Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].BrC[CH2:11][C:12]([O:14][CH3:15])=[O:13].O>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8]
Reactant: COC(=O)CCBr
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
Sodium hydride (4.44 g, 60% dispersion in oil, 111 mmol) was added to a solution of 1,4-butanediol (10.0 g, 111 mmol) in THF (200 mL). After stirring 1 h at rt, the mixture was cooled to 0° C. and methyl bromomethylacetate (10.82 mL, 114 mmol) was added and the reaction was allowed to warm to room temperature. After 16 h, water (100 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (20%→30% EtOAc/Hexane) to afford 2.88 g (16%) of (4-hydroxy-butoxy)-acetic acid methyl ester as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([N:32]([CH3:36])[C:33](=[O:35])[CH3:34])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:30]=[C:31]([N:32]([CH3:36])[C:33](=[O:35])[CH3:34])[C:26]([O:25][CH3:24])=[N:27][CH:28]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N(C)C(C)=O
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1N(C)C(C)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-N-methyl-acetamide (Stage 62.1.1) to give the title compound as a white solid. (HPLC: tR 2.52 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.40-8.31 (m, 1H), 8.18-8.06 (m, 2H), 8.03-7.90 (m, 1H), 7.86-7.71 (m, 1H), 7.55-7.43 (m, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.57 (s, 3H), 3.07 (s, 3H), 1.94 (s, 3H), 1.74 (s, 3H))
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][C:18]=1[CH:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:33].CN(C1C=CC=CN=1)C.CCOCC>CN(C=O)C>[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][C:18]=1/[CH:23]=[C:24]1\[C:25](=[O:33])[N:26]([C:13](=[O:15])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:27]2[C:32]\1=[CH:31][CH:30]=[CH:29][CH:28]=2
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)CNC(=O)OCc3ccccc3)c3ccccc32)[nH]1
Temperature: 55 °C

Procedure:
A mixture of N-(benzyloxycarbonyl)glycine (4.9 g, 23 mmol), 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one (2.38 g, 10 mmol), dimethylaminopyridine (1.28 g, 10 mmol) in DMF (20 mL) was heated at 55° C. for 2 h. The solution was cooled, ether (10 mL) was added and the precipitate of the title compound was filtered off and dried to give 2.35 g, mp 193-196+ C. HPLC Rt 7.04 min. 1H NMR (CDCl3) δ2.34 (s, 3H), 2.42 (s, 3H), 4.87 (d, 2H), 5.18 (s, 2H), 5.74 (t, 1H), 6.06 (d, 1H), 7.2 (m, 3H), 7.3-7.65 (m, 7H), 7.49 (m, 1H), and 8.23 (m, 1H), for C25H23N3O4: C, 69.92; H, 5.40; N, 9.78. Found: C, 69.91; H, 5.50; N, 9.86.
Reaction SMILES: [CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8]C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([S:24][CH3:25])[N:18]=1>ClC1C=CC=CC=1Cl>[CH:1]1([P:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)([C:17]2[CH:22]=[C:21]([P:7]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[N:20]=[C:19]([S:24][CH3:25])[N:18]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COP(C1CCCCC1)C1CCCCC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: Clc1ccccc1Cl
Product: CSc1nc(P(=O)(C2CCCCC2)C2CCCCC2)cc(P(=O)(C2CCCCC2)C2CCCCC2)n1
Yield: 5.3 %

Procedure:
A mixture of 2.50 g of methyl dicyclohexylphosphinite and 1.00 g of 4,6-dichloro-2-methylthiopyrimidine in 20 ml of o-dichlorobenzene was refluxed under nitrogen for 6.5 hours. Volatiles were removed from the mixture under vacuum, and the resulting oily residue was recrystallized twice from cyclohexane with decolorizing charcoal treatment and dried at 100° C./0.1 mm (13 Pa) to give 0.15 g of 4,6-bis(dicyclohexylphosphinyl)-2-methylthiopyrimidine as white crystals, mp 197°-198.5° C. Anal. Calcd for C29H48N2O2P2S: C, 63.25; H, 8.79; N, 5.07; S, 5.82. Found: C, 63.19; H, 8.81; N, 4.89; S, 6.04.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[N:12]O)[CH3:11])=[CH:2]1.C(O)(=O)C.[H][H]>C(O)C.[C].[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([NH2:12])[CH3:11])=[CH:2]1
Reactant: CC(=NO)c1c[nH]c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(N)c1c[nH]c2ccccc12
Yield: 74.5 %

Procedure:
10% palladium-carbon (water content: 50%, 12.2 mg) was added to a solution of 1-(1H-indol-3-yl)ethanone oxime (0.20 g) obtained as above and acetic acid (0.7 mL) in ethanol (7 mL) at room temperature. The reaction mixture was stirred in a hydrogen stream at room temperature for 10 hours, and then filtered on a celite. The filtrate was concentrated under reduced pressure. The residue was extracted with chloroform. The organic layer was washed sequentially with a 1 N aqueous solution of sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:chloroform-methanol system) to obtain 0.137 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:20][CH:21]([F:31])[CH2:22]OS(C(F)(F)F)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:22][CH:21]([F:31])[F:20])[CH:3]=1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cc(Br)cc(NCC(F)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
4-Bromo-pyridine-2,6-diamine (2.2 g) was dissolved under an argon atmosphere in THF (15 mL) and cooled to 0° C. At this temperature LiHMDS (12.9 mL 1 M solution in THF) was added slowly to the solution. The reaction mixture was stirred at 0° C. for 1 h. After that difluorethyltriflate (2.76 g) was added and the reaction mixture was stirred at 25° C. for 18 h. Complete conversion was observed by LC-MS analysis. The reaction mixture was evaporated to dryness, dissolved in ethyl acetate and extracted with water and brine. The organic layer was dried over Na2SO4, filtrated and evaporated to dryness. The crude product was purified by flash chromatography over silica gel (70 g SiO2, gradient ethyl acetate/n-heptane 1:4->1:0) to yield 4-bromo-N-(2,2-difluoroethyl)-pyridine-2,6-diamine (0.943 g; 32%) as a dark red oil.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2c1CCCC2
Reaction time: 72 h

Procedure:
5,6,7,8-Tetrahydro-1-naphthol (9.85 g, 66 mM), methyl iodide (30.6 g, 215 mM) and potassium carbonate (15 g, 90.8 mM) in acetone (500 ml) were heated under reflux with stirring for 3 days. The mixture was evaporated and the residue was extracted with 2M sodium hydroxide and ether. The organic layer was washed and dried to give 1-methoxy-5,6,7,8-tetrahydronaphthalene as as oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][CH:31]([N:34]6[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]6)[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(C2CCN(c3cccc(Br)c3)CC2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(C2CCN(c3cccc(Nc4nc5c(-c6ccc(S(C)(=O)=O)cc6)cccn5n4)c3)CC2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-{3-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (55.0 mg, 0.191 mmol) and 1-[1-(3-bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine (69.0 mg, 0.204 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.035 g, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1.[C:30]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:31]=1.C([Sn](CCCC)(CCCC)C=C)CCC>CN1CCCC1=O.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.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([CH:30]=[CH2:31])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: C=Cc1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 153.4 %

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (1.0 g, 1.90 mmol) in N-methyl-2-pyrrolidinone (25 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol), triphenylarsine (60 mg, 0.2 mmol) and copper iodide (10 mg, 0.05 mmol) followed by tributyl(vinyl)tin (0.63 mL, 2.09 mmol). The reaction solution was heated to 105° C., stirred for 8 h, partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the layers separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with 10% 2 M ammonia/methanol solution in dichloromethane. The chromatography product was slurried in methanol and filtered to give 131 mg (16%) of a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][CH3:19]>>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][O:13][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COCCCCl
Reactant: O=c1ccc2ccc(CO)cc2[nH]1
Product: COCCCOc1ccc2ccc(CO)cc2n1

Procedure:
Analogously to Example 2c, 2.66 g of 7-hydroxymethyl-1H-quinolin-2-one are reacted with 3.34 ml of 1-chloro-3-methoxypropane. The title compounds are obtained as slightly yellowish oils.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:11])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[NH2:39].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][O:36][C:37](=[O:42])[C:38]([NH:39][C:8]([C:5]1[CH:4]=[C:3]([I:11])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:41])[CH3:40]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cc(I)c(Cl)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1cc(I)c(Cl)cn1
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-4-iodo-2-pyridinecarboxylic acid (CAN 120643-06-3, 100 mg, 353 μmol) in DMF (2 mL) was added TBTU (170 mg, 529 μmol) and 2-methyl-alanine methyl ester hydrochloride (59.6 mg, 388 μmol) to give a light yellow suspension. DIEA (308 μL, 1.77 mmol) was added and the reaction mixture was stirred for 3 h. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) to deliver the desired compound (40.5 mg, 30%) as yellow oil. MS (ESI, m/z): 382.9 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Br:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-bromo-4-methylphenol (5.0 g, 27 mmol) and K2CO3 (7.4 g, 53 mmol) in DMF (20 mL) was added benzyl bromide (3.5 mL, 29 mmol) at ambient temperature. It was stirred at 70° C., for 12 h. The mixture was poured into water (50 mL), extracted with EtOAc (150 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1) to give the title compound (3a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14]Br)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C-:20]#[N:21].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][C:20]#[N:21])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(Sc2ccccc2CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(Sc2ccccc2CC#N)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
2-(3,5-Dimethoxyphenylthio)benzyl bromide (9.53 g) was dissolved in dimethyl sulfoxide (90 ml), sodium cyanide (2.77 g) was added thereto and the mixture was stirred at 80° C. for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1) to give 2-(3,5-dimethoxyphenylthio)-benzyl cyanide (4.91 g, yield of 61%).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH2:24][CH2:25]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:25][CH2:24][CH:23]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: ClCCC=C(c1ccccc1)c1ccccc1
Product: O=C(NC1CCN(CCC=C(c2ccccc2)c2ccccc2)CC1)c1ccccc1

Procedure:
Using the procedure of Example 77 over a period of 20 hours, 4-benzamidopiperidine (7.473 g.) was alkylated with 1,1-diphenyl-4-chlorobut-1-ene (8.879 g.). The title compound was filteredoff after addition of water and ether to the reaction mixture and a furthercrop was obtained from the ether washings. Conversion of the combined product to the hydrochloride using ethanolic hydrogen chloride gave 6.308 g. (38.2%). m.p. 220°-230° (dec.). C28H30N2O.HCl.1/4H2O requires C, 74.46; H, 7.03; N, 6.20. Found: C, 74.77; H,7.26; N, 6.14%.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35])[C:27](OC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO.O1CCOCC1>[CH2:32]([C:31]1[N:6]=[C:4]([CH:3]([CH3:7])[CH3:2])[NH:5][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: CC(C)C(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nc(C(C)C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 62.8 %

Procedure:
A solution of 2-methylpropanimidamide hydrochloride (10 g), 28% sodium methoxide (25 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (14 g) in methanol (140 mL) and 1,4-dioxane (70 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (9.7 g, 62%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[C:7]([Cl:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C([O:33]CC)C>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:33])=[C:7]([Cl:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C=O)c(Cl)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a diethyl ether (17 ml) solution of 6-tert-butyl-2-chloronicotinonitrile (Tetrahedron 1965, 21, 2453-2467, 1.0 g, 5.4 mmol) was added 0.94 M diisobutylaluminum hydride in toluene solution (8.6 ml, 8.0 mmol) at −78° C. and the reaction was allowed to warm to room temperature over 2 hours with stirring. Then the reaction was quenched with 10% potassium sodium tartrate tetrahydrate aqueous solution and the whole was extracted with EtOAc, and washed with 2M sodium hydroxide aqueous solution and brine. The organic layer was evaporated and purified by silica gel column chromatography, eluting with hexane/EtOAc (5:1), to give 6-tert-butyl-2-chloronicotinaldehyde (1.0 g, 95%). To a THF (24 ml) suspension of methyltriphenylphosphonium bromide (5.3 g, 14.8 mmol) was added 1.60 M n-butyllithium (9.3 ml, 14.8 mmol) in hexane solution at 0° C. and the reaction was stirred for 30 minutes. Then to this mixture was added a THF (5 ml) solution of the 6-tert-butyl-2-chloronicotinaldehyde (1.0 g, 5.2 mmol) at 0° C., and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution, and the whole was extracted with EtOAc, and dried over magnesium sulfate. The organic layer was evaporated and purified by silica gel column chromatography, eluting with hexane/EtOAc (10:1), to give the title compound (735 mg, 71%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14].C([Li])CCC.Cl[CH:21]([SiH3:23])Cl>CCCCCC.O>[CH3:21][SiH:23]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: [SiH3]C(Cl)Cl
Reactant: Cc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: C[SiH]1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 1 L rb flask equipped with a Teflon covered magnetic stirring bar and a reflux condenser was placed potassium tert-butoxide (36 g; 0.32 mol), o-xylene (17 mL; 0.15 mol) and 700 mL of hexanes. n-Butyllithium (128 mL; 2.5M) in hexane was added to the above mixture via a syringe. The red color of the o-xylene dianion appeared. The resulting mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temp. The suspension of the dianion was transferred via a cannula to a sintered glass filter. The solvent was removed by suction filtration. The precipitated dianion was rinsed with fresh hexane. It was then resuspended in 500 mL of hexane and the suspension returned via a cannula to the original apparatus. Freshly distilled dichloromethylsilane (17 mL; 0.16 mol) was added. The mixture was stirred overnight a room temperature. 50 mL water was added. The organic layer was washed three times with water, dried over anhydrous calcium chloride, filtered and the solvents removed by evaporation under reduced pressure. The residue was purified by fractional distillation through a 15 cm vacuum jacketed Vigreux column. A central fraction, b.p. 43°-44° C./0.7 mmHg, was obtained. Yield: 5.5 g(25%).
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:56])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[CH3:57][N:58]([CH3:63])[S:59](Cl)(=[O:61])=[O:60]>>[Cl:55][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][C:51]=1[Cl:54])[CH2:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([C@H:38]2[CH2:37][O:36][C:32]3=[CH:33][C:34]4[CH2:35][C@@H:26]([C:24]([NH:23][C@@H:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([O:14][C:15]6[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=6[CH3:22])=[CH:12][CH:13]=5)[C:5]([OH:4])=[O:56])=[O:25])[N:27]([S:59](=[O:61])(=[O:60])[N:58]([CH3:63])[CH3:57])[CH2:28][C:29]=4[CH:30]=[C:31]3[O:39]2)=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Product: Cc1nccc(Oc2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3S(=O)(=O)N(C)C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester bis hydrochloride was coupled with N,N-dimethylsulfamoyl chloride according to General Procedure E. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (9 mg). LCMS (m/z) 862.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[C:22](=O)[CH2:23][N:24]([CH3:28])[S:25](=[O:27])(=[O:26])[C:20]=4[CH:19]=[CH:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[C:22](=[N:31][OH:32])[CH2:23][N:24]([CH3:28])[S:25](=[O:27])(=[O:26])[C:20]=4[CH:19]=[CH:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CN1CC(=O)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC(=NO)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Temperature: 60 °C
Reaction time: 21 h
Yield: 82.7 %

Procedure:
A suspension of 168 mg (0.4 mmol) of Compound 25 and 111 mg (1.6 mmol) of hydroxylamine hydrochloride in 10 ml of pyridine was stirred for 21 hours over an oil bath of 60° C. Post-treatment was conducted in a similar manner as in Example 18. The residue was purified by chromatography on a silica gel column (eluent:methanol/chloroform=1/99), whereby 144 mg of the title compound were obtained (yield: 83%).