Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][O:5][CH:4]=[C:3]1[O:8][CH2:9][C:10]([O:12]CC)=[O:11]>Cl>[OH2:1].[O:1]=[C:2]1[CH:7]=[CH:6][O:5][CH:4]=[C:3]1[O:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)COc1coccc1=O
Agent: Cl
Product: O
Product: O=C(O)COc1coccc1=O
Yield: 1.9 %

Procedure:
A mixture of ethyl 2-(4-oxo-4H-pyran-3-yloxy)acetate (198 g) in 10% hydrochloric acid (10 ml) was heated at 70° to 75° C. for an hour under stirring. The reaction mixture was cooled and concentrated to the volume of about 5 ml. Precipitated crystals were collected by filtration washed with water and dried to give crystals (1.8 g) of 2-(4-oxo-4H-pyran-3-yloxy)acetic acid monohydrate, mp 155° to 157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][CH2:29][Mg+].[Br-].O>C1COCC1.C(Cl)Cl>[NH2:16][C:15]1([C:13]2[N:14]=[C:9]([N:8]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:29][CH2:28]1
Reactant: CC[Mg+]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cccc(C#N)n2)cc1
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cccc(C3(N)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of 6-[bis-(4-methoxy-benzyl)-amino]-pyridine-2-carbonitrile (1.83 g, 5.09 mmol) in anhydrous THF (64 mL) was added Ti(Oi-Pr)4 (1.79 mL, 6.11 mmol) in one portion followed by EtMgBr (3.0 M solution in THF, 4.07 mL, 12.2 mmol) slowly over 5 min. The reaction was stirred at room temperature overnight. Additional Ti(Oi-Pr)4 (0.5 mL, 1.7 mmol) and EtMgBr (1.2 mL, 3.60 mmol) were added and stirring was continued for 2 h. Additional Ti(Oi-Pr)4 (1.8 mL, 6.1 mmol) and EtMgBr (3 M, 4.1 mL, 12 mmol) were added and stirring was continued for 3 h. Water (12 mL) was added to the reaction mixture causing the formation of a precipitate. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo to give an orange/red oil. The concentrate was re-dissolved in CH2Cl2, causing precipitation of a white solid. After filtration, the filtrate was concentrated in vacuo and purified via iterative flash chromatography on silica gel (1→10% MeOH/CH2Cl2) to give 381 mg of the title compound as a light orange viscous oil, m/z 391.08 [M+2]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[F:13][C:14]1[CH:15]=[C:16]([C:20](O)=[O:21])[CH:17]=[N:18][CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[NH:12][C:20]([C:16]2[CH:17]=[N:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[O:21])[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)cc1NC1CC1
Reactant: O=C(O)c1cncc(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1NC1CC1)c1cncc(F)c1

Procedure:
To a solution of the title compound from N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.065 g, 0.39 mmol) in dichloromethane (1.96 mL) were added 5-fluoropyridine-3-carboxylic acid (0.061 g, 0.43 mmol), EDC (0.082 g, 0.43 mmol), HOBt (0.066 g, 0.43 mmol), and diisopropylethylamine (0.280 mL, 1.56 mmol). The reaction was stirred at room temperature overnight, then diluted with dichloromethane, washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-50% ethyl acetate in hexanes) provided the title compound: LCMS m/z 290.14 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.90 (s, 1 H), 8.66 (d, J=2.0 Hz, 1 H), 7.97 (d, J=8.3 Hz, 1 H), 7.48 (br s, 1 H), 7.19 (m, 1 H), 6.92 (d, J=10.9 Hz, 1 H), 6.52-6.49 (m, 1 H), 4.50 (br s, 1 H), 2.47-2.44 (m, 1 H), 0.81-0.77 (m, 2 H), 0.54-0.51 (m, 2 H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1)(=O)C>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A mixture of 227a (131 mg, 0.20 mmol) and lithium hydroxide·1 water (120 mg, 2.0 mmol) in i-propanol/THF/water (4 mL/4 mL/2 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was extracted with dichloromethane (3×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 227 as a white solid (75 mg, 62%). MS-ESI: [M+H]+ 611.2. 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.64 (s, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.79-7.77 (m, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.43 (d, J=5.0 Hz, 1H), 6.58 (s, 1H), 4.82 (s, 1H), 4.60-4.57 (m, 1H), 4.38-4.36 (m, 1H), 4.29-4.19 (m, 2H), 4.10-4.05 (m, 1H), 3.93-3.90 (m, 1H), 3.80 (s, 3H), 3.60-3.50 (m, overlap, 8H), 2.66-2.54 (m, 2H), 2.48-2.46 (m, 2H), 1.81-1.66 (m, 4H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH:11]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:28][CH:27]=1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C(c1ccc2nc(Oc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 80 °C

Procedure:
A suspension of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethyl-butan-2-amine (54 mg, 0.14 mmol), methyl-4-hydroxybenzoate (21.7 mg, 0.14 mmol) and potassium carbonate (21.6 mg, 0.16 mmol) in 1 mL of DMF was heated at 80° C. overnight. The mixture was concentration in vacuo and the residue partitioned between water and DCM. After extracting the aqueous layer, the combined DCM extracts were dried over Na2SO4, decanted and concentrated in vacuo. The residue was purified using PTLC and eluting with 5% MeOH (2N NH3)/DCM to provide methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate. MS (ESI+) m/z 451.17 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([I:19])[CH:8]=[C:9]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20](OCC)=[O:21].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:20]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:8][C:7]=3[I:19])=[O:21])=[CH:28][CH:27]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Temperature: 180 °C
Yield: 75 %

Procedure:
A suspension of ethyl 4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate (0.8 g) and 4-chlorobenzylamine (1.54 mL) is heated to 180° C. for 1 h. The reaction is cooled to room temperature. The resulting solid is collected and washed with Et2O. The crude solid is adsorbed onto silica and chromatographed (Biotage flash 40S, eluent 1% MeOH/CH2Cl2 then 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The resulting solid is triturated with EtOAc/hexanes to yield 0.73 g (75%) of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].Cl.[CH3:13]O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1F
Agent: Cl
Product: COC(=O)Cc1ccccc1F
Temperature: 68 °C

Procedure:
To a stirred solution of 2-fluorophenylacetic acid (9.6 g, 62 mmol) in MeOH (100 mL) was added concentrated HCl (0.7 mL, 19 mmol). The mixture was heated at 68° C. for 4 hours, and then the reaction was concentrated in vacuo to remove MeOH. The residue was dissolved in ether and then washed with saturated NaHCO3 solution (1×50 mL). The organic extracts were separated, dried with Na2SO4, filtered, and concentrated in vacuo to give a yellow oil (10 g). MS (m/z)=169.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@H:5]2[C@H:4](NC(=O)OCC2C=CC=CC=2)[CH2:3]1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O.[C:33]([O:36][CH2:37][CH3:38])(=[O:35])C>CN(C)C=O>[CH2:37]([O:36][C:33]([C@H:4]1[C@@H:5]2[O:9][C:8]([CH3:10])([CH3:11])[O:7][C@@H:6]2[C@@H:2]([O:1][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:3]1)=[O:35])[C:38]1[CH:5]=[CH:6][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CBr
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CO[C@H]1C[C@@H](C(=O)OCc2ccccc2)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Benzyl (3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate (12.29 g, 39.99 mmol, 1.00 equiv.) was added to a solution of sodium hydride (70%) (1.44 g, 60.00 mmol, 1.05 equiv.) in dimethylformamide (200 mL). The solution was stirred at about −30° C. for about 30 minutes, and then ethyl 2-bromoacetate (7.68 g, 45.99 mmol, 1.20 equiv) was added. The resulting solution was stirred at ambient temperature for about 5.5 hours, and then water was added (500 mL). Following standard extractive workup with ethyl acetate (3×200 mL), the resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (1:10)) to afford the title product as a colorless solid (0.9 g; yield=69%). 1H NMR (300 MHz, CD3OD) δ: 7.30-7.35 (m, 5H), 5.07 (s, 2H), 4.60 (d, J=5.7 Hz, 1H), 4.51 (d, J=5.7 Hz, 1H), 4.12-4.29 (q, J=16.5 Hz, 2H), 4.10-4.22 (q, J=7.2 Hz, 2H), 4.00 (d, J=5.7 Hz, 1H), 3.92 (J=4.3 Hz, 1H), 2.17-2.19 (m, 1H), 1.84 (d, J=14.7 Hz, 1H), 1.38 (s, 3H), 1.26 (s, 3H), 1.11-1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12.[CH:11](O)=[O:12].C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH:11]([NH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)=[O:12]
Reactant: O=CO
Reactant: NCc1ncn2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=CNCc1ncn2ccsc12
Temperature: 0 °C

Procedure:
To the ice-cooled solution of the whole amount of the crude 7-aminomethyl-imidazo[5,1-b]thiazole in 5 ml of dichloromethane was added a mixture of 0.5 ml of formic acid and 0.5 ml of acetic anhydride which had been preliminarily sitrred and reacted at 50° C. for 10 minutes. The resulting mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture were added 10 ml of water, 20 ml of dichloromethane and 5 ml of a 50% aqueous potassium carbonate solution, and the organic layer was separated. The aqueous layer was further extracted thrice with 20 ml of dichloromethane. The combined organic layer was purified by flash column chromatography on silica gel (eluted with chloroform: methanol=15:1) to give the title compound in a yield of 0.088 g (36%). NMR (CDCl3) δ: 4.53 (2H, d, J=5.8 Hz), 6.84 (1H, d, J=4.2 Hz), 6.86 (1H, br), 7.38 (1H, d, J=4.2 Hz), 7.93 (1H, s), 8.26 (1H, s).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].CN(C)[CH:13]=[O:14].N1(C2[CH2:26][CH2:25][S:24][CH2:23][CH:22]=2)CCCC1>O>[CH2:1]([CH:22]1[C:13](=[O:14])[CH2:26][CH2:25][S:24][CH2:23]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: C1=C(N2CCCC2)CCSC1
Reactant: CN(C)C=O
Solvent: O
Product: O=C(CC1CSCCC1=O)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 56.3 g (0.28 mole) of phenacyl bromide in 100 ml. of dimethylformamide is added dropwise during 20 minutes under nitrogen to a cold stirred solution of 47.6 g (0.28 mole) of 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran and 300 ml. of anhydrous dimethylformamide. After 2 hours, the solution is diluted with H2O and extracted with chloroform. The chloroform solution is washed with water, dried over magnesium sulfate and concentrated. The product is crystallized from ethanol to give crystals of 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one. This is recrystallized from ethanol to yield crystals; m.p. 101.5° to 103.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[I-:19].[Na+].CNCCNC>O1CCOCC1.[Cu]I>[I:19][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(Br)n1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1

Procedure:
Alternatively the title compound was prepared from 2-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.48) (101.0 g, 320 mmol), sodium iodide (91.04 g, 608 mmol), copper(I) iodide (2.89 g, 5 mol %) and N,N′-dimethylethylenediamine (3.31 mL, 11 mol %) in dioxane (304 mL) according to the general procedure Ia to d preparation of iodides. Obtained as a light yellow solid (112.5 g, 100%). MS (ISP) 364.0 [(M+H)+]; mp 91-93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].[C:25]1([CH3:31])C=CC=C[CH:26]=1.ClC(Cl)([O:35][C:36](=O)[O:37]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CC(O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36](=[O:35])[O:37][CH:25]([CH3:31])[CH3:26])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: Cc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)C)c(C)c3C)c2cc1OC
Yield: 75 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-propanol (14 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 75%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>CN(C)C=O>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: CN(C)C=O
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorbenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and N,N-dimethylformamide (125 ml) is stirred at about 80° C. for 24 hours. Unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide as well as N,N-dimethylformamide are distilled off (distillate 100 ml) by raising the external temperature to about 130° C. and gradually evacuating to about 100 mbar. After cooling to 100° C., water (100 ml) is allowed to run in. The crystallization of the product is initiated by seeding the brown emulsion. The mixture is cooled to about 20° C. and the suspension is stirred at about 20° C. for 30 minutes. The product is isolated by filtration and washed with water (100 ml). The product is dried in vacuo at about 60° C. Yield: 34.40 g=78.1% (beige crystals).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[NH2:14][C:15]1[CH:20]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:17][C:16]=1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:29]([O:28][C:27]([NH:26][C:16]1[CH:17]=[CH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[CH:20][C:15]=1[NH:14][C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3])=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-(chlorocarbonyl)benzoate (1.40 g, 7.07 mmol) and tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (2.05 g, 7.07 mmol) were combined in pyridine (10 mL) and stirred at room temperature for 18 h. The reaction mixture was poured into 3:1 CHCl3:MeOH, washed with 2 N HCl and 2 N NaOH, dried (Na2SO4), and evaporated to give the desired product as a colorless solid. MS: cal'd 475 (MNa+), exp 475 (MNa+).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C@@H:9]([NH2:23])[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:11][CH2:12][CH:13]=[CH2:14])=[N:5][CH:6]=[CH:7][N:8]=1.[C:24]([O:28][C:29](OC([O-])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(Cl)Cl>[Br:2][C:3]1[C:4]([C@@H:9]([NH:23][C:29](=[O:30])[O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:11][CH2:12][CH:13]=[CH2:14])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: C=CCC[C@@H](c1cccc(F)c1F)[C@H](N)c1nccnc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1nccnc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
In a 250 mL round-bottomed flask was (R)—N-((1S)-1-(3-bromopyrazin-2-yl)-2-(2,3-difluorophenyl)hex-5-enyl)-2-methylpropane-2-sulfinamide (1.96 g, 4.16 mmol) in methanol (17 mL) to give a tan solution. HCl (4M in dioxane, 4.2 mL, 17 mmol) was added, and the mixture was stirred at rt for 1 h. Volatiles were removed in vacuo and the tan residue was diluted with ether and concentrated. The remaining tan foam was directly used in the next reaction. In the same round-bottomed flask was dissolved (1S,2S)-1-(3-bromopyrazin-2-yl)-2-(2,3-difluorophenyl)hex-5-en-1-amine (1.532 g, 4.16 mmol) (crude HCl salt) and t-butylpyrocarbonate (1.449 mL, 6.24 mmol) in methylene chloride (22 mL) to give a tan solution. triethylamine (1.28 mL, 9.15 mmol) was added dropwise, and the mixture was stirred at rt for 2 h. LCMS showed complete conversion. It was concentrated to dryness, and directly subject to flash column chromatography up to 40% ethyl acetate/hexane to afford the desired product (1.80 g, 92% for 2 steps) as colorless oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27 (d, J=17.07 Hz, 2H) 6.92-7.14 (m, 3H) 5.69 (dd, J=10.29, 5.77 Hz, 1H) 5.63 (dd, J=9.41, 5.90 Hz, 1H) 5.41 (d, J=9.54 Hz, 1H) 4.84-4.95 (m, 2H) 3.65 (br. s., 1H) 1.88-2.08 (m, 3H) 1.81 (br. s., 1H) 1.30-1.41 (m, 9H). A slightly more polar diastereomer (generally <10% if there was minimum epimerization at the aldehyde stage) could be removed at this stage: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (d, J=2.26 Hz, 1H) 8.20 (d, J=2.51 Hz, 1H) 6.88-7.11 (m, 3H) 5.66-5.81 (m, 1H) 5.60 (t, J=8.91 Hz, 1H) 5.51 (d, J=9.29 Hz, 1H) 4.83-5.00 (m, 2H) 3.55 (d, Hz, 1H) 1.87-2.06 (m, 3H) 1.73-1.86 (m, 1H) 1.44 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.[OH-:17].[Sr+2:18].[OH-:19]>O>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O-:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1].[Sr+2:18].[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O-:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1].[C:13](=[O:16])([O-:19])[O-:17]
Reactant: [OH-]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [Sr+2]
Solvent: O
Product: CCCCCCCCCc1ccccc1[O-]
Product: O=C([O-])[O-]
Temperature: 155 °C
Reaction time: 5 h
Yield: 15 %

Procedure:
To a mixture of 134 g of nonylphenol, 174 g of process oil (Mentor 28:Esso Petroleum) and 62 g of an aromatic hydrocarbon solvent (Solvesso 100: Esso Petroleum) was added 243 g of strontium hydroxide (octahydrate salt) gradually to disperse it, the mixture was subjected to reaction at 105° C. for one hour, and water was completely removed at 130° C. Carbon dioxide (10 L/hour) was blown thereinto for 5 hours to progress reaction, and the mixture was gradually heated to 155° C. to continue reaction while water was distilled off, and then filtered to give a brown solution of an overbased strontium nonylphenolate-carbonate complex (Sr=15%; metal ratio=2.9) (this product is designated S-5).
Reaction SMILES: CS(Cl)(=O)=O.O[C:7]1([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>ClCCl>[NH3:18].[C:7]1([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: OC1(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CCCCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C1=C(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CCCC1
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %
Yield: 92.6 %

Procedure:
Methanesulfonyl chloride (0.042 mL, 0.54 mmol) was added to a solution of 5-(1-hydroxycyclohex-1-yl)-3-(2-pyrrolidinylethyl)-1H-indole (Example 13a, 50.6 mg, 0.16 mmol) and triethylamine (0.15 mL, 1.06 mmol) in dichloromethane (2.5 mL) at 0° C. The reaction was allowed to warm slowly to room temperature and stirring was continued overnight. The reaction mixture was diluted with dichloromethane (100 mL) and washed sequentially with water and brine, dried over sodium sulfate and the solvent was removed in vacuo. Flash chromatography (silica, 5-8% 2M methanolic ammonia in dichloromethane) yielded 5-(cyclohex-1-en-1-yl)-3-(2-pyrrolidinylethyl)-1H-indole (21.8 mg, 46%); HRMS-FAB+ for C20H26N2 :calculated MH+ :295.21744; found MH+ :295.21953.