Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:57][C@@H:58]1[CH2:63][CH2:62][CH2:61][CH2:60][C@H:59]1[OH:64]>CN(C=O)C>[CH2:1]([O:5][C:6]1[C:14]([C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[CH:13][C:9]([C:10]([NH:57][C@@H:58]2[CH2:63][CH2:62][CH2:61][CH2:60][C@H:59]2[OH:64])=[O:12])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CCCCOc1ncc(C(=O)O)cc1-c1cc(C(F)(F)F)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
6-Butoxy-5-(2-fluoro-5-trifluoromethyl-phenyl)-nicotinic acid (0.10 g, 0.3 mmol) was dissolved in DMF (5 mL). To the solution was added TBTU (0.10 g, 0.3 mmol), N,N-diisopropylethyl amine (0.24 mL, 1.4 mmol) and (1R,2R)-2-amino-cyclohexanol (47 mg, 0.3 mmol). The reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 78 mg of the title compound as a light yellow solid, mp 172-178° C., MS (ISP) 455.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][CH2:38][C:39]2[NH:48][C:42]3=[N:43][CH:44]=[C:45](I)[CH:46]=[C:41]3[N:40]=2)[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.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].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][CH2:38][C:39]2[NH:48][C:42]3=[N:43][CH:44]=[C:45]([C:2]4[CH:3]=[CH:4][C:5]([S:8]([N:11]5[CH2:12][CH2:13][N:14]([C:17]6[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=6)[CH2:15][CH2:16]5)(=[O:10])=[O:9])=[CH:6][CH:7]=4)[CH:46]=[C:41]3[N:40]=2)[CH:32]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: Cc1ccc(N2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCN(c6ccc(C)cc6)CC5)cc4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 37.5 %

Procedure:
A mixture of 0.395 g of 1-(4-bromo-benzene-sulfonyl)-4-(p-tolyl)-piperazine, 0.28 g of bis-(pinacolato)-diboron, 0.017 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.022 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.294 g of potassium acetate in 6 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2 for 16 hours. To the resulting mixture 4 ml of degassed dioxane, 0.228 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.069 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.165 g of potassium carbonate and 0.051 g of lithium chloride in 4 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 7.5 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with ethylacetate. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-20:1). Concentration of the chromatographically pure fractions and crystallization of the residue from ethylacetate/diethylether gives 0.128 g of the title compound as a brownish solid of m.p. 150-154° C. The mass spectrum shows the molecular peak MH+ at 569.5 Da.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[N:13][CH:12]=[CH:11]2)=[O:5].[CH3:17][Mg]Br>C1COCC1>[CH:14]1[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH3:17])[CH:11]=[CH:12][N:13]=1
Reactant: CON(C)C(=O)c1cccc2ccncc12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cccc2ccncc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-methoxy-N-methylisoquinoline-8-carboxamide (1.04 g, 4.81 mmol) in THF (40.1 ml) at 0° C. was treated with methylmagnesium bromide (11.22 ml, 33.7 mmol) in THF. Reaction was stirred at 0° C. for 1 hours before quenching with a saturated ammonium chloride solution (5 mL). After reaching RT, solution extracted with EtOAc (3×75 mL). Combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purified by normal phase chromatography (0-50% EtOAc in hexane) to yield 1-(isoquinolin-8-yl)ethanone as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[CH2:20]([C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6])[CH2:21][CH2:22][CH3:23]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: CCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 65.5 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.3 g of 1-iodobutane were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 7 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.1 g of 2-butyl-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (80)).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]([CH3:36])([CH3:35])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:24][C:25]([CH3:36])([CH3:35])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:23])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.225 mmol), tert-butyl 2-amino-2-methylpropylcarbamate (64 mg, 0.338 mmol), HATU (171 mg, 0.45 mmol) and DIPEA (58 mg, 0.45 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The mixture was poured into water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was used in the next step without further purification. MS: (M+H)+=482.1.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[C:8]2[CH3:25])=[CH:4][CH:3]=1.[Li+].[CH3:29]C([N-]C(C)C)C.IC>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]([CH3:29])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[C:8]2[CH3:25])=[CH:4][CH:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Product: COC(=O)C(C)(C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a -78° C. solution of the ester from Step 1 (35 mg, 0.08 mmol) in 3 mL THF was added LDA (1.5M in cyclohexane, 0.1 mL, 0.15 mmol), and the solution was stirred for 30 min. A solution of iodomethane (0.1 mL, 1.6 mmol) in 1 mL HMPA was then added by syringe. The solution was stirred 15 min at -78° C., then warmed to 0° C. and quenched with saturated NH4Cl. The mixture was partitioned between ether and water and the organic layer was washed with water and brine and dried over MgSO4. The residue was purified by flash chromatography (15% ethyl acetate/hexanes) to provide 24 mg of the title compound.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Cl)(Cl)=O.[NH:41]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[CH2:42][C:43]([O:45][CH3:46])=[O:44]>>[CH3:51][O:50][C:48](=[O:49])[CH2:47][N:41]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:23](=[O:25])[C:22]1[CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: COC(=O)CNCC(=O)OC
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)N(CC(=O)OC)CC(=O)OC)c1

Procedure:
Conversion of 3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid to the acid chloride with thionyl chloride followed by treatment with dimethyl iminodiacetate gave N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy)benzoyl]glycine methyl ester as an oil after chromatography on 50 g of silica gel using 25% ethyl acetate-hexane. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=O)=[C:4]([N:11]([CH3:20])[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[CH3:21].BrC1SC(C(OC)=O)=C(NC)C=1C.CCN(C(C)C)C(C)C.ClC(=O)CC(OCC)=O>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]2[C:7]([OH:9])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12](=[O:19])[N:11]([CH3:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: CCOC(=O)CC(=O)N(C)c1c(C(=O)OC)sc(Br)c1C
Agent: CCOC(=O)CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: CNc1c(C(=O)OC)sc(Br)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2sc(Br)c(C)c2n(C)c1=O
Reaction time: 18 h

Procedure:
Methyl 5-bromo-3-(3-ethoxy-N-methyl-3-oxopropanamido)-4-methylthiophene-2-carboxylate. A solution of methyl 5-bromo-4-methyl-3-(methylamino)thiophene-2-carboxylate (0.28 g, 1.1 mmol), DIEA (0.22 mL, 1.3 mmol), N,N-dimethylpyridin-4-amine (0.020 g, 0.16 mmol) in DMF (4 mL) was treated at room temperature with ethyl 3-chloro-3-oxopropanoate (0.16 mL, 1.3 mmol) and stirred for 18 hours. The mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give the title compound. MS (ESI) m/z: Calculated 378.2; Observed; 379.0. 1H NMR (300 MHz, CDCl3) δ ppm 4.12-4.11 (2H, m), 3.86 (3H, s), 3.16 (3H, s), 3.12 (2H, s), 2.10 (3H, s), 1.23 (3H, t, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=O)=[CH:12][N:11]=[C:10]([CH2:17][N:18]2[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]2)[N:9]=1.N1C(C)=CC=CC=1C.CS(Cl)(=O)=O.[NH2:40][C:41]1[C:49]([CH3:50])=[CH:48][C:47]([Cl:51])=[CH:46][C:42]=1[C:43]([OH:45])=[O:44]>C(#N)C>[Cl:51][C:47]1[CH:48]=[C:49]([CH3:50])[C:41]2[N:40]=[C:14]([C:13]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:9][C:10]([CH2:17][N:18]4[N:22]=[N:21][C:20]([C:23]([F:24])([F:26])[F:25])=[N:19]4)=[N:11][CH:12]=3)[O:44][C:43](=[O:45])[C:42]=2[CH:46]=1
Reactant: O=C(O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cnc(Cn4nnc(C(F)(F)F)n4)nc3-c3ccccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At RT, 385 mg (1.30 mmol) of 4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}pyrimidine-5-carboxylic acid was initially charged in 5 ml of acetonitrile, and 0.27 ml (2.33 mmol) of lutidine was added. With stirring, the solution was then cooled to 0° C., 0.14 ml (1.78 mmol) of methanesulphonyl chloride, dissolved in 2 ml of acetonitrile, was added dropwise and the mixture was stirred at 0° C. for another 15 min. A little at a time, an acetonitrile suspension (3 ml) of 0.53 ml (4.54 mmol) of lutidine and 289 mg (1.56 mmol) of 2-amino-5-chloro-3-methylbenzoic acid was then added to this reaction mixture, and stirring was continued for another 15 min. 0.14 ml (1.78 mmol) of methanesulphonyl chloride, dissolved in 2 ml of acetonitrile, was then added dropwise. The reaction was stirred overnight, with the temperature increasing to RT. The solvent was removed under reduced pressure. The residue was then poured into ice-water and mixed in an ultrasonic bath. The residue was filtered off, again taken up in water and sonicated once more. The residue is filtered off, washed with water and dried under reduced pressure. 708 mg (88% of theory; content 86%) of the desired product were isolated. There was not further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:3][C:4]([OH:6])=O.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:3][C:4]([NH:26][CH2:25][CH2:23][OH:24])=[O:6]
Reactant: NCCO
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(=O)NCCO
Yield: 92 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-6,10,14-hexadecatrienoic acid and 1.8 ml of ethanolamine were used as starting materials. 6.4 g (yield 92%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:18](N=C=NCCCN(C)C)[CH3:19].C(O)C>C(OCC)C.CN(C)C1C=CN=CC=1>[CH2:18]([O:15][C:14](=[O:16])[CH2:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[CH3:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CC(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 95 %

Procedure:
In an oven-dried 250 mL round bottom flask under nitrogen, ((3R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (2.181 mmol) dissolved in diethyl ether (5 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.4 mmol), 4-(dimethylamino)pyridine (0.218 mmol), and ethanol (4.8 mmol) at room temperature and the mixture was stirred overnight. The resulting white gummy precipitate was diluted with ether (100 mL) and washed with 1M aq sodium hydrogen sulfate solution (100 mL), saturated aq sodium bicarbonate solution (100 mL), and brine (100 mL). The organic phase was isolated, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a clear oil (95%). MS(ES)+ m/e 258.1 [M+H]+, 280.0 [M+Na]+.
Reaction SMILES: CN(C)C=[N:4][C:5]1[S:6][C:7]([C:13]#[N:14])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([C:13]#[N:14])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11]
Reactant: CN(C)C=Nc1sc(C#N)c(Cl)c1C#N
Agent: Cl
Solvent: CCO
Product: N#Cc1sc(N)c(C#N)c1Cl
Yield: 92 %

Procedure:
A mixture of 5.4 parts of N,N-dimethyl-N'-(4-chloro-3,5-dicyanothien-2-yl)-formamidine, 40 parts of ethanol and 4.5 parts of concentrated hydrochloric acid is heated at the boil for 2 hours and filtered while hot, and the filtrate is poured into 100 parts of water. The precipitate which separates out is filtered off under suction, washed with water and dried. 3.8 g (92% of theory) of 2-amino-4-chloro-3,5-dicyanothiophene are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[CH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[S:50](Cl)(=[O:52])=[O:51]>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:50]([C:41]1[CH:42]=[CH:43][C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=1)(=[O:52])=[O:51])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccc4ccccc4c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 53 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1)was added 2-naphthalenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 53% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.OB(O)[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=2)[CH:11]=1
Reactant: Brc1ccccc1CC(c1cccnc1)c1cccnc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2ccccc2CC(c2cccnc2)c2cccnc2)c1

Procedure:
A solution of 3,3′-[2-(2-bromophenyl)ethane-1,1-diyl]dipyridine (30 mg, 0.05 mmol), 3-(dihydroxyboryl)benzoic acid (14 mg, 0.08 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5 mg, 0.006 mmol) in THF (2.0 mL) was treated aqueous Cs2CO3 (1.0 mL of a 1 M solution, 1.0 mmol) and sealed in a 5 mL microwave reaction tube. The mixture was irradiated at 160° C. for 10 min, cooled, and the phases separated. The organic phase was blown down under a stream of N2 and purified by reverse phase chromatography to provide the title compound. ESI+MS: 381.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14](O)[C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([Br:24])[C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(O)[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C(Br)[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
(S)-2-[Hydroxy-(6-methoxy-pyridin-3-yl)-methyl]-morpholine-4-carboxylic acid tert-butyl ester (290 mg, 0.90 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0° C. Tetrabromomethane (593 mg, 1.79 mmol) was added. Triphenylphosphine (305 mg, 1.16 mmol) was then added portionwise and the resulting reaction mixture was stirred at 0° C. for 10 min., then at room temperature for 1.25 h. Reaction was not complete so additional triphenylphosphine (45 mg) was added and the reaction was stirred at room temperature for 2.5 h. The reaction mixture was concentrated and purified by flash chromatography (1:2 EtOAc/heptane eluent) to afford (S)-2-[bromo-(6-methoxy-pyridin-3-yl)-methyl]-morpholine-4-carboxylic acid tert-butyl ester (295 mg, 85%) as a colorless liquid. The product was a mixture of diastereomers by NMR: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 3.5H) 1.48 (s, 5.5H) 2.54-3.06 (m, 2H) 3.47 (d, J=2.69 Hz, 0.65H) 3.54-3.64 (m, 0.45H) 3.66-3.88 (m, 3H) 3.93 (s, 3H) 3.97-4.06 (m, 0.45H) 4.23-4.48 (m, 0.55H) 4.83 (d, J=7.25 Hz, 1H) 6.70-6.78 (m, 1H) 7.69 (dd, J=8.60, 2.69 Hz, 1H) 8.13 (d, J=2.42 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]([CH:13]=1)=[N:10][O:11][N:12]=2.[ClH:14].[CH3:15][S:16]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[O:33][C:27]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:26][C:25](=[O:34])[C:24]=2[CH:35]=1)(=[O:18])=[O:17].C(=O)(O)[O-].[Na+].[I-].[K+].Cl>C(#N)C.CCOC(C)=O>[ClH:14].[N:12]1[O:11][N:10]=[C:9]2[CH:13]=[C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][C:27]4([CH2:26][C:25](=[O:34])[C:24]5[CH:35]=[C:20]([NH:19][S:16]([CH3:15])(=[O:17])=[O:18])[CH:21]=[CH:22][C:23]=5[O:33]4)[CH2:28][CH2:29]3)[CH:6]=[CH:7][C:8]=12
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: BrCCOc1ccc2nonc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCOc3ccc4nonc4c3)CC1)O2
Reaction time: 2 h
Yield: 62.2 %

Procedure:
5-(2-Bromoethoxy)benzofurazan (87 mg, 0.36 mmol), 3,4-Dihydro-6-methanesulfonamidospiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one hydrochloride (125 mg, 0.36 mmol), sodium bicarbonate (91 mg, 1.08 mmol) and potassium iodide (30 mg, 0.18 mmol) in acetonitrile (4 ml) were heated under reflux for 24 hr, cooled and aqueous sodium bicarbonate (saturated, 10 ml) was added. The mixture was extracted with dichloromethane (3×10 ml) and the combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (97:3:0.3), to give a yellow foam which was dissolved in EtOAc (2 ml). Ethanolic HCl (Ca. 1M, 2 ml) was added, the mixture was stirred for 2 h. and the solid was collected and dried in vacuo to give the hydrochloride as a white solid (114 mg, 62%), m.p.>250° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-benzyl-4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (2.11 g, 4.1 mmol) dissolved in TBF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.11 g (56%); white solid; mp 201° C.; MS: 485.9 (M+H)+