Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:24][O:25][C:26](=[O:30])[C@@H:27]([CH3:29])[NH2:28].CCN(C(C)C)C(C)C.CO.C(Cl)Cl>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:28][C@H:27]([CH3:29])[C:26]([O:25][CH3:24])=[O:30])=[N:11][C:10]2[C:5]([N:4]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 100 °C
Yield: 62.9 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 37.7 mg, 0.089 mmol), D-alanine methyl ester hydrochloride (Aldrich; 37.3 mg, 0.267 mmol), and DIPEA (0.093 mL, 0.534 mmol) in DMSO (0.8 mL), heating at 100° C. for 30 min. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished (R)-methyl 2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)propanoate (21.3 mg, 0.056 mmol, 63% yield) as a yellow-orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (1H, br. s.), 7.87 (1H, dd, J=7.5, 1.1 Hz), 7.58 (1H, dd, J=7.9, 1.1 Hz), 7.44 (1H, d, J=6.7 Hz), 7.34 (1H, t, J=7.8 Hz), 6.94 (1H, s), 6.89 (1H, d, J=2.2 Hz), 4.72 (1H, quin, J=7.1 Hz), 3.50 (3H, s), 3.42 (2H, td, J=6.7, 2.2 Hz), 2.91 (2H, td, J=6.8, 2.8 Hz), 2.59 (3H, s), 1.57 (3H, d, J=7.2 Hz). m/z (ESI, +ve) 380.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[OH:4].C=O.[C:21](O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:21][NH:1][CH2:2][CH:3]2[OH:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NCC(O)c1cccc(OCc2ccccc2)c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OC1CNCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C

Procedure:
To 10 g (41 mmol) 2-amino-1-[3-(benzyloxy)phenyl]ethan-1-ol and 4.6 mL (62 mmol) formaldehyde (37% solution in water) in 100 mL DCM are added slowly 6.3 mL (82 mmol) TFA and the resulting mixture is stirred at r.t. over night. The reaction is neutralised by the addition of a sat. aq. NaHCO3 solution and extracted with DCM. The organic layer is washed with a sat. aq. NaCl solution, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH2:1]([N:10]=C=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].C1(=[O:20])NCCCCC1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:1]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1=[O:9])(=[O:20])[NH2:10]
Reactant: O=C=NCCCCCCN=C=O
Reactant: O=C1CCCCCN1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: NC(=O)C1CCCCNC1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 817.2 %

Procedure:
To the flask were added 0.01 g of dibutyltin dilaurate and then 17.0 g of hexamethylene diisocyanate to effect reaction with the polyoxytetramethylene di-ol. After stirring for 2 hours, 12.0 g of dry ε-caprolactam was added to the reaction mixture, and the inner temperature was raised up to 80° C., at which the reaction was continued for an additional 2 hours. There was obtained 129 g of carbamoyl caprolactam-terminated polyoxytetramethylene.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:30]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[C:34]=2[CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH:30]1[C:39]2[C:34](=[C:35]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][CH:15]([N:18]6[CH2:23][CH2:22][O:21][CH2:20][CH2:19]6)[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCOCC5)CC4)cc3n2)c2ccncc2c1
Temperature: 130 °C
Yield: 27.2 %

Procedure:
A sealable tube was charged with 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine (0.100 g, 0.229 mmol), isoquinoline-5-boronic acid (0.048 g, 0.275 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.008 g, 0.012 mmol), 1 N aqueous sodium carbonate solution (1 mL) and acetonitrile (3 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in ethyl acetate and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 10 to 20% methanol in dichloromethane) to give 101 (0.033 g, 27%) as a yellow solid. MS m/e 531 [M+H]+; 1H NMR (300 MHz, CDCl3) δ ppm 1.54-1.71 (m, 2 H) 1.87 (d, J=11.3 Hz, 2 H) 2.09-2.30 (m, 3 H) 2.52-2.63 (m, 4 H) 3.01-3.11 (m, 2 H) 3.70-3.78 (m, 4 H) 3.85 (s, 2 H) 3.87-3.94 (m, 4 H) 4.03-4.12 (m, 4 H) 7.35 (s, 1 H) 7.67-7.75 (m, 1 H) 8.06 (d, J=8.3 Hz, 1 H) 8.31-8.37 (m, 1 H) 8.52-8.58 (m, 1 H) 8.61-8.67 (m, 1 H) 9.30 (s, 1 H)
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])=[O:8]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Clc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccccc1C(=O)c1cc(Cl)ccc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
A mixture of o-toluoyl chloride (22 g, 0.17 mol) and 1,4-dichlorobenzene (120 g, 0.82 mol) was heated to 100° C. in a flask. Aluminum chloride (60 g, 0.45 mol) was added in one portion. The mixture was heated to 170° C. in 30 min and stirred at this temperature for 3 hours. The resulting brownish solution was cooled to about 80° C. and poured onto ice. Ether (50 ml) was added. The organic layer was separated and distilled under vacuum after the removal of ether. The residue from distillation was recrystallized twice from hexane to give 16 g of white crystals (36%).
Reaction SMILES: C(O[C:4]([C:6]1[S:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:5])C.[OH-].[Na+].[CH:27]([O:29][CH2:30][CH2:31][O:32][NH2:33])=[CH2:28].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[CH:27]([O:29][CH2:30][CH2:31][O:32][NH:33][C:4]([C:6]1[S:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:5])=[CH2:28]
Reactant: C=COCCON
Reactant: CCOC(=O)c1sc2c(F)cncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Product: C=COCCONC(=O)c1sc2c(F)cncc2c1Nc1ccc(I)cc1F
Temperature: 65 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
To a solution 7-fluoro-3-(2-fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (175 mg, 0.38 mmol) in IMS (4 mL) was added a 1.0 M aqueous solution of sodium hydroxide (0.5 mL, 0.5 mmol). The reaction mixture was heated to 65° C. for 1 hour before being cooled to room temperature and concentrated in vacuo. The resulting residue was azeotroped with toluene (3×10 mL), and then suspended in THF (5 mL). O-(2-Vinyloxy-ethyl)-hydroxylamine (78 mg, 0.76 mmol), N—N-diisopropylethylamine (0.26 mL, 1.52 mmol), EDCI (146 mg, 0.76 mmol), and HOBt (103 mg, 0.76 mmol) were then added sequentially, and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with a saturated solution of sodium hydrogenocarbonate and brine, dried over sodium sulfate, filtered and concentrated to give a residue, which was purified by column chromatography (Si-SPE, gradient 0-2% methanol in DCM) to afford the title compound as a pale yellow solid (106 mg, 54%). LCMS (method B): RT=3.92 min. M+H+=518.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([NH2:16])=[S:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C1COCC1.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](=O)[CH2:31]Br>CCOC(C)=O>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]3[S:15][C:30]([C:26]4[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=4)=[CH:31][N:16]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cccc1C(=O)CBr
Reactant: N#Cc1ccc(Cn2cncc2CC(N)=S)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cccc1-c1cnc(Cc2cncn2Cc2ccc(C#N)cc2)s1
Temperature: 50 °C

Procedure:
To a 25 mL round bottomed flask with a stirring bar reflux condenser and an argon inlet is added 1-(4-cyanobenzyl)-5-(aminothiocarbonyl)methyl-1H-imidazole (0.12 g, 0.468 mmol), dry THF (10 mL), and N-methyl-a-bromoacetylpyrrole (0.098 g, 0.491 mmol). This mixture is heated at 50° C. for 7 hours. The cooled reaction mixture is diluted with EtOAc and washed sucessively with aq. NaHCO3, water, and brine. The organic extract is dried, (MgSO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:16](=[O:18])[CH3:17])=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1.CC(O)C.C1COCC1>Cl>[OH:4][C:5]1[C:6]([C:16](=[O:18])[CH3:17])=[CH:7][C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[N:9][CH:10]=1
Reactant: COCOc1cnc(CC(C)(C)C)cc1C(C)=O
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(=O)c1cc(CC(C)(C)C)ncc1O

Procedure:
A solution of 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone (21.6 g, 86 mmol) in (2:1:1) 5 M HCl:i-PrOH:THF (800 mL) was stirred 4 h at rt. The mixture was concentrated to remove the THF and i-PrOH. The resulting solution consisting of the product in aqueous HCl was quenched by slow addition to a solution of saturated aqueous NaHCO3 (500 mL) containing excess solid NaHCO3 (50 g). The aqueous layer was extracted with CH2Cl2 (3×250 mL), the organic layers combined and washed with saturated aqueous NaCl (250 mL), dried (MgSO4), and concentrated to give 1-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone as a brown oil.
Reaction SMILES: C([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[ClH:16]>Cl.CO>[ClH:16].[NH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(=O)NC(CC(=O)O)c1ccccc1
Agent: Cl
Solvent: CO
Product: NC(CC(=O)O)c1ccccc1
Reaction time: 3 h
Yield: 39.2 %

Procedure:
(+)-3-acetylamino-3-phenylpropanoic acid (207 mg, 1.00 mmol) prepared by the same manner as in Example 3 and 2.0 ml of 2M hydrochloric acid were added to a 30-ml two-necked flask equipped with a stirrer and heated to reflux for 3 hours. After 3 hours, 1 drop of concentrated hydrochloric acid was added to the reaction solution using a Pasteur pipette and the mixture was heated to reflux for 2 hours more. After completion of the reaction, the reaction solution was evaporated to dryness in vacuo, and the resulting residue was washed with a mixed solvent of methanol/diisopropyl and recrystallized from a mixed solvent of 2-propanol/99% ethanol to give 79 mg (0.392 mmol) of (+)-3-amino-3-phenylpropanoic acid hydrochloride in a yield of 39.2% (melting point: 195 to 196° C., [α]D=−3.03° (c=1.0, methanol)).
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)=[CH:6][C:5]=1[OH:15].[CH:17]1([Mg]Cl)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[NH4+].[Cl-]>C1COCC1>[CH:17]1([C:3]([CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)([OH:16])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:11]=[CH:12][CH:13]=[CH:14]3)=[CH:6][C:5]=2[OH:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: COC(=O)c1ccc(-n2cccc2)cc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Oc1cc(-n2cccc2)ccc1C(O)(C1CCCCC1)C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of 217 mg of 2-Hydroxy-4-pyrrol-1-yl-benzoic acid methyl ester in 4 ml of THF, 2 ml of a solution of cyclohexylmagnesium chloride in THF (2 M) was added slowly at room temperature. The reaction mixture was then heated to reflux for 4 h. After cooling to room temperature it was hydrolized with ice. Saturated aqueous NH4Cl was added until the white precipitate was dissolved. The aqueous phase was extracted with ether. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was used in the next reaction step. Yield: 504 mg.
Reaction SMILES: Br[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[O:15]1[CH2:20][CH2:19][O:18][CH2:17]C1>C(Cl)Cl.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>[O:15]1[C:20]2[CH:3]=[C:2]([C:2]3[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=3)[CH:7]=[CH:6][C:19]=2[O:18][CH2:17]1
Reactant: Clc1ncccc1Br
Reactant: C1COCCO1
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: ClCCl
Product: Clc1ncccc1-c1ccc2c(c1)OCO2

Procedure:
Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,3-(benzo[d][1,3]dioxol-6-yl)-2-chloropyridine was prepared by heating the mixture of 3,4-(methylenedioxy)phenyl boronic acid (3.0 g, 18.1 mmol), 3-bromo-2-chloropyridine (4.2 g, 1.8 mmol), Pd(PPh3)4 (1.2 g, 1.0 mmol) and 2M aq. Na2CO3 (27 mL, 54 mmol) in 1,4-dioxane (125 mL) under argon atmosphere for 12 h. LC/MS indicated three products. The crude concentrate that was obtained after the extractive work-up dissolved in CH2Cl2, adsorbed on to silica gel and dried. Subsequent purification by flash silica gel column chromatography (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes eluting solvent gradient upon dry powder loading) provided 3-(benzo[d][1,3]dioxol-6-yl)-2-chloropyridine as a white solid 2.3 g, (38%). 1H NMR (DMSO-d6): δ 8.38 (dd, 1H, J=1.7 and 4.7 Hz), 7.82 (dd, 1H, J=2.0 and 7.6 Hz), 7.47 (dd, 1H, J=4.7 and 7.6 Hz), 7.05 (d, 1H, J=1.7 Hz), 7.01 (d, 1H, J=7.9 Hz), 6.90 (dd, 1H, J=1.7 and 7.9 Hz), 6.07 (s, 2H LCMS: rt 7.27 min (A), purity 96%, MS (m/e) 234 (MH+).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]=[C:9]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:10]2[C:11](=[O:20])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])(=O)=O.[N:26]1[C:34]([SH:35])=[C:33]2[C:29]([NH:30][CH:31]=[N:32]2)=[N:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:25][C:21]1[N:10]2[C:11](=[O:20])[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[C:7]([CH2:6][S:35][C:34]3[N:26]=[CH:27][N:28]=[C:29]4[C:33]=3[N:32]=[CH:31][NH:30]4)[N:8]=[C:9]2[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccccc1-c1c(COS(C)(=O)=O)nc2cccc(C)n2c1=O
Reactant: Sc1ncnc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-c1c(CSc2ncnc3[nH]cnc23)nc2cccc(C)n2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (6-methyl-4-oxo-3-o-tolyl-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl methanesulfonate (100 mg, 0.28 mmol), 9H-purine-6-thiol (51 mg, 1.2 eq) and K2CO3 (46 mg, 1.2 eq) in 2 mL DMF was stirred at rt overnight. Water was added and the resulting solid was washed with water and dried in the open air. 6-Methyl-3-(2-methylphenyl)-2-((9H-purin-6-ylsulfanyl)methyl)-4H-pyrido[1,2-a]-pyrimidin-4-one was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.49 (1 H, s), 8.47 (1 H, s), 8.40 (1 H, s), 7.68 (1 H, t, J=8.0 Hz), 7.43 (1 H, d, J=8.0 Hz), 7.23-7.19 (4 H, m), 6.95 (1 H, d, J=8.0 Hz), 4.45 (1 H, d, J=12.0 Hz), 4.29 (1 H, d, J=12.0 Hz), 2.90 (3 H, s), 2.10 (3 H, s); Mass Spectrum (ESI) m/e=415 (M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:15][C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[C:17]([Cl:19])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:30](O)([C:32]([F:35])([F:34])[F:33])=O>>[Cl:19][C:17]1[N:18]=[C:14]([C:11]2[CH2:10][CH2:9][N:8]([C:6]3[C:30]([C:32]([F:35])([F:34])[F:33])=[CH:11][CH:10]=[CH:9][N:8]=3)[CH2:13][CH:12]=2)[NH:15][C:16]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc(Cl)c(-c3ccc(C(F)(F)F)cc3)[nH]2)CC1
Product: FC(F)(F)c1ccc(-c2[nH]c(C3=CCN(c4ncccc4C(F)(F)F)CC3)nc2Cl)cc1

Procedure:
4-[4-Chloro-5-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from step (a) above (540 mg, 1.26 mmol) reacted with TFA under the conditions of Example 22(c) to give the title compound as a light-brown oil, which was used directly in the next step without additional purification. MS (ESI, positive ion) m/z: 328 (M+1).
Reaction SMILES: C(OC(=O)N)(C)(C)C.ClC1C=CC(C2(O)CCNCC2)=CC=1.C(OC(=O)[NH:29][CH:30]1[CH:35]2[CH:31]1[CH2:32][N:33]([CH2:36][C:37](=[O:54])[NH:38][C:39]1[CH:40]=[CH:41][C:42]3[N:43]([CH2:52][CH3:53])[C:44]4[C:49]([C:50]=3[CH:51]=1)=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:34]2)(C)(C)C.Cl.O1CCOCC1>>[CH2:52]([N:43]1[C:42]2[CH:41]=[CH:40][C:39]([NH:38][C:37](=[O:54])[CH2:36][N:33]3[CH2:32][CH:31]4[CH:35]([CH:30]4[NH2:29])[CH2:34]3)=[CH:51][C:50]=2[C:49]2[C:44]1=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH3:53]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CN3CC4C(C3)C4NC(=O)OC(C)(C)C)ccc21
Agent: CC(C)(C)OC(N)=O
Agent: Cl
Agent: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: C1COCCO1
Product: CCn1c2ccccc2c2cc(NC(=O)CN3CC4C(N)C4C3)ccc21

Procedure:
3-[(9-Ethyl-9H-carbazol-3-ylcarbamoyl)-methyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamic acid tert-butyl ester was synthesized similarly to example 44, substituting 3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester for 4-(4-Chlorophenyl)-4-hydroxypiperidine and substituting the compound of example 19 for the compound of example 40. A solution of {3-[(9-ethyl-9H-carbazol-3-ylcarbamoyl)-methyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamic acid tert-butyl ester (4.6 mmol) in 1:1 4 M HCl/dioxane (25 mL) was stirred at room temperature for 16 hours. The reaction mixture was then concentrated, and the residue was concentrated from diethyl ether (2×25 mL). The pale yellow foam remaining (723 mg, 37%) was N-(9-ethyl-9H-carbazol-3-yl)-2-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-acetamide.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:21][CH2:22][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:29]([NH:33][C:17]([C:14]1[CH:15]=[C:16]2[C:11]3=[C:12]([CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][CH2:22][N:10]3[CH2:9][CH2:8][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1)=[O:19])[CH2:30][CH2:31][CH3:32]
Reactant: O=C(O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Reactant: CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxylic acid (14), (189 mg, 0.512 mmol) in dichloromethane (10 mL) were added butyl amine (0.027 mL, 0.512 mmol), EDCl (196 mg, 1.02 mmol), followed DMAP (4-(Dimethylamino)pyridine) (70 mg, 1.02 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The reaction was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 25 to 30% EtOAc:Hexane to give N-butyl-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carboxamide (481), (113 mg 52%). 1H NMR (300 MHz, CDCl3) ppm 1H NMR (300 MHz, Solvent) ppm 0.87 (t, J=6.0 Hz, 3H) 1.17-1.38 (m, 2H) 1.36-1.52 (m, 2H) 2.03-2.17 (m, 2H) 2.18-2.36 (m, 2H) 3.06-3.37 (m, 6H) 4.21 (t, J=5.27 Hz, 2H) 5.61-5.75 (m, 1H) 7.03-7.16 (m, 4H) 7.17-7.37 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:17]1C=CC(S(O)=O)=CC=1C(O)=O.C(N)C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH2:13][CH3:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Agent: CCN
Product: CCNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 78 %

Procedure:
The title compound was synthesised according to the procedure described for 2-Chloro-5-methylsulfamoyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and ethylamine and obtained in 78% yield. MS (m/e): 262.2 (MH−, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+].[I-].[K+]>C(O)(=O)C.O>[C:12]([O:15][CH2:2][CH2:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCC(=O)c1ccccc1
Temperature: 130 °C

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (1.0 g, 5.93 mmol) in acetic acid (8 mL) was added sodium acetate (2.43 g, 29.7 mmol) and potassium iodide (100 mg). The mixture was heated in a sealed tube at 130° C. overnight. After cooling, the reaction was diluted with water (20 mL) and extracted with methylene chloride (3×20 mL). The combined organic extracts were washed with water (2×50 mL), saturated solution of sodium bicarbonate (2×50 mL) and brine (20 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (1.0 g, 88%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:22](O)=[O:23])[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)C1CCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCC4)cc23)CC1
Yield: 96.3 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.10 mMol) cyclobutanecarboxylic acid, 15.0 mg (96%) of the title compound were recovered. MS(m/e): 312(M+1)