Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+](C1C=CC([O:14][C:15]([NH:17][C@@H:18]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:19](=[O:40])[CH2:20][N:21]([CH3:39])[C:22]([N:24]2[CH2:38][CH2:37][CH2:36][C@H:25]2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[O:23])=O)=CC=1)([O-])=O.C1(C)C=CC=CC=1.N1CCC[C@H]1C(OCC1C=CC=CC=1)=O>C(OCC)(=O)C>[CH3:39][N:21]([CH2:20][C:19](=[O:40])[C@@H:18]([NH:17][C:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:14])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23]
Reactant: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: C1COCCN1
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
Morpholine (1 ml., 11.4 mmole) is added to a stirring solution of 1-[[[(S)-3-[[(4-nitrophenoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester (0.9 g., 1.58 mmole) ih toluene at 0° in one portion. The reaction mixture turns yellow in 15 minutes and TLC indicates complete loss of starting material after 30 minutes. The resulting solution is washed sequentially with water, 1N hydrochloric acid, and 10% sodium bicarbonate. The organic layer is dried (MgSO4) and concentrated. The crude product is purified by preparative layer chromatography to give 0.26 g. of 1-[[methyl[(S)-3-[(4-morpholinylcarbonyl)amino]carbonyl]-2-oxo-4-phenylbutyl]amino]carbonyl]L-proline, phenylmethyl ester as a yellow oil. TLC (ethyl acetate) Rf =0.18.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35].N>C(Cl)Cl.CO>[CH3:31][O:32][CH2:33][C:34]([NH:21][C:17]1[CH:16]=[C:15]([O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:20]=[CH:19][N:18]=1)=[O:35]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reactant: COCC(=O)Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirred suspension of 4-(4-nitronaphthalen-1-yloxy)pyridin-2-amine (71.8 g, 255 mmol) in dry DCM (1.1 L) and DIPEA (84.0 mL, 511 mmol), cooled in an ice bath, was added dropwise 2-methoxyacetyl chloride (35.0 mL, 383 mmol) over 20 min. The resulting red solution was stirred at RT for 1 hr and was then treated with a solution of NH3 in MeOH (7 M, 100 mL). A precipitate formed immediately and the reaction mixture was stirred for a further 15 min and the volatiles were evaporated in vacuo. The solid residue was triturated with water (900 mL), collected by filtration and washed with water (2×250 mL) to give the title compound as a yellow solid (89.1 g, 96%): m/z 354 (M+H)+ (ES+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=O)[O:5][C:6]2=[O:12].C([O-])(=O)C.[Na+].C(O)(=O)C.[NH2:23][NH2:24]>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:5])[NH:23][NH:24][C:6]2=[O:12]
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c(F)ccc(F)c12
Temperature: 25 °C

Procedure:
To 4,7-difluoroisobenzofuran-1,3-dione (1.00 g, 5.43 mmol) and sodium acetate (0.535 g, 6.52 mmol) was added water (14 mL), acetic acid (7.15 ml, 125 mmol) and hydrazine (0.205 ml, 6.52 mmol)(slowly). A water condenser was attached and the mixture was heated to reflux for 20 hours. Cooled to RT and filtered the resulting solid. Washed with water and dried to yield 5,8-difluoro-2,3-dihydrophthalazine-1,4-dione as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=O.[CH:12]1([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[N-:20]=[N+:21]=[N-:22].[Na+].C(N(CC)CC)C>O1CCCC1.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH:12]1([CH2:18][NH:19][C:10]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[N:22]=[N:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NCC1CCCCC1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: [Hg+2]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1cccc(-n2nnnc2NCC2CCCCC2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
To a solution of 2,3 dichlorophenylisocyanate (0.1 g, 0.49 mmol) in 5 mL anhydrous tetrahydrofuran was added cyclohexylmethylamine (0.1 g). The solution was stirred at room temperature for 2 h when mercury (II) acetate (0.13 g, 0.49 mmol), sodium azide (0.095 g, 1.47 mmol) and triethylamine (0.148 g, 1.47 mmol) were added. The resulting suspension was stirred at room temperature for 12 hours, at which time the precipitate was filtered through Celite and the organics concentrated in vacuo. The crude residue was purified by column chromatography (gradient elution; 25% ethyl acetate/hexanes to 35%) to give 0.09 g of the title compound as a sticky foam. MS (ESI/NH3) m/z 325 (M+H)+ 1H NMR (δ, DMSO-d6) 0.8-0.95 (m, 2H), 1.05-1.3 (m, 3H), 1.5-1.8 (m, 7H), 3.05-3.12 (t, 2H), 7.05-7.17 (t, 1H), 7.58-7.65 (m, 2H), 7.90-7.95 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([OH:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(O)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-hydroxybenzyl)oxy]-1H-pyrazole-4-carboxylate (2.00 g), benzyl bromide (0.97 g) potassium carbonate (0.53 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give ethyl 1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (1.51 g, yield 64%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C(C)(C)C)=O)=[CH:4][C:3]=1[F:16].C(O)(C(F)(F)F)=O.[NH2:24][C:25]1[N:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:37]([N:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([F:16])[CH:4]=3)=[N:30][CH:29]=2)[CH2:36][CH2:35]1)(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)Cc1cnc(Cl)c(F)c1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2-(6-chloro-5-fluoropyridin-3-yl)acetate 190-3 (123 mg, 0.50 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(6-chloro-5-fluoropyridin-3-yl)acetic acid 190-4, was dissolved in DMF (3 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (110 mg, 0.50 mmol) and DIEA (500 uL, 2.87 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (285 mg, 0.75 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was purified by silica gel flash chromatography and eluted with 5% MeOH in CH2Cl2 to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-fluoropyridin-3-yl)acetamide 190-5. MS m/z 392.2 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].OC1C=CC(S[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([NH2:29])[CH:21]=2)=CC=1.[H-].[Na+]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([NH2:29])[CH:21]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Nc1cc(Sc2ccc(O)cc2)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])c(N)c2)cc1

Procedure:
4-(4-Acetylaminophenoxy)-2-amino-nitrobenzene (46.57 g) was prepared from 4-acetylaminophenol (30.2 g; 0.2 mol) using the general method described for 4-(4-hydroxyphenylsulphanyl)-2-amino-nitrobenzene in Example 2, except that one equivalent of NaH was used.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](Br)[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.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:14]([O:13][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH:6]=[C:7]1[C:26]1[CH:25]=[N:24][CH:23]=[C:22]([OH:21])[CH:27]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Reactant: Oc1cncc(Br)c1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2cncc(O)c2)cc2ccc(Cl)cc21
Temperature: 110 °C

Procedure:
A microwave flask is charged with 6-chloro-1-Boc-indole-2-boronic acid (1.91 g, 6.46 mmol), 3-hydroxy-5-bromopyridine (0.750 g, 4.31 mmol), potassium phosphate (1.83 g, 8.62 mmol) and DMF (15 mL). The flask is evacuated and filled with nitrogen thrice and Pd(PPh3)4 (0.250 g, 0.215 mmol) is added. The flask is evacuated and filled with nitrogen thrice again, and heated to 110° C. under microwave irradiation for 45 min. Pd(PPh3)4 (0.100 g, 0.086 mmol) is added and the vial is heated again to 110° C. under microwave irradiation for 45 min. The mixture is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford 6-chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester as a solid. MS (ESI) m/z 345.06 (M+H)+
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]([O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:10]([OH:26])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(C)(C)C.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C1COCC1>[CH2:1]([C:8]1[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]([O:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[C:10]([O:26][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Cc2ccccc2)nc(O)c1OC(=O)OC(C)(C)C
Reactant: ClCCN1CCOCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1nc(Cc2ccccc2)nc(OCCN2CCOCC2)c1OC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 2-benzyl-5-[(tert-butoxycarbonyl)oxy]-6-hydroxypyrimidine-4-carboxylate (N-1) (prepared from B-5 in Example 3, Step 1 by protection of the 5-hydroxyl group with pivaloyl chloride using a procedure similar to those set forth in Example 6, Step 2) in THF, CsCO3 (2 eq.) and 4-(2-chloroethyl)morpholine (1.5 eq.) hydrochloride were added and mixture reacted at 60° C. for 1 h. Further addition of 4-(2-chloroethyl)morpholine (1 eq.) allowed the complete consumption of starting material after 2 h. The mixture was then allowed to cool to room temperature, poured into EtOAc, extracted with brine, dried (Na2SO4), filtered and concentrated.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].[SH:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=1.Cl>[OH-].[Na+]>[CH2:1]([S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Oc1cc(O)nc(S)n1
Reactant: CCCCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCSc1nc(O)cc(O)n1

Procedure:
An amount of 184.1 g of n-butyliodide is added to 144.2 g of 2-mercapto-4,6-dihydroxy-pyrimidine dissolved in 1000 ml of 2-n aqueous sodium hydroxide solution, and the whole heated for 2 hours at 85°-90°C. After cooling, the reaction mixture is rendered acid, to a congo-red indicator, with ice and concentrated hydrochloric acid. The 2-n-butylthio-4,6-dihydroxy-pyrimidine obtained as a precipitate is separated and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O=[C:25]1[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:21][CH:25]4[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]4)=[CH:22][CH:23]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3)n2)cc1Cl
Reactant: O=C1CC(C(=O)O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(NC4CC(C(=O)O)C4)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (250 mg, 0.531 mmol) in Methanol (1478 μl) at room temperature was added 3-oxocyclobutanecarboxylic acid (60.5 mg, 0.531 mmol) followed by acetic acid (814 μl, 14.22 mmol). The reaction mixture was stirred at room temperature for 5 minutes before the addition of sodium cyanoborohydride (16.67 mg, 0.265 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed and the crude material purified by FCC (50% ethyl acetate/heptane) to afford 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)cyclobutanecarboxylic acid (139 mg, 0.302 mmol, 56.9% yield) as a white solid. LCMS (Table A, Method b) 2.89 min, (M+H)+ 428.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([O:16][CH3:17])=[O:15])[N:9]=[C:10]2[CH3:13])=[CH:5][CH:4]=1.[H][H]>[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([O:16][CH3:17])=[O:15])[NH:9][CH:10]2[CH3:13])=[CH:5][CH:4]=1
Reactant: COC(=O)C1Cc2ccc(OC)cc2C(C)=N1
Reactant: [H][H]
Agent: [Pd]
Product: COC(=O)C1Cc2ccc(OC)cc2C(C)N1
Yield: 94 %

Procedure:
To a solution of 3,4-dihydro-7-methoxy-3-methoxycarbonyl-1-methyl-isoquinoline (2.0 g. 8.57 mmol). obtained from the previous step, in veOH (I 50 mL) was added Pd/C (0.g). The reaction mixture was hydrogenated for 21 hr at 4 atm hydrogen pressure. The catalyst was filtered off and the filtrate was concentrated in vacuo. The oily residue (2 g) was purified by a silica gel column using (1: 1) ethyl acetate/ hexane to yield a yellowish oil (94 %): IR (MIC) U 3340, 2951, 1739, 1616, 1503, 1436, 1290, 1228, 1035 cm-1 ; 1H-NMR (CDCl3, δ): 1.51 (d.J=6.6 Hz, 3H). 2.75 (broad s, 1H), 2.89- 3.03 (m. 2H), 3.72 (dd, J=4.5, 11.1 Hz, 1H). 3.79 (s. 6H), 4.14 (q. J=6.6 Hz, 1H), 6.71- 6.75 (m, 2H), 7.02 (d, J=7.8 Hz, I H): MS showed (M+H) +@ 236; Anal. Calcd for C13Hl7NO3 . HCl: C, 57.46; H, 6.68; N, 5.15; Found: C, 57.42; H, 6.64; N, 5.02.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:23][CH:19]3[CH2:22][CH2:21][CH2:20]3)[C:10]=2[N:11]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: NC1CCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(NC3CCC3)c2n1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclobutanamine (0.047 ml, 0.550 mmol), PdCl2(dppf)-CH2Cl2Adduct (4.08 mg, 5.00 μmol) and sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give 6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine (0.098 g, 84%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.79-1.89 (2H, m), 2.06-2.17 (2H, m), 2.48-2.56 (2H, m), 4.71-4.82 (1H, m), 7.11 (1H, brs), 7.61 (1H, d, J=8.8 Hz), 8.03 (1H, d, J=8.8 Hz), 8.61 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:24]=1[CH2:25]Br.C(Cl)Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH2:10][CH2:11][CH2:12][O:13][CH2:25][C:24]1[CH:27]=[C:28]([Br:31])[CH:29]=[CH:30][C:23]=1[F:22])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CC(C)(CCCO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CCCOCc1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A stirred solution of 4-(t-butoxycarbonylamino)-4,4-dimethylbutan-1-ol (1.11 g, 5.11 mmol) in tetrahydrofuran (49 ml) at −45° C. was treated with potassium t-butoxide (1 M in tetrahydrofuran, 5.62 ml, 5.62 mmol). The anion was stirred for 30 minutes at −45° C., then cooled to −78° C. and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow mixture was slowly warmed to 0° C. and stirred for about four hours. The reaction mixture was diluted wtih methylene chloride (100 ml) and washed with 1 M potassium carbonate (20 ml). The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.53 grams (74%) of the title intermediate as a colorless oil.
Reaction SMILES: [F:1]C(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40](C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:40][N:24]1[CH2:25][C@@H:26]2[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]2[CH2:23]1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3cccc(F)c3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-fluorobenzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.61 (t, J=8.0, 1H), 7.64 (dd, J=4.1, 7.0, 2H), 7.37-7.16 (m, 5H), 7.13 (d, J=7.6, 1H), 7.04 (s, 1H), 4.33 (dd, J=5.7, 12.4, 1H), 3.57 (d, J=13.5, 0.5H), 3.48 (d, J=13.4, 0.5H), 3.42 (d, J=13.5, 0.5H), 3.30 (d, J=13.5, 0.5H), 3.23 (d, J=10.5, 1H), 2.90 (dd, J=2.9, 9.1, 0.5H), 2.70-2.61 (m, 1H), 2.59-2.53 (m, 1H), 2.53-2.45 (m, 1H), 2.44-2.31 (m, J=18.5, 1H), 2.27 (t, J=7.7, 1H), 2.19 (dd, J=6.3, 13.0, 1H), 2.12 (dd, J=6.0, 12.3, 0.5H), 1.93-1.80 (m, J=6.9, 12.4, 20.6, 1H), 1.79-1.64 (m, 1H), 1.47-1.24 (m, 2H), 1.20 (dd, J=3.1, 6.4, 3H), 0.70 (d, J=6.7, 3H); MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[N:28]=[CH:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][C:34]2[NH:26][CH:27]=[N:28][C:29]=2[CH2:30]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1nc2c([nH]1)CCNC2
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCc3[nH]cnc3C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.80 minutes; C23H20Cl2N6O2 (483.36); mass spectrum: (M−H)−=482/484/486 (chlorine isotope).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7]/[C:6](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)/[C:5]1=[O:20])(=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[CH:21](=[C:9]1/[C:8](=[O:10])[NH:7]/[C:6](=[CH:11]\[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)/[C:5](=[O:20])[NH:4]/1)\[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(/C=C2\NC(=O)CN(C(C)=O)C2=O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(/C=c2\[nH]c(=O)/c(=C/c3ccccc3)[nH]c2=O)cc1
Temperature: 130 °C

Procedure:
A mixture of (3Z)-1-acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9) (1.0 g, 3.6 mmol), benzaldehyde (430 μl, 4.2 mmol) and triethylamine (1.14 ml), 8.2 mmol), in dry DMF (20 ml), was heated at 130° C. for 18 h. The reaction mixture was cooled to room temperature and poured into ethyl acetate (100 ml). A yellow solid precipitated which was filtered off and dried. Yield 360 mg (31%).