Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:27](I)[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([O:13][CH2:27][CH3:28])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reaction time: 71 h
Yield: 95.1 %

Procedure:
To a suspension of (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (9.98 g, 27.9 mmol) and NaHCO3 (4.68 g, 55.7 mmol) in DMF (45 mL) is added Ethyl iodide (6.75 mL, 84 mmol) at room temperature under nitrogen. After stirring for 71 hours, the reaction is quenched with H2O (300 mL), and then precipitated solid is collected and washed with H2O (500 mL) to give (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (10.25 g, 94%). HPLC retention time=1.48 minutes (condition B); MS (ES+)=329.9 (m-tBu+2); 286.0 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.2 Hz, 3H) 1.40 (s, 9H), 2.43 (A of ABX, Jab=15.8 Hz, Jax=5.7 Hz, 1H) 2.50 (B of ABX, Jab=15.8 Hz, Jbx=5.4 Hz, 1H) 2.74-2.90 (m, 2H) 4.11 (br s) 4.15 (q, J=7.1 Hz, 2H) 5.04 (br d) 7.07 (d, J=8.3 Hz, 2H) 7.40-7.43 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:53][CH2:52][CH2:51][CH:50]2[C:54]([O:56][CH3:57])=[O:55])=[CH:45][CH:44]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:53][CH2:52][CH2:51][CH:50]3[C:54]([O:56][CH3:57])=[O:55])=[CH:45][CH:44]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCN1c1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCCN1c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmole) in dichloromethane (6 ml) were added N,N-DIISOPROPYLETHYLAMINE (104 mg, 140 μl, 0.802 mmol) and methyl 1-(4-aminophenyl)pyrrolidine-2-carboxylate hydrochloride (50.2 mg, 0.196 mmol, Beta Pharma) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (90.3 mg, 0237 mmole, Chem-Impex) and the reaction mixture was stirred at rt for 1 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 5% to 100% EtOAc in hexanes) to give methyl 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylate (72.4 mg, 84%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 669. found: 669.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)=[N:14][CH:15]=1
Reactant: Nc1ccc(F)cn1
Reactant: Clc1nccc2cccnc12
Product: Fc1ccc(Nc2nccc3cccnc23)nc1

Procedure:
The title compound, MS: m/e=241.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-[1,7]naphthyridine and 2-amino-5-fluoropyridine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:14][NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:14][N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3-Trifluoromethylbenzoyl chloride (30 mg, 0.14 mmol, CAS RN 2251-65-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (20 mg, 0.10 mmol, example 1, intermediate a) and DIPEA (30 μL, 0.17 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (17 mg, 46%). MS (ESI): m/z=371.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[C:12]1([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.CC(C)=O>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:1][C:22]([NH:21][S:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:20])=[O:19])=[O:23])[N:7]=1
Reactant: Cc1cc(N(C)C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cc(N(C)C)nc(NC(=O)NS(=O)(=O)c2ccccc2)n1
Reaction time: 4 h

Procedure:
To a suspension of 15.2 g of 2-amino-4-dimethylamino-6-methylpyrimidine in 400 ml of methylene chloride at ambient temperature was added slowly 18.3 g of benzenesulfonylisocyanate. After stirring for four hours the mixture was stripped in-vacuo and the white semisolid residue triturated with ethyl ether and isolated by filtration. The solid was then slurried in hot acetone, cooled and refiltered to yield the solid named above which decomposed at 180°-182°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:31])[C:18]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:31])[C:18]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)([OH:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)[CH:3]=1
Reactant: Cc1ccnc(C=O)c1
Reactant: O=C(NC1CCNCC1)C(O)(c1ccccc1)C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccnc(CN2CCC(NC(=O)C(O)(c3ccccc3)C3CCCC3)CC2)c1

Procedure:
75 Milligrams of 4-methyl-2-pyridinecarbaldehyde, 58.3 mg of N-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide and 12 mg of acetic acid were dissolved in 10 ml of dichloroethane. To the solution 68 mg of sodium triacetoxyborohydride was added at room temperature, followed by an hour's stirring at the same temperature. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The residue was purified by preparative thin layer chromatography [Kieselgel™ 60F254Art 5744 (Merck), chloroform/methanol=9/1] to give 49.5 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][C:3]=1[F:23].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:20])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=2)=[O:15])=[CH:4][C:3]=1[F:23]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Reactant: COc1cc(CN)on1
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)c(F)c3)c2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BR) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 100%, 458.0537 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>CN(C)C=O>[C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1)(=[O:21])[CH:19]=[CH2:20]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc(C(N)=O)cc1
Yield: 60 %

Procedure:
4-Aminobenzamide (29 mmol) and triethylamine (33 mmol) were dissolved in dimethylformamide (100 mL) and acryloyl chloride (33 mmol) was dropped thereinto under ice-cooling. After the completion of the addition, the resultant mixture was stirred at room temperature for 2 hours. After filtering off the precipitate, the solvent was distilled off. Then the solid matter thus obtained was recrystallized from a solvent mixture of water with methanol to give 4-acrylamidobenzamide at a yield of 60%.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)=[O:2].OO.[O-:20]Cl=O.[Na+].OS([O-])=O.[Na+]>C(#N)C.O>[C:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)([OH:20])=[O:2]
Reactant: COC(=O)C[C@H]1CCc2c1ccc(C=O)c2C
Reactant: [O-][Cl+][O-]
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C[C@H]1CCc2c1ccc(C(=O)O)c2C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To an ice-cold solution of methyl (R)-(5-formyl-4-methyl-indan-1-yl)acetate (872 mg, 3.76 mmol, from Step C), NaH2PO4 (150 mg) and 30% H2O2 (500 μL) in acetonitrile (10 mL) and H2O (2.5 mL), a solution of NaClO2 (615 mg) in H2O (4 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature over 1 hr. After another hour, NaHSO3 (1.0 g) was added and the mixture was partitioned between EtOAc (30 mL) and 2.0 N HCl (15 mL). The layers were separated and the organic layer was washed with H2O (2×15 mL), brine (1×15 mL) dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give 854 mg of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.74-1.82 (m, 1H), 2.40-2.50 (m, 2H), 2.56 (s, 3H), 2.78 (dd, 1H, J=5.5, 15.5 Hz), 2.82-2.93 (m, 1H), 2.94-2.99 (m, 1H), 3.61-3.66 (m, 1H), 3.73 (s, 3H), 7.07 (d, 1H, J=7.8 Hz), 7.89 (d, 1H, J=8.0 Hz), 10.8-12.0 (br, s 1H); HPLC A: rt=2.74 min, m/z=249 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=[O:16])[CH2:4][CH3:5].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CO>[CH2:17]([N:11]1[C:10]2[C:9](=[O:15])[NH:8][C:7](=[O:16])[N:6]([CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=[CH:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4.12 g (0.103 mol) of sodium hydroxide dissolved in 41 ml of water were added to a suspension of 20 g (0.103 mol) of 3-propylxanthine in 112 ml of methanol and the reaction mixture was stirred at 70° C. for one hour, then treated dropwise at the same temperature with 12.23 ml (0.103 mol) of benzyl bromide and kept between 70° and 80° C. for 4 hours. The mixture was cooled, filtered cold on a suction filter, and the product was washed with water on the suction filter and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](I)=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[O:27])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([C:23]4[CH:22]=[C:21]([NH:25][C:26]([NH:28][CH2:29][C:30]([F:31])([F:32])[F:33])=[O:27])[CH:20]=[CH:19][CH:24]=4)=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccn3c(I)cnc3c2)cc1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Temperature: 80 °C
Yield: 76.8 %

Procedure:
A mixture of 7-(4-fluoro-phenyl)-3-iodo-imidazo[1,2-a]pyridine (10.1 g, 29.8 mmol), 1-(3-bromo-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (12.3 g, 35.8 mmol) and 2M sodium carbonate (120 mL) in dimethoxyethane (595 mL) was deoxygenated by evacuation/refill with N2 (×3). Tetrakis(triphenylphosphine)palladium (1.72 g, 1.49 mmol) was added, the resulting mixture was deoxygenated again (×3) and then heated at 80° C. under N2 overnight. The reaction was allowed to cool to RT, and solvents were removed under reduced pressure. The crude mixture was diluted with water (100 mL), EtOAc (100 mL) and DCM (100 mL) with stirring. The resulting slurry was filtered, the solid was washed with EtOAc and dried under vacuum to give the title compound (9.8 g). 1H NMR (400 MHz, DMSO-d6) δ 8.98 (1H, s), 8.61 (1H, d), 7.99 (1H, s), 7.96-7.87 (2H, m), 7.79 (2H, s), 7.45 (2H, d), 7.41-7.30 (3H, m), 7.30-7.23 (1H, m), 6.87 (1H, bt), 4.00-3.89 (2H, m). MS: [M+H]+ 429
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:14]([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:20]([CH3:21])[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)OC(C)(C)C)n1ccccc1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 71.7 %

Procedure:
To a stirred solution of 9.5 g (0.10 mol) of 2-hydroxypyridine in 250 mL of DMF was added 16.6 g (0.120 mol) of potassium carbonate followed by 25.0 g (0.120 mol) of 2-bromopropionic acid tert-butyl ester. The resulting mixture was stirred at ambient temperature for 7 h then diluted with 1 L of water. The aqueous phase was extracted with ethyl acetate (3×200 mL) and the combined organics were washed with water (2×100 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexanes to afford the title compound as a clear gum 16 g (72%). LC-MS: m/z (ES) 224 (MH)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC2CCCCO2)cc1
Yield: 99.9 %

Procedure:
In a manner similar to Preparation 5 stir 4-methoxyphenol (0.161 mol), 3,4-dihydro-2H-pyran (0.193 mol), CH2Cl2 (50 mL), p-TsOH (0.161 mol) at 0° C. for 10 minutes, then add triethylamine (1.77 mol). Evaporate, add diethyl ether (Et2O), and extractively work up to give 33.5 g (100%) of 2-(4-methoxyphenoxy)tetrahydro-2H-pyran as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.06-6.95 (m, 2H), 6.89-6.77 (m, 2H), 5.31 (t, J=3.3 Hz, 1H), 4.00-3.89 (m, 1H), 3.78 (s, 3H), 3.64-3.56 (m, 1H), 2.07-1.93 (m, 1H), 1.88-1.83 (m, 2H), 1.65 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 154.49, 151.09, 117.78, 114.49, 97.31, 62.11, 55.67, 30.50, 25.27, 18.95.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=O.C(N(CC)CC)C.ClC(OCC)=O.[C:27]1([CH2:33][CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:27]1([CH2:33][CH2:34][NH:35][C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(C(=O)NCCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
20.1 g (0.1 mol) of 4-carboxy-benzenesulfonamide were suspended in 300 ml of anhydrous tetrahydrofuran, and 15.2 ml (0.11 mol) of triethylamine were added dropwise at 0° C., while stirring. After 30 minutes, 10.5 ml (0.11 mol) of ethyl chloroformate were added dropwise at 0° C., the mixture was stirred at this temperature for 1 hour and cooled to -10° C., and 12.1 g (0.1 mol, 12.5 ml) of 2-phenylethylamine in 30 ml of anhydrous tetrahydrofuran were added dropwise. After 1 hour at 0° C., the mixture was warmed to 20° C. and concentrated in vacuo and the solid residue was treated with water, filtered off with suction and recrystallized from ethanol to give 20.4 g of product, melting point 243° to 245° C.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:16][C:15](C(OCC)=O)=[N:14][N:13]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:16][CH:15]=[N:14][N:13]=1)=[CH:8]2)[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3nncs3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A mixture of ethyl 5-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3,4-thiadiazole-2-carboxylate (0.20 g), 8N aqueous sodium hydroxide solution (0.14 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were dissolved in tetrahydrofuran, treated with activated carbon, and concentrated to give the title compound (0.13 g, yield 78%) as yellow crystals. melting point 270-271° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[NH:6][C:5]2=[O:21].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[C:22]1([S:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[NH:6][C:5]3=[O:21])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(Cc2nc3ccc(N)cc3c(=O)[nH]2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: N#Cc1ccc(Cc2nc3ccc(NS(=O)(=O)c4ccccc4)cc3c(=O)[nH]2)cc1

Procedure:
Prepared analogously to Example 1e from 4-[(6-amino-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl]-benzonitrile, benzenesulphonic acid chloride and dimethylaminopyridine in pyridine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CNC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(c1ncccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Reaction time: 120 h

Procedure:
A mixture of 1-benzyl-4-methylaminopiperidine (EXAMPLE 9, 10.8 g), 2-chloro-3-nitropyridine (6.7 g) and anhydrous potassium carbonate (14.6 g) in dry acetonitrile (211 ml) is stirred under nitrogen at 20°-25° for 5 days. The mixture is then concentrated under reduced pressure, diluted with methylene chloride (200 ml) and water (50 ml), and the phases are separated. The organic phase is washed with saline (50 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed (silica gel, 70-230 mesh, 100 g; eluting with ethyl acetate/hexane (50/50) to give the title compound, mp=92°-95°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:2].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([O:3][C:4]([CH2:6][N:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCNCC(=O)OCC
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCC
Temperature: 25 °C

Procedure:
To a mixture of 49 g of ethyl N-(ethoxycarbonylmethyl)-β-alaninate and 30 ml of water cooled to -10° is added dropwise 27.6 ml of ethyl chloroformate followed by a solution of 12.7 g of sodium carbonate in 50 ml of water. The mixture is warmed to room temperature then heated at 55° for 50 minutes. The mixture is cooled, extracted with toluene, the extract is washed with 2N hydrochloric acid and water. The extract is dried over sodium sulfate, filtered, concentrated and distilled in vacuo to yield ethyl N-(ethoxycarbonylmethyl)-N-(ethoxycarbonyl)-β-alaninate.
Reaction SMILES: [O:1]1[C:7]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:2]1[CH2:3][N:4]([CH3:14])[CH2:5][CH2:6]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:27]([OH:31])(=[O:30])[CH2:28][CH3:29]>>[OH:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:30][C:27](=[O:31])[CH2:28][CH3:29])[CH2:6][CH2:5][N:4]([CH3:14])[CH2:3]1
Reactant: CCC(=O)O
Reactant: CN1CCC2(c3ccccc3)OC2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC(=O)OC1(c2ccccc2)CCN(C)CC1O

Procedure:
A solution of 4.0 g of 3,4-epoxy-1-methyl-4-phenyl-piperidine and 4.5 g of p-toluenesulfonic acid monohydrate in 50 ml of propionic acid was stirred at room temperature for 10 minutes then the mixture evaporated to dryness. Water was added to the residue and the mixture made alkaline with sodium carbonate. The residual solid was filtered off and washed with water. Recrystallization of this solid from hot ethyl acetate gave 2.4 g of 3-hydroxy-1-methyl-4-phenyl-4-propionoxy-piperidine with a melting point of 142°-3° C. The corresponding hydrochloride salt had a melting point of 186°-8° C.