Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([O:30]CC)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([OH:30])=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2cc(N3CCOCC3)ccc2cc1NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
To a mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylate (0.065 g, 0.15 mmol) in 1,4-dioxane (2.0 mL) was added 2.5 M aq. NaOH (1.0 mL, 2.5 mmol). The reaction mixture was heated at 80° C. for 0.5 h, then cooled and neutralized with 2.5 mL 1 M HCl to pH=7. The precipitated solid was collected by filtration and air-dried overnight to yield the sub-title compound (0.042 g, 69%). LCMS (ESI) calc. for C22H22N3O5 [M+H]+: m/z=408.2. found: 408.2.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:17]([OH:20])(=[O:19])=[O:18].Cl.C[O-].[Na+:24]>C(Cl)(Cl)Cl>[S:17]([O-:20])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:19])=[O:18].[Na+:24]
Reactant: CCCCCCC(C)CCCCCCO
Reactant: O=S(=O)(O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Into a dried 1L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-methyltridecanol (107 g, 0.5 mol), prepared as an intermediate in Example I. Chlorosulfonic acid (61.3 g, 0.52 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with an ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until a aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added methanol (1L) and 300 ml of 1-butanol. Vacuum filter off the inorganic salt precipitate and remove methanol from the filtrate on a rotary evaporator. Cool to room temperature, add 1L of ethyl ether and let stand for 1 hour. The precipitate is collected by vacuum filtration. The product is dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (76 g, 90% active by cat SO3 titration).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[S:45])[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)NCC4)cc2)CCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=S)NCC4)cc2)CCC1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
To a solution of tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (223 mg, 0.47 mmol) in toluene (15 mL) was added lawesson's reagent (192 mg, 0.47 mmol) under nitrogen. The resulting mixture was heated under reflux for 2 h. After cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 1% MeOH in dichloromethane) to give the title compound as a yellow solid (231 mg, quantitative). 1H NMR (500 MHz, MeOD): 8.76 (1H, s), 7.37-7.33 (4H, m), 7.31-7.28 (3H, m), 7.22-7.20 (2H, m), 3.69 (2H, t), 3.25 (2H, t), 2.49-2.39 (4H, m), 2.15-2.05 (1H, m), 1.91-1.80 (1H, m), 1.45-1.15 (9H, br).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]=O>C(O)=O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH3:31])[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Solvent: O=CO
Product: CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Yield: 95 %

Procedure:
A mixture of (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.5 g, 1.24 mmol), formic acid (10 ml) and 37% formaldehyde (7.5 ml) was heated for 3 hours at reflux temperature and evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate (25 ml) and 1 N sodium hydroxide (25 ml). The organic phase was isolated, washed once with water, dried over magnesium sulphate and evaporated in vacuo to give (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-methylpyrrolidine (0.49 g, yield: 95%) as a golden oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH:27]([F:29])[F:28])[CH:23]=[CH:22][N:21]=1>>[F:29][CH:27]([F:28])[O:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:19][N:15]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH:13]([CH3:17])[C:14]2=[O:16])[CH:25]=1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Reactant: FC(F)Oc1ccnc(CBr)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cc(OC(F)F)ccn1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with 2-(bromomethyl)-4-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.67 min.; [M+H]+: 393.08 g/mol.
Reaction SMILES: [S:1]1([CH2:7][CH:6]=[CH:5][CH2:4]1)(=[O:3])=[O:2].[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.O(C)[Na]>[OH-].[Na+].CO>[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[C:4]1[CH:5]=[CH:6][C:7](=[CH:13][C:9]2[NH:8][CH:12]=[CH:11][CH:10]=2)[S:1]1(=[O:3])=[O:2]
Reactant: O=S1(=O)CC=CC1
Reactant: O=Cc1ccc[nH]1
Agent: CO[Na]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S1(=O)C(=Cc2ccc[nH]2)C=CC1=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
About 20 mmol (2.36 g) of 3-sulfolene (MW=118) and 42 mmol (4 g) of pyrrole-2-aldehyde (MW=95) were dissolved in an alkaline solution of 1.5 g of NaOH and 1.9 g of NaOCH3 in 70 ml of methanol. The mixture was stirred at room temperature for 5 days. The black-brown reaction mixture was concentrated.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][N:15]=[C:16]=[S:17]>>[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][NH:15][C:16]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[S:17]
Reactant: NCCNCc1nccs1
Reactant: CN(C)CCN=C=S
Product: CN(C)CCNC(=S)NCCNCc1nccs1

Procedure:
Treating N-(2-thiazolylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40, then concentrating and separating by column chromatography gives the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Ca+2]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(O)cc1N1CCOCC1
Temperature: 130 °C
Yield: 94 %

Procedure:
3-Fluoro4-nitrophenol (300 mg), morpholine (800 μl), and calcium carbonate (50 mg) were added to dimethylformamide (3 ml), and the mixture was heated at 130° C. for 12 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 3-morpholino-4-nitrophenol (400 mg, yield 94%). The resultant 3-morpholino-4-nitrophenol (400 mg) was added to dimethylformamide (3 ml). Palladium hydroxid-carbon (110 mg) and hydrogen were added thereto, and the mixture was stirred at room temperature for 4 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was then purified by chromatography on silica gel using chloroform/acetone for development to give 4-amino-3-morpholinophenol (296 mg, yield 85%). The resultant 4-amino-3-morpholinophenol (296 mg), 4-chloro-6,7-dimethoxyquinazoline (479 mg), and n-tetraethylammonium bromide (244 mg) were dissolved in ethyl methyl ketone (10 ml) to prepare a solution. A solution (10 ml) of sodium hydroxide (479 mg) in water was added to the solution, and the mixture was sitrred at 80° C. for 4 hr. Water was added to the reaction solution, and the organic layer was extracted and was concentrated. The residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (396 mg, yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]([NH2:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.ClCC1C=CC(C(F)(F)F)=CC=1.C(N(CC)C(C)C)(C)C.Cl[C:46]1[C:51]([N+:52]([O-:54])=[O:53])=[CH:50][C:49]([I:55])=[CH:48][N:47]=1>C(#N)C.O>[I:55][C:49]1[CH:50]=[C:51]([N+:52]([O-:54])=[O:53])[C:46]([NH:23][CH:21]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:22])=[N:47][CH:48]=1
Reactant: COc1cc(C(C)N)ccc1OCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Agent: FC(F)(F)c1ccc(CCl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(C(C)Nc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
To a stirred solution of 1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethanamine [prepared from 1-(chloromethyl)-4-(trifluoromethyl)benzene using the procedures described in Example 3-45-1 through Example 3-45-3] (2.52 g, 7.75 mmol) and N,N-diisopropylethylamine (2.7 mL, 15.18 mmol) in acetonitrile (30 mL) was added 2-chloro-5-iodo-3-nitropyridine (2.39 g, 8.13 mmol), The orange solution was heated to reflux. After 15 h, the brown reaction mixture was allowed to cool to room temperature and was diluted with water (60 mL). As the mixture was stirred, a yellow precipitate formed. The solids were isolated by filtration and washed with water (50 mL), and dried to provide 4.19 g (94%) of 5-iodo-N-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3-nitropyridin-2-amine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([F:25])[C:8]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[F:24])=[C:9]([C:12]([NH:14][NH2:15])=[O:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.Br[C:27]#[N:28].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:28][C:27]1[O:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[C:7]([F:25])[C:8]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[F:24])[N:5]=[N:4][CH:3]=[C:2]3[NH2:1])=[N:14][N:15]=1
Reactant: NNC(=O)c1cc2c(N)cnnc2c(F)c1Nc1ccc(Br)cc1F
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(-c2cc3c(N)cnnc3c(F)c2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-amino-7-(4-bromo-2-fluorophenylamino)-8-fluorocinnoline-6-carboxylic acid hydrazide (1.00 equiv.) in 1,4-dioxane at room temperature is added BrCN (2.00 equiv.) followed by a solution of NaHCO3 (1.00 equiv.) in H2O. After stirring for 3 hours at room temperature, the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is purified by trituration or flash column chromatography to afford 6-(5-amino-[1,3,4]oxadiazol-2-yl)-N7-(4-bromo-2-fluoro-phenyl)-8-fluorocinnoline-4,7-diamine.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:43]=[CH:42][C:31]([O:32][C:33]4([C:37](OCC)=[O:38])[CH2:36][CH2:35][CH2:34]4)=[CH:30][CH:29]=3)[C:24]([CH2:44][CH3:45])=[N:23][C:22]=2[CH2:46][CH2:47][CH3:48])=[CH:16][CH:15]=1)#[N:7]>O1CCCC1.C(O)C.C(OCC)(=O)C>[CH2:44]([C:24]1[N:25]([C:28]2[CH:43]=[CH:42][C:31]([O:32][C:33]3([CH2:37][OH:38])[CH2:34][CH2:35][CH2:36]3)=[CH:30][CH:29]=2)[C:26](=[O:27])[C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[C:8]([C:6]#[N:7])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:19][CH:18]=2)=[C:22]([CH2:46][CH2:47][CH3:48])[N:23]=1)[CH3:45]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3(C(=O)OCC)CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3(CO)CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Sodium borohydride (0.3 g) was dissolved in tetrahydrofuran (10 mL) and ethanol (10 mL), and calcium chloride (0.44 g) was added at 0° C. The reaction solution was stirred at 0° C. for 1 hr, ethyl 1-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}cyclobutanecarboxylate (0.76 g) was added, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.5 g, 73%) as a pale-yellow liquid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[CH3:9][C:10]([CH3:12])=[CH2:11].S(=O)(=O)(O)O.C(=O)=O.CC(C)=C.[OH-].[Na+]>O1CCOCC1.CCOCC>[C:10]([O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])([CH3:12])([CH3:11])[CH3:9]
Reactant: O=C(O)c1ccc[nH]1
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc[nH]1
Temperature: 0 °C
Yield: 60 %

Procedure:
Lit. Tetrahedron, 41:5633 (1985). To a stirred solution of 10.0 g (90.0 mmol) pyrrole-2-carboxylic acid in 180 ml dioxane was added dropwise at 0° C. 18 ml concentrated sulphuric acid 2-methylpropene was then condensed into the reaction flask over the course of 1 h, using a dry-ice condenser, and stirring continued for 16 h at 0° C. while the dry-ice condenser was periodically refilled so as to maintain a slow reflux of 2-methylpropene. The reaction mixture was then poured cautiously into an ice-cooled mixture of 400 ml ether and 150 ml 2 M sodium hydroxide solution. The phases were separated and the aqueous phase extracted twice more with ether. The combined organic phases were washed successively with 2 M sodium hydroxide solution, water and finally with saturated brine, then dried over sodium sulphate and concentrated in vacuo to afford 9.07 g (60%) of the title compound as a colorless oil which still contained some dioxane. 1H NMR d (250 MHz, CDCl3) 9.60 (1H, br s), 6.90 (1 H, m), 6.83 (1 H, m), 6.22 (1 H, m), 1.56 (9H, s).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[C:7]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:6]=1)[CH2:2][CH3:3].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][C:56]1[CH:57]=[C:58]([NH:62][C:63](=[O:73])[CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH:59]=[CH:60][CH:61]=1.[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[O:73]=[C:63]([NH:62][C:58]1[CH:59]=[CH:60][CH:61]=[C:56]([NH:55][C:11]([C:10]2[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:8][CH:9]=2)=[O:13])[CH:57]=1)[CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a suspension of 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid (A3, 301 mg) in N,N-dimethylformamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (211 mg) and 1-hydroxybenzotriazole monohydrate (162 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, a solution of N,N-diisopropylethylamine (511 μL) and tert-butyl (2-((3-aminophenyl)amino)-2-oxoethyl)carbamate (B1, 292 mg) in N,N-dimethylformamide (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 5 hours. To the reaction mixture, saturated aqueous sodium chloride and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 93% ethyl acetate in methanol) to obtain oily tert-butyl (2-oxo-2-((3-(4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamido)phenyl)amino)ethyl)carbamate (B2, 437 mg).
Reaction SMILES: [F:1][C:2]1([F:26])[C:11]2[CH:10]=[N:9][C:8]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:27].CC(O)C>C(Cl)Cl>[ClH:27].[F:26][C:2]1([F:1])[C:11]2[CH:10]=[N:9][C:8]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:7][C:6]=2[CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(NC3CCOCC3)ncc2C(F)(F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: FC1(F)CNCc2nc(NC3CCOCC3)ncc21
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 206 (215 mg, 0.5805 mmol) in DCM (4 mL) at RT under nitrogen was added 5M HCl in IPA (1.161 mL, 5.805 mmol) by pipet. After stirring overnight, the reaction was concentrated to dryness by rotovap and high vacuum to afford 106 mg (100%) of 5,5-difluoro-N-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine hydrochloride (208) which was used without additional purification.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:32][O:33][CH3:34])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12]C)=[O:11])([CH3:4])[CH3:3].[OH-].[Na+]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:32][O:33][CH3:34])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3]
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 75.4 %

Procedure:
A solution of 462 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 82(b)] in 4 ml of a 1N aqueous solution of sodium hydroxide was stirred at room temperature for 5 hours. At the end of this time, the insoluble matter was filtered off, and 4 ml of a 1N aqueous solution of hydrochloric acid were added to the filtrate. The resulting crystalline powder was then collected by filtration, to give 338 mg of the title compound, melting at 187° C. (with decomposition at 192°-195° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:31])=O>CN(C=O)C>[Cl:31][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1

Procedure:
Distilled THF (10 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (200 mg, 0.52 mmol), thionyl chloride (136.8 mg, 1.15 mmol, 0.08 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-nitrobenzyl)isoindolin-1-one was produced as a viscous yellow oil (208.5 mg, 0.52 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-nitrobenzyl)isoindolin-1-one (208.5 mg, 0.52 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (260 mg, 2.6 mmol) and dried potassium carbonate (359 mg, 2.6 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a yellow oil (262 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as a yellow viscous oil. (211 mg, 44.4 mmol, 85%). 1H NMR: (300 MHz, DMSO) δ ppm 1.34, (m, 1H, H15H16) 1.74, 2.2 (m, 1H, H15/H16) 4.22 (dt, 1H, H16) 4.40 (d, 1H, J=15.99 Hz, H9/H9′), 4.63 (d, 1H, J=16.02 Hz, H9/H9′), 4.93, 4.98, (dd, 1H, H17/H18), 5.15, 5.29 (dd, 1H, H17/H18), 5.76 (m, 1H, H14) 7.26 (m, 7H, H1-H5, H10, H13), 7.66 (m, 2H, H6-H7), 7.88 (d, 1H, H8), 8.00 (m, 2H, H11, H12).