Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:18][C:19]1[C:20]([OH:29])=[CH:21][C:22]2[CH2:26][O:25][B:24]([OH:27])[C:23]=2[CH:28]=1>>[Cl:1][C:2]1[C:3]([O:29][C:20]2[C:19]([F:18])=[CH:28][C:23]3[B:24]([OH:27])[O:25][CH2:26][C:22]=3[CH:21]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(C)OCCOc1nc(Cl)c(Cl)cc1C#N
Reactant: OB1OCc2cc(O)c(F)cc21
Product: CC(C)OCCOc1nc(Oc2cc3c(cc2F)B(O)OC3)c(Cl)cc1C#N

Procedure:
This compound was prepared from 5,6-dichloro-2-(2-isopropoxyethoxy)nicotinonitrile and 6-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.0 (d, J=4.5 Hz, 6H), 3.32-3.45 (m, 3H), 4.04-4.05 (m, 2H), 5.0 (s, 2H), 7.53 (d, J=4.8 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 8.63 (s, 1H), 9.4 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7].[OH-].[Na+]>CO>[CH3:30][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NCCN(C)C)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1

Procedure:
A mixture of methyl 2-(3-(2-(dimethylamino)ethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (157 mg, 0.38 mmol) in methanol (6.5 mL) and 1M sodium hydroxide aqueous solution (5.1 mL, 5.1 mmol, 13.0 eq.) was heated to reflux for 30 min, LC-MS showed the reaction was complete and only the desired product formed. The solvent was concentrate in vacuo and the residue was dissolved in water and acidified with 1 M hydrochloric acid solution to pH=6. The white precipitated solid was collected by filtration and dried in vacuo to afford 122 mg of 2-(3-(2-(dimethylamino)ethylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 80.5%. MS (ESI+APCI) M+1=396.2.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](O)[CH:8]=2)[N:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28]1.Br[CH2:48][C:49]([O:51][CH3:52])=[O:50]>>[O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[CH:8]=2)[N:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28]1
Reactant: COC(=O)CBr
Reactant: CCOC(=O)CCCCn1c(=O)c2cc(O)ccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Product: COC(=O)Cc1ccc2c(c1)c(=O)n(CCCCC(=O)O)c(=O)n2CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 72.2 %

Procedure:
Using the method similar to that in Example 106 and starting from ethyl 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate (1.31 g, 2.09 mmol) obtained in Example 105, and also using methyl bromoacetate (237 ml, 2.50 mmol) instead of benzyl bromide, the ethyl ester of the title compound (990 mg, 68%) was obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])=[CH:28][CH:27]=2)[CH:10]([CH2:46][OH:47])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:48](Br)[CH:49]=[CH2:50]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])=[CH:30][CH:31]=2)[CH:10]([CH2:46][O:47][CH2:50][CH:49]=[CH2:48])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc(C2C(CO)CN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Reactant: C=CCBr
Product: C=CCOCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
In an analogous manner to that described in Example 13 (g), by alkylating (3SR,4RS,5RS)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester with allylbromide there was obtained (3SR,4RS,5RS)-3-allyloxymethyl-4-[4-[3-(2-methoxy-benzyloxy )-propoxy]-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil; MS: 682 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:10][C:9]2=[O:16])=[C:5]([C:17]#[N:18])[N:4]=[CH:3]1.C[OH:20]>O.[OH-].[Na+]>[CH3:1][N:2]1[C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:10][C:9]2=[O:16])=[C:5]([C:17]([NH2:18])=[O:20])[N:4]=[CH:3]1
Reactant: CO
Reactant: CCCC1CC(=O)N(Cc2c(C#N)ncn2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(C(N)=O)ncn2C)C1
Temperature: 25 °C
Yield: 43 %

Procedure:
In a 25 ml, three-necked flask fitted with a magnetic stirrer, a reflux condenser and a dropping funnel under inert atmosphere, 150 mg (0.61 mmol) of 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile 122 is dissolved in MeOH (9 ml) with water (3 ml) and aqueous NaOH (35% w/w, 30 μl). The reaction mixture is refluxed 72 h, cooled down to room temperature and the solvent is evaporated to dryness. The crude reaction mixture is purified by preparative chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4 (v/v/v/v)) and recristallized in CH2Cl2/hexane to afford 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide 123 (0.07 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]4[C:25]([C:29]([NH2:31])=[O:30])=[N:26][N:27]([CH3:28])[C:18]=4[C:17]=3[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>C(O)C.[Pd]>[CH3:28][N:27]1[C:18]2[C:17]3[N:16]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:24]=[CH:23][C:22]=3[CH2:21][CH2:20][C:19]=2[C:25]([C:29]([NH2:31])=[O:30])=[N:26]1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCN(Cc4ccccc4)CC3)ncc1CC2
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCNCC3)ncc1CC2
Temperature: 60 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
To a solution of 1 g (2.4 mmol) of 8-[(1-benzylpiperidin-4-yl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide in 90 mL of absolute ethanol 1 g of palladium on charcoal 10% w and 30 mL of 98% formic acid were added. The resulting mixture was stirred at 60° C. for 12 hours. The catalyst was then filtered on celite and the filtrate evaporated. The crude was purified by chromatography on a silica gel column eluted with a mixture CH2Cl2-MeOH-Et3N, giving 350 mg (45% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([C:21]#[N:22])[CH:15]=3)=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:21]([C:16]1[CH:15]=[C:14]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=3)[N:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=2)[N:18]([CH2:19][CH3:20])[N:17]=1)#[N:22]
Reactant: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(N)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(NS(C)(=O)=O)ccc12
Yield: 90.4 %

Procedure:
Stir a solution of 5-(6-Amino-1-isopropyl-1H-indol-3-yl)-1-ethyl-1H-pyrazole-3-carbonitrile (0.126 g, 0.393 mmol), pyridine (0.062 g, 0.786 mmol) and methanesulfonyl chloride (0.068 g, 0.590 mmol) in methylene chloride (3 mL) at room temperature for 2.5 h. After this time, Purify the reaction directly by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) then freeze-dried from acetonitrile/water to afford N-[3-(5-Cyano-2-ethyl-2H-pyrazol-3-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (0.132 g, 90%) as alight purple solid: mp 144-145° C.; 1H NMR (500 MHz, DMSO-d0.6 δ0.60 (s, 1H), 7.84 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.11 (s, 1H), 7.04 (dd, J=8.5, 1.5 Hz, 1H), 4.73 (m, 1H), 4.27 (q, J=7.0 Hz, 21H), 2.96 (s, 3H), 1.52 (d, J=6.5 Hz, 6H), 1.35 (t, J=7.0 Hz, 3H) LCMS (Method 4)>99%, 6.96 min, m/z 372 [M+H]+.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH3:16])(=O)=O.[C-:17]#[N:18].[Na+]>C(#N)C.O>[CH3:16][C:8]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:17]#[N:18]
Reactant: [C-]#N
Reactant: Cc1c(COS(C)(=O)=O)cccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1c(CC#N)cccc1[N+](=O)[O-]
Temperature: 87.5 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-3-nitrobenzyl methanesulfonate (207 g ) dissolved in Acetonitrile (625 ml). A solution of (41.5 g) sodium cyanide in 200 ml pure water was added to the above solution and refluxed at 80-95° C. until the completion of reaction. Acetonitrile was distilled out and 1000 ml water was added to the residue followed by addition of 1000 ml dichloromethane. The mixture was stirred for 15 minutes followed by extraction. Dichloromethane is distilled out from organic layer and Cyclohexane is to the residue and stirred for 30 minutes to get 2-Methyl-3-nitro-phenylacetonitrile. It is filtered and dried to give 2-Methyl-3-nitro phenylacetonitrile (150-160 g) as brown solid.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].[OH-].[Na+]>>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:9])[NH:20][CH2:17][CH2:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCNC(=O)N(c1ccccc1)c1ccccc1

Procedure:
By way of illustration, one mole of diphenylamine is reacted with a 10% molar excess of phosgene in a suitable solvent such as monochlorobenzene, to yield diphenylcarbamyl chloride. The carbamyl chloride thus produced is reacted further with n-propyl amine in stoichiometric amounts, in the presence of a mole of caustic soda. Diphenyl propyl urea (DPPU) is formed in essentially stoichiometric amounts. The DPPU formed may be either separated from the solvent or, if desired, supplied as a solution in its reaction solvent. DPPU pyrolyzes at 210°-220° C. to yield n-propyl isocyanate of 99% purity and greater than 90% yield. The diphenylamine remaining may be returned easily in tankcars or tankwagons for reprocessing.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])[CH2:6][CH3:7].[I-].C[N+](C)(C)[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=2[CH3:34])[N:27]([CH3:36])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=3[CH3:34])[N:27]([CH3:36])[CH:26]=2)[C:9]1=[O:19])[CH2:6][CH3:7]
Reactant: CC[C@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Reactant: Cc1cc(C)c2c(C[N+](C)(C)C)cn(C)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Temperature: 65 °C
Yield: 35.3 %

Procedure:
A mixture of 1.75 g of (R)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester, 2.5 g of trimethyl-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-ammonium iodide and 1.7 g of potassium carbonate in 50 mL of N,N-dimethylformamide is heated at 65° C. for 3 h. The resulting mixture is diluted with water and the product is extracted with ethyl acetate. The organic layer is washed with brine, dried (sodium sulfate) filtered and concentrated. The residue is purified by flash chromatography on silica gel to give 1.0 g (35%) of (R)-3-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])=[O:4].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 91.8 %

Procedure:
To a stirred solution of 4-(methoxycarbonylmethoxy)-3-nitrophenol (6.0 g, 26.8 mmol), 1-(tert-butyloxycarbonyl)-4-hydroxypiperidine (13.8 g, 68.9 mmol) and triphenylphosphine (18.0 g, 68.9 mmol) in tetrahydrofuran (80 mL) at 20° C. under argon was added diisopropyl azodicarboxylate (13.9 g, 68.9 mmol), dropwise over 0.75 h. The resulting solution was stirred at 20° C. for 4 h, then evaporated in vacuo. Chromatography of the residue on silica (400 g) eluting with 5–50% ether in hexane gave the title compound (10.1 g, 93%) as a yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH:8]=[C:7]([NH:11][CH3:12])[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:3][CH2:2]1.[CH3:22][CH:23]([C:27]([OH:29])=O)[C:24]([OH:26])=O.C(OC(=O)C)(=O)C>>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:27]([OH:29])=[C:23]([CH3:22])[C:24](=[O:26])[N:11]([CH3:12])[C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:2][CH2:3]1
Reactant: CC(C(=O)O)C(=O)O
Reactant: CNc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Solvent: CC(=O)OC(C)=O
Product: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a 2:1 mixture (34.6 g) of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52 and 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)6-methylamino-1H-pyrimidine-2,4,-dione 53 obtained in Step 4, and 2-methylmalonic acid 54 (10.2 g) was added acetic anhydride (173 ml), and the mixture was stirred at 100° C. for 2 hrs. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. Acetone (104 ml) was added to the residue, and the mixture was stirred with heating under reflux for 30 min. After allowing to cool to room temperature, the precipitated crystals were collected by filtration and dried to give 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (15.1 g, yield from 48, 21%) as colorless crystals.
Reaction SMILES: C1(C=[N:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)C=CC=CC=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(CCN2CCC(CN)CC2)cc1

Procedure:
To a stirred solution of N-[phenylmethylidene]-1-(piperidin-4-yl)methanamine (compound iii; 0.158 moles; 31.9 g), prepared as described in WO2004/101548 in absolute ethanol (70 ml), 1-(2-bromoethyl)-4-methoxybenzene (compound iv; 0.237 moles; 32.7 g) and potassium carbonate were added.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)#N.Cl.CC[O:13]CC>>[C:1]1(=[O:13])[C:9]2[N:5]([CH:6]=[CH:7][CH:8]=2)[CH2:4][CH2:3]1
Reactant: CCOCC
Reactant: N#CCCn1cccc1
Agent: Cl
Product: O=C1CCn2cccc21
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 10 g N-cyanoethylpyrrole in 100 ml ether was added 2.5 g ZnCI2. Dried HCl was passed into the mixture at 5°-10° C. After 2 hours, the reaction mixture was allowed to stand at room temperature for 4 hours. Removed the solvent by suction, 20%. Aqueous NaOH was added until pH 3. The mixture was stirred at 80°-90° C. for 2 hours. Extracted with methylene chloride, dried over Na2SO4, evaporated the solvent, 8 g yellow solid was obtained. The crude product was crystallized from petroleum ether, 6.5 g compound (1) was obtained, as white crystals, mp 53°-54.5° C., yield 65%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6])(=[O:29])=[O:28]
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(NS(=O)(=O)c2cc(F)ccc2F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of methyl 3-amino-4-fluorobenzoate (25 g, 149 mmol) in DCM (150 mL) were added pyridine (35.3 g, 446 mmol) and a catalytic amount of DMAP (1.8 g, 14.9 mmol). The mixture was cooled to 0° C. 2,5-Difluorobenzene-1-sulfonyl chloride (34.7 g, 212 mmol) in DCM (20 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. Then the reaction was washed with water (300 mL), and extracted with DCM (2×400 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether to afford the title compound of Step A (48.2 g, 94.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.12-8.18 (m, 1H), 7.73-7.80 (m, 1H), 7.47-7.53 (m, 1H), 7.10-7.25 (m, 1H), 7.00-7.07 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH3:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1ccc(O)cc1C
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(C)c(C)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3,4-dimethylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.26 (1H, d, J=7.4 Hz), 8.14 (1H, d, J=2.6 Hz), 8.00 (2H, dd, J=6.6, 1.8 Hz), 7.42 (2H, d, J=8.4 Hz), 7.22 (1H, d, J=8.1 Hz), 6.97–6.87 (2H, m), 5.42–5.32 (1H, m), 3.90 (3H, s), 2.29 (6H, s), 1.58 (3H, d, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[Br:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(C)OC)=[O:22])=[CH:19][CH:18]=1.O>C1COCC1>[Br:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([C:6]2[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([F:1])[CH:7]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: COc1ccc(Br)cc1F
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a stirred solution of 2-fluoro-4-bromoanisole (3.03 g, 14.8 mmol) in anhydrous THF (100 mL) was added n-butyllithium (1.6 M in hexanes, 10.2 mL, 16.3 mol) dropwise at −78° C. The reaction mixture was stirred for 1 h and 80 (4.02 g, 16.3 mmol) dissolved in THF (20 mL) was added dropwise. The reaction mixture was warmed to −20° C. over 1 h, water (100 mL) was added, and the volatiles were removed under reduced pressure. The mixture was extracted with ether (3×100 mL) and the combined extracts were washed with water (100 mL) and brine (100 mL). The mixture was dried over MgSO4 and concentrated. The residue was chromatographed on silica gel (20:1 to 5:1 hexanes:EtOAc) to afford 2.35 g (51%) of 81 as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 3.97 (s, 3H), 7.01 (t, J=8.4 Hz, 1H), 7.55-7.62 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](Cl)=[O:27])=[CH:21][CH:20]=[CH:19]2.[F:29][C@H:30]1[CH2:32][C@H:31]1[NH2:33]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([NH:33][C@@H:31]1[CH2:32][C@@H:30]1[F:29])=[O:27])=[CH:21][CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)Cl)cccc4c3)c2cc1OC
Reactant: N[C@@H]1C[C@@H]1F
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4c(C(=O)N[C@@H]5C[C@@H]5F)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)-1-naphthoyl chloride (200 mg, 0.50 mmol) was suspended in CH2Cl2 and TEA (210 μL, 1.5 mmol) was added. The mixture was blanketed with nitrogen, cis-2-fluorocyclopropylamine (131 mg, 0.54 mmol) was added and the reaction was stirred at RT for 1 h. The mixture was washed with water, dried with Na2SO4, filtered and concentrated in-vacuo. The residue was purified by column chromatography to give the title compounds. MS (ESI pos. ion) m/z: 433.2 (M+H). Calc'd for C28H21FN2O4−432.46.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][CH2:22]Cl>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:20][O:21][CH3:22])=[C:6]([Br:12])[CH:5]=1
Reactant: COC(=O)c1cc(F)c(O)c(Br)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COCOc1c(F)cc(C(=O)OC)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of 3-bromo-5-fluoro-4-hydroxybenzoic acid methyl ester (637 mg) in acetone (7 mL) were added potassium carbonate (708 mg) and chloromethyl methyl ether (412 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1, v/v) to give the title compound (608 mg).