Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cncc(-c3ccc(C#N)c(Cl)c3)c2)cc1
Yield: 44.3 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added 4-methyl-benzenesulfonyl chloride (18.3 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-methyl-benzenesulfonamide (14.8 mg, >95% purity, yield: 44.3%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 384 [M+H]+, retention time=2.35 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 7.31-7.36 (m, 2H) 7.64-7.68 (m, 2H) 7.73 (d, J=1.64 Hz, 1H) 7.75 (d, J=2.02 Hz, 1H) 7.99 (d, J=1.52 Hz, 1H) 8.07 (d, J=8.21 Hz, 1H) 8.28 (d, J=2.27 Hz, 1H) 8.62 (d, J=1.77 Hz, 1H) 10.64 (br. s., 1H).
Reaction SMILES: CS(O[CH:6]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1)[CH2:7][O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:14]1[N:13]=[CH:12][N:11]2[CH:6]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[CH2:7][O:8][CH2:9][C:10]=12
Reactant: CS(=O)(=O)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2COCc3cncn32)cc1
Temperature: 80 °C

Procedure:
A solution of 1.00 mmol of 1-(4-cyanophenyl)-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl methanesulphonate in 5 ml of N,N-dimethylformamide is mixed with 2.50 mmol of caesium carbonate and heated at 80° C. for 6 hours. The reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate (2×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained from the residue as yellowish crystals by flash chromatography (SiO2 60F). Rf=0.61 (dichloromethane-methanol-25% aqueous ammonia solution 200:10:1); Rt=3.54 (gradient II).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([NH2:14])=[O:13])[C:6]1([CH3:16])[CH3:15])=[O:4].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([NH2:14])=[O:13])[C:6]1([CH3:16])[CH3:15])=[O:4])(=[O:19])[CH3:18]
Reactant: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CN
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCC(=O)N1CC(=O)N(CC(N)=O)C1(C)C

Procedure:
A solution of 3-(2-aminoacetyl)-2,2-dimethyl-5-oxo-1-imidazolidineacetamide (2 g) in acetic anhydride (10 ml) was stirred at 80° C. for 5 minutes. After cooling, the precipitate was collected and washed with acetone, affording the title compound as a white powder, m.p. 222° C. dec.
Reaction SMILES: [O:1]([CH3:11])[C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4].C(N(CC)CC)C.[C:19]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:23]([CH:9]([OH:10])[C@H:7]1[O:8][C@@H:2]([O:1][CH3:11])[C@H:3]([OH:4])[C@@H:5]1[OH:6])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a mixture of methyl β-D-ribofuranoside (Sigma Chemical Co., 460 mg, 2.8 mmol) and anhydrous methylene chloride (20 ml) were added triethylamine (0.468 ml, 3.36 mmol), t-butyldiphenylchlorosilane (0.9 ml, 3.46 mmol), and DMAP (13.7 mg, 0.112 mmol) successively at room temperature. The reaction mixture was stirred for 18 h at room temperature under nitrogen. The reaction mixture was washed with water (20 ml), saturated ammonium chloride (20 ml), and brine (20 ml), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was separated by silica gel column chromatography (CHCl3 --MeOH, 50:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside [Rf =0.48 (CHCl3 --MeOH, 10:1), 618 mg, 54.8%] as a thick syrup. 1H NMR (DMSO-d6) d 0.96 (s, 9H, t-Bu), 3.22 (s, 3H, --OCH3), 3.61 (dd, J=11.0 and 5.3 Hz, 1H), 3.74 (d, J=4.4 Hz, 1H), 3.81 (dd, J=11.0 and 2.7 Hz, 1H), 3.90 (m, 1H), 4.00 (m, 1H), 4.68 (s, 1H, H-1'), 4.84 (br s, 1H, exchangeable with D2O, OH), 5.05 (br s, 1H, exchangeable with D2O, OH), 7.45 and 7.67 (m, 10H, Ph2). Anal. Calcd for C22H30O5Si: C, 65.64; H, 7.51; Found: C, 65.73; H, 7.55.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[S:8]([NH2:11])(=[O:10])=[O:9].[BH4-].[Na+].Cl>C1COCC1.CO>[OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)C1COCCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)C1COCCC1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
4-Oxotetrahydropyran-3-sulfonamide (1.09 g) was dissolved in 2:1 THF/methanol (110 ml), sodium borohydride (0.23 g) was added in portions and the mixture was stirred at room temperature for 18 hours. Concentrated hydrochloric acid was then used to set the pH to 2 and then the solvent was removed under reduced pressure. The residue was purified by chromatography (solvent: dichloromethane/methanol). This gave the product (0.65 g) with a molecular weight of 181.2 g/mol (C5H11NO4S).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:20][CH2:19][CH2:18][N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1]
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1nc2ccccc2n(CCO)c1=O

Procedure:
3,4-Dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (1 g), 2-bromoethanol (1.15 g) and anhydrous potassium carbonate (3 g) were heated under reflux in butanone (100 ml) for 5 hours. The mixture was cooled and the solid was filtered off. The filtrate was evaporated to give an oil which was crystallised from a mixture of benzene and light petroleum (b.p. 60°-80°). It had m.p. 137°-138°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:15][C:12]([CH3:16])([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:13]#[CH:14]
Reactant: N#Cc1ccc(O)cc1F
Reactant: C#CC(C)(C)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C#CC(C)(C)Oc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
10 g (0.072 M) of 2-fluoro-4-hydroxybenzonitrile, 0.072 M of 3-chloro-3,3-dimethylpropyn and 15 g (equivalent to 16.3 ml or 0.036 M) of benzyl-trimethylammonium hydroxide (40% strength in methanol) are suspended in 80 ml of methylene chloride, a solution of 4.32 g (0.108 M) of NaOH in 80 ml of water is added, and the mixture is stirred at room temperature for 3 days. The phases are separated, and the aqueous phase is extracted several times with methylene chloride. The organic solution is washed with 10% strength NaOH and then with water and the organic solvent is distilled off under reduced pressure. 4-(1,1-Dimethyl-2-propynyloxy)-2-fluorobenzonitrile is obtained as a red-colored oily product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][CH:33]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[C:23]([Br:22])[CH:24]=3)[C:27]2=[O:28])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(N2C(=O)c3ccc(Br)cc3C2=O)cc1)NC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 70.3 %

Procedure:
To a suspension of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (6.78 mmol, 1.99 g) in dichloromethane (90 mL) was added a solution of 4-bromophthalic anhydride (6.78 mmol, 1.54 g) in dichloromethane (30 mL) and 1,1′-carbonyldiimidazole (6.78 mmol, 1.1 g) at room temperature. The resulting solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water (100 mL) and layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave a crude product which was purified by silica gel column chromatography to obtained 2.4 g (70%) of a white solid: mp 168-170° C. HR MS C23H23BrN2O6): Obs mass, 525.0656. Calcd mass, 525.0637 (M+Na).
Reaction SMILES: C([O:8][N:9]1[CH:12]([CH2:13][O:14]CC2C=CC=CC=2)[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:27](=[O:31])[NH:26][C:25]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:24][C:23]2=3)[C:10]1=[O:41])C1C=CC=CC=1.[H][H]>[Ni].CO>[OH:8][N:9]1[CH:12]([CH2:13][OH:14])[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:27](=[O:31])[NH:26][C:25]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:24][C:23]2=3)[C:10]1=[O:41]
Reactant: O=C(Nc1nc2c(ncn2C2C(=O)N(OCc3ccccc3)C2COCc2ccccc2)c(=O)[nH]1)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: O=C(Nc1nc2c(ncn2C2C(=O)N(O)C2CO)c(=O)[nH]1)c1ccccc1

Procedure:
1-N-Benzyloxy-3-(N-benzoylguanin-9-yl)-4-benzyloxymethyl-2-azetidinone (10 mmole) and methanol (50 ml) is hydrogenated using Raney nickel (5 g) and hydrogen at a pressure of 40 psi for 6 hours. The reaction mixture is filtered, the catalyst washed with methanol (20 ml) and the combined methanol fractions are concentrated to give the title compound as a solid.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH2:9][CH3:10])[C:4](=[O:8])[CH:5]([Cl:7])[Cl:6].O.C(=O)(O)[O-].[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:29])[C:27]=1[CH3:28])[C:22](Cl)=[O:23]>C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:29])[C:27]=1[CH3:28])[C:22]([NH:2][C:3]([CH2:9][CH3:10])([CH3:11])[C:4](=[O:8])[CH:5]([Cl:7])[Cl:6])=[O:23]
Reactant: CCC(C)(N)C(=O)C(Cl)Cl
Reactant: Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(C)(NC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)C(Cl)Cl
Yield: 85.9 %

Procedure:
In a 100 mL three-necked round bottomed flask was placed 0.93 g of 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride and 5 mL of water. To the resulting solution was added 0.76 g of sodium bicarbonate followed by 20 mL of ethyl acetate. To the resulting well-stirred mixture was added 0.94 g of 3,5-dichloro-4-methylbenzoyl chloride dissolved in 20 mL of ethyl acetate at room temperature over a period of 5 minutes. After the addition was complete the reaction mixture was stirred at room temperature for 1 hour. The two phases were separated and the organic layer was washed with water (2×25 mL), brine (1×25 mL), dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator yielding 1.34 g (84% yield) of 3,5-dichloro-N-(3,3-dichloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide as a white solid. This solid was used as such in the following step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCOCC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 4, Step D) and morpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C19H17IN4O4S, 524.0; m/z found, 523 [M−H]−. HPLC (reverse phase): RT=8.32 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 9.06 (d, J=1.8 Hz, 1H), 9.02 (d, J=1.8 Hz, 1H), 9.01 (br s, 1H), 8.51 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.90 (dd, J=8.4, 7.4 Hz, 1H), 7.38 (dd, J=8.0, 1.6 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 3.70-3.40 (br m, 6H), 3.30-3.05 (br m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH:19]=[C:18]([CH2:20][OH:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[N:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].C(OC(N1CCC(N2C=NC(C[O:45][S:46]([CH3:49])(=O)=[O:47])=N2)CC1)=O)(C)(C)C>>[CH3:49][S:46]([O:21][CH2:20][C:18]1[C:17]([C:22]([F:25])([F:24])[F:23])=[N:16][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)[CH2:14][CH2:13]2)[CH:19]=1)(=[O:47])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(COS(C)(=O)=O)n2)CC1
Reactant: CCc1cnc(N2CCC(n3cc(CO)c(C(F)(F)F)n3)CC2)nc1
Product: CCc1cnc(N2CCC(n3cc(COS(C)(=O)=O)c(C(F)(F)F)n3)CC2)nc1

Procedure:
The title compound was synthesized using (1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol in a manner similar to that described in Intermediate 1, Step 3.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[N:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1=CCNCC1
Product: O=C(c1ccccc1)N1CC=CCC1

Procedure:
The target compounds were synthesized as depicted in Schemes 1-3. The synthesis started with 1,2,3,6-tetrahydropyridine, in which the secondary amine was first protected by reacting with benzoyl chloride to form benzamide 10. The alkenyl double bond of compound 10 was oxidized by meta-chloroperoxybenzoic acid (m-CPBA) to form epoxide 11. The epoxide 11 was refluxed with substituted 4-benzoylpiperidine hydrochloride salts, namely (4-(4′-fluorobenzoyl)piperidine hydrochloride or 4-(4′-methoxybenzoyl)piperidine hydrochloride), in ethanol with triethylamine as the base to afford tertiary amino alcohol intermediates. To improve the yield, commercially available 4′-substituted 4-benzoylpiperidine hydrochloride salts were used in excess and the reaction temperature was kept below 75° C. This reaction afforded (3′-hydroxy-1,4′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates and their regioisomers, (4′-hydroxy-1,3′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates. The separation of these regioisomers by silica gel chromatography was difficult. The mixture of corresponding regioisomers was reacted with acetic anhydride to convert the free hydroxyl group to the corresponding acetates 12a-d. Subsequently, 12a and 12b were separated easily by silica gel chromatography. To confirm the structures of the regioisomers (12a(c) and 12b(d)), in addition to 1D NMR, 2D NMR was performed for regioisomers, 12c and 12d. The 1H, 13C NMR and HMQC spectra showed δH=5.31/2.68, 3.79/3.12, 2.06/1.47, 3.70, 2.48 and δH=4.89/2.66, 4.09/2.82, 1.95/1.41, 3.43 and 2.41 belong to the CH2-a, CH2-c, CH-d and CH-e (FIG. 2). The exact regioisomer (12a(c) or 12b(d)) were further verified by 1H-1H COSY. For regioisomer 12c, the correlations were observed between δH=5.31 (CH-a)/δH=2.68 (CH-a′) and δH=2.48 (CH-e); δH=3.79 (CH-b)/δH=3.12 (CH-b′) and δH=2.06 (CH-c)/δH=1.47 (CH-c′). In contrast, for regioisomer 12d, δH=4.89 (CH-a)/δH=2.66 (CH-a′) has no correlation with δH=2.41 (CH-e), and δH=4.09 (CH-b)/δH=2.82 (CH-b′) and has no correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′), but it has correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′) and δH=1.4I(CH-d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][OH:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1.N1C=CC=CC=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCO
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-hydroxyethoxy)benzoylamino]-nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g )in pyridine (10 ml) is added with stirring methanesulfonyl chloride (0.1 ml) under ice-cooling, and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dissolved in dichloromethane. The mixture is washed successively with diluted hydrochloric acid and water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.59 g) as white powder.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[C@H:14]([C:15]([F:18])([F:17])[F:16])[CH2:13][NH:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[NH2:8][CH2:9][C@H:10]1[C@H:14]([C:15]([F:18])([F:16])[F:17])[CH2:13][NH:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H]1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@@H]1CNC[C@H]1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
In 1 ml of dichloromethane, is dissolved 202 mg (0.754 mmol) of trans-3-(tert-butoxycarbonylaminomethyl)-4-trifluoromethylpyrrolidine. To the above solution, is added 1 ml of trifluoroacetic acid on cooling with ice, and the mixture is stirred at 0° C. for 1 hour. To the reaction mixture, is added 0.19 ml of conc-hydrochloride, and the mixture was concentrated under reduced pressure to give 161 mg of the objective substance as a slightly yellow powder (yield 88.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:26])=O>>[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Yield: 87 %

Procedure:
A mixture of 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (638 mg, 2 mmol) and thionyl chloride (8 ml) was heated at reflux for 30 minutes. Excess thionyl chloride was removed by evaporation and by azeotroping with toluene (x2). The residue was suspended in methylene chloride and 10% aqueous solution of sodium hydrogen carbonate was added to the mixture. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, the solid was collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (590 mg, 87%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([N:16]([CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)(=[O:18])=[O:19])[C:10]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1[C@H](N(CCN2CCOCC2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Temperature: 50 °C
Yield: 79.9 %

Procedure:
To a solution of 1.51 g of N-(1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-4-(4-chloro-phenoxy)-benzenesulfonamide from Example 1 Step E in 20 mL of methylsulfoxide (DMSO) was added 2.9 g of Cs2CO3(s) and 1.2 g of 4-(2-chloroethyl)-morpholine hydrochloride. The mixture was heated to 50° C. for 1 hour. The reaction was cooled, and then dissolved with ethyl acetate. The organic layer was washed with NH4Cl(aq) and NaCl(aq) solutions. The aqueous layers were re-extracted with ethyl acetate, and the organic layers were combined and dried over Na2SO4(s). Filtration and solvent removal was followed by column chromatography on silica gel using a hexanes-ethyl acetate gradient. Obtained 1.48 g of a pale brown oil (80% yield). MS: 612 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]3)=[O:16])[NH:12][C:9]2=[N:10][CH:11]=1.[CH3:25][C@H:26]1[NH:30][C@H:29]([CH3:31])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:23][C:20]1([F:24])[CH2:21][CH2:22][N:17]([C:15]([C:13]2[NH:12][C:9]3=[N:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:30]4[C@H:26]([CH3:25])[CH2:27][CH2:28][C@H:29]4[CH3:31])[CH:7]=[C:8]3[CH:14]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: O=C(c1cc2cc(OCCCCl)cnc2[nH]1)N1CCC(F)(F)CC1
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CC[C@@H](C)N1CCCOc1cnc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Yield: 6 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from [5-(3-chloro-propoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, (2R,5R)-(−)-trans-2,5-dimethylpyrrolidine (commercially available) and potassium carbonate in acetonitrile to give 23 mg (6%) of the desired product as a light yellow solid.