Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[O:21])=[CH:18][C:17]=1[O:35][CH3:36])=[O:4].[OH-].[Na+].O.Cl>C(OCCCC)(=O)C.O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[O:21])=[CH:18][C:17]=1[O:35][CH3:36])([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCOC(C)=O
Solvent: O
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)O)cc12
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of the product of step d) (15 g, 23.8 mmole), concentrated sodium hydroxide liquor (6.75 ml, 119 mmole), water (85 ml) and tetrahydrofuran (18 ml) was stirred for three hours at 65° C., and the now homogeneous solution cooled to 50°-55° C. and maintained at this temperature during the subsequent acidification and extraction. Concentrated hydrochloric acid was added to a pH of 7-8, followed by addition of tetrahydrofuran (44 ml) and n-butyl acetate (29 ml), and further adjustment of the pH to 1-2. The reaction mixture was allowed to settle and the lower aqueous layer separated. The organic layer was washed with 5% brine solution (2×20 ml). The tetrahydrofuran was removed by distillation (ca 40 ml distillate collected at a jacket temperature of 95° C.), and the residual mixture cooled to 15°-20° C. The product was collected by filtration, washed with butyl acetate (15 ml) and dried at 50° C. The yield of 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)-benzamide was 11.08 g (94%); m.p. 264°-267° C.; NMR (250 MHz, DMSO-d6): 2.63 (s, 3H, ArCH3), 3.78 (s, 3H, NCH3), 3.95 (s, 3H, OCH3), 4.08 (s, 2H, ArCH2Ar'), 7.18 (d, 1H), 7.22 (s, 1H), 7.38-7.65 (m, 6H), 7.79 (d, 1H), 8.06 (d, 1H), 8.20 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6](Cl)=[O:7].[CH2:23]([OH:25])[CH3:24]>CC1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([O:25][CH2:23][CH3:24])=[O:7]
Reactant: O=C(Cl)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 30 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetyl chloride, 9.3 parts of ethanol and 90 parts of methylbenzene was stirred overnight at room temperature. The reaction mixture was evaporated, the residue was taken up in ethanol and the latter was evaporated again. The residue was taken up in 2,2'-oxybispropane. The whole was washed with a saturate sodium hydrogen carbonate solution and with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and hexane (50:50 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 19.6 parts of ethyl α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetate as a residue (intermediate 23).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16](OC)=[O:17].C(OCC)(=O)C.[Cl-].[NH4+]>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][OH:17]
Reactant: COC(=O)CCc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCCc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 gm of lithium aluminum hydride was suspended in 110 ml of dried THF and stirred for 1 hour at room temperature. To the suspension was slowly added over 15 minutes a solution of 5 gm of the compound prepared in (2) above in 50 ml of THF. The mixture was stirred for 12 hours at room temperature, and after the addition of 20 ml of ethyl acetate, for a further 3 hours. Then, 5 ml of saturated aqueous solution of ammonium chloride was added to the mixture, followed by further stirring for 30 minutes. After removing the precipitate by filtration, the filtrate was washed with water and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 4.27 gm of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].[NH2:21][CH2:22][C@@H:23]([C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=1)[OH:24]>>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:21][CH2:22][C@H:23]([OH:24])[C:25]3[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)/C=C/c1ccc(N2CCC(=O)CC2)cc1
Product: CCOC(=O)/C=C/c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from (E)-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-acrylic acid ethyl ester (which was obtained in Example 169) (0.27 g, 1.0 mmol) and N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.27 g, 1.1 mmol) according to the procedure shown for Example 180 to give 0.40 g of yellow solid; m.p. 103–106° C.; 1H NMR (DMSO-d6) δ 1.24 (t, 3 H), 1.20–1.45 (m, 2 H), 1.75–1.95 (m, 2 H), 2.55–2.95 (m, 5 H), 2.92 (t, 3 H), 3.67–3.85 (m, 2 H), 4.14 (q, 2 H), 4.46–4.50 (m, 1 H), 6.34 (d, 1 H), 6.96 (d, 1 H), 6.79–7.05 (m, 3 H), 7.05 (d, 1 H), 7.17 (d, 1 H), 7.56 (d, 2 H); MS (ES) m/z: 504.0 (MH+).
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)(OP([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(O)=O)C)C.[Br-].[Li+].C(N(CC)CC)C>C1COCC1>[CH:1]1(/[CH:6]=[CH:16]/[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(C)(CC)OP(=O)(O)CC(=O)OCc1ccccc1
Reactant: O=CC1CCCC1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/C1CCCC1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of cyclopentanecaboxaldehyde (0.069 g, 0.70 mmol), benzyl (diethylethyl phosphono)acetate (0.100 g, 0.35 mmol), lithium bromide (0.030 g, 0.35 mmol), and triethylamine (0.049 mL, 0.35 mmol) in THF (1 mL) at room temperature was stirred for 16 hours, quenched with water, stirred for 15 minutes, diluted with ethyl acetate, washed sequentially with pH 7 buffer and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 231 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:44]=[CH:43][C:5]2[CH:6]([C:16]3[C:17](=[O:42])[NH:18][C:19](=[O:41])[N:20]([C:22]4[N:27]=[C:26]([NH:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:25]([C:37]([O:39][CH3:40])=[O:38])=[CH:24][N:23]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.CO>FC(F)(F)C(O)=O.ClCCl>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[O:42])[NH:18][C:19](=[O:41])[N:20]([C:22]4[N:27]=[C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])[C:25]([C:37]([O:39][CH3:40])=[O:38])=[CH:24][N:23]=4)[CH:21]=3)[C:5]3[CH:43]=[CH:44][C:2]([CH3:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: COC(=O)c1cnc(-n2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)nc1NCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(-n2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)nc1NCC(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of the product of step (iii) (0.57 g) in trifluoroacetic acid (5 ml) and dichloromethane (10 ml) was stirred at room temperature for 5 hours. Methanol (30 ml) was added and the precipitate collected. The solid was dissolved in methanol and sodium hydroxide solution and the product precipitated out by addition of 2M HCl. Yield 0.26 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[C:14]1[C:18]([Cl:19])=[C:17]([C:20]([F:23])([F:22])[F:21])[N:16]([CH3:24])[N:15]=1.[Br:25][C:26]([CH3:31])([CH3:30])[C:27](Br)=[O:28]>O1CCOCC1>[Br:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[C:14]1[C:18]([Cl:19])=[C:17]([C:20]([F:23])([F:22])[F:21])[N:16]([CH3:24])[N:15]=1)=[O:28]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cn1nc(-c2c(F)cc3c(c2N)NC(=O)CO3)c(Cl)c1C(F)(F)F
Solvent: C1COCCO1
Product: Cn1nc(-c2c(F)cc3c(c2NC(=O)C(C)(C)Br)NC(=O)CO3)c(Cl)c1C(F)(F)F
Yield: 75.4 %

Procedure:
5-Amino-7-fluoro-6-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-1,4-benzoxazine-3(4H)-one (1.0 g, 2.64 mmol) was dissolved in anhydrous dioxane (40 ml) and 2-bromoisobutyryl bromide (0.67 g, 2.91 mmol) was added. Solution was refluxed for 2 hr and solvent was then evaporated. The residue was triturated with ether to afford the title compound (1.02 g, 1.99 mmol).
Reaction SMILES: N(OCCC(C)C)=O.[CH2:9]([O:16][C:17]1[CH:44]=[CH:43][CH:42]=[CH:41][C:18]=1[O:19][C:20]1[CH:26]=[C:25]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])[C:24]([F:40])=[CH:23][C:21]=1N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:21]1[CH:23]=[C:24]([F:40])[C:25]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])=[CH:26][C:20]=1[O:19][C:18]1[CH:41]=[CH:42][CH:43]=[CH:44][C:17]=1[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(N)cc2F)c1=O
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(Cl)cc2F)c1=O
Reaction time: 1 h

Procedure:
First, 4.46 g of isoamyl nitrite was added dropwise to a mixture of 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 2.45 g of copper(I) chloride, 5.04 g of copper(II) chloride, and 90 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 4.6 g of ([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([C:19]#[N:20])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Oc1ccc2cccnc2c1)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccc2cccnc2c1
Temperature: 100 °C
Yield: 97 %

Procedure:
A solution of 7-quinolinyl trifluoromethanesulfonate (1.88 g, 6.8 mmol) in DMF (40 ml) was degassed for 10 minutes with Argon. Zinc(II) cyanide (0.48 g, 4.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (155 mg, 2.5% mmol) and 1,1′-bis(diphenylphospino)ferrocene (188 mg, 5% mmol) was then added and the mixture was heated at 100° C. under argon for 1.5 h. The solvent was evaporated and residue dissolved in DCM and organic phase washed with a saturated solution of sodium bicarbonate. The aqueous phase was extracted with DCM (3×80 ml). The combined organic phases were dried, evaporated and the residue was chromatographed on silica gel, eluting with 0-10% methanol-DCM to afford the desired compound (1.01 g, 97%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[CH:11]1([C:14]([CH3:16])=[O:15])[CH2:13][CH2:12]1.C[O-].[Na+].C1C=CC=CC=1>O>[CH:11]1([C:14](=[O:15])[CH2:16][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:13][CH2:12]1
Reactant: COC(=O)c1cnccn1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(CC(=O)C1CC1)c1cnccn1

Procedure:
A stirred mixture of 14.0 g. of methyl pyrazinoate, 16.8 g. of cyclopropylmethyl ketone, 6.0 g. of sodium methoxide and 200 ml. of benzene is heated under reflux for 5 hours. A 400 ml. volume of water is added to the mixture. The benzene phase is separated and the aqueous solution is made weakly acidic with dilute hydrochloric acid. A yellow solid precipitates, which is collected and recrystallized from hexane to give white crystals, m.p. 111°-112°C.
Reaction SMILES: CC1C=CC(N2C3C(=CC=CC=3)C=C2)=CC=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.I[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1>>[CH3:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([C:33]5[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])[CH:36]=[CH:37][CH:38]=5)[CH2:29][CH2:28]4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:47][CH:48]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: COc1ccc(I)cc1
Agent: Cc1ccc(-n2ccc3ccccc32)cc1
Product: COc1ccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)cc1
Yield: 56.1 %

Procedure:
According to the procedure used for the synthesis of 1-(4-methylphenyl)1H-indole, N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide (37.5 mg, 0.100 mmol) and 1-iodo-4-methoxybenzene (46.8 mg, 0.200 mmol) gave the desired product (27 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.70-6.58 (m, 14H), 3.88 (s, 3H), 3.67 (s, 2H), 3.14-3.01 (m, 2H), 2.57-2.41 (m, 2H), 2.25-2.01 (m, 2H), 1.93-1.69 (m, 4H), 1.24 (d, 6H, J=7.2 Hz); ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:13])[O:12][C@H:10]([CH3:11])[CH2:9]1.C([O-])([O-])=O.[K+].[K+]>>[C:2]1([NH:1][C@@H:10]([CH3:11])[CH2:9][C:8]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CC(=O)O1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H](CC(=O)O)Nc1ccccc1
Temperature: 80.8499984741211 °C

Procedure:
A jacketed 30-L 3-neck bottom-valve cylindrical reactor equipped with overhead stirrer, reflux condenser, addition funnel, and N2 inlet was flushed with N2. Water (8.7 L) was charged followed by aniline (423 L, 4.9 mol). Stirring was initiated and the internal temperature set for 80° C. After the internal temperature reached 77° C., (R)-β-butyrolactone was charged over 1.5 h via addition funnel. The internal temperature was maintained between 80-81.7° C. during the course of addition. Once addition was completed, reaction was cooled to 20° C. over 1 h. K2CO3 (250 g, 1.8 mol, 0.75 equiv) was charged as a solid, and the aqueous pH was determined to be 10. The aqueous phase was extracted with MTBE (3×2 L), and the extracts were discarded. After adjusting the pH of the aqueous phase to 5 with 6 N HCl (225 mL), it was extracted with EtOAc (3×2 L). After each extraction, the pH was checked and was readjusted to 5 with 6 N HCl as necessary. The combined EtOAc extracts were washed with saturated brine (2 L), dried with MgSO4, and concentrated via rotary evaporation to produce a pink oil. Recovery: 300 g (72%). Enantiomeric excess was determined by chiral HPLC to be 94%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:12].O.[C:14](=S)=[S:15]>C(O)C>[NH:1]1[C@@H:2]2[C:11]3[C:6]([CH2:5][CH2:4][C@H:3]2[NH:12][C:14]1=[S:15])=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: N[C@@H]1CCc2ccccc2[C@H]1N
Reactant: S=C=S
Solvent: O
Solvent: CCO
Product: S=C1N[C@@H]2c3ccccc3CC[C@H]2N1
Temperature: 25 °C
Yield: 60 %

Procedure:
Trans-1,2-diamino-1,2,3,4-tetrahydronaphthalene (461 mg, 2.84 m mol) was dissolved in ethanol (8 ml), water (4 ml) was added to the solution, then carbon disulfide (190 μl, 3.17 m mol) was added thereto under stirring at room temperature. The mixture was heated under reflux for 4 hours and cooled in an ice-water bath. The crystals precipitating out were separated by filtration, washed with ether and dried in vacuum to give trans-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione (350 mg, 1.71 m mol) in 60% yield. The data spectroscopy and elemental analysis were as follows:
Reaction SMILES: N#N.Cl.[F:4][C:5]1([F:10])[CH2:9][CH2:8][NH:7][CH2:6]1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:4][C:5]1([F:10])[CH2:9][CH2:8][N:7]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])[CH2:6]1
Reactant: OCCOCCCl
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: OCCOCCN1CCC(F)(F)C1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 3,3-difluoropyrrolidine hydrochloride (258 mg, 1.74 mmol) and 2-(2-chloroethoxy)ethanol (3.77 mL, 34.83 mmol) in dry toluene (10 mL) were added K2CO3 (1.32 g, 9.58 mmol) and KI (29 mg, 0.17 mmol). The reaction mixture was stirred at reflux for 2 d. The mixture was cooled down to rt, filtered and concentrated under reduced pressure. The crude residue was purified by FC(CH2Cl2/MeOH/NH4OH, 1:0:0→98:2:0.5) and the title compound obtained as a pale yellow oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)O1.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[N:22]=1
Reactant: CC1(C)OB(c2cccc(C(F)(F)F)c2)OC1(C)C
Reactant: Brc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1cccc(-c2cccc(Br)n2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 4,4,5,5-tetramethyl-2-(3-trifluoromethyl-phenyl)-[1,3,2]dioxaborolane and 2,6-dibromo-pyridine. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=1)[CH3:2].CO[CH2:26][N:27]([CH2:35][Si](C)(C)C)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.FC(F)(F)C(O)=O>[C:19]([O:18][C:16]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C@H:6]2[C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH2:35][N:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26]2)=[CH:8]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of trans-tert-butyl 3-(3-ethoxy-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (2.70 g, 8.57 mmol) and N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine (2.21 mL) in dichloromethane (11 mL) was added 4 drops of trifluoroacetic acid and the mixture was stirred at 40° C. for 1 hr. Then another 0.15 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine and 2 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for another 2 hr. After cooling down to room temperature, the mixture was concentrated under vacuum to give the title compound as a pale yellow sticky oil (quantitative yield). 1H NMR (400 MHz, CDCl3) δ 1.21 (3H, t, J=7.2 Hz), 1.65 (9H, s), 2.86 (2H, q, J=8 Hz), 3.03 (1H, t, J=8 Hz), 3.11 (1H, t, J=8 Hz), 3.19 (1H, q, J=8 Hz), 3.70 (2H, dd, J=16 28 Hz), 3.91 (1H, q, J=8 Hz), 4.13 (2H, q, J=8 Hz), 7.20–7.38 (7H, m), 7.45 (1H, s), 7.74 (1H, d, J=8 Hz), 8.10 (1H, brd s). HPLC purity (retention time): 100% (1.84 min, method C). MS: 449.38 (M+Na+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=O)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C1(S(O)(=O)=O)C=CC=CC=1.[BH4-].[Na+].[OH-].[Na+]>O.C(O)C>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][CH:7]([C:6]2[CH:15]=[CH:16][C:3]([F:2])=[CH:4][CH:5]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=S(=O)(O)c1ccccc1
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (40.0 g, 0.164 mole), 4-fluoroaniline (22.0 g, 0.197 mole), and benzenesulfonic acid (0.14 g) in xylenes (820 mL) was heated at reflux temperature for 18 hr during which time 3 mL of water was collected in a Dean-Stark trap. After cooling to 50° C., sodium borohydride (12.5 g, 0.328 mole) was added slowly. Ethanol (100 mL) was added and the mixture heated at 60° C. for 1 h. After stirring for 18 h under a nitrogen atmosphere at room temperature, the mixture was chilled to 5° C. with an ice bath and chilled water added cautiously. A rapid evolution of gas occurred causing a portion of the reaction mixture to spill over into the ice bath. The contents of the ice bath and the remainder of the reaction mixture were combined and basified with 50% sodium hydroxide solution, causing a viscous insoluble oil to separate from the mixture. The material was dissolved in ethyl acetate. The ethyl acetate solution and the xylene layer were combined and washed with additional dilute aqueous NaOH solution. The aqueous layers were combined and extracted with ethyl acetate-acetonitrile (60:40). The organic layers were combined and extracted twice with 300 mL portions of 3N HCl solution. The acid extract was basified with 50% sodium hydroxide solution and extracted twice with 600 mL portions of ethyl acetate-acetonitrile (60:40). The extracts were combined, treated with charcoal, dried (MgSO4), and concentrated. The residual material was heated at 100° C. under vacuum for 1 h to remove excess 4-fluoroaniline. The yield was 24.8 g (50.5%).