Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[NH:7][C:8]1[C:13]([C:14](=[O:16])[NH2:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:3])=[O:2].[H-].[Na+].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].O>O1CCCC1.CCOC(C)=O.CCOCC>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:16])[NH:15][C:22]2=[O:23])[CH:17]=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
2-(3-Nitroanilino)-3-carbamoylpyridine (20 g, 77.5 mmole) was dissolved in tetrahydrofuran (2000 ml). Sodium hydride (60% dispersion in oil) (12.4 g, 310.0 mmole) was washed in hexanes and added to the solution. The solution was stirred for 5 minutes at room temperature under an inert atmosphere. To the solution, CDI (1,1'-carbonyldiimidazole) (18.8 g, 116.2 mmole) was added in a gradual manner over a period of 15 minutes, the resulting mixture was stirred at room temperature for 1 hour and subsequently refluxed for 24 hours. The solvent was removed resulting in a brown residue. Water was added to the residue and the resulting solution was extracted with ethyl acetate (5×300 ml). The phases were separated and the product was recrystallized from EtOAc/Et2O yielding a 12 g (42.4 mmole, 54.5% yield) of 1-N-(3-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (mp 262°-263° C.).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH3:27]
Reactant: CC(C)(N)c1ccccn1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,α-dimethyl-2-pyridinemethanamine (CAN 52568-28-2) as starting materials, LC-MS (UV peak area/ESI) 100%, 352.2021 (M+H)+.
Reaction SMILES: C([O:4][C@@:5]1([CH2:45][CH3:46])[C:42]2[CH:41]=[C:40]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:20]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:43])[C:9]=2[CH2:8][O:7][C:6]1=[O:44])(=O)C.NN.Cl>CO>[C:31]([O:30][C:28]([NH:27][CH2:26][C:20]1[N:19]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:18]2=[C:13]3[CH2:12][N:11]4[C:40](=[CH:41][C:42]5[C@:5]([CH2:45][CH3:46])([OH:4])[C:6](=[O:44])[O:7][CH2:8][C:9]=5[C:10]4=[O:43])[C:14]3=[N:15][C:16]3[C:17]2=[C:22]([CH:23]=[CH:24][CH:25]=3)[N:21]=1)=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: CCCCCN1C(CNC(=O)OC(C)(C)C)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(C)=O
Agent: Cl
Agent: NN
Solvent: CO
Product: CCCCCN1C(CNC(=O)OC(C)(C)C)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of (9S)-9-acetoxy-2-(t-butoxycarbonylamino)methyl-9-ethyl-1-pentyl-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (56 mg, 0.089 mmol) in methanol (2 ml) cooled in an ice-bath was added anhydrous hydrazine (50 μl) and the mixture was stirred for 1 hr. at room temperature. Concentrated hydrochloric acid solution (0.3 ml) was added dropwise to the reaction mixture with cooling in an ice-bath, and the mixture was stirred for 1 hr. at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol=25/1) to give pure product (33 mg, 63%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH3:5][O:6][C:7](=[O:35])[C@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[CH:23][CH:22]=1)[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[Cl:18].CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:5][O:6][C:7](=[O:35])[C@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[CH:23][CH:22]=1)[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:3]([NH:2][CH3:1])=[S:4])=[CH:13][C:12]=1[Cl:18]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(N)cc1Cl
Reactant: CN=C=S
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=S)Nc1ccc(C(=O)N[C@@H](Cc2ccc(-c3ccccc3OC)cc2)C(=O)OC)c(Cl)c1
Temperature: 90 °C

Procedure:
Methylisothiocyanate (43 μL) was added to a solution of N-(4-amino-2-chlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (55.1 mg) in anhydrous DMF (1 mL) containing DIEA (22 μL) and DMAP (catalitic amount). The resulting mixture was then heated at 90° C. under N2 for 1 d. After cooling, the mixture was diluted with EtOAc, washed sequentially with 1N HCl, satd. NaHCO3 and water, dried (MgSO4) and evaporated. The residue was purified by preparative TLC (silica gel) using CH2Cl2/MeOH (15:1) as an eluent to give N-[2-chloro-4-(3-methylthioureido)benzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (22.7 mg). ESMS: m/z 512 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[N:23]1([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:26]1[CH2:25][CH2:24][N:23]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1)[CH:11]=[CH:10]2
Reactant: CCOC(=O)CN1CCNCC1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: CCOC(=O)CN1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)CC1

Procedure:
Prepared according to the method of example 30, using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide Example 43(a)) (200 mg) and 1-piperazineacetic acid, ethyl ester (500 mg) to afford the subtitle compound as a solid (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=2[Cl:34])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: CS(=O)(=O)OCCCc1c(Cl)cccc1Cl
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3c(Cl)cccc3Cl)n2)ccc1F
Yield: 89.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2,6-dichlorophenyl)-1-propanol methanesulfonate were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1 (7) to yield the title compound as a pale yellow solid (yield: 89.8%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]3[CH:21]=[CH:20][N:19]=[C:10]3[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.[Cl:22]C1C=CC=C(C(OO)=[O:30])C=1.Cl>C(Cl)Cl.CCOCC>[ClH:22].[CH3:1][N+:2]1([O-:30])[CH2:7][CH2:6][N:5]([C:8]2[N:9]3[CH:21]=[CH:20][N:19]=[C:10]3[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[N+]1([O-])CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of 88 mg of 5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 1 ml of methylene chloride, 74 mg of m-chloroperbenzoic acid are added at 0° C. The mixture is stirred at 0° C. overnight; this is diluted with 1 ml of ether, one equivalent of ethereal hydrochloric acid solution is added and the resulting precipitate is collected. Recrystallization from methanol-ethyl acetate yields 5-(4-methyl-4-oxidopiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine hydrochloride, melting at 155° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:24]C)=[C:14]3[C:19](=[O:20])[N:18]([CH2:21][CH3:22])[CH2:17][C@H:16]([CH3:23])[N:15]3[C:9]=2[C:8]([C:26]([NH:28][CH3:29])=[O:27])=[N:7]1.B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([OH:24])=[C:14]3[C:19](=[O:20])[N:18]([CH2:21][CH3:22])[CH2:17][C@H:16]([CH3:23])[N:15]3[C:9]=2[C:8]([C:26]([NH:28][CH3:29])=[O:27])=[N:7]1
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)NC)c32)C1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCN1C[C@H](C)n2c(c(O)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)NC)c32)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (6S)-2-(3-chloro-4-fluorobenzyl)-8-ethyl-10-methoxy-N,6-dimethyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-carboxamide (1.15 g, 2.41 mmol) in anhydrous dichloromethane (800 mL), a solution of boron tribromide in dichloromethane (3.14 mL, 3.14 mmol; 1 M) was added. After stirring at room temperature for 5 minutes, the reaction mixture was treated with anhydrous methanol, stirred for 30 minutes, and concentrated under vacuum. The procedure was repeated twice. The residue was dissolved in a mixture of methanol and acetonitrile and treated with aqueous sodium hydroxide. The mixture was subjected to purification on preparative reverse phase high pressure column chromatography. Collection and lyophilization of appropriate fractions provided the title compound as white amorphous solid.
Reaction SMILES: O1CCCC1.[CH2:6]([OH:9])[CH2:7][OH:8].[H-].[Na+].[Cl:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:17](Cl)[N:16]=[CH:15][N:14]=1>C(O)(=O)C>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([O:8][CH2:7][CH2:6][OH:9])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: OCCO
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(Cl)ncnc2OCCO)cc1

Procedure:
To a mixture of tetrahydrofuran (400 ml) and ethylene glycol (60 ml) is added with stirring sodium hydride (60% dispersion, 3.38 g) under ice-cooling, and thereto is added 4,6-dichloro-5-(4-methylphenyl)pyrimidine (20.0 g). The mixture is stirred under ice-cooling for 30 minutes, and then stirred at room temperature for two hours. The mixture is weakly acidified with acetic acid, and concentrated under reduced pressure. The residue is dissolved in ethyl acetate, and washed, dried, and concentrated to dryness under reduced pressure. The residue is crystallized from hexane to give 2-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (21.85 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=2)[NH:10][N:9]=1.Cl>CO.O1CCCC1.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=2)[NH:10][N:9]=1
Reactant: COC(=O)c1ccc2[nH]nc(-c3ccccc3F)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]nc(-c3ccccc3F)c2c1
Temperature: 70 °C

Procedure:
A total of 1.6 g of methyl 3-(2-fluorophenyl)-1H-5-indazolecarboxylate was dissolved in 15 ml of a 1:1 solvent mixture of methanol and tetrahydrofuran, 2 ml of 5 N aqueous sodium hydroxide solution was added, followed by heating at 70° C. for 6 hours. After cooling to room temperature, the reaction mixture was added with diluted hydrochloric acid and was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 1.5 9 of the title compound as a colorless powder.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[S:7][CH:8]=1)([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH2:9][C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:12]=2)(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: NCCCCNS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)c1csc(COc2cccc(C=O)c2)n1
Solvent: CCO
Product: CC(C)c1csc(COc2cccc(CNCCCCNS(=O)(=O)c3ccc(Cl)cc3)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.27 g (8.69 mmol) of 3-[(4-isopropyl-2-thiazolyl)methoxy]benzaldehyde and 2.27 g (8.69 mmol) of 4-(4-chlorophenylsulfonylamino)butanamine were dissolved in 150 ml of ethanol and refluxed together with 4.0 g of molecular sieves 3A for 16 hours. The molecular sieves 3A was filtered out, and the filtrate was stirred together with 873 mg of sodium borohydride at room temperature for 3 hours. The reaction solution was evaporated in vacuo for removal of ethanol as the solvent and mixed with water and ethyl acetate for ethyl acetate extraction. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo for removal of the solvent. The residue was purified by silica gel column chromatography (eluent; chloroform to chloroform:methanol=98:2) to give N-[4-(4-chlorobenzenesulfonylamino)butyl]-3-[(4-isopropyl-2-thiazolyl)methoxy]benzylamine (Compound No.1a).
Reaction SMILES: [O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:32])=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34 mg of (R)-4-{5-[1-(2-Phenoxy-acetyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzoic acid were treated with 1 eq HATU/DIPEA in DMF and added to 1 eq of Rink-Resin. The reaction was shaken overnight at room temperature. The resin was washed with DMF, MeOH, DCM (3 times each) and then treated with TFA/DCM (1:1) for 2 h. The resulting yellow oil was purified via preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[N:13][CH:11]=1
Reactant: NC=O
Reactant: Nc1ncccc1C(=O)O
Product: Oc1ncnc2ncccc12
Yield: 69.7 %

Procedure:
2-aminonicotinic acid (7 g) and formamide (22.8 g) were heated at 167 C (internal temperature) for 2.5 hours. After cooling, the solid was recrystallized from 100 mL of hot water to give Pyrido[2,3-d]pyrimidin-4-ol as pale yellow powder (5.2 g, 69.7%). 1H NMR (DMSO, 400 MHz) δ 12.60 (br, 1H), 8.90 (br, 1H), 8.50 (m, 1H), 8.37 (s, 1H), 7.50 (m, 1H). Rt 0.87 min. MS (ESI+) [M+H]+148.
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1[CH3:29])=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH:40][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:11]4[CH2:10][CH:9]([CH3:29])[NH:8][CH:13]([CH3:14])[CH2:12]4)[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Reactant: NCCc1cc(F)cc(F)c1
Product: CC1CN(Cc2cccc(-c3ccnc(NCCc4cc(F)cc(F)c4)n3)c2)CC(C)N1

Procedure:
Intermediate 142 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 438. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.32 (s, 1H) 8.12 (d, 1H)) 7.98 (d, 1H) 7.47 (m, 2H) 7.12 (d, 1H) 6.90 (d, 2H) 6.75 (d, 1H) 3.75 (t, 2H) 3.60 (m, 4H) 3.47 (t, 2H) 2.98 (t, 2H) 2.90 (t, 2H) 1.04 (d, 6H).
Reaction SMILES: [Mg].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6](Cl)[CH2:5][CH2:4]1.[Cl-].[NH4+].[C:12]([OH:17])(=[O:16])[C:13]([OH:15])=[O:14]>C(Br)C.O1CCCC1.CCOCC.C(O)(C)C>[C:12]([OH:17])(=[O:16])[C:13]([OH:15])=[O:14].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:5]2[CH:4]=[C:12]([CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH2:5][CH2:4]1
Reactant: CN1CCC(Cl)CC1
Agent: O=C(O)C(=O)O
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cccc(C2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A few drops of ethyl bromide are added to a stirring suspension, under nitrogen, of 3.2 g of magnesium turnings in 10 ml of tetrahydrofuran. After a reaction begins, 17.7 g of N-methyl-4-chloropiperidine in 50 ml of tetrahydrofuran are added dropwise while maintaining a moderate reflux. After total addition, the reaction mixture is heated at reflux for 1 hour and 15.2 g of 3-tolylnitrile in 10 ml of tetrahydrofuran are slowly added. After this addition is complete the reaction mixture is heated at reflux for an additional 2 hours and then permitted to stir at ambient temperature for 16 hours. The reaction mixture is poured into a solution of 35 g of ammonium chloride in 500 ml of ice-water and heated on a steam bath for 3 hours, cooled and extracted with benzene. The combined benzene extracts are dried and most of the benzene is removed, leaving the orange oil. The oil is dissolved in ether and the oxalate salt is prepared by the addition of a solution of anhydrous oxalic acid in isopropanol. The white oxalate salt is recrystallized twice from ethanol to give the product, mp 183°-185° C., 1-methyl-4-(3-toluyl)piperidine oxalate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:35])([CH3:34])[CH2:14][CH2:15][N:16]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:25])[C:17](=O)[O:18]C(C)(C)C)=[CH:9][CH:8]=1.[H-].[Na+]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2([CH3:34])[O:35][C:17](=[O:18])[N:16]([C@H:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH3:25])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: COc1ccc([C@H](C)N(CCC(C)(O)c2ccc(C3OCCCO3)cc2)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc([C@H](C)N2CCC(C)(c3ccc(C4OCCCO4)cc3)OC2=O)cc1

Procedure:
A mixture of tert-butyl 3-(4-(1,3-dioxan-2-yl)phenyl)-3-hydroxybutyl((S)-1-(4-methoxyphenyl)ethyl)carbamate, obtained as described above, and 1.340 g of 60% NaH in THF (10 mL) was heated to reflux for 24 h. The reaction was then quenched with 1.5 mL of H2O, diluted with CH2Cl2, dried over Na2SO4. Removal of the solvent afforded crude 6-(4-(1,3-dioxan-2-yl)phenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-6-methyl-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.65, 1.69 min, m/z=412 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[S:11])=[CH:5][CH:4]=1.[C:21]([C:26](O)=[O:27])#[C:22][C:23]([OH:25])=[O:24]>>[O:27]=[C:26]1[C:21](=[CH:22][C:23]([OH:25])=[O:24])[S:11][C:10](=[N:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:12]1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: O=C(O)C#CC(=O)O
Reactant: COc1ccc(NC(=S)Nc2ccc(OC)cc2)cc1
Product: COc1ccc(N=C2SC(=CC(=O)O)C(=O)N2c2ccc(OC)cc2)cc1
Yield: 65.7 %

Procedure:
Prepared by the method described in Example 1 from N,N'-bis(4-methoxyphenyl)thiourea (11.5 g, 40 mmoles) and acetylenedicarboxylic acid (4.6 g, 40 mmoles). Recrystallization from methanol gave the product (10.1 g), mp 184°-187° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].COS(=O)O[CH2:16][CH2:17][NH:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN(C=O)C>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:18][CH2:17][CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COS(=O)OCCNc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCNc2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-hydroxybenzaldehyde (6.1 g, 50 mmol) in dry DMF (40 mL), was added sodium hydride (2.2 g, 55 mmol, 60% suspension) under stirring, in a nitrogen atmosphere at room temperature. The thick solution was diluted with dry DMF (20 mL). Sulfurous acid 2-(benzooxazol-2-ylamino)-ethyl ester methyl ester [compound of Step III] (14 g, 55 mmol) dissolved in dry DMF was added dropwise to the reaction mixture over a period of 20 min and the resulting mixture was heated to 80° C. for 1 hour. The reaction mixture was poured on crushed ice and then extracted with ethyl acetate (3×200 mL). The ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified using silica gel column and 50% ethyl acetate in petroleum ether to give 4-[2-(benzooxazol-2-ylamino)-ethoxy]-benzaldehyde.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH2:60][CH2:61][CH2:62][O:63][Si](C(C)(C)C)(C)C)[CH:55]=[CH:54]4)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH2:60][CH2:61][CH2:62][OH:63])[CH:55]=[CH:54]4)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5c(ccn5CCCO[Si](C)(C)C(C)(C)C)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5c(ccn5CCCO)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-t-butyldimethylsilyloxy-propyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (144 mg) in CH2Cl2 (4 mL.) at rt was added a solution of p-toluene sulfonic acid (20 mg.) in CH3OH (4 mL.). The reaction mixture was stirred for 3 hr., quenched with saturated NaHCO3, then extracted with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give 81 mg of the title compound. Partial 1H NMR (CDCl3, 200 MHz) d: 7.22 (d, J=9 Hz, 1H); 7.18 (d, J=3 Hz, 1H); 7.07 (d, J=3 Hz, 1H); 6.89 (dd, J=3 Hz and J=9 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.20 (t, J=6.5 Hz, 2H); 2.00 (m, 2H).