Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=O)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:16])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:16][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: O=c1cccc(-c2ccccc2)[nH]1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
A mixture of 6-phenyl pyridone (3 g, 17.5 mmol; prepared according to Example 6) and phosphoryl bromide (7.2 g, 25.0 mmol) is heated to 100° C. for 5 h. The cooled mixture is poured into water (40 ml) and the pH is adjusted to 9 by addition of saturated aqueous sodium carbonate. Then the layers are separated and the aqueous layer is extracted with ethyl acetate (50 ml). The combined organic layers are dried with anhydrous magnesium sulphate and the solvent is evaporated in vacuo. The crude product is crystallized from aqueous ethanol. Subsequent purification by flash chromatography (silica gel, hexane/ethyl acetate 9/1 v/v) gives 2-bromo-6-phenyl pyridine (3.1 g, 76% of th.) as light brown crystals with mp 50° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](Cl)=[O:28]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:24]([F:23])[CH:25]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3-fluoro-5-(trifluoromethyl)benzoic acid chloride (CAS RN 171243-30-4) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow foam (39%). MS (ESI): m/z=509.091 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH3:21].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:18][CH2:19][O:20][CH3:21])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(C(C)=O)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 2.00 g) and 1-bromo-2-methoxyethane (1.5 g) were dissolved in DMF (20 ml), and sodium hydride (259 mg) was added. After stirring at RT for 3 h, the mixture was left to stand overnight. Then the DMF was drawn off and the residue was taken up in EA. The EA phase was washed with water, dried, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA 0-40% within 60 min). 1.17 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][O:21]2)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cc(CCO)ccc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(CCOC2CCCCO2)ccc1OCc1ccccc1
Yield: 90.7 %

Procedure:
A mixture of Example 69B (0.89 g, 3.27 mmol), 3,4-dihydro-2H-pyran (1.49 mL, 16.34 mmol) and p-TsOH.H2O (5 mg) in dichloromethane (20 mL) were stirred at room temperature overnight. The reaction solution was dried with silica gel powder (15 g). 20% ethyl acetate in hexanes (1 L) was used to run flash chromatography to give the title compound (1.06 g, 91%). MS (DCI) m/z 375.13 (M+NH4)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.42–1.62 (m, 4 H) 1.68 (m, 1 H) 1.79 (m, 1 H) 2.88 (t, J=6.60 Hz, 2 H) 3.45 (m, 1 H) 3.59 (m, 1 H) 3.70 (m, 1 H) 3.94 (m, 1 H) 4.58 (t, J=3.38 Hz, 1 H) 5.21 (s, 2 H) 7.03 (d, J=8.59 Hz, 1 H) 7.28–7.48 (m, 6 H) 7.77 (d, J=2.15 Hz, 1 H).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:17]=2[N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:21][CH2:20]2)[NH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][CH2:27][CH2:26][C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]2[C:16]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:15][N:14]=[C:13]3[NH:12][CH:11]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[C:18]=23)[CH2:20][CH2:21]1)=[O:36]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
tert-Butyl 3-(4-(3-(nicotinamido)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.020 g, 0.035 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added to a stirring solution of 1M HCl in ether. The resulting solid product was filtered, washed with ether and dried to give the product N-(4-(4-(3-aminopropanoyl)piperazin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.008 g, 39% yield) as the trihydrochloride salt. MS APCI (+) m/z 470 detected.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[C:18]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][NH:32][CH3:33])[CH2:26][CH2:25]1)=[N:17][N:16]=[CH:15]2>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[C:18]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][N:32]([CH3:33])[C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])[CH2:26][CH2:25]1)=[N:17][N:16]=[CH:15]2
Reactant: CNCCC1CCN(c2nncc3cc(OC)c(OC)cc23)CC1
Reactant: O=C=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: COc1cc2cnnc(N3CCC(CCN(C)C(=O)NC4CCCCC4)CC3)c2cc1OC
Temperature: 0 °C

Procedure:
Cyclohexyl isocyanate (0.5 g.) in dry chloroform (5 ml.) was added dropwise to 6,7-dimethoxy-1-[4-[2-(methylamino)ethyl]piperidino]phthalazine (1.0 g.) in dry chloroform (10 ml.) with stirring and ice-water cooling. After further stirring at room temperature (20°) for 1 hour the mixture was concentrated in vacuo, triturated with minimum quantity of ethyl acetate and filtered. The resultant solid was dissolved in methylene chloride (10 ml.), filtered, treated with ethyl acetate (20 ml.) and gently distilled to remove methylene chloride. The residual ethyl acetate solution was left standing in the refrigerator overnight to precipitate crystalline 6,7-dimethoxy-1-[4-[2-(3-cyclohexyl-1-methylureido)ethyl]piperidino]phthalazine (820 mg.), m.p. 204°-206° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[C:11]([CH2:30][OH:31])=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:26]([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:29])[CH:13]=[CH:14][CH:15]=2)[CH:3]=1.O=C1CCC(=O)N1[O:39][C:40](=O)[CH2:41][C:42]#[N:43]>O1CCOCC1.C(O)C.C(OC(=O)C)C>[C:42]([CH2:41][C:40]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:26]([CH3:27])[CH3:28])[CH:22]=4)[C:17]3=[O:29])[C:11]=2[CH2:30][OH:31])[CH:3]=1)=[O:39])#[N:43]
Reactant: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(N)c(=O)n(C)c3)c1CO)C2=O
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(NC(=O)CC#N)c(=O)n(C)c3)c1CO)C2=O
Temperature: 55 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
2-[3-(5-Amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-hydroxymethyl-phenyl]-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (40 mg, 0.095 mmol) was placed in a mixture of 1.5 ml dioxane and 0.5 ml of ethanol. To this mixture was added cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester, at first 1 equivalent (17.4 mg, 0.095 mmol), and then over a period of 3 days 5 more equivalents of this reagent at 2-4 hours intervals. During this time the reaction mixture was heated at 50-60° C. After cooling, the reaction mixture was diluted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by Prep TLC with 5% methanol in dichloromethylene to afford 12 mg (26% yield) of 2-Cyano-N-{5-[3-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-acetamide.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 47 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 47% yield: mp 217-218° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.1 Hz, 2H), 7.38-7.21 (m, 7H), 6.02 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.35-4.24 (m, 1H), 3.98-3.89 (m, 1H), 3.49-3.41 (m, 1H), 2.93-2.74 (m, 2H), 2.63 (s, 3H), 2.12-1.68 (m, 3H), 1.62-1.42 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.6, 162.6, 156.9, 152.1, 143.2, 137.9, 129.6, 128.8, 127.9, 127.7, 125.9, 125.5, 125.4, 119.9, 47.9, 44.1, 43.9, 37.3, 24.9, 21.3, 17.4; MS (ES+) m/z 488.1 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20]O)[CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:7]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=2[F:5])[CH2:14][CH2:15]1
Reactant: O=S(Cl)Cl
Reactant: OCCN1CCN(c2ccc(F)cc2F)CC1
Solvent: ClC(Cl)Cl
Product: Cl
Product: Fc1ccc(N2CCN(CCCl)CC2)c(F)c1

Procedure:
40 ml of thionyl chloride are added dropwise to a solution of 60 g of 2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethanol, prepared in Example 2, in 300 ml of chloroform. When the addition is complete, the reaction mixture is heated under reflux for 5 hours. After return to room temperature, the crystals formed are filtered off, carefully washed with acetone and then dried to give 70 g of 1-chloro-2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethane hydrochloride in the form of crystals melting at 218° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:68]([SH:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1.C(N(C(C)C)CC)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH2:68]([S:75][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3s2)CC1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(OC(c2cccc(SCc3ccccc3)c2)c2nc3ccccc3s2)CC1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A screw-cap tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (208 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), benzyl mercaptan (59 μL), diisopropylethylamine (174 μL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 15 h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 95/5/0.5). The residual yellowish oil is re-crystallized from hot acetonitrile to give 2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole melting at 195° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cc(C)on5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.044 g, 0.11 mmol) and EtOH (3 ml) was added 4-methoxybenzaldehyde (0.023 g, 0.17 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 70° C. for 18 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v:v; 3:7) and then 2.5% methanol in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.023 g, 43%); 1H-NMR (500 MHz, DMSO-d6) 2.40 (s, 3H, isoxazole 5-CH3), 2.64 (br s, 4H, piperazine N(CH2)2), 3.60 (s, 2H, NCH2), 3.65 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 6.25 (s, 1H, isoxazole 4-H), 7.10 (d, J=8.9 Hz, 2H) and 8.13 (d, J=8.8 Hz, 2H) (3,5-C6H4 OMe and 2,6-C6H4OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.35 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10](=O)[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:13][C:14]([NH2:16])=[S:15].II.[OH-].[Na+]>O>[CH:1]1([CH2:7][CH2:8][C:9]2[S:15][C:14]([NH2:16])=[N:13][C:10]=2[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)CCCC1CCCCC1
Reactant: NC(N)=S
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(N)sc1CCC1CCCCC1
Reaction time: 23 h
Yield: 36.8 %

Procedure:
A mixture of 22.2 g of 5-cyclohexyl-2-pentanone, 20.10 g of thiourea, and 33.48 g of iodine was stirred for 23 hours at a bath temperature of from 100° to 120° C. To the mixture was added 150 ml of water, followed by refluxing for 30 minutes. After cooling, an aqueous sodium hydroxide solution was added to neutralize. The mixture was extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography. Recrystallization from aqueous methanol yielded 10.9 g of the titled compound.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].[H][H].[CH3:18]I>>[CH3:3][S:4]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH3:18])=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2ccc(S(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of sodium hydride (60% in mineral oil, 0.90 g, 23 mmol) was added in portions 6-(methylsulfonyl)-1H-indole (4.0 g, 20 mmol) over 5 minutes at 5-10° C. The reaction mixture was stirred at rt for 1 h until hydrogen evolution ceased, and methyl iodide was added dropwise over 5 minutes at 10-20° C. The mixture was stirred at rt for 1 h, quenched with ice/water, and extracted with tert-butylmethyl ether. The organics were washed, dried and concentrated. The residue was crystallized from ether/hexane to yield the desired compound (3.8 g) as a yellowish solid. MS (ISP): m/e 210.1 (M+H)+
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[O:20][CH3:21])[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[C:24]([N:28]1[N:32]=[N:31][C:30]([NH2:33])=[N:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[N:32]=[N:31][C:30]([NH:33][C:2]2[CH:23]=[CH:22][C:5]3[N:6]=[C:7]([NH:10][CH:11]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]=5[O:20][CH3:21])[CH2:13][CH2:12]4)[O:8][CH2:9][C:4]=3[CH:3]=2)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)n1nnc(N)n1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4nnn(C(C)(C)C)n4)cc3CO1)CC2
Yield: 15.7 %

Procedure:
The title compound (34 mg, 16%), off-white foam, MS (ISP): m/e=434.4 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(7-methoxy-indan-1-yl)-amine (Example 74) (187 mg, 0.5 mmol) and commercially available 2-tert.-butyl-2H-tetrazole-5-yl-amine (141 mg, 1.0 mmol).
Reaction SMILES: C(O)(C)(C)C.[OH:6][CH2:7][CH:8]([S:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.ClCCl>[O:6]=[CH:7][CH:8]([S:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C@@H:9]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(CSC(CO)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(CSC(C=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of t-butanol (167 mg, 1.05 eq), 1,1,1-triacetoxy-2,1-benoxiodol-3(3H)-one (954 mg, 1.05 eq) and dry methylene chloride (8 ml) was stirred under argon at room temperature for 15 minutes. The mixture was then treated with a solution of (1S)-[3-hydroxy-2-[[(4-methoxyphenyl)methyl]thio]-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (890 mg, 2.14 mmol) and dichloromethane (8 ml). After stirring for 15 minutes, the reaction was diluted with ether and poured into 1N sodium bicarbonate containing a seven-fold excess of sodium thiosulfate (3.9 g, 15.75 mmol). The mixture was stirred until all solids dissolved. The layers were separated and the organic phase washed with 1N sodium bicarbonate, water and brine. Drying over anhydrous magnesium sulfate and removal of solvent yielded the title compound as a pale yellow solid: 860 mg (2.08 mmol); Rf =0.75 (silica gel, benzene: ethyl acetate, 4:1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 2-chloro-3-fluorobenzoic acid (3.32 g, 19.02 mmol) in DMF (60 mL) was added N,O-dimethylhydroxylamine hydrochloride, 98% (2.30 g, 23.58 mmol), O-(-7-azabenzotriazol-1-yl)-N,′N,′N,′N′-tetramethyluronium-hexafluorophosphate (HATU) (8.82 g, 23.20 mmol) and triethylamine (6.63 mL, 47.5 mmol). The mixture was stirred at rt for 3 h. The reaction was quenched with saturated Na2CO3 and extracted with EtOAc. The organic solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (80 g, 10-100% EtOAc/hexane in 25 min) to give 2-chloro-3-fluoro-N-methoxy-N-methylbenzamide as colorless oil, which turned to solid on vacuum (3.95 g, 95% yield). MS m/z=218 [M+H]+. Calculated for C9H9ClFNO2: 217.6.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([OH:9])[CH2:2]2.[Na].[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21](OCC)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]([O:9][C@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnn2c(C)cccc12
Reactant: O[C@@H]1CN2CCC1CC2
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cccc2c(C(=O)O[C@@H]3CN4CCC3CC4)cnn12
Reaction time: 2.5 h
Yield: 236.8 %

Procedure:
After a suspension of 760 mg (0.76 mmol) of (S)-(+)-3-quinuclidinol, which had been prepared in accordance with the procedure disclosed in "Eur. J. Med. Chem.", 14, 111-114 (1979), in 60 ml of benzene was refluxed for 1.5 hours by using a Dean-Stark apparatus, 0.2 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2.5 hours. Unreacted sodium was removed and 440 mg (2.2 mmol) of ethyl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform:methanol=10:1), whereby 500 mg (1.8 mmol) of the title compound were obtained as white crystals (yield: 81%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:9])[CH:13]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CN1CCC(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(C(=O)Nc2cc(Cl)ccn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask was flame dried and placed under a nitrogen atmosphere. 1-methylpiperidine-4-carbonyl chloride (1 eq) in anhydrous methylene chloride was added to the flask and brought to 0° C. To this was added the solution containing 4-chloropyridin-2-amine (1 eq), and diisopropylethylamine (5 eq) in anhydrous methylene chloride, which was stirred for 1 hour at 0° C. Reaction concentrated and partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to give the crude product. Purification on silica gel, 10% methanol in methylene chloride to yield N-(4-chloropyridin-2-yl)-1-methylpiperidine-4-carboxamide as a slightly yellow crystal solid. HPLC=2.39 min; MS: MH+=254.