Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[C:12]([O:40][CH3:41])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[OH:42][CH:43]1[CH2:46][NH:45][CH2:44]1>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([N:45]4[CH2:46][CH:43]([OH:42])[CH2:44]4)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[C:12]([O:40][CH3:41])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: OC1CNC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CC(O)C4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 3-hydroxyazetidine. MS (ES+): m/z 651.24 (100) [MH+]; HPLC: tR=0.91 min (UPLC, purity).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:13])[C:8]=2[NH2:12])[CH:3]=1.[C:14]([O:18][C:19]([N:21]1[C@H:26]([C:27](O)=[O:28])[C@H:25]2[CH2:30][C@@H:22]1[CH2:23][CH2:24]2)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH:13][C:27]([C@@H:26]1[C@H:25]2[CH2:30][C@H:22]([CH2:23][CH2:24]2)[N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:28]
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)O
Reactant: Nc1ccc2cc(Br)ccc2c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)Nc1ccc2cc(Br)ccc2c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 6-bromonaphthalene-1,2-diamine (1.08 g, 4.56 mmol), and (1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.10 g, 4.56 mmol) and HATU (2.08 g, 5.47 mmol) in methylene chloride (45 mL) was added DIPEA (3.98 mL, 22.79 mmol). The mixture was stirred at room temperature for two hours. Upon completion, the reaction was concentrated in vacuo, diluted with ethyl acetate and washed with water. The aqueous layer was back extracted with ethyl acetate twice. The combined organic layers were washed with brine, concentrated, and purified by normal phase chromatography (30-80% ethyl acetate (5% MeOH) in hexanes) to give (1S,3S,4R)-tert-butyl 3-(1-amino-6-bromonaphthalen-2-ylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.01 g, 95%). LCMS-ESI+: calc'd for C22H26BrN3O3: 459.12 (M+); Found: 460.9 (M+H+).
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].Cl[C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:11]=[CH:10][N:9]=1>O.O1CCOCC1>[OH:6][CH2:5][CH2:4][S:3][C:8]1[C:13]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[N:12][CH:11]=[CH:10][N:9]=1
Reactant: OCCS
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2SCCO)CC1
Temperature: 100 °C
Yield: 65.2 %

Procedure:
Sodium hydroxide (0.92 g, 23 mmol) was dissolved in water (9 mL) and dioxane (15 mL). 2-Mercaptoethanol (0.54 mL, 7.7 mmol) was added while stirring and 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (2.3 g, 7.7 mmol, from Example 52, step 1) in dioxane (10 mL) was added. The reaction mixture was heated at 100° C. for 22 h. After cooling to room temperature, it was extracted with EtOAc. The organic layer was dried (K2CO3) and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel using hexane/EtOAc (1:1) as eluent to give 1.71 g (65%) of the title compound as an orange oil. MS m/z 341 (M+H)+.
Reaction SMILES: O[NH:2][C@H:3]([C:16](N)=[O:17])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)(Cl)=[O:20]>C1COCC1>[NH2:2][C@H:3]([C:16]([OH:17])=[O:20])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(=O)[C@H](CCC(=O)OCc1ccccc1)NO
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Temperature: 50 °C
Yield: 99.7 %

Procedure:
HO-Glu(Bzl)-NH2 (30.0 g, 126.0 mmol) was suspended in 300 mL of anhydrous THF and heated to 50° C. Phosgene (20% in toluene) (81.3 mL, 164.6 mmol) was added to the amino acid suspension by syringe, and the amino acid dissolved over the course of approx. 30 minutes, forming a clear solution. The solution was concentrated by rotory evaporation, dissolved in ˜150 mL of anhydrous THF, and transferred to an Erlenmeyer flask. Hexane was added and the product was allowed to crystallize overnight. The NCA was isolated by filtration and dried in vacuo. 29.8 g (90% yield) of Glu(Bzl) NCA was isolated as a white, crystalline solid. 1H NMR (CDCl3) δ 7.36 (5H), 6.22 (1H), 5.14 (2H), 4.35 (1H), 2.61 (2H), 2.29 (1H), 2.14 (1H) ppm.
Reaction SMILES: [Sn].[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][C:4]=1[N+:14]([O-])=O.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(NC1C=CC=CC=1)(=O)C>Cl.C(O)(=O)C.O>[C:17]([NH:14][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[Cl:2])[CH:7]=[CH:8][C:9]([OH:11])=[O:10])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C=CC(=O)O)ccc1Cl
Temperature: 45 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Tin II chloride dihydrate (103 g, 0.46 mol) was dissolved in concentrated HCl (120 mL). Warming was necessary to obtain a clear solution. 4-Chloro-3-nitrocinnamic acid (25 g, 0.11 mol) was added portionwise with stirring. After about 20% of the starting material had been added, the mixture was warmed with a heat gun to 45° C. to initiate reaction. The rate of addition was controlled to maintain a temperature of 65-75° C. Cooling with a water bath was used to prevent the temperature exceeding 80° C. After the addition was complete and reaction started to subside, the mixture was transferred to an oil bath at 65° C. for 1 h. The mixture was cooled to room temperature. The solid was filtered, washed with 2 M HCl, (60 mL) and sucked dry. The filter cake was dried in a vacuum oven for 1 h, then in air overnight, to give about 34 g crude product. This material was suspended in acetic acid (100 mL) with stirring and acetic anhydride (100 mL, 1.1 mol) was added in one portion. The temperature rose to 35° C. After the initial exotherm subsided, the mixture was stirred in an oil bath at 110° C. for 2 h, but did not dissolve. LCMS showed complete conversion to the desired acetanilide. The solution was cooled and water (50 mL) was added cautiously. The mixture was concentrated to about 200 mL. More water (100 mL) and 2 M HCl (50 mL) were added. The precipitate was filtered, washed with water and dried to give 3-acetamido-4-chlorocinnamic acid (25.0 g, 95%).
Reaction SMILES: [NH:1]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]([CH2:40][C:41](C)(C)C)(C)C)[N:33]=[C:32]([NH:45][C:46]([CH2:49][C:50](C)(C)C)(C)C)[N:31]=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:25][C:23]1([CH3:26])[CH2:24][CH:19]([N:1]([C:30]2[N:31]=[C:32]([NH:45][CH2:46][CH:49]=[CH2:50])[N:33]=[C:34]([NH:36][CH2:37][CH:40]=[CH2:41])[N:35]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:30]2[N:31]=[C:32]([NH:45][CH2:46][CH:49]=[CH2:50])[N:33]=[C:34]([NH:36][CH2:37][CH:40]=[CH2:41])[N:35]=2)[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]2)[CH2:20][C:21]([CH3:28])([CH3:27])[NH:22]1
Reactant: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(NC(C)(C)CC(C)(C)C)n1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: C=CCNc1nc(NCC=C)nc(N(CCCCCCN(c2nc(NCC=C)nc(NCC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A stirred mixture of 4,4'(hexamethylenediimino)bis(2,2,6,6-tetramethylpiperidine) (6.36 grams; 0.0161 mole), 2-chloro-4,6-bis(t-octylamino)-1,3,5-triazine (9.56 grams; 0.0322 mole), and powdered sodium hydroxide (1.29 grams; 0.0322 mole) in xylene (75 mls) is stirred and heated at reflux while removing water therein by means of a water trap. The reaction mixture is stirred and heated at reflux for 18 hours, cooled to 25° C., and treated with acetonitrile (200 mls). The reaction mixture is filtered to recover a precipitate, and the solid is washed successively with water and acetone, and dried to obtain 10.0 grams of product which melts at 208°-209° C. after recrystallization from xylene.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([N:14]3[CH2:17][CH2:16][CH2:15]3)[N:11]=[C:10]([S:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=3)[N:9]=2)[CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][C:10]2[N:9]=[C:8]([NH:7][C:4]3[NH:5][N:6]=[C:2]([CH3:1])[CH:3]=3)[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][CH2:17]3)[N:11]=2)=[CH:20][CH:21]=1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)n2)n[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(N)cc3)n2)[nH]n1
Reaction time: 8 h

Procedure:
tert-butyl 4-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-(azetidin-1-yl)pyrimidin-2-ylthio)phenylcarbamate (prepared using method similar to that described for example 6) (2.53 g, 5.6 mmol) was dissolved in 1:1 TFA-DCM (20 mL) and the resulting solution allowed to stand overnight at room temperature. The solution was concentrated in vacuo. The residue was taken up in EtOAc and washed with saturated aqueous sodium bicarbonate solution (×2) then brine and dried over sodium sulfate. The resulting tan solid (1.8 g, 91%) [MS (ES+) 354] was used without further purification or characterization in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[CH2:16]([Mg]Cl)[CH3:17].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:16][CH3:17])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(CC)c1
Reaction time: 0.5 h

Procedure:
To a solution of 4-nitrophenylacetic acid ethyl ester (1.63 g) in tetrahydrofuran (100 mL) was dropwise added 2M ethyl magnesium chloride in tetrahydrofuran (3 mL) at −15° C. under argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. After further dropwise addition of 2M ethyl magnesium chloride in tetrahydrofuran (3 mL), the mixture was stirred at −15° C. for one hour, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.0 g) was added thereto at the same temperature. The mixture was stirred overnight, and water (300 mL) was added thereto, followed by extraction with chloroform (150 mL×3). The organic layers were combined, washed with saturated brine, dried over sodium sulfate and purified by column chromatography on silica gel with hexane:ethyl acetate=10:1 to give the title compound (1.09 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([CH:45]=[CH:46][CH:47]=2)[NH:17][C:18](=[O:44])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([N:25]2[CH:30]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:29]([C:38]([O:40][CH3:41])=[O:39])=[C:28]([CH3:42])[NH:27][C:26]2=[O:43])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH:30]2[C:29]([C:38]([O:40][CH3:41])=[O:39])=[C:28]([CH3:42])[NH:27][C:26](=[O:43])[N:25]2[C:23]([NH:22][CH2:21][CH2:20][CH2:19][C:18](=[O:44])[NH:17][C:16]2[CH:45]=[CH:46][CH:47]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:15]=2)=[O:24])=[CH:32][CH:33]=1
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCNCC3)c2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
Into a solution of methyl 3-{[(4-{3-[1-(tert-butoxycarbonyl)-4-piperidinyl]anilino}-4-oxobutyl)amino]carbonyl}-4-(4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (40.9 mg, 0.0628 mmol) in dichloromethane (2.00 mL) at 0° C. was slowly added trifluoroacetic acid (71.6 mg, 0.628 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in iso-PrOH/CHCl3 (1:3, 10 mL) and basified to pH 11 with 10% KOH solution, washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the desired product (34.6 mg, 99%): 1H NMR (400 MHz, CDCl3) δ 8.00 (m, 3H), 7.67 (s, 1H), 7.35-7.27 (m, 4H), 7.04-6.98 (m, 3H), 6.65 (s, 1H), 3.72 (s, 3H), 3.5-3.48 (m, 2H), 3.20-3.11 (m, 3H), 2.42 (t, 2H, J=7.5 Hz), 2.36 (s, 3H), 2.13-2.06 (m, 2H), 1.97-1.88 (m, 4H); ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1([OH:14])[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].CC1C=C(C(C)(C)C)[C:19]([OH:26])=[C:18]([C:27](C)(C)C)[CH:17]=1.C(N(CC)CC)C.CC(C(Cl)=O)=C>O1CCCC1>[C:1]([C:4]1([OH:14])[CH:12]=[C:11]([O:13][C:19](=[O:26])[C:18]([CH3:27])=[CH2:17])[CH:10]=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)C1(O)C=C(O)C=CC1C(=O)O
Agent: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1=CC(O)(C(C)=O)C(C(=O)O)C=C1
Temperature: 0 °C

Procedure:
2-acetyl-4-hydroxysalicylic acid (15.0 millimole, 2.9 g) and butylhydroxytoluene (10 mg) was dissolved in tetrahydrofuran (THF). To the solution was added triethylamine (0.5 g), and the solution was cooled to 0° C. by ice bath. While stirring under a flow of nitrogen gas, methacryl chloride (20 millimole, 2.41 g) was added to the solution using a syringe over a period of 20 minutes, and the solution was kept stirred for another hour after completing the addition. After the reaction was over, the solvent was evaporated to give pale yellow powder. The powder was washed by dichloromethane and recrystallized by an aqueous solution of 0.5% hydroquinone. Dried under a reduced pressure, colorless crystal having a needle shape was obtained: m.p. 152.7° C.; yield 2.54 g, 64.1%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:5])[CH3:2].[H][H]>O1CCCC1CO.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=CCn1c(=O)[nH]c(=O)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: OCC1CCCO1
Product: CCOC(=O)CCCn1c(=O)[nH]c(=O)c2ccccc21
Reaction time: 6 h
Yield: 94.6 %

Procedure:
To a solution of 1-(3-ethoxycarbonyl-2-propenyl)-2,4-(1H,3H)-quinazolinedione (5.50 g) in tetrahydrofuran-methanol (200 ml, 3:1 V/V) was added 10% palladium on carbon (550 mg). The mixture was stirred vigorously under atmospheric pressure of hydrogen. After 6 hours, the catalyst was filtered off, and the solvent was evaporated. 1-(3-Ethoxycarbonylpropyl)-2,4(1H,3H)-quinazolinedione (5.24 g) as a crystal was obtained by recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=O.N1CCCCC1.[CH3:20][CH:21](C(OCC)=O)[C:22](OCC)=[O:23]>>[CH2:10]([C:4]1[N:5]=[C:6]([CH2:8][CH3:9])[CH:7]=[C:2]2[C:3]=1[CH:12]=[C:21]([CH3:20])[C:22](=[O:23])[NH:1]2)[CH3:11]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Solvent: C1CCNCC1
Product: CCc1cc2[nH]c(=O)c(C)cc2c(CC)n1
Temperature: 120 °C

Procedure:
A mixture of 4-amino-2,6-diethylpyridine-3-carbaldehyde (2.0 g), piperidine (0.5 ml) and diethyl methylmalonate (3.0 ml) was heated together at 120° C. for 24 hours. The mixture was then purified by flash chromatography, eluting with ether, to give 5,7-diethyl-3-methyl-1,6-naphthyridin-2(1H)-one as a solid (0.265 g); m.p. 163°-166° C. dec. (after recrystallisation from acetone); NMR (d6 -DMSO): 1.22(t, 3H), 1.24(t, 3H), 2.11(s, 3H), 2.71(q, 2H), 2.99(q, 2H), 6.88(s, 1H), 7.96(s, 1H), 11.84(broad, 1H); mass spectrum (CI, ammonia): 217 (M+H)+ ; microanalysis, found: C, 72.3; H, 7.4; N, 13.1%; C13H16N2O requires: C, 72.2; H, 7.5; N, 13.0%.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH2:12]Cl.C1(C)C=CC=CC=1.[P:21]([S-:27])(=[S:26])([O:24][CH3:25])[O:22][CH3:23].[NH4+]>CO>[P:21]([S:27][CH2:12][C:3]1[N:4]=[C:5]2[S:11][CH:10]=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Cl:1])(=[S:26])([O:24][CH3:25])[O:22][CH3:23]
Reactant: COP(=S)([S-])OC
Reactant: O=c1c(Cl)c(CCl)nc2sccn12
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COP(=S)(OC)SCc1nc2sccn2c(=O)c1Cl
Reaction time: 6 h

Procedure:
The compound of EXAMPLE 2 (7 g) and 100 ml of toluene was stirred and heated to 70°. To this mixture was added, dropwise, a solution of 14 g ammonium dimethyl phosphorodithioate in 200 ml methanol. The resulting mixture was kept at 70° for 6 hours, then the methanol was distilled off. Toluene (400 ml) was added, and the mixture was washed with water, separated, dried and evaporated under reduced pressure. The solid which remained was washed with toluene and filtered. The solid, m.p. 125°-130°, weighed 2.5 g.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([OH:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15]>>[OH:13][CH:8]1[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=3)[C:3]=2[CH2:10][C:9]1([CH3:12])[CH3:11]
Reactant: CC1(C)Cc2c(Br)cncc2C1O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC1(C)Cc2c(-c3ccc(C#N)cc3)cncc2C1O

Procedure:
In analogy to the procedure described for the preparation of examples 85 and 86, 4-bromo-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-17) and 4-cyanophenylboronic acid gave racemic 4-[7-hydroxy-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-4-yl]benzonitrile. SFC separation afforded (+)-4-[(7R or 7S)-7-hydroxy-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-4-yl]benzonitrile (example 87) and (−)-4-[(7S or 7R)-7-hydroxy-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-4-yl]benzonitrile (example 88) as white solids. MS: 264.9 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1cccc(I)c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(C#N)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (103 mg, 0.55 mmol) and 3-iodobenzonitrile (134 mg, 0.59 mmol) according to the general procedure IC to give 68 mg (58%) of an orange-brown solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.26 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.79-7.78 (m, 1H), 7.73-7.70 (m, 1H), 7.61-7.57 (m, 1H), 7.48-7.43 (m, 3H), 7.22-7.18 (m, 2H), 3.67 (s, 3H), 3.00-2.95 (t, 2H, J=7.8 Hz), 2.67-2.62 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 141.7, 135.5, 134.8, 131.9, 131.3, 129.2, 128.5, 125.0, 120.2, 118.1, 116.7, 112.8, 91.7, 86.6, 51.7, 35.3, 30.8; EI-MS m/z 289 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[Br:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccccc1Br
Product: Nc1cc2ncnc(Nc3ccccc3Br)c2cn1
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 33.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (198 mg, 1.03 mmol) (described in a previous experimental) and 2-bromoaniline (1.00 mL, 9.18 mmol) is stirred under N2 at 180° C. for 2.5 h, and the resulting product is chromatographed on alumina (1% EtOH/CHCl3) to give 7-amino-4-(2-bromoanilino)pyrido[4,3-d]pyrimidine (108 mg, 33%) as a pale yellow solid, 1H NMR (DMSO) δ 9.91 (1H, brs), 9.27 (1H, s), 8.20 (1H, s), 7.73 (1H, d, J=7.9 Hz), 7.50 (1H, m), 7.44 (1H, t, J=6.9 Hz), 7.25 (1H, m), 6.59 (2H, brs), 6.42 (1H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:5]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2][NH:20][CH:17]2[CH2:19][CH2:18]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(C(CCNC2CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-bromo-1,1-diphenylpropane 9 (2.06 g, 7.49 mmol) in DMF (15 mL) at room temperature was added cyclopropylamine (3.26 g, 57.1 mmol, 4.0 mL) and cesium carbonate (3.19 g, 9.79 mmol). The reaction mixture was stirred at room temperature for 20 h and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 1% to 6% MeOH (2 M NH3) in DCM) gave N-(3,3-diphenylpropyl)cyclopropanamine 10 as a colorless oil. Mass spectrum: calculated for C18H21N 251.2; found 252.2 (M++1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([OH:3])=[O:2].O.[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([O:3][CH2:14][CH3:15])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCC1CCCC1=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCC1CCCC1=O

Procedure:
In the manner described in Example 3, treatment of 2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluene sulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93°C. (0.10 mm).