dissolved in anhydrous benzene is added slowly with stirring and ice-bath cooling to the above solution. Solid material forms after 10 to 15 mins. The reaction mixture is stirred at room temperature overnight. The solid is collected (m.p. = 138°-141° C.) and titurated with hot CH2Cl2. The material which does not dissolve is filtered off. Removal of the methylene chloride and recrystallizations from methanol of the subsequent solid product, 1-(1-methyl-2-pyrrolidylidene)-3-p-chlorophenylurea, yields the pure material, m.p. - 142°-144° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[O:4][N:3]=1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:6]=[C:5](/[CH:7]=[N:15]/[S:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14])[O:4][N:3]=1
Reactant: O=Cc1cc(Br)no1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1cc(Br)no1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 3-bromo-isoxazole-5-carbaldehyde (182 mg, 1.03 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (150 mg, 121 mmol) in CH2Cl2 (2 mL) was added titanium (IV) isopropoxide (0.667 mL, 2.28 mmol) and the mixture was warmed at reflux. After 22 hours, the solvent was concentrated in vacuo and the remaining solution was diluted with EtOAc (33 mL) and saturated aqueous NaCl (6 mL) was added. The resultant heterogeneous mixture was stir at room temperature. After 30 minutes, the mixture was filtered through a pad of diatomaceous earth. The EtOAc layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to afford 2-methyl-propane-2-sulfinic acid 1-(3-bromo-isoxazol-5-yl)-meth-(E)-ylideneamide.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:3]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[O:2]
Reactant: COC=C1CCc2cc(C#N)ccc21
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC2C=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(Methoxymethylene)indane-5-carbonitrile (1.5 g, 8.1 mmol) in DCM (40 mL) was added BBr3 (6 g, 24 mmol) at −78° C. The mixture was stirred for 3 hours at −78° C. Then water was added. The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude 1-Formylindane-5-carbonitrile, which was used for next step without further purification. MS m/z: 172 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33].N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: CC(C)=CCBr
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Agent: N
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(CC=C(C)C)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (25 mg, 71%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 4-bromo-2-methyl-2-butene (23 mg, 0.15 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.65 (s, 3H), 1.79 (s, 3H), 2.12-2.22 (m, 3H), 2.24-2.40 (m, 1H), 2.57 (se, J=7.7 Hz, 2H), 2.72 (t, J=6.6 Hz, 2H), 2.74-2.84 (br, 1H), 3.05-3.45 (m, 6H), 3.59-3.77 (m, 1H), 3.86 (s, 3H), 5.42-5.55 (br, 1H), 6.83 (s, 1H), 6.85 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.17-7.25 (m, 2H) ppm. MS (CI, NH3): 457.2 (base, M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH3:16][CH2:17]O>C(Cl)(Cl)Cl.[Pd]>[CH2:16]([O:8][C:7](=[O:9])[CH2:6][CH2:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:3]=1[O:2][CH3:1])[CH3:17]
Reactant: CCO
Reactant: COc1cccc(C=CC(=O)O)c1OC
Agent: [Pd]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cccc(OC)c1OC

Procedure:
A mixture of (20 g, 0.0961 mole) of 2,3-dimethoxycinnannic acid in 120 mL of CHCl3 and 200 mL of EtOH was hydrogenated at 30 psig in the presence of 2.0 g of 10% Pd/C catalyst to form ethyl-3-(2,3-dimethoxy-phenyl)propionate (hereinafter, "Compound 1"). The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was distillated under reduced pressure to give 22 g (96% yield) of liquid with a boiling point of 143° C./1.15 mmHg. Elemental analysis gave C13H18O4 (C,H,N).