Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([C:6]2[CH:7]=[N:8][C:3]([CH2:2][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)=[O:10])=[CH:13][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)nc1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCOCC2)nc1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide was dissolved in DMSO (1 mL) treated with morpholine (33 uL) for 1 h. The reaction was concentrated, and the crude residue was purified by reverse phase HPLC to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(morpholinomethyl)pyridine-3-carboxamide. MS (Q1) 409.3 (M)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([Cl:11])[CH:3]=1.P(Br)(Br)Br.[CH:16]1(O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([CH2:9][O:10][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][C:7]=1[F:8]
Reactant: OC1CCCCC1
Reactant: OCc1cc(F)c(Br)cc1Cl
Agent: BrP(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cc(COC2CCCCC2)c(Cl)cc1Br
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a solution of (4-bromo-2-chloro-5-fluorophenyl)methanol (5.00 g, 21.00 mmol) in dichloromethane (150 mL) was added phosphorous tribromide (8.53 g, 31.50 mmol) at 0° C. The clear reaction solution was stirred at the same temperature for 1 hour, then at an ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo to dryness to obtain viscous yellow liquid which was added to a stirred mixture of cyclohexanol (1.68 g, 16.80 mmol) and sodium hydride (60% dispersion in mineral oil, 1.93 g, 21.00 mmol,) in N,N-dimethylformamide (15 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 16 hours and quenched with addition of saturated ammonium chloride (100 mL). The organic layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered the solid. The filtrate was concentrated in vacuo to dryness. The residue was purified by flash column chromatography with ethyl acetate in hexanes (10%) to afford the title compound (2.60 g, 38%) as a viscous liquid: MS (ES+) m/z 320.9, 318.9 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:8][CH:7]=[CH:6][C:5]([C:9]([OH:11])=[O:10])=[CH:4]1.[CH2:12](O)[CH3:13]>>[ClH:1].[NH2:2][CH:3]1[CH2:8][CH:7]=[CH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4]1
Reactant: NC1C=C(C(=O)O)C=CC1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1=CC(N)CC=C1
Temperature: 0 °C

Procedure:
3-Amino-1,5-cyclohexadiene carboxylic acid hydrochloride (200 mg) is dissolved in ethanol containing anhydrous HCl, and the resulting solution is stirred over night at 0° C. Evaporation of the solvent affords ethyl 3-amino-1,5-cyclohexadienecarboxylate hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[F:12][C:11]([F:14])([F:13])[S:8]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1cccc(Br)c1)C(F)(F)F
Reactant: C1CNCCN1
Product: O=S(=O)(c1cccc(N2CCNCC2)c1)C(F)(F)F

Procedure:
Beginning with 3-bromo-trifluoromethanesulfonyl-benzene and piperazine, the titled cmp was recovered by the procedure described in Preparation 17. MS m/z (rel. intensity, 70 eV) 294 (M+, 22), 252 (bp), 119 (32), 104 (10), 56 (15). (45).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH2:34]1[O:36][CH2:35]1>C1C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][OH:36])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C1CO1
Reactant: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2)cc1OC
Solvent: CO
Solvent: c1ccccc1
Product: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2CCO)cc1OC
Yield: 97.7 %

Procedure:
50 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-piperazine (cf. Example 2) are dissolved in 200 ml of benzene and 400 ml of methanol and heated for 48 hours in a pressure vessel at 60° C. with addition of 22 g of ethylene oxide. Subsequently, the solution is evaporated to dryness. The residue is dissolved in 500 ml of diethylether, combined with 60 ml of 2N HCl, and vigorously stirred. The organic phase is separated and washed halide-free with water. The aqueous acid extract is alkalized with ammonium hydroxide solution and extracted with diethyl ether. The extract is dried, filtered, and the solvent is removed by distillation. 54 g (98 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-hydroxyethylpiperazine are obtained as a colorless resin.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].O=[C:15]([CH3:27])[CH2:16][O:17][C:18]1[C:19]([C:24]([NH2:26])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=1.[BH4-].[Na+].Cl>C(O)C>[CH3:27][CH:15]([NH:1][CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[CH2:16][O:17][C:18]1[C:19]([C:24](=[O:25])[NH2:26])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)COc1cccnc1C(N)=O
Reactant: Cc1ccccc1OCC(O)CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1OCC(O)CNC(C)COc1cccnc1C(N)=O
Temperature: 25 °C

Procedure:
A solution of 4.5 g of 1-amino-3-(2-methyl-phenyloxy)-2-propanol and 4.85 g of 3-(2-oxo-propyloxy)-2-pyridinecarboxylic acid amide in 100 ml of ethanol is heated under reflux for 3 hours. After cooling to room temperature, 1.9 g of sodium borohydride are added whilst stirring; the temperature gradually rises to 45° C. After the reaction has subsided, the mixture is stirred for a further hour. The reaction mixture is then acidified with 2 N hydrochloric acid whilst cooling, and is extracted with 20 ml of ethyl acetate. The aqueous phase is rendered alkaline with a concentrated aqueous sodium hydroxide solution and is extracted with three times 50 ml of ethyl acetate. After drying over sodium sulphate and evaporation of the organic solution, only, crude 1-[1-methyl-2-(2-carbamoyl-3-pyridyloxy)-ethyl-amino]-3-(2-methyl-phenyloxy)-2-propanol is obtained, which forms a neutral fumaric acid salt, melting point 145°-161° C. after recrystallisation from a mixture of methanol and ethyl methyl ketone.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1C(C)C([O-])=O.[Na+].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:36])[CH:32](Br)[CH2:33][CH3:34])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:36])[CH:32]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:33][CH3:34])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24]
Reactant: CC(C(=O)[O-])c1nccs1
Reactant: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium 2-(2-thiazolyl)propionate (148 mg) is introduced into DMF (5 ml), and 2-(1-benzothien-2-yl)-5-[(2-bromobutanoyl)amino]benzamide (Example 8A; 171 mg), HATU (291 mg) and 4-methylmorpholine (194 mg) are added. The reaction mixture is stirred at RT overnight. The reaction mixture is concentrated and the residue is purified by preparative HPLC. 101 mg (36% of theory) of product are isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]([OH:18])[CH2:13][CH:14](C)[CH2:15]3)=[C:10]3[N:19]([CH3:26])[C:20](=[O:25])[N:21]([CH3:24])[C:22](=[O:23])[C:9]=23)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28]C(C)CC(OC)=O.S[C@@H](C)CN1C(C2C=CC=CC=2)=C2C(N(C)C(=O)N(C)C2=O)=C1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]([OH:18])[CH:13]([CH3:28])[CH2:14][CH2:15]3)=[C:10]3[N:19]([CH3:26])[C:20](=[O:25])[N:21]([CH3:24])[C:22](=[O:23])[C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(O)c2c3c(c(-c4cccc(F)c4)n2C1)c(=O)n(C)c(=O)n3C
Reactant: COC(=O)CC(C)CBr
Agent: C[C@H](S)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Product: CC1CCn2c(-c3cccc(F)c3)c3c(=O)n(C)c(=O)n(C)c3c2C1O

Procedure:
The title compound was prepared analogously to 5-(3-fluorophenyl)-10-hydroxy-1,3,8-trimethyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (Intermediate La) by replacing Methyl 4-bromo-3-methylbutanoate (Intermediate T) with methyl 4-bromo-2-methylbutanoate (Intermediate S).
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][N:9]([CH3:25])[C:10](=[S:24])[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[O:20]COC>CO>[CH3:25][N:9]([CH3:8])[C:10](=[S:24])[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[OH:20]
Reactant: COCOc1c(OC)cccc1SC(=S)N(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccc(SC(=S)N(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
4 N hydrogen chloride/dioxane solution (50 mL) was added to a methanol (200 mL) solution of the compound (70.49 g) synthesized in the above (2), and stirred at room temperature for 2 hours. The reaction liquid was concentrated and extracted with chloroform. The organic layer was washed with saturated saline, then dried with sodium sulfate, and concentrated to obtain the intended compound (46.65 g, 78%) as a brown solid.
Reaction SMILES: [ClH:1].[F:2][CH:3]([F:28])[CH2:4][N:5]1[CH2:10][C:9]2([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[O:8][CH:7]([C:23]2[O:24][CH:25]=[CH:26][N:27]=2)[CH2:6]1>C(Cl)Cl>[ClH:1].[F:28][CH:3]([F:2])[CH2:4][N:5]1[CH2:10][C:9]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:8][CH:7]([C:23]2[O:24][CH:25]=[CH:26][N:27]=2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(c1ncco1)O2
Agent: Cl
Solvent: ClCCl
Product: FC(F)CN1CC(c2ncco2)OC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
HCl (781 μL of 4 M in dioxane, 3.12 mmol) was added to a solution of tert-butyl 4-(2,2-difluoroethyl)-2-(oxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (121 mg, 0.31 mmol) in DCM (0.7 mL) and the reaction mixture was stirred for 1 hour at room temperature. The solvent and excess HCl was removed under reduced pressure and the resulting solid was dissolved in methanol (3 mL) and purified by Waters mass directed LC/MS: (1-99% ACN/H2O (5 mM HCl)). The desired fractions were combined and concentrated in vacuo to yield 4-(2,2-difluoroethyl)-2-(oxazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane hydrochloride salt (95 mg, 94%) as a white solid. ESI-MS m/z calc. 287.1. Found 288.3 (M+1)+; Retention time: 0.96 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 8.15 (d, J=0.8 Hz, 1H), 7.23 (d, J=0.8 Hz, 1H), 6.22 (tt, J=55.1, 4.0 Hz, 1H), 4.94 (dd, J=10.8, 2.6 Hz, 1H), 3.19-2.79 (m, 8H), 2.65-2.54 (m, 2H), 2.25 (dd, J=11.9, 1.5 Hz, 1H), 1.83-1.70 (m, 2H), 1.65 (dd, J=15.1, 3.9 Hz, 1H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:6][CH:5]=1.O.NN.O>C(O)COCCO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCC(=O)CCc1ccc(Cl)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCCCCCCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a solution of 3.4 gms KOH in 23 ml diethylene glycol was added 5.4 gms 9(4-chlorophenyl)-7-ketononanoic acid and 3 ml hydrazine hydrate. The resulting mixture was heated at 145° for 1 hour. The mixture was cooled, attached to a water aspirator, and the excess water and hydrazine distilled off. The mixture was then re-heated to 145° for 3 hours and cooled. The oily reaction mixture was diluted with water, acidified with conc. HCl, and the precipitated solid filtered off. Since the NMR showed starting material still present, the solid was dissolved in 25 ml diethylene glycol and 4.1 ml hydrazine hydrate was added. This solution was refluxed for 3 hr, then the water and hydrazine were distilled off under vacuum as before. 5.2 gms KOH was added and the resulting mixture was heated at 160° for 3.5 hours, then cooled to room temperature overnight. It was dissolved in water and acidified with conc. HCl. The precipitated solid was dissolved in 10% KOH solution, washed three times with ether, filtered, acidified with conc. HCl, and placed in the cold overnight. The solid was filtered off, dried and recrystallized from hexanes to give 3.1 gm white solid of m.p. 73°-5° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([OH:28])=O)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][NH:35][CH3:36].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([N:35]([CH3:36])[CH3:34])=[O:28])[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-3-carboxylic acid (0.066 g) in N,N-dimethylformamide (5 mL) were added N,N-dimethylamine (0.038 mL), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (57 mg) and N,N-diisopropylethylamine (0.069 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=70:30-100:0, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.058 g, yield 84%) as colorless crystals. MS: 514 (MH+). melting point 180-182° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[OH:23])=[O:15])=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2.[C:24]1(C)C=CC=CC=1>CN(C(OC)OC)C>[Br:13][C:5]1[CH:4]=[C:3]2[C:2](=[C:11]3[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=13)[N:1]=[CH:24][N:16]([C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[OH:23])[C:14]2=[O:15]
Reactant: Cc1ccccc1
Reactant: CN1CCCc2c(Br)cc(C(=O)N[C@H]3CCCC[C@@H]3O)c(N)c21
Agent: COC(OC)N(C)C
Product: CN1CCCc2c(Br)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21

Procedure:
A solution of 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxamide (758 mg, 1.98 mmol) in toluene (6 mL) and DMF-DMA (5.3 mL) was heated in a sealed tube at 135° C. for 3 h. The resulting mixture was concentrated and purified by silica gel chromatography (0-4% MeOH/CH2Cl2) to afford 6-bromo-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-7,8,9,10-tetrahydropyrido[3,2-h]quinazolin-4(3H)-one in pure form.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1)([OH:3])=O.[CH2:16]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(OCC)C>[CH2:16]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:1]([C:4]2[CH:5]=[C:6]([O:14][CH3:15])[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=2)=[O:3])=[CH:25][CH:24]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCOc1ccc(N)cc1
Reactant: COC(=O)c1ncc(C(=O)O)cc1OC
Solvent: CCOCC
Product: CCCCCCOc1ccc(NC(=O)c2cnc(C(=O)OC)c(OC)c2)cc1

Procedure:
Methyl 5-(((4-n-hexyloxyphenyl)amino)carbonyl)-3-methoxypyridine-2-carboxylate was prepared from methyl 5-carboxy-3-methoxypyridine-2-carboxylate and 4-hexyloxyaniline, m.p. 118°-119° C. (from diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([NH:8][C:9]([NH2:11])=[O:10])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:19][CH:21]2[CH2:22][O:23]2)=[C:6]([NH:8][C:9]([NH2:11])=[O:10])[CH:7]=1
Reactant: BrCC1CO1
Reactant: NC(=O)Nc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)Nc1cc(Cl)ccc1OCC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.5 %

Procedure:
A suspension of N-(5-chloro-2-hydroxyphenyl)urea (53 mg, 0.28 mmol), cesium carbonate (92 mg, 0.28 mmol) and epibromohydrine (49 mg, 0.36 mmol) in dry DMF (0.6 mL) was stirred at room temperature for 24 hours. The mixture was then partitioned between ethyl acetate and water. The organic phase was washed with water three times, dried and concentrated to a solid residue. This crude product was recrystallized (ethyl ether and heptane to afford the subtitle compound (18 mg, 26.5%).
Reaction SMILES: [CH:1]1([C@H:4]([O:6][C:7](=[O:31])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:30][CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1.O>CN(C=O)C>[CH:1]1([C@H:4]([O:6][C:7](=[O:31])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:28][CH2:29][CH2:30]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1)C1CC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CCC2)cc1)C1CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A mixture of (R)-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (0.083 g, 0.2 mmol), Cs2CO3 (0.163 g, 0.5 mmol), 2-chloropyrimidine (0.046 g, 0.4 mmol) in DMF (2.0 mL) was stirred at 70° C. for 2 h. After cooling to room temperature, the mixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water, purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide (R)-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamic acid 1-cyclopropyl-ethyl ester (0.073 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([F:17])[C:12]([C:18]#[N:19])=[C:11]([F:20])[C:10]=1F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C>[NH:1]([C:11]1([F:20])[CH:10]=[C:9]([F:8])[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CC1=C(F)C(C#N)C(F)(Nc2ccccc2)C=C1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 0.85 g of aniline in 20 ml of acetonitrile was dropwise added, while stirring, to a solution of 2.0 g of tetrafluoroisophthalonitrile and 2.0 g of triethylamine in 30 ml of acetonitrile. After dropwise adding, the mixture was stirred at room temperature for 1 hour and an aqueous sodium bicarbonate solution was then added. The mixture was extracted with chloroform and the chloroform extract was washed 5 times with an aqueous sodium chloride solution. After drying with magnesium sulfate, the chloroform was distilled off. The resultant crude crystal was purified by silica gel chromatography (solvent:hexane). Thus, 2.3 g (87% yield) of the desired compound No. 6 was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:6].C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:48]([NH2:56])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:9]=1[C:10]([NH:56][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:12])=[O:6]
Reactant: COc1ccc(C(=O)Nc2ccc(Oc3ccccc3)cc2C(=O)O)cc1Cl
Reactant: NCCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(Oc3ccccc3)cc2C(=O)NCCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A solution of 43D (17 mg, 0.043 mmol) in DMF (1 mL) was treated with diisopropylcarbodiimide (6 mg, 0.047 mmol) and HOBt (12 mg, 0.086 mmol). The reaction was stirred for 1 hour at room temperature and then phenethylamine (104 mg, 0.86 mmol) was added. The resulting solution was stirred for 3 hours at room temperature, and then concentrated. The crude material was purified by chromatography (SiO2, 5% to 20% EtOAc in Hexanes) to afford 43E (16 mg, 75%). HPLC retention time=4.50 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1I.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C.[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(C(F)(F)F)c(F)cc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(F)c(C(F)(F)F)cc2F)OC1(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 101.4 %

Procedure:
1,4-difluoro-2-iodo-5-(trifluoromethyl)benzene (500 mg, 1.6 mmol) was dissolved in dry THF (7 mL), cooled to 0° C. and treated in portions with isopropyl magnesium chloride-lithium chloride complex (1.4 mL, 1.3 M, 1.8 mmol) and stirred for 40 min at 5° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (360 μl, 330 mg, 1.8 mmol) was added and stirring was continued for 1 h. After treating with sat. NH4Cl, the mixture was shaken with ethyl acetate. The organic phase was washed with saturated NaCl, dried (Na2SO4), and evaporated to give the title compound as a light brown oil (500 mg, 100%). The material was used without further purification: 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J=9.9, 4.3 Hz, 1H), 727 (dd, J=8.0, 5.2 Hz, 2H), 1.37 (s, 12H). 19F NMR (376 MHz, CDCl3) δ −62.10, −62.13, −106.85, −106.90, −121.81, −121.87, −121.90.