Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:17]([O-])=O)=[CH:5][C:6]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][C:9](=[O:15])[NH:8][C:7]=2[CH:16]=1>CO.[Pd]>[NH2:17][C:4]1[C:3]([O:2][CH3:1])=[CH:16][C:7]2[NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])C(C)(C)CCC(=O)N2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)C(C)(C)CCC(=O)N2
Yield: 86.8 %

Procedure:
8-Methoxy-5,5-dimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (160 mg, 0.60 mmol) was hydrogenated in the presence of 10% Pd/C, 50% wet (80 mg) in Methanol (15 mL) overnight (balloon). Conc. of the filtered reaction afforded 7-Amino-8-methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (122 mg, 86%), which was used without purification. 1H-NMR (CDCl3): 6.94 (s, 1H), 6.76 (s, 1H), 6.38 (s, 1H), 3.85 (s, 3H), 3.76 (s, 2H), 2.35 (t, 2H, J=7.0 Hz), 2.07 (t, 2H, J=7.0 Hz), 1.37 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:13]([CH:14]=[O:15])=[C:12]([Cl:16])[N:11]=[CH:10][N:9]=1.[OH:17][C:18]1[C:19]([CH3:24])=[N:20][CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[OH:17][C:18]1[C:19]([CH3:24])=[N:20][CH:21]=[CH:22][CH:23]=1.[Cl:16][C:12]1[C:13]([CH:14]=[O:15])=[C:8]([O:17][C:18]2[C:19]([CH3:24])=[N:20][CH:21]=[CH:22][CH:23]=2)[N:9]=[CH:10][N:11]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1ncnc(Cl)c1C=O
Temperature: 25 °C

Procedure:
Potassium carbonate (10.22 g, 74 mmol) was added to a mixture of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 5.0 g, 28.3 mmol) and 3-hydroxy-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 3.66 g, 33.5 mmol) in anhydrous dimethylformamide (100 mL). The mixture was stirred at room temperature. The mixture was cooled to 0° C. and water (100 mL) was slowly added. The temperature rose to 18° C. during the addition. The mixture was recooled to 0° C. and stored in the freezer overnight. The precipitate was filtered off. LC-MS indicated that this was the result of the addition of two 3-hydroxy-2-methylpyridine moieties to the pyrimidine. The mother liquor was extracted with ethyl acetate and the extract was concentrated and purified using a Supelco 100 g column, eluting with 0-5% methanol/dichloromethane. Fractions containing the desired product were pooled, concentrated, and held under vacuum to give 4-chloro-6-(2-methyl-pyridin-3-yloxy)-pyrimidine-5-carbaldehyde (521 mg, 7%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 2.32 (s, 3H), 7.36 (dd, 1H, J=4.8, 8.2 Hz), 7.66 (dd, 1H, J=1.2, 8.2 Hz), 7.8.41 (dd, 1H, J=1.5, 4.8 Hz), 8.72 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[C:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)(O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([C:41]3[CH:46]=[CH:45][C:44]([CH:47]=[C:48]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:43][CH:42]=3)(O)[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I-].[K+].O.[PH2](=O)[O-].[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7]([CH:6]=1)=[C:8]([C:41]1[CH:46]=[CH:45][C:44]([CH:47]=[C:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:43][CH:42]=1)[C:9]1[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]=2[C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:25]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)C(O)(c1ccc(C=C(c3ccccc3)c3ccccc3)cc1)c1ccccc1C2(O)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c3ccccc3c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c2c1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
2-t-Butyl-9,10-bis(4-(2,2-diphenylvinyl)phenyl)-9,10-dihydroxy-9,10-dihydroanthracene (3.3 g, 4.3 mmole) was dissolved into acetic acid (30 ml). To the resultant solution, potassium iodide (1.9 g, 11 mmole, 2.7 eq) and sodium phosphinate monohydrate (0.6 g, 5.7 mmole) were added and the obtained mixture was stirred for 2 hours. The reaction mixture was filtered and washed with water, methanol and acetone and a light yellow solid (2.8 g, 88%) was obtained.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[NH2:15].N1C=CC=CC=1>C1COCC1.C(OCC)(=O)C.Cl>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][C:18]=1[C:19]([F:21])([F:22])[F:20]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)c(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenyl chloroformate (0.86 mL) was added slowly to a stirring solution of 3-chloro-4-trifluoromethyl aniline (933 mg) in THF (10 mL) containing pyridine (1.07 mL) under an argon atmosphere. The reaction was stirred for 18 h then diluted with ethyl acetate (35 mL) and 1M HCl (20 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 then dried (MgSO4), filtered and evaporated. Trituration with 1:9 EtOAc:isohexanes (10 mL) at reflux followed by cooling to RT afforded a solid which was filtered to afford 1.15 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH2:19]([O:11][C:7]1[C:6]([Br:12])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:9][C:8]=1[Br:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)c(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3,5-dibromo-4-hydroxyacetophenone from Example 45A (15 g, 51.2 mmol) in DMF (51 mL) was added K2CO3 (10.2 g, 74.1 mmol) and benzyl bromide (6.0 mL, 50.7 mmol). The reaction stirred at room temperature for 45 minutes. It was diluted with water (200 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with 2M NaOH solution (2×75 mL), water (75 mL), and brine (75 mL) and then dried over MgSO4 and concentrated in vacuo to give 1-(4-benzyloxy-3,5-dibromo-phenyl)-ethanone as an off white solid (14.3 g, 37.2 mmol, 73% yield).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:32])[CH2:4][NH:5][C@H:6]1[C:14]2[C:9](=[C:10]([C:15]3[N:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([CH:27]=4)[C:25]#[N:26])[O:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>CC#N>[OH:32][CH:3]1[CH2:4][N:5]([C@H:6]2[C:14]3[C:9](=[C:10]([C:15]4[N:19]=[C:18]([C:20]5[CH:21]=[CH:22][C:23]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([CH:27]=5)[C:25]#[N:26])[O:17][N:16]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:2]1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCC(O)CCl)no2)cc1C#N
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N3CC(O)C3)no2)cc1C#N
Temperature: 75 °C
Yield: 27 %

Procedure:
To a flask containing 5-(3-((1R)-1-(3-chloro-2-hydroxypropylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile INT-15 (77.0 mg, 0.17 mmol) in CH3CN (4 mL) was added TEA (44.5 μL, 0.32 mmol). The reaction mixture was heated at 75° C. overnight then concentrated in vacuo, dissolved in DCM and purified by chromatography (MeOH/DCM) to provide 19 mg (27%) of (R)-5-(3-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 83 as a white solid. LCMS-ESI (m/z) calculated for C24H24N4O3: 416.5. found 417.1 [M+H]+, tR=6.19 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 8.09 (dd, J=7.7, 0.7 Hz, 1H), 7.44 (d, J=7.4 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 4.79 (dt, J=12.2, 6.1 Hz, 1H), 4.46 (p, J=5.8 Hz, 1H), 3.99 (dd, J=7.0, 3.5 Hz, 1H), 3.70 (dt, J=19.2, 5.6 Hz, 2H), 3.47 (d, J=6.7 Hz, 1H), 3.41 (dd, J=16.6, 8.7 Hz, 1H), 3.28 (ddd, J=17.5, 8.8, 4.2 Hz, 1H), 3.20-3.13 (m, 1H), 3.13-3.05 (m, 1H), 2.13 (dddd, J=16.9, 12.6, 8.4, 5.5 Hz, 2H), 1.47 (d, J=6.1 Hz, 6H). (S)-5-(3-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 84 was prepared in an analogous fashion from (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[CH:20]=[CH:19]4)[N:10]=2)[N:3]=1>ClCCl.O=[Mn]=O>[CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[CH:20]=[CH:19]4)[N:10]=2)[N:3]=1
Reactant: Cc1nn(-c2ccnc(Nc3ccc4c(ccn4C)c3)n2)cc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nn(-c2ccnc(Nc3ccc4c(ccn4C)c3)n2)cc1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 362 %

Procedure:
To a solution of intermediate 7 (214 mg, 0.64 mmol) in 100 mL of dichloromethane (DCM), was added 58% of activated MnO2 (0.58 g, 6 equiv.). After being stirred for 12 hours at room temperature, the reaction mixture was passed through a pad of Celite and rinsed with dichloromethane. The filtrate was concentrated in vacuo to give desired intermediate 8 as a pale yellow solid (0.77 g, 36%); MS (ESI) m/z 333 [M+H]+
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)[C@@H](O)c1ccccc1
Temperature: 10 °C
Yield: 42 %

Procedure:
L-Mandelic acid (10 g.), 6.91 g. of benzyl alcohol, and 75 mg. of p-toluenesulfonic acid in 70 ml. of benzene was refluxed under a Dean-Stark trap for a total of 28 hours on 4 consecutive days. The crude benzyl ester was obtained by successively concentrating the liquor and cooling it to about 10° C. a number of times. The fractions melting between 97° C. and 105° C. were combined, dissolved in CHCl3 and washed twice with 15 ml. portions of 5% aqueous NaHCO3 solution. After evaporation of the CHCl3, the product was recrystallized from benzene to give benzyl L-mandelate, m.p. 104°-106° C., yield 42%.
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[CH:5][C:4]([Br:24])=[N:3]1.[Br-].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([Zn+])=[N:31][CH:32]=1.O1CCCC1>CN(C)C=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:30]2[CH:29]=[CH:28][C:27]([CH3:26])=[CH:32][N:31]=2)=[CH:5][C:4]([Br:24])=[N:3]1
Reactant: Cn1nc(Br)cc1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc([Zn+])nc1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(Br)nn2C)nc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
A solution of 1-methyl-3-bromo-5-(nonafluorobutanesulfonyloxy)pyrazole from Step 2 (0.36 g, 0.784 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.09 g, 10 mol %) in dry N,N-dimethylformamide (2 mL) was stirred under nitrogen at 60° C. for 10 min, followed by addition of a solution of 5-methylpyridin-2-ylzinc bromide in tetrahydrofuran (0.5M, 1.8 mL, 0.9 mmol). The solution was stirred at 60° C. for 18 hours then cooled, diluted with water (30 mL), and extracted with ethyl acetate (2×20 mL). The extracts were dried (Na2SO4) and concentrated. Flash column chromatography on silica, eluting with 10% ethyl acetate—isohexane, gave 1-methyl-3-bromo-5-(5-methylpyridin-2-yl)pyrazole (0.081 g, 41%) as a yellow solid. MS (ES+) 252, 254 ([MH]+). Step 4: [6S,9R,11R] 2′,3′,4′,5,5′,6,7,8,9,10-decahydro-2-(5-(5-methylprid-2-yl)-1-methyl-pyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[P:14](=[O:17])([OH:16])O>O1CCCC1>[CH:10]1[C:9]2[PH:14](=[O:16])[O:17][C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=P(O)(O)c1ccccc1-c1ccccc1O
Solvent: C1CCOC1
Product: O=[PH]1Oc2ccccc2-c2ccccc21
Temperature: 106 °C
Yield: 93 %

Procedure:
500 g of 2-(2-hydroxyphenyl)phenylphosphonic acid (HPPA) was placed in a 300 ml flask which was connected to a vacuum system. The content was heated to its molten state (106° C.) under full vacuum for dehydration. The temperature was slowly increased from 106 to 160° C. until the dehydration was complete. White solids of DOPO (9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide) (yield 93%) with m.p. 119-120° C. after recrystallization from tetrahydrofuran was obtained. I.r.: 1168, 965 (P—Ph), 1196 (P═O), 2384 (P—H), 1587 cm−1 (P—Ph). Anal. Calcd. for C12H9O2P: C, 66.67; H, 4.17; O, 14.81; P, 14.35. Found: C, 66.64; H, 4.31; O, 14.59; P, 14.66. MS, m/z: 216 (100, M+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][NH2:20]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:4](=[O:3])[C:5]([NH:20][CH2:19][CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)=[O:1])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCCc1ccccn1
Reactant: NCc1ccc2c(c1)OCO2
Product: O=C(NCCc1ccccn1)C(=O)NCc1ccc2c(c1)OCO2
Yield: 35 %

Procedure:
Prepared in a similar manner to example 125 using benzo[d][1,3]dioxol-5-ylmethanamine, ethyl oxalyl chloride, and 2-(2-pyridinyl)ethyl amine; yield 35%; m/e=328 [M+1].
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O>[CH:24]1([N:23]([CH3:22])[C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CNC1CCCCC1
Solvent: CS(C)=O
Product: CN(c1cc2nc3c(cc2cc1F)c(=O)c(C(=O)O)cn3C)C1CCCCC1

Procedure:
8-[(Cyclohexyl)(methyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 1, but from 1.5 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.3 cm3 of N-methylcyclohexylamine in 30 cm3 of dimethyl sulphoxide. After washing 2 times with with 15 cm3 of ethanol, 1.7 g of 8-[(cyclohexyl)(methyl)amino]-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 265° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:38][O:39][CH2:40][CH3:41])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])(C(C)(C)C)(C)C>O1CCCC1>[CH2:40]([O:39][CH2:38][C@H:27]([OH:26])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])[CH3:41]
Reactant: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC[C@H](O)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (3.25 mL, 3.25 mmol) was added in one portion to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate G2) (1.1 g, 3.25 mmol) in tetrahydrofuran (25 mL). The resulting solution was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated and diluted with EtOAc (50 mL) washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford (2S)-3-ethoxy-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (730 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 1.24 (3H, t), 2.30 (3H, s), 3.60 (2H, q), 3.76-3.79 (2H, m), 3.87 (1H, s), 4.33-4.38 (1H, m), 7.52 (1H, dd), 8.11-8.13 (2H, m), 9.20 (1H, s); m/z (ESI+) (M+H)+=225; HPLC tR=0.96 min.
Reaction SMILES: ClC1C=C2C(N)COC2=CN=1.CO[N:14]=[C:15]1[C:23]2[C:18](=[N:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[O:17][CH2:16]1>>[Cl:24][C:20]1[N:19]=[C:18]2[O:17][CH2:16][CH:15]([NH2:14])[C:23]2=[CH:22][CH:21]=1
Reactant: CON=C1COc2nc(Cl)ccc21
Agent: NC1COc2cnc(Cl)cc21
Product: NC1COc2nc(Cl)ccc21

Procedure:
This compound was prepared using a method analogous to that of 5-chloro-2,3-dihydrofuro[2,3-c]pyridin-3-amine (A.2.9.3), 6-chlorofuro[2,3-b]pyridin-3(2H)-one O-methyl oxime replacing 5-chlorofuro[2,3-c]pyridin-3(2H)-one O-methyl oxime;
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:11]2[CH:16]=[C:15]([Cl:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:11]3[CH:16]=[C:15]([Cl:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-chloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].S([O-])([O-])(=O)=S.[Na+].[Na+].I[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=1[F:24]>CN(C=O)C.C(N(CC)CC)C.[Cu](I)I>[OH:7][CH:3]([CH2:4][CH2:5][CH3:6])[C:2]#[C:1][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=1[F:24]
Reactant: C#CC(O)CCC
Reactant: Fc1ccc(I)c(F)c1F
Agent: I[Cu]I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(O)C#Cc1ccc(F)c(F)c1F
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, 4-iodo-1,2,3-trifluorobenzene was dissolved into DMF, into which triethylamine, copper iodide (I), and tetrakistriphenylphosphine palladium (0) were added and heated to 55° C. Then, the DMF solution containing 1-hexine-3-ol was added dropwise for 20 minutes, and stirred for 3 hours. After the reaction mixture was poured into a sodium thiosulfate aqueous solution, and stirred for a while, an organic layer was separated, and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water, 10% hydrochloric acid twice, water, a saturated sodium hydrogen carbonate aqueous solution, and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by column chromatography (silica gel, toluene/hexane) to obtain 1-(3-hydroxy-1-hexynyl)-2,3,4-trifluorobenzene.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1>>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[CH2:2][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Fc1cccc(Cl)c1CBr
Product: Cc1cc(O)nc(SCc2c(F)cccc2Cl)n1
Yield: 82 %

Procedure:
As per procedure from Example 1, 2-(bromomethyl)-1-chloro-3-fluorobenzene and 6-methyl-2-sulfanylpyrimidin-4-ol were reacted together to provide the title compound as a white solid (1.04 g, 82% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 4.53 (s, 2H), 6.01 (bs, 1H), 7.26 (m, 1H), 7.38 (m, 2H); M+282.06.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1.CC(C)([O-])C.[K+].[CH3:36][C:37]([O:40][C:41](=[O:44])[CH2:42]Br)([CH3:39])[CH3:38]>O1CCCC1>[C:37]([O:40][C:41](=[O:44])[CH2:42][O:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1)([CH3:39])([CH3:38])[CH3:36]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)[C@H]1C[C@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](OCC(=O)OC(C)(C)C)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl(2S,3S,5S)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (50.0 mg, 0.000123 mol) in tetrahydrofuran (0.50 mL, 0.0062 mol) was added 1.00 M of potassium tert-butoxide in tetrahydrofuran (0.150 mL). After stirred at rt for 30 min, to the mixture was added bromo-acetic acid 1,1-dimethylethyl ester (0.0228 mL, 0.000154 mol). The resulting mixture was stirred at rt overnight and then concentrated to dry.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N+:8]([CH3:13])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[Na+].[Na+].[C:20]1(=[O:33])[N:24]([CH2:25][CH2:26][Br:27])[C:23](=[O:28])[C:22]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:21]12>C(#N)C>[Br-:27].[CH3:13][N+:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH2:26][CH2:25][N:24]3[C:20](=[O:33])[C:21]4=[CH:32][CH:31]=[CH:30][CH:29]=[C:22]4[C:23]3=[O:28])[CH:4]=2)[CH:9]=1
Reactant: C[n+]1ccc2cc(O)ccc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Product: C[n+]1ccc2cc(OCCN3C(=O)c4ccccc4C3=O)ccc2c1

Procedure:
6-Hydroxy-2-methylisoquinolinium bromide (2.4 g.), sodium carbonate (5 g.) and phthalimidoethyl bromide (2.6 g.) in acetonitrile (100 ml) were heated under reflux for 9 days. The mixture was filtered hot and the filtrate evaporated to give an oily solid. It was washed with chloroform, and light petroleum ether (b.p. 40°-60°) was added to give an oil that solidified on trituration, m.p. 165°-169°.
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[CH2:7][CH:8]([C:10]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)[CH3:9].C(=O)([O-])O.[Na+]>O1CCCC1>[F:16][C:13]1[CH:14]=[N:15][C:10]([CH:8]([CH3:9])[CH2:7][CH:3]=[O:2])=[N:11][CH:12]=1
Reactant: CC(CC1OCCO1)c1ncc(F)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CC=O)c1ncc(F)cn1
Reaction time: 3 h
Yield: 34.4 %

Procedure:
Concentrated hydrochloric acid (1 m) was added to a stirring solution of 2-[2-(1,3-dioxolan-2-yl)-1-methylethyl]-5-fluoropyrimidine (1.1 g) in tetrahydrofuran (10 ml) at ambient temperature, stirred for 3 hours then added solid sodium hydrogen carbonate to neutral pH. The mixture was poured onto a Chemelute carrtridge and washed with ethyl acetate (3×20 ml), the combined organics were dried over Na2SO4 and evaporated in vacuo to afford 3-(5-fluoropyrimidin-2-yl)butanal (300 mg, 35%) which was used without further purification.