Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:14]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan -8-ol (1.18 g, 7.46 mmol) and NaH (0.358 g, 8.96 mmol) in DMF (5 mL) at 0° C. was added benzyl bromide (1.06 mL, 8.95 mmol). After being stirred overnight under N2, water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed using 10% EtOAc/hexane to give 1.524 g of the title compound. MS (EI) calcd: (M+1)+=249.1; found: 249.2. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.35 (5H, m), 4.52 (2H, s), 3.95 (4H, m), 3.5 (1H, m), 1.95-1.50 (8H, m).
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=2)=[O:7])[CH:5]=[CH:4]N=C1.[Br-:17].[Br-].NCC[CH2:22][N+:23]([CH2:34][CH2:35][CH2:36][NH2:37])([CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N+:29]([CH3:32])([CH3:31])[CH3:30].C([N:41]([CH:44]([CH3:46])[CH3:45])[CH2:42]C)(C)C>C(O)C>[Br-:17].[Br-:17].[CH3:32][N+:29]([CH3:30])([CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N+:23]([CH3:22])([CH2:33][CH2:4][CH2:5][NH:1][C:6]([NH:8][C:9]1[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=1)=[O:7])[CH2:34][CH2:35][CH2:36][NH:37][C:6]([NH:1][C:42]1[NH:41][C:44]([CH3:45])=[CH:46][C:13](=[O:15])[N:14]=1)=[O:7]
Reactant: Cc1cc(=O)nc(NC(=O)n2ccnc2)[nH]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[N+](C)(C)CCCCC[N+](C)(CCCN)CCCN
Agent: [Br-]
Solvent: CCO
Product: Cc1cc(=O)nc(NC(=O)NCCC[N+](C)(CCCCC[N+](C)(C)C)CCCNC(=O)Nc2nc(=O)cc(C)[nH]2)[nH]1
Yield: 239.1 %

Procedure:
2 g of 2-(1-imidazolylcarbonylamino)-6-methyl-4[1H]-pyrimidinone (9.2 mmol) are added to a solution of 2 g of N,N-bis(3-aminopropyl)-N,N′,N′,N′-tetramethylpentane-1,5-diaminium dibromide (4.6 mmol) and 1.2 g of diisopropylethylamine (9.2 mmol) in 100 ml of ethanol. The solution is stirred at reflux for 5 hours. The product is precipitated from acetone. After filtration and washing with acetone, the product is dried under reduced pressure and 3.2 g (5.5 mmol) of desired compound are obtained in the form of a white powder, with a yield of 99% (hygroscopic product).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)cc(Cl)n1
Solvent: ClCCl
Product: Cc1cc(Cl)cc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
2-Methyl-4,6-dichloropyridine (256 mmol) is dissolved in dichloromethane (200 mL) and chilled to −78° C. in an inert atmosphere. Morpholine (550 mol) dissolved in dichloromethane (100 mL) is added slowly. The reaction is allowed to warm to room temperature while stirring overnight. The organic layer is washed with saturated ammonium chloride (2×100 mL), dried with sodium sulfate, and evaporated to give 2-methyl-4-chloro-6-morpholino-pyridine.
Reaction SMILES: FC(F)(F)C(O)=O.C([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]2[CH:22]=[N:23][C:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:14]2[C:13]1=[O:32])(C)(C)C>C(Cl)Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]=[CH:22][N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:12][C:13](=[O:32])[C:14]=23)=[CH:26][CH:27]=1
Reactant: CC(C)(C)n1c(=O)c2c(-c3ccc(F)cc3)ncn2c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ccccc2n2cnc(-c3ccc(F)cc3)c12
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (50.0 ml) is added to a solution of 5-tert-butyl-3-(4-fluorophenyl)-4,5-dihydroimidazo[1,5-a]quinoxalin-4-one (XXXIV, EXAMPLE 245, 4.01 g) and methylene chloride (50.0 ml) at 0°. The solution is stirred for 1 hr at 0° and is concentrated. The residue is triturated with water, filtered, washed with water (2×100 ml), ether (2×100 ml), and dried under reduced pressure to give the title compound, mp>300°; IR (mineral oil) 2955, 2922, 2868, 2855, 1667, 1499, 1377 and 1366 cm-1 ; NMR (d6 -DMSO) 11.45, 9.16, 8.3-8.45, 8.21 and 7.2-7.45 δ; MS (EI, m/z) 279, 251 and 223.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=[O:19])[N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1.[Br:20]N1C(=O)CCC1=O.CN(C)C=O.CC(O)C>O>[Br:20][C:9]1[C:10](=[O:19])[N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccc(-c2ccccn2)cn1-c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: O
Product: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
5-(2-Pyridyl)-1-phenyl-1,2-dihydropyridine-2-one (300 g), N-bromosuccinimide (236.5 g) and N,N-dimethylformamide (1.8 L) were placed in a 10-L reactor, and the reaction mixture was stirred at 30° C. (external temperature) in a nitrogen stream for 3 hours and 15 minutes. 2-Propanol (4.2 L) was added dropwise to the reaction mixture over a period of 9 minutes, followed by adding thereto water (2.1 L) over a period of 7 minutes. The resulting mixture was heated at 85° C. (external temperature) with stirring. After confirming the dissolution of the contents, the resulting solution was stirred at an external temperature of 55° C. for 1 hour. Thereafter, the solution was stirred at 40° C. (external temperature) for another 22 minutes, at 30° C. (external temperature) for further another 23 minutes, and then at 10° C. (external temperature) for still another 15 hours and 15 minutes. The reaction mixture was filtered and the precipitate was washed with 50% 2-propanol-water (2.4 L) and then dried under reduced pressure (60° C., 6 hours) to obtain 341.45 g of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one. Yield: 86.4%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19]I>C(#N)C>[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: ClCCCCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
To a solution of 4-iodophenol (1.0 g) in acetonitrile (10 mL), cesium carbonate (3.0 g) and 1-chloro-4-iodobutane (1.2 g) were added and the mixture was heated to 100° C., at which it was stirred for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=7:3 to 1:1) to give the titled compound (1.4 g, 99%) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=3[F:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:2]3[N:19]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=5[F:18])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: COc1ccc(-c2cccn3nc(Cl)nc23)c(F)c1
Product: COc1ccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c(F)c1

Procedure:
4-{4-[8-(2-Fluoro-4-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-fluoro-4-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.250 g, 0.900 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.298 g, 1.08 mmol) in a manner analogous to Example 311a and 311b to give product (0.253 g, 41%). MP=93-95° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 8.79 (d, 1H), 7.80 (m, 1H), 7.58 (m, 3H), 7.15 (m, 3H), 6.98 (m, 2H), 4.05 (m, 2H), 3.85 (s, 3H), 2.75 (br m, 2H), 2.55 (m, 1H) 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H). MS=518 (MH)+.
Reaction SMILES: [P:1]([O:21]C)([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].C[Si](Br)(C)C.[OH-].[Na+:29]>C(#N)C.CO>[P:1]([O-:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:2].[Na+:29]
Reactant: COP(=O)(OCCc1ccccc1)OCCc1ccccc1
Agent: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: O=P([O-])(OCCc1ccccc1)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.26 g (0.8 mmol) of bis(phenethyl) methyl phosphate in 3.2 mL of dry acetonitrile was stirred at 0° C. under N2 while 0.23 mL (2.18 eq.) of TMSBr was added dropwise. The solution was stirred at 0° C. for 1.5 hours. The solvent was removed and the residue was dissolved in NaOH (1.0 eq.) in MeOH solution. After 30 minutes at room temperature, the solution was concentrated, and the white solid was taken up in ether (6.0 mL) and filtered to give sodium bis(phenethyl) phosphate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:25])=[C:4]([CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[CH:30][CH:29]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([OH:25])=[C:4]([CH:9]=[C:10]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)=[CH:32][CH:33]=2)[C:11]=1[C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH3:8])=[O:6].[Cl:1][C:2]1[C:3]([OH:25])=[C:4]([CH:9]=[C:10]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)=[CH:32][CH:33]=2)[C:11]=1[C:12]([F:13])([F:14])[F:15])[C:5]([OH:7])=[O:6]
Reactant: ClCc1ccc(-n2cccn2)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C(F)(F)F)c(Cl)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c(Cl)c1O
Product: O=C(O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c(Cl)c1O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 3-chloro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoate (1.50 g) in 1,4-dioxane (30.0 mL) were added 1-(4-(chloromethyl)phenyl)-1H-pyrazole (0.76 g), tetrakis(triphenylphosphine)palladium(0) (0.23 g) and tripotassium phosphate trihydrate (2.10 g), and the mixture was stirred at 90° C. for 16 hr under nitrogen atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give methyl 3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate (0.12 g) and 3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoic acid (0.70 g).
Reaction SMILES: C([NH:5][C:6]1[S:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH:18]=3)[O:13][CH:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)[N:10]=1)(C)(C)C.[OH-:34].[Na+]>Cl>[NH2:5][C:6]1[S:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]([NH2:24])=[O:34])[CH:18]=3)[O:13][CH:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)[N:10]=1
Reactant: CC(C)(C)NC1=NC2(CS1)CC(c1ccccc1)Oc1ccc(-c3cccc(C#N)c3)cc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NC(=O)c1cccc(-c2ccc3c(c2)C2(CSC(N)=N2)CC(c2ccccc2)O3)c1
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 3-(2′-(tert-butylamino)-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (30 mg, 0.066 mmol) in concentrated HCl (5 mL) was stirred at 100 for 2 h. Aqueous NaOH (6 N) was added until pH=8. The mixture was extracted with EtOAc and the organic layer was dried and concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzamide (20 mg, 73%).
Reaction SMILES: [N+]([O-])([O-])=O.[K+].S[CH2:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[CH3:20].[S:21]([Cl:25])(Cl)(=[O:23])=[O:22]>CC#N.ClCCl>[CH3:16][N:15]([CH3:17])[C:13]([C:12]1[CH:18]=[CH:19][C:9]([CH2:8][CH2:7][S:21]([Cl:25])(=[O:23])=[O:22])=[C:10]([CH3:20])[CH:11]=1)=[O:14]
Reactant: Cc1cc(C(=O)N(C)C)ccc1CCS
Reactant: O=S(=O)(Cl)Cl
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc(C(=O)N(C)C)ccc1CCS(=O)(=O)Cl
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 73.7 %

Procedure:
Potassium nitrate (583 mg, 5.77 mmol) was added to a solution of 4-(2-mercapto-ethyl)-3,N,N-trimethyl-benzamide (514 mg, 2.30 mmol) in MeCN (23 ml) at room temperature. The mixture was cooled to −40° C., and sulfuryl chloride (1.68 M solution in dichloromethane, 3.46 ml, 5.81 mmol) was then added dropwise over 15 minutes. After stirring at −40° C. to −20° C. for 2.5 hours, the reaction mixture was diluted with dichloromethane (80 ml) and quenched with a saturated aqueous sodium bicarbonate solution (20 ml). The organic layer and the aqueous layer were separated, and the organic layer was then washed with a saturated aqueous sodium chloride solution (30 ml), dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→1/2) to give 2-(4-dimethylcarbamoyl-2-methyl-phenyl)-ethanesulfonyl chloride as a colorless solid (491 mg, 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>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>[CH3:8][O:7][C:5]([C:4]1[CH:3]=[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cccc(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
n.m.r. δ values include 3.96 (s, 3 H), 7.57 (t, 1 H), 7.64 (t, 1 H), 7.81 (d, 1 H), 7.94 (d,1 H), 8.09 (d, 1 H), 8.23 (dd, 1 H), 8.30 (s, 1 H), 8.48 (t, 1 H), m.p., 88-90° C.; from methyl 3-bromobenzoate (2.0 g), tetrakis(triphenylphosphine)palladium(0) (348mg) and 3-nitrophenylboronic acid (1.9 g).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[O:5])=[O:3].O[CH2:7][C:8](=[O:10])[CH3:9].C(O)(=O)C.[OH2:15]>>[OH:15][CH:7]([CH:4]([OH:5])[C:2](=[O:3])[CH3:1])[C:8](=[O:10])[CH3:9]
Reactant: O
Reactant: CC(=O)C=O
Reactant: CC(=O)CO
Solvent: CC(=O)O
Product: CC(=O)C(O)C(O)C(C)=O
Yield: 56 %

Procedure:
A solution of methyl glyoxal 43% wt in water (2.00 g, 11.9 mmol), hydroxy-acetone (4.42 g, 59.7 mmol), and acetic acid (1.43 g, 23.8 mmol) in water (0.9 ml) were stirred during 16 hours at 70° C. (pH of the reaction medium was around 2.0). At the end of the reaction the reaction mixture was concentrated under reduced pressure giving 2.1 g of the crude 3,4-dihydroxyhexane-2,5-dione (56% purity measured by GC vs. internal standard). Crude 3,4-dihydroxyhexane-2,5-dione was distilled under reduced pressure to give 3,4-dihydroxyhexane-2,5-dione (1.56 g, 74% purity, 66% yield) as a pale yellow solid. The product obtained had the same 1H-NMR spectra as those described in Büchi et al, J. Org. Chem., 1973, 38, 123.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)=[O:6].[CH3:14][C@@H:15]([CH2:31][CH3:32])[CH2:16][CH2:17][CH2:18]OC1C=C(S([O-])(=O)=O)C(C)=CC=1.CC(CC)CCCO>CO>[CH3:14][C@@H:15]([CH2:31][CH3:32])[CH2:16][CH2:17][CH2:18][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:8][CH:9]=1
Reactant: CC[C@H](C)CCCOc1ccc(C)c(S(=O)(=O)[O-])c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCC(C)CCCO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)CCCOc1ccc(C(=O)OC)cc1
Yield: 97 %

Procedure:
KOH (5 g, 0.09 mol) was added to a solution of methyl p-hydroxybenzoate (13.6 g, 0.09 mol) dissolved in methanol (66 ml), followed by dissolving these together on heating, adding (S)-p-(4-methylhexyloxy)toluenesulfonate (20 g, 0.07 mol) prepared from 4-methylhexanol in the same manner as in Example 1, (ii), heating the mixture under reflux for 10 hours, extracting the reaction mixture with toluene after completion of the reaction, distilling off the solvent, to obtain methyl (S)-p-(4-methylhexyloxy)benzoate (17 g), adding to a solution of this product dissolved in ethanol (7.5 ml), a solution of NaOH (4.9 g, 0.14 mol) dissolved in water (24.6 ml), heating the mixture under reflux for 5 hours, pouring the resulting reaction mixture into 6N-hydrochloric acid (90 ml) having the ice added, allowing the mixture to stand overnight, recrystallizing the resulting crystals from heptane to obtain (S)-p-(4-methylhexyloxy)benzoic acid (6.5 g), adding thionyl chloride (20 ml) to the benzoic acid (5 g, 0.02 mol), heating the mixture under reflux for one hour, and distilling off excess thionyl chloride to obtain p-(4-methylhexyloxy)benzoic acid chloride (XI) (5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Product: Fc1ccc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)cc1

Procedure:
6-Chloro-N-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and 4-fluoroaniline in a similar manner as described in Example 13 to give 63 mg (43% yield) of a yellow solid. 1H-NMR (CDCl3): δ 8.03 (s, 1H), 7.46 (m, 1H), 7.23-7.05 (m, 2H), 6.95 (m, 2H), 6.66 (m, 2H), 4.72 (s, 1H), 3.70 (s, 1H), 2.70 (m, 2H), 2.21 (m, 1H), 2.01 (m, 1H), 1.93-1.71 (m, 2H); MS m/z 313 (M−1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[ClH:11].[CH3:12][NH2:13].[C-:14]#[N:15].[K+]>CO.O>[ClH:11].[CH3:12][NH:13][C:2]1([C:14]#[N:15])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: O=C1Cc2ccccc2C1
Reactant: CN
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNC1(C#N)Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-indanone (20.0 g, 151 mmol) in MeOH (20 mL) was added methylamine hydrochloride (10.2 g, 151 mmol). To the stirred mixture was added H2O (20 mL) and a fine homogenous slurry developed. The reaction mixture was cooled to 0° C. and KCN (9.84 g, 151 mmol) in H2O (20 mL) was added slowly over 30 min, such that the temperature did not exceed 10° C., then stirring was continued at ambient temperature for 18 h. The reaction mixture was extracted with Et2O (250 mL) and the organic extract was washed with brine (50 mL) then dried over MgSO4. HCl (g) was bubbled through the vigorously stirred solution for 10 minutes and a white solid precipitated. The solid was filtered, washed with Et2O, and dried to yield the title compound. MS: m/z=173 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=1
Reactant: Cc1ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc([C@H](C)N)n(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To a solution of [(S)-1-(6-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (969 mg, 2.76 mmol) in DCM (7.5 mL) was added TFA (2.5 mL) and the mixture was stirred at RT for 20 h. Volatiles were removed under reduced pressure and the resulting residue was dissolved in DCM (30 mL) and washed with a saturated solution of NaHCO3 (40 mL). The two phase system was stirred for 10 min, then the organic layer was dried (Na2SO4) and concentrated in vacuo affording (S)-1-(6-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown solid (583 mg, 84%). LCMS: RT 3.02 min [M+H]+ 252.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:13][C:14]2[NH:15][C:16]3[C:21]([N:22]=2)=[C:20]([NH2:23])[N:19]=[CH:18][N:17]=3)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([CH2:27][CH2:26][CH2:25][N:17]2[C:16]3[C:21]([N:22]=[C:14]([S:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[N:15]=3)=[C:20]([NH2:23])[N:19]=[CH:18]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCCc1ccccc1
Reactant: COc1cc(Sc2nc3c(N)ncnc3[nH]2)cc(OC)c1OC
Product: COc1cc(Sc2nc3c(N)ncn(CCCc4ccccc4)c-3n2)cc(OC)c1OC

Procedure:
The title compounds were prepared from 8-(3,4,5-trimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and (3-bromo-propyl)-benzene by a procedure similar to examples 1 and 2. The isomers were separated by preparative HPLC. 9-(3-Phenyl-propyl)-8-(3,4,5-trimethoxy-phenylsulfanyl)-9H-purin-6-ylamine: Yield 34%, 1H NMR (DMSO-d6) δ 8.30 (s, 1H), 7.26-7.22 (m, 2H), 7.16 (tt, J=7.6, 1.2 Hz, 1H), 7.12-7.10 (m, 2H), 6.78 (s, 2H), 4.24 (t, J=7.2 Hz, 2H), 3.72 (s, 6H), 3.63 (s, 3H), 2.56 (t, J=7.6 Hz, 2H), 1.94 (tt, J=7.6, 7.2 Hz, 2H); LC-MS [M+H]+ 452.0. 3-(3-Phenyl-propyl)-8-(3,4,5-trimethoxy-phenylsulfanyl)-3H-purin-6-ylamine: Yield, 13%, 1H NMR (DMSO-d6) δ 8.61 (s, 1H), 7.27-7.23 (m, 2H), 7.18-7.15 (m, 3H), 7.06 (s, 2H), 4.35 (t, J=7.2 Hz, 2H), 3.77 (s, 6H), 3.71 (s, 3H) 2.64 (t, J=7.2 Hz, 2H), 2.20 (quintet, J=7.2 Hz, 2H); LC-MS [M+H]+ 452.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[F:21])C(OC)=O.[Cl-].[Li+].O.C(OCC)(=O)C>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[F:21]
Reactant: COC(=O)C(C(=O)OC)c1c(F)cnc2ccc(OC)nc12
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1c(F)cnc2ccc(OC)nc12
Temperature: 100 °C

Procedure:
A mixture of dimethyl[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]propanedioate (52 g, 169 mmol), lithium chloride (14.5 g, 340 mmol) and water (3.43 ml, 190 mmol) in DMSO (1175 ml) was heated at 100° C. for 24 hours and cooled. The solution was shaken with water and ethyl acetate, separated and the organic phase washed twice with water. The total aqueous was re-extracted with ethyl acetate and this water-washed. The combined organic phase was dried and evaporated and the residue chromatographed, using a hexane/ethyl acetate gradient, to give the desired product containing about 10% of starting material (35.79 g).