Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.[F:33][C:34]([F:50])([F:49])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[C:37]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:36]=1>CN(C=O)C>[F:49][C:34]([F:33])([F:50])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:2]=2[NH2:1])=[C:37]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:36]=1
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Nc1c(O)cccc1C(=O)NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
2-amino-3-hydroxybenzoic acid (1 g, 6.5 mmol) was dissolved in 20 ml of DMF and at 0° C. EDCI (1.4 g, 1.2 equiv.), hydroxybenzotriazole (1 g, 1.2 equiv.) and amine 2c (2 g, 1.2 equiv.) were added. The mixture was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from EtOAc/ether gave 1.6 g of a beige solid. Yield=62.5% [M+1] 393.4 (C20H22F3N3O2 requires 393.4).
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][OH:17].C([O-])([O-])=[O:19].[Na+].[Na+]>O>[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([OH:19])=[O:17]
Reactant: OCc1nc2cccnc2[nH]1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1nc2cccnc2[nH]1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a boiling solution of KMnO4 (0.38 g, 2.4 mmol) in water (8 mL), a boiling solution of 3H-imidazo[4,5-b]pyridin-2-ylmethanol (0.20 g, 1.4 mmol) and Na2CO3 (0.19 g, 1.5 mmol) in water (6 mL) is added. The resulting mixture is heated at reflux for 4 hr. The hot mixture is filtered, the filtrate is cooled to rt, and the pH adjusted to 2 using conc. HCl. The resulting precipitate is collected by vacuum filtration to afford 3H-imidazo[4,5-b]pyridine-2-carboxylic acid in 100% yield: MS for C7H5N3O2: m/z 164 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:27]1([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([NH:33][C:34]([C:36]2[CH:37]=[CH:38][C:39]([C:40]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14]([C:16]5[CH:17]=[N:18][C:19]([N:22]6[CH2:26][CH2:25][CH2:24][CH2:23]6)=[N:20][CH:21]=5)=[O:15])=[CH:5][C:4]=4[N:1]=3)=[CH:42][CH:43]=2)=[O:35])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cnc(N2CCCC2)nc1
Product: O=C(Nc1ccccc1)c1ccc(-c2nc3cc(NC(=O)c4cnc(N5CCCC5)nc4)ccc3[nH]2)cc1

Procedure:
Compound 221 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C29H25N7O2: 504.22; found: 503.92.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[CH:16]=[CH:17][C:18]=2C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[CH:16]=[CH:17][C:18]=2[OH:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccccc1-c1ccc(C=O)c(OC2CN(C(=O)OC(C)(C)C)C2)c1
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(O)c(OC2CN(C(=O)OC(C)(C)C)C2)c1
Reaction time: 15 h
Yield: 81.2 %

Procedure:
To a CH2Cl2 (6 mL) solution of the title compound of Step A (1.40 g, 3.81 mmol) was added m-CPBA (77 wt %, 1.30 g, 5.70 mmol). After 15 h, 10 wt % Na2S2O5 (aq.) was added and the solution allowed to stir until the aqueous was KI paper negative and extracted with CH2Cl2 (2×). The combined organic layers were washed with saturated NaHCO3 (aq.), concentrated and treated with MeOH (30 mL) and 1N NaOH (15 mL). After 15 h, the reaction was partially concentrated to remove the MeOH and acidified with 1M KHSO4 then extracted with EtOAc (2×). The combined organic layers were dried and concentrated to give the 1.1 g of the title compound that was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:25])[C@@H:7]([N:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH3:13])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:12]([CH3:13])[C@@H:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:25])=[O:5])=[CH:16][CH:17]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N(C)Cc1ccc(C(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)O)N(C)Cc1ccc(C(C)(C)C)cc1
Reaction time: 1 h

Procedure:
Step, iii: (S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid tert-butyl ester (0.5 g, 1.4 mmol) was dissolved in CH2Cl2 (10 mL) and treated with TFA (1mL). After 1 hour, 0.5 mL TFA was added, followed by another 1 mL TFA at 2.5 hours. The reaction was stirred overnight, then concentrated to give (S)-2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid (IIc).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12](=[O:19])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccncc1)c1cnc2cc(Cl)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(c1ccncc1)c1cnc2cc(Cl)ccc2c1Cl
Yield: 53 %

Procedure:
2.7 g of 7-chloro 4-hydroxy 3-isonicotinoyl quinoline are added under nitrogen to 60 ml of POCl3 and refluxed for 5 hours. After being filtered off, the precipitate is poured onto ice. The aqueous solution is made alkaline with sodium carbonate before the chlorinated derivative is extracted into dichloromethane: crystals (isopropyl ether). M.p.=132° C. (Yield 53%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.[F-].[Cs+]>>[F:38][C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)=[O:29]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1cccc(F)c1F
Agent: [Cs+]
Agent: [F-]
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cccc(F)c2F)ccc2cc(O)ccc12
Temperature: 85 °C
Yield: 72.1 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.0 g, 3.7 mmol), 2,3 difluorophenyl boronic acid (1.17 g, 7.4 mmol) palladium dichloride bis(triphenylphosphine) (518 mg, 0.74 mmol) and cesium fluoride (5.06 g, 33.3 mmol) and add 250 mL degassed acetonitrile. Heat the mixture at 85° C. for two hours, cool the reaction and filter off any solids. Purify on an SCX column eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (70%) of the title compound: 1H-NMR (CD3OD, 400 MHz) δ7.92 (d, J=8.8 Hz, 1H); 7.54 (dd, J=8.4, 4.0 Hz, 3H); 7.43 (dd, J=8.4, 1.6 Hz, 1H); 7.31 (d, J=2.8 Hz, 1H); 7.09 (dd, J=9.2, 2.4 Hz, 1H); 7.05-6.92 (m, 3H); 6.79 (d, J=8.8 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 3.93 (s, 3H); 2.73 (t, J=5.2 Hz, 2H); 2.50-2.50 (m, 4H); 1.62-1.57 (m, 4H); 1.48-1.43 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:33](O)=[O:34]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:33]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][N:27]=4)=[O:34])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(O)c1cnccn1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5cnccn5)c4)CC3)cccc2n1
Yield: 89 %

Procedure:
The title compound was prepared in 89% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-pyrazinecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[C:5]2[C:6]([N:19]=1)=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[N:8]=[N:9][CH:10]=2.[OH-].[Na+].P(Cl)(Cl)([Cl:25])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]2[C:6]([N:19]=1)=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[N:8]=[N:9][CH:10]=2
Reactant: Cc1cc(O)c2cnnc(-c3ccc(Cl)c(Cl)c3)c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)c2cnnc(-c3ccc(Cl)c(Cl)c3)c2n1

Procedure:
Reflux a mixture of 2-methyl-4-hydroxy-8-(3,4-dichlorophenyl)pyrido[2,3-d]pyridazine (3) (4.5 g, 15 mmol) in phosphorous oxychloride (15 mL) for 2 hrs. Cool the reaction mixture, pour onto cracked ice and neutralize the solution with 1N NaOH. Extract the solution with ethyl acetate (2×100 mL) and wash the combined organic layers with brine. Dry the solution (Na2SO4) and evaporate in vacuo to obtain 4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C@@H:19]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:36]([CH3:37])=[CH:35][C:33]([NH2:34])=[C:32]([O:38][CH3:39])[CH:31]=3)[CH2:26][CH2:25]2)[CH2:20]1>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:34][C:33]2[CH:35]=[C:36]([CH3:37])[C:30]([N:27]3[CH2:28][CH2:29][CH:24]([N:21]4[CH2:22][CH2:23][C@@H:19]([F:18])[CH2:20]4)[CH2:25][CH2:26]3)=[CH:31][C:32]=2[O:38][CH3:39])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)c(C)cc1N
Product: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)c(C)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and (R)-4-(4-(3-fluoropyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylaniline (INTERMEDIATE 36).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:25]=[CH:24][C:15](/[CH:16]=[CH:17]/[C:18]4[N:22]([CH3:23])[N:21]=[N:20][N:19]=4)=[CH:14][CH:13]=3)=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=3)[S:8][C:7]=2[CH:34]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([C:9]2[S:8][C:7]3[CH:34]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=3[C:10]=2[O:11][C:12]2[CH:25]=[CH:24][C:15](/[CH:16]=[CH:17]/[C:18]3[N:22]([CH3:23])[N:21]=[N:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3nnnn3C)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nnnc1/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30133334 %

Procedure:
To a 30 mL vial containing (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazole (12 mg, 0.03 mmol) in DCM (1 mL) was added BBr3 (1 M in heptane, 0.077 mL, 0.08 mmol) and the reaction was stirred for 1 h at room temperature. The reaction mixture was quenched with 4 mL MeOH and stirred for 10 min at room temperature. The reaction mixture was concentrated to 50% volume and the crude product was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 1-100% CH3CN/H2O) to afford (E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-tetrazol-5-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (4 mg, 9.04 mol, 35% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.52 (d, J=16.67 Hz, 1H), 7.38-7.48 (m, 4H), 7.09 (d, J=2.02 Hz, 1H), 7.06 (d, J=8.59 Hz, 1H), 6.96 (d, J=16.67 Hz, 1H), 6.81-6.90 (m, 2H), 6.61-6.73 (m, 3H), 4.24 (s, 3H). LC/MS (m/z, MH+): 443.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH:17]=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CN(C=O)C>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][N:11]([CH:17]=[O:18])[CH2:12][CH2:13]1)([O-:10])=[O:9]
Reactant: O=CN1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 33 %

Procedure:
A mixture of 1-chloro-2-nitrobenzene (6.54 g, 41.5 mmol), piperazine-1-carboxaldehyde (4.7 g, 41.5 mmol) and DMF (18 mL) was heated 48 hours at 100° C. The reaction mixture then was cooled, diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with water, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (98:2) to give 4-(2-nitrophenyl)piperazine-1-carbaldehyde (3.2 g, 13.7 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J5) (205 mg, 0.79 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (302 mg, 0.97 mmol) according to the general procedure M. Obtained as a pink foam (340 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1cccc(Cl)c1Cl
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc(Cl)c1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,3-dichloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:13].[C:14]1(=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[O:15]1.CC1C=CC=CC=1>O>[O:15]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:1]1[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:13]
Reactant: CCOC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC[C@@H](N2C(=O)c3ccccc3C2=O)[C@H](O)C1

Procedure:
A mixture of 4.7 parts of ethyl trans-4-amino-3-hydroxy-1-piperidinecarboxylate, 3.7 parts of 1,3-dihydroisobenzofuran-1,3-dione and 45 parts of methylbenzene was stirred and refluxed for 2 hours using a water-separator. The reaction mixture was decanted from some insoluble tar. The methylbenzene-phase was evaporated in vacuo in a boiling water-bath. The residue was boiled in 2,2'-oxybispropane. After cooling, the solvent was decanted. The remaining oil solidified on scratching in 2,2'-oxybispropane. The product was filtered off and dissolved in dichloromethane. The solution was washed successively with a dilute hydrochloric acid solution, water, a dilute sodium hydroxide solution and again water. The organic phase was dried, filtered and evaporated in vacuo. The residue solidified on scratching in 2,2'-oxybispropane. The product was filtered off and crystallized from 2-propanol, yielding 2.12 parts of ethyl trans-4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-hydroxy-1-piperidinecarboxylate; mp. 128.4° C. (intermediate 57).
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:14]([OH:16])=[O:15].C([Li])(C)(C)C.[F:22]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1.CCCCC>[F:22][C:3]1[C:4]2[CH2:5][O:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[S:1][C:2]=1[C:14]([OH:16])=[O:15]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cc2c(s1)-c1ccccc1OC2
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=C(O)c1sc2c(c1F)COc1ccccc1-2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 4H-thieno[3,2-c]chromene-2-carboxylic acid (1.65 g, 7.10 mmol) in THF (70 mL) at −78° C. was added a 1.5 M solution of tert-butyllithium in pentane (15 mL). The resulting solution stirred 1 hr at −78° C. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (7.2 g, 23 mmol) was added and the reaction warmed to room temperature over 2 hr. The reaction was quenched by the addition of 1 M HCl to effect pH 3. The aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to yield 3-fluoro-4H-thieno[3,2-c]chromene-2-carboxylic acid, which contained less than 40% 4H-thieno[3,2-c]chromene-2-carboxylic acid, which was utilized in the next step without purification (1.0 g). MS (Q1) 249 (M)+
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([O:5][C@H:6]([C@@H:9]1[CH2:13][C@@H:12]([O:14]C(=O)C)[C@H:11]([N:18]2[C:22]3[N:23]=[C:24]([NH2:28])[NH:25][C:26](=[O:27])[C:21]=3[S:20][C:19]2=[O:29])[O:10]1)[CH2:7][CH3:8])=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.O1CCCC1>[CH3:30][CH:2]([CH3:1])[C:3]([O:5][C@H:6]([C@@H:9]1[CH2:13][C@@H:12]([OH:14])[C@H:11]([N:18]2[C:22]3[N:23]=[C:24]([NH2:28])[NH:25][C:26](=[O:27])[C:21]=3[S:20][C:19]2=[O:29])[O:10]1)[CH2:7][CH3:8])=[O:4]
Reactant: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A mixture of [(1S)-1-[(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]propyl] 2-methylpropanoate (compound 42c, 70 mg, 0.16 mmol) and K2CO3 (13.2 mg, 0.096 mmol) in methanol (0.5 mL) and tetrahydrofuran (2 mL) was stirred at room temperature overnight. The reaction was quenched by addition of acetic acid (1 drop). The resulting mixture was concentrated in vacuo to remove the solvents and the residue was purified by preparative HPLC to afford 18.2 mg of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] 2-methylpropanoate (Example 42) as a pale solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][Br:16])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Br)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccnc(Br)n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
To a stirred solution of 2-bromo-4-methylpyrimidine (1.5 g, 8.67 mmol) in CCl4 (15 mL) was added NBS (3.39 g, 19.07 mmol) and benzoyl peroxide (0.476 g, 1.907 mmol) then it was heated to 80° C. After 48 hours, the reaction mixture was cooled to ambient temperature and filtered. The black solid was discarded and liquid was concentrated to brown solid which was purified by column chromatography (10% EtOAc/Hex) to obtained a yellow solid of 2-bromo-4-(bromomethyl)pyrimidine (437.6 mg, 1.737 mmol, 20.04% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.74 (d, J=4.9 Hz, 1H), 7.75 (d, J=4.9 Hz, 1H), 4.66 (s, 2H)), Mass spec.: 252.9 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1ccc(Cl)cc1Cl

Procedure:
From 2,4-dichlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=439.0, tR (minutes, Method E)=0.81
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:4]([C:22]([O:24]CC)=[O:23])[C:3]1=[O:27].[OH-].[K+].C(O)C.Cl>O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:4]([C:22]([OH:24])=[O:23])[C:3]1=[O:27]
Reactant: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2n(C)c1=O)CCC3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1c(C(=O)O)c(=O)n(C)c2cc3c(cc12)CCC3
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
A mixture of ethyl 1-methyl-4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (2.0 g), potassium hydroxide (1.55 g) and 80% ethanol (20 ml) was stirred at 80° C. for 20 minutes. The mixture was diluted with water and acidified with 2N HCl to give crystals of 1-methyl-4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylic acid (1.85 g, 99.6%).
Reaction SMILES: NC1C=CC(OC)=CC=1[C:4](N)=[O:5].[C:13]1([C:19]2[N:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:4][O:5][C:23]1[CH:22]=[C:21]2[C:26]([C:27]([OH:29])=[N:28][C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:20]2)=[CH:25][CH:24]=1
Reactant: Oc1nc(-c2ccccc2)nc2ccccc12
Reactant: COc1ccc(N)c(C(N)=O)c1
Product: COc1ccc2c(O)nc(-c3ccccc3)nc2c1

Procedure:
Treatment of 2-amino-5-methoxy-benzamide according the procedure described by Raid J. Abdel-Jalil, Wolfgang Voelter and Muhammad Saeed in Tetrahedron Letters 45 (2004) 3475-3476 for the preparation of 2-phenyl-quinazoline 4-ol gave the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:11]([CH3:23])[CH:10]=2)[C:3]=1[NH2:24].[I-:25].[Na+].O.C(=O)([O-])O.[Na+]>I.C(OCC)(=O)C>[IH:25].[I:25][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:11]([CH3:23])[CH:10]=2)[C:3]=1[NH2:24]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(Cl)c3N)cc2C)cn1
Reactant: [I-]
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Temperature: 70 °C
Yield: 95.3 %

Procedure:
6-Chloro-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine (400 mg) was suspended in 55% hydriodic acid (6.16 mL), sodium iodide (878 mg) was added, and the mixture was stirred with heating at 70° C. for 10 min. After cooling to room temperature, water (40 mL)/ethyl acetate (30 mL) was added. After adjusting its pH to not less than 7 with aqueous sodium hydrogen carbonate, and the mixture was stirred at room temperature for 15 min. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (626 mg).