Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:40])[CH2:21][NH:22][C:23]([CH3:39])([CH3:38])[CH2:24][C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[OH:40][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[CH2:21][NH:22][C:23]([CH3:38])([CH3:39])[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=1
Reactant: CC(C)(Cc1ccc(OCCCC(=O)O)cc1)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(Cc1ccc(OCCCC(=O)O)cc1)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
0.70 g (1.28 mmol) of 4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin -8-yl)-2-hydroxyethylamino]-2-methylpropyl}phenoxy)butyric acid is dissolved in 25 mL methanol and 2 mL acetic acid and hydrogenated in the presence of 150 mg palladium on charcoal (10%) at ambient temperature and normal pressure. The catalyst is filtered off and the filtrate is freed from solvent. The product is obtained by crystallization from a methanol-acetone mixture. Yield: 0.40 g (68%); melting point: 201° C.-204° C.; mass spectroscopy: [M+H]+=459.
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=[C:3]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]3[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]3=[N:23][CH:22]=2)[CH:2]=1.C=O.[C:35]([BH3-])#N.[Na+]>CS(C)=O.O>[CH3:35][N:19]([C:3]1[CH:2]=[CH:1][C:6]([C:7]([NH:9][CH:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=1)[CH2:20][C:21]1[CH:26]=[C:25]2[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]2=[N:23][CH:22]=1
Reactant: Nc1nc(N)c2cc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Yield: 85 %

Procedure:
Reductive alkylation of diethyl p-aminobenzoyl-L-glutamate) (VI; R=H; R1 =C2H5) with III (Y=CHO) and hydrogen in 70% acetic acid containing Raney nickel gave a 32% yield of 5-deazaaminopterin diethyl ester. Saponification of the ester groups in a mixture of dimethyl sulfoxide-water at ambient temperature gave an 87% yield of 5-deazaaminopterin (II, R=H). Methylation of the latter compound was accomplished by treatment of II (R=H) with formaldehyde and sodium cyanoborohydride in aqueous solution at pH 6.4 to give an 85% yield of 5-deazamethotrexate, (II, R=CH3). The structure of II (R=CH3) was established as described hereinafter in Example 8C by oxidation with alkaline potassium permanganate to give the previously prepared 2-amino-4(3H)oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (VIII), which indicated that methylation had occurred either on the 4- or 10-amino group. Methylation of the 4-amino group was eliminated from consideration by alkaline hydrolysis of the 4-amino group to give 5-deaza-10-methylfolic acid (I, R=CH3).
Reaction SMILES: C([O:8][C:9](=[O:47])[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:46])[C@@H:15]([NH:38]C(OC(C)(C)C)=O)[CH2:16][C@@H:17]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])C1C=CC=CC=1.[ClH:48]>O1CCOCC1>[ClH:48].[CH2:23]([N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:46])[C@@H:15]([NH2:38])[CH2:16][C@@H:17]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:9](=[O:47])[OH:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](CNC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNC(=O)OCc1ccccc1)C[C@H](N)C(=O)NCCN(Cc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
53 mg (0.08 mmol) of the compound from Example 95A are cooled to 0° C., and 1 ml of 4N hydrogen chloride in dioxane is added. After 1 h, concentration in vacuo results in the title compound.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.[Cl:7][C:8]1[C:13](/[CH:14]=[CH:15]/[N+:16]([O-])=O)=[CH:12][CH:11]=[C:10]([C:19]([F:22])([F:21])[F:20])[N:9]=1>O1CCCC1.Cl>[Cl:7][C:8]1[C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:11]=[C:10]([C:19]([F:20])([F:21])[F:22])[N:9]=1.[ClH:7]
Reactant: O=[N+]([O-])/C=C/c1ccc(C(F)(F)F)nc1Cl
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Product: NCCc1ccc(C(F)(F)F)nc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a stirred solution of NaBH4 (16.0 g, 4.2 eq.) in tetrahydrofuran (125 mL) was added BF3 etherate (125 mL) at 0° C. The resulting reaction mixture was allowed to room temperature and stirred for 15 min 2-Chloro-3-[(E)-2-nitrovinyl]-6-(trifluoromethyl)pyridine (Int-19) (25.0 g, 1.0 eq) in tetrahydrofuran (125 mL) was added to above reaction mixture at room temperature. The reaction mixture was heated to 70° C. and stirred for 2 h. The resulting reaction mixture was allowed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched in ice water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (1×100 mL), brine (1×100 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to get crude amine. The amine compound was dissolved in ethanolic HCl (50 mL) and stirred at room temperature for 2.0 h. The reaction mixture was concentrated under reduced pressure to get crude 2-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]ethanamine (IIb-35) hydrochloride (15.0 g, 58.3%).
Reaction SMILES: [N:1]1[C:9]([S:10]CC2OC(=O)C3C(C=2C2C=CC=CC=2)=CC=CC=3)=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.Br[CH:30]([C:32]1[O:33][C:34](=[O:49])[C:35]2[C:40]([C:41]=1[C:42]1[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:31].O.N1C(S)=C2C(NC=N2)=NC=1.C([O-])([O-])=O.[K+].[K+]>>[N:1]1[C:9]([S:10][CH:30]([C:32]2[O:33][C:34](=[O:49])[C:35]3[C:40]([C:41]=2[C:42]2[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:31])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: Cc1cccc(-c2c(C(C)Br)oc(=O)c3ccccc23)c1
Reactant: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: Sc1ncnc2[nH]cnc12
Agent: [K+]
Solvent: O
Product: Cc1cccc(-c2c(C(C)Sc3ncnc4[nH]cnc34)oc(=O)c3ccccc23)c1
Yield: 87 %

Procedure:
The title compound was made in a similar way as that of the compound of example 10, 3-(1-bromoethyl)-4-m-tolyl-1H-isochromen-1-one (intermediate C5, 67 mg, 0.195 mmol), 9H-purine-6-thiol hydrate (33.2 mg, 0.195 mmol)) and K2CO3 (27 mg, 0.111 mmol) to give to give the title compound (70 mg, 87%)
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH2:7]2)[N:6]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=4)[C:27]#[N:28])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: COc1cccc(C2CC3(N=C(N)N(C)C3=O)c3cc(Br)ccc3O2)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1cccc(C2CC3(N=C(N)N(C)C3=O)c3cc(-c4cccc(C#N)c4)ccc3O2)c1
Yield: 20.7 %

Procedure:
Pd(PPh3)2Cl2 (20 mg) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-2-(3-methoxyphenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (46 mg, 0.11 mmol) in 1,4-dioxane (5 mL), Cs2CO3 (2 N, 0.5 mL) and 4-cyanophenylboronic acid (32.6 mg, 0.22 mmol). The mixture was refluxed under Ar for 2 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-2-(3-methoxyphenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (10 mg, 20%). 1H-NMR (CDCl3): 2.26 (m, 1H), 2.48 (m, 1H), 3.72 (s, 3H), 5.62 (m, 1H), 6.79 (m, 3H), 6.94 (d, 1H), 7.12 (d, 1H), 7.20 (s, 1H), 7.29 (m, 1H), 7.36 (m, 1H), 7.41 (t, 1H), 7.61 (d, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([S:12][C@H:13]1[N:16]([CH:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])O)[C:15](=[O:32])[C@@H:14]1[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37])[CH3:34])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:57])=O>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]([S:12][C@H:13]1[N:16]([CH:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[Cl:57])[C:15](=[O:32])[C@@H:14]1[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37])[CH3:34])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CO[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of 0.27 g of 4(R)-t-butyldimethylsilyloxyacetylthio-3(S)-[1(R)-p-nitrobenzyloxycarbonyloxyethyl]-1-(1-p-nitrobenzyloxycarbonyl-1-hydroxymethyl)-azetidin-2-one in 3 ml of anhydrous tetrahydrofuran was cooled at 0° C. 0.045 ml of pyridine and 0.03 ml of thionyl chloride were added. After 10 minutes the mixture was filtered.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 50 °C

Procedure:
Sodium (0.23 g) was added to 15 ml of absolute ethanol and the mixture was stirred at room temperature for 30 minutes in a nitrogen flow to give a 10 mmol solution of sodium ethoxide in ethanol. To this solution, 1.98 g of diethyl 2-acetamidomalonate was added and the mixture was heated at 50° C. for 30 minutes in a stream of nitrogen. 3-Phenylpropyl bromide was added thereto at room temperature and the mixture was refluxed under heating for 24 hours. The mixture was neutralized with dilute hydrochloric acid and ethanol was distilled away. The resultant residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4-1:1) and recrystallized from diisopropyl ether-hexane to give 800 mg of diethyl 2-acetamido-2-(3-phenylpropyl)malonate as white crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[CH3:9][CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[CH:32]=[C:31]3[O:33][CH2:34][O:35][C:30]3=[CH:29][C:28]=2I)=[N:24][C:18]2[C:19]([NH2:23])=[N:20][CH:21]=[N:22][C:17]1=2)[CH3:11].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:28]1[C:27]([S:26][C:25]2[N:16]([CH2:15][CH2:14][CH2:13][NH:12][CH:10]([CH3:11])[CH3:9])[C:17]3[C:18]([N:24]=2)=[C:19]([NH2:23])[N:20]=[CH:21][N:22]=3)=[CH:32][C:31]2[O:33][CH2:34][O:35][C:30]=2[CH:29]=1
Reactant: OB(O)c1ccco1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccco2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C

Procedure:
2-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 12.5:1) to give 19.1 mg (72%) of DZ3-4. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.18 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.25 (s, 1H), 6.96 (s, 1H), 6.71 (d, J=3.3 Hz, 1H), 6.47 (dd, J=1.8, 3.2 Hz, 1H), 6.06 (s, 2H), 4.20 (t, J=7.0 Hz, 2H), 2.87 (m, 1H), 2.61 (t, J=6.9 Hz, 2H), 2.00 (m, 2H), 1.14 (d, J=6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.3, 152.2, 151.2, 150.9, 149.5, 148.14, 148.08, 142.4, 129.0, 119.2, 117.5, 114.5, 111.5, 110.0, 109.0, 102.3, 42.8, 41.0, 28.5, 21.2; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O3S, 453.1709; found. 453.1705; HPLC: method A Rt=6.23, method B Rt=6.82.
Reaction SMILES: Cl[C:2]1[C:3]([C:9]2[CH:13]=[C:12](C(F)(F)F)[NH:11][N:10]=2)=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CI.C(OCC)C>CN1CCCC1=O.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C:9]1[NH:10][N:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1cc(-c2ncc(Cl)cc2Cl)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: c1ccc(-c2ccn[nH]2)nc1
Temperature: 55 °C
Yield: 86.6 %

Procedure:
8.88 g of 3-(3,5-dichloro-2-pyridyl)-5-trifluoromethyl-[1H]-pyrazole (Example P10) are introduced into 35 ml of N-methylpyrrolidone. After the addition of 13.0 g of potassium carbonate, the mixture is stirred and heated to 55° C. 2.36 ml of methyl iodide in 5.0 ml of N-methylpyrrolidone are then slowly added dropwise. After subsequently stirring for 2 hours, diethyl ether and water are added, the mixture is extracted by shaking and the organic phase is separated off. The separated ethereal phase is washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product is purified by means of flash chromatography (silica gel; eluant: toluene/ethyl acetate 100/1). First of all 3.96 g of the 5-pyridylpyrazole isomer (yield 42%) are isolated in the form of a yellow oil and then 1.96 g of the 3-pyridylpyrazole (yield 21%) are isolated in the form of a yellow solid. The Rf values of the 3- and 5-pyridylpyrazole isomers on silica gel 60 F254 using toluene/ethyl acetate 30/1 as eluant (UV) are:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:9]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Cl)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 30.1 using 5,6-dichloronicotinic acid and 4-(trifluoromethoxy)aniline to afford an off-white solid. UPLC-MS (Condition 1) tR=3.05 min, m/z=350.9/352.9 [M+H]+, m/z=348.9/351.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.6 Hz, 2H) 7.86 (d, J=9.3 Hz, 2H) 8.63 (d, J=2.0 Hz, 1H) 8.90 (d, J=2.2 Hz, 1H) 10.70 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[S:15])[NH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1.[CH3:20][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[S:15])[NH:13][C:12]([C:16]([O:18][CH3:20])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(Nc2cc(N)ncn2)c(=S)[nH]c1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1[nH]c(=S)c(Nc2cc(N)ncn2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylic acid (5, 0.5 g, 1.72 mmol) in tetrahydrofuran (10 mL) and methanol is added (trimethylsilyl)diazomethane (2 M in hexanes, 1.29 mL, 2.58 mmol). The reaction is stirred at room temperature for 1 h. The resulting mixture is concentrated and purified via column chromatography to afford methyl 5-(6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylate (6).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=O.[Na+].[Na+]>O>[CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)=[O:2]
Reactant: COC(=O)c1ccc(C=O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(C(=O)O)c2ccccc12
Yield: 87 %

Procedure:
A mixture of the methyl 4-formylnaphthoate above (2.3 g, 1 mmol) and Na2CO3 (1.25 g, 12 mmol) in water (30 mL) was heated in a water bath for approximately 2 hr until a clear solution was obtained. The solution was cooled and filtered. The filtrate was acidified with conc. HCl to give a yellow precipitate. The solids were collected and dried over night to give the desired product (1.86 g, 87%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][CH3:17])=[C:4](OC)[C:5]([O:10][CH2:11][CH3:12])=[C:6]([OH:9])[C:7]=1[CH3:8].[H-].[Na+].[CH3:20][O:21][CH2:22]Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:15][CH2:16][CH3:17])=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([O:9][CH2:20][O:21][CH3:22])[C:7]=1[CH3:8]
Reactant: CCOc1c(O)c(C)c(Br)c(OCC)c1OC
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)c(OCOC)c(C)c1Br
Temperature: 0 °C

Procedure:
54 g of 5-bromo-2,4-diethoxy-3-methoxy-6-methylphenol prepared in Referential Example 7 was dissolved in 250 ml of DMF, and 8.5 g of sodium hydride (55% oil suspension) was added thereto and cooled by ice while stirring. The mixture was stirred at room temperature for 30 min and cooled again with ice, and 17.1 g of methoxymethyl chloride was dropwise added thereto. After the completion of the dropwise addition, the mixture was further stirred at room temperature for 30 min. Ice water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography (eluent; n-hexane : ethyl acetate=95 : 5) to prepare 43.6 g of the product compound as a colorless oleaginous substance.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([NH2:9])[N:3]=1.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]2[NH:8][C:7]3[C:2]([N:1]=2)=[N:3][C:4]([NH2:9])=[CH:5][CH:6]=3)=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Nc1ccc(N)c(N)n1
Product: Nc1ccc2[nH]c(-c3ccc(F)cc3)nc2n1

Procedure:
2,3,6-Triaminopyridine (Austin Products; 372 mg 3 mmol) and 4-fluorobenzoic acid (420 mg 3 mmol) are treated with polyphosphoric acid (30 g) at 150° C. for 1 h. The reaction mixture is poured on ice-water/NH3conc. and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude product, which is purified by SiO2 chromatography (acetone/cyclohexane 20/80 to 50/80) and rendered the title compound as pale yellow crystals (200 mg 29%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([S:13]([N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]2=3)(=[O:15])=[O:14])=[CH:4][C:3]=1[C:27]1[C:28]([CH3:35])=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=1.C(#N)C.[OH2:39].CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:27]2[CH:32]=[N:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=2[CH3:35])=[CH:4][C:5]([S:13]([N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]2=3)(=[O:15])=[O:14])=[C:6]([CH:7]=1)[O:8][CH2:9][CH2:10][C:11]([OH:39])=[O:12]
Reactant: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(OCCCO)cc1Cl
Reactant: O
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(OCCC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 5-[2-chloro-4-(3-hydroxy-propoxy)-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-4-methyl-pyridine-2-carbonitrile 8-1 (31 mg, 0.06 mmol) in a mixture of DCM (0.3 mL), acetonitrile (0.3 mL) and water (0.4 mL) was added NalO4 (38 mg, 0.18 mmol) and RuCl3 (2.5 mg, 0.012 mmol). The mixture was stirred at rt for 40 minutes, then 1 mL of methanol was added. The mixture was filtered and purified by prep. LCMS to afford 3-[5-chloro-4-(6-cyano-4-methyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-propionic acid 10-1. MS: 526.0 (M+H)+; tR=4.65 min (method 4). NMR (CDCl3), δ, 8.378 (1H, s), 7.649 (1H, s), 7.621 (1H, s), 7.259 (1H, s), 7.136-7.203 (2H, m), 6.981-7.038 (1H, m), 6.746 (1H, d, J=7.8 Hz), 4.423 (2H, t), 3.728 (2H, m), 2.803-2.842 (4H, m), 2.162 (3H, s), 1.894-1.929 (2H, m), 1.658 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].[F:16][C:17]1[N:22]=[CH:21][C:20](N)=[CH:19][CH:18]=1.N1C=CN=C1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([C:20]1[CH:21]=[N:22][C:17]([F:16])=[CH:18][CH:19]=1)[C:5]2=[O:15]
Reactant: Nc1ccc(F)nc1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(c1ccc(F)nc1)C2=O
Temperature: 200 °C
Yield: 12.7 %

Procedure:
5-Amino-6-nitroisoindoline-1,3-dione (2.00 g, 9.66 mmol), 6-fluoropyridin-3-amine (3.25 g, 28.98 mmol) and imidazole (1.32 g, 19.32 mmol) were suspended in diphenyl ether (50 mL). The mixture was stirred and heated to 200° C. for 24 h under argon. Then, the solid was filtered, washed with hexanes and purified by column chromatography (silica-gel, CH2Cl2/Acetone=7/3 v/v) to give a yellow solid product, 0.37 g, 12.7% yield. MS: 300.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.47 (s, 2H), 8.45 (s, 1H), 8.13-8.06 (m, 1H), 8.34 (d, 1H, J=2.1 Hz), 7.56 (s, 1H), 7.41 (dd, 1H, J1=8.7 Hz, J2=3.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Mg].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[CH:20]=[O:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[OH:21])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Agent: [Mg]
Product: COc1cc(C(O)c2cc(OC)c(OC)c(OC)c2)ccc1[N+](=O)[O-]
Yield: 59.5 %

Procedure:
(3-Methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol was prepared analogously to (4-methoxy-3-nitro-phenyl)-(3,4,5-trimthoxy-phenyl)-methanol using 3,4,5-trimethoxy-bromobenzene (3.0 g, 12.1 mmol), magnesium turning (1.0 g, 24.3 mmol) and 3-methoxy-4-nitro-benzaldehyde (1.8 g, 10.1 mmol). The crude product was purified by flash chromatography (silica gel, Hexane:EtOAc 7:3) to afford (3-methoxy-4-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.1 g, 60%): 1H NMR (CDCl3) δ 7.82 (d, J=8 Hz, 1H), 7.23 (s, 1H), 6.97 (d, J=8 Hz, 1H), 6,54 (s, 2H), 5,76 (s, 1H), 4.76 (s, 1H), 3.96 (s, 3H), 3.85 (s, 9H).