Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=1.FC1C=C(Br)C=CC=1C(Cl)=O.C(N(C(C)C)CC)(C)C.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(Cl)Cl.O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:14])=[C:10]([F:17])[CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(Br)cc1F)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.8 ml (44 mmol) oxalyl chloride in 30 ml CH2Cl2 is added dropwise to a iced-cooled solution of 4.88 g (21.9 mmol) 4-bromo-2-fluorobenzoic acid in 180 ml CH2Cl2. After complete addition, the cooling bath is removed and stirring maintained for 15 h at RT. The solvent is evaporated to dryness, the resultant colorless residue is dried under vacuum and then diluted with 80 ml CH2Cl2. This solution of 2-Fluoro-4-bromobenzoyl chloride (CAS 151982-51-3) is then added dropwise to a mixture of 9.55 ml (54.7 mmol) of diisopropylethylamine, 2.01 ml (23 mmol) of morpholine in 100 ml CH2Cl2. After 1 h 30, the reaction mixture is diluted with water and the two phases are separated. The aqueous phase is re-extracted with CH2Cl2 and the combined organic extracts are washed with water, saturated brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford, after drying in HV, the title compound which is used in the next step without further purification.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH:60]([F:62])[F:61])[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:34]([CH2:38][I:39])[CH2:35][S:36](=[O:37])[C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1.[CH:69](OC(C)C)(C)C>O1CCCC1>[I-:39].[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:58][O:59][CH:60]([F:62])[F:61])[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:34]([CH:38]([CH3:69])[NH+:64]4[CH2:68][CH2:67][CH2:66][CH2:65]4)[CH2:35][S:36](=[O:37])[C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)OC(C)C
Reactant: CN1CCCC1
Solvent: C1CCOC1
Product: CC(C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(F)F)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2S(=O)C1)[NH+]1CCCC1
Product: [I-]

Procedure:
A solution of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (1.97 g) and N-methylpyrrolidine (204 mg) in tetrahydrofuran (10 ml) was stirred for 40 minutes at 0°-5° C. and then diisopropyl ether was added thereto. The resultant precipitates were collected by filtration, washed with diisopropyl ether and air-dried to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(1-methyl-1-pyrrolidiniomethyl)-3-cephem-4-carboxylate-1-oxide iodide (syn isomer) (2.12 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O.CCOCC>[Si:12]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CO
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of 33.93 g of ethyl glycolate, 62.7 g of t-butyldimethylchlorosilane and 58.5 g of imidazole in 150 ml of dimethylformamide is stirred at room temperature for 15 h. The mixture is diluted with ether and washed with water (2×100 ml), brine, dried (MgSO4) and evaporated. The residue is distilled to give ethyl t-butyldimethylsilyloxyacetate, b.p. 100°-105° C. (14 mm/Hg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([CH3:11])=[CH:9][S:10][C:3]=12.[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[C:23]([NH:26][C:27]3[N:32]=[CH:31][C:30]([S:33]CCC(OC)=O)=[CH:29][C:28]=3[O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[S:24][CH:25]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13].CC([O-])(C)C.[K+]>CS(C)=O>[CH3:11][C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([S:33][C:30]3[CH:29]=[C:28]([O:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:27]([NH:26][C:23]4[S:24][CH:25]=[C:21]([CH:18]5[CH2:19][CH2:20][N:15]([C:12](=[O:14])[CH3:13])[CH2:16][CH2:17]5)[N:22]=4)=[N:32][CH:31]=3)=[C:3]2[S:10][CH:9]=1
Reactant: Cc1csc2c(Cl)ccnc12
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5c(C)csc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
7-chloro-3-methylthieno[3,2-b]pyridine (0.072 g, 0.39 mmol) and methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (0.20 g, 0.39 mmol) were dissolved in DMSO (3 mL). The solution was degassed for 15 minutes under nitrogen. KOtBu (0.13 g, 1.2 mmol) was added and the reaction stirred at room temperature for two hours. The solution was quenched with water, extracted with dichloromethane, dried, and concentrated. Flash chromatography gave the title compound (0.100 g, 44% yield). 1H NMR (400 MHz, CDCl3) δ 1.60-1.72 (m, 2H), 2.03-2.09 (m, 2H), 2.11 (s, 3H), 2.51 (s, 3H), 2.66-2.73 (m, 1H), 2.83-2.90 (m, 1H), 3.15-3.22 (m, 1H), 3.88-3.94 (m, 1H), 4.70-4.73 (m, 1H), 6.51 (s, 1H), 6.75 (d, 1H), 7.05 (d, 2H), 7.17-7.25 (m, 2H), 7.36-7.40 (m, 3H), 8.30 (d, 1H), 8.48 (d, 1H), 8.84 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl-].[Li+].[C:11](Cl)(=[O:21])[C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15](Cl)=[O:16])[CH:13]=1.[OH2:23]>CN1C(=O)CCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:21])[C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:23])=[O:16])[CH:13]=1
Reactant: O
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccccc1O)c1cccc(C(=O)Nc2ccccc2O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 260 mL of NMP were dissolved 27.548 g of o-aminophenol and 11.484 g of lithium chloride. To the solution was added 25 g of isophthaloyl chloride under ice-cooling, and the solution was further stirred at room temperature overnight. The reaction mixture was then poured into water, and the precipitation was filtered and washed with water. The obtained precipitation was dissolved in 500 mL of tetrahydrofuran again and dried over magnesium sulfate. The solvent was then evaporated off under a reduced pressure to obtain 40 g of N,N′-di(2-hydroxyphenyl)isophthalamide.
Reaction SMILES: O1C[CH2:5][N:4]([CH:7]=[O:8])[CH2:3]C1.CNC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]3[CH:26]=[C:27]4[C:31](=[C:32](C(O)=O)[CH:33]=3)[NH:30][N:29]=[CH:28]4)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][C:14]=1[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(#N)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]3[CH:26]=[C:27]4[C:31](=[C:32]([C:7]([N:4]([CH3:5])[CH3:3])=[O:8])[CH:33]=3)[NH:30][N:29]=[CH:28]4)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][C:14]=1[CH3:37]
Reactant: O=CN1CCOCC1
Reactant: Cc1cc(-c2ncccc2-c2cc(C(=O)O)c3[nH]ncc3c2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ncccc2-c2cc(C(=O)N(C)C)c3[nH]ncc3c2)ccc1F

Procedure:
5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamide was prepared analogous to the preparation of 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanone by the reaction of dimethyl amine (0.55 mL, 1.1 mmol, 2M in THF) with 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylic acid (100 mg, 0.28 mmol), HBTU (140 mg, 0.36 mmol), NEt3 (57 mg, 0.08 mL, 0.57 mmol) in acetonitrile (4 mL). Extractive work-up followed by preparative HPLC purification and neutralization procedure as discussed previously provided desired 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamide as a white solid. 1H NMR (DMSO-d6): δ 13.05 (s, 1H), 8.63 (dd, 1H, J=1.7 and 4.7 Hz), 8.13 (s, 1H), 7.87 (dd, 1H, J=1.4 and 7.6 Hz), 7.81 (s, 1H), 7.46 (dd, 1H, J=4.7 and 7.6 Hz), 7.32 (d, 1H, J=7.3 Hz), 7.02-6.98 (m, 1H), 6.95-6.89 (app m. 2H), 2.93 (br s, 3H), 2.57 (br s, 3H), 2.09 (s, 3H).19F NMR (DMSO-d6): δ −118.91. LCMS: rt 4.63 min (A), purity 97%, MS (m/e) 375 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:27]([CH3:29])[CH3:28])([CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:30][OH:31].[C]=[O:33].C(N(CC)CC)C>C1C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH:27]([CH3:29])[CH3:28])[CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[C:30]([OH:33])=[O:31])#[N:13]
Reactant: COc1ccc(C(C#N)(CCCN(C)CCc2ccccc2)C(C)C)cc1OC
Reactant: [C]=O
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(C(C#N)(CCCN(C)CCc2ccccc2C(=O)O)C(C)C)cc1OC
Temperature: 22 °C
Reaction time: 72 h

Procedure:
To 331 mg (0.839 mmol) of 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile in 8.3 mL of benzene was added 226 mg (1.01 mmol) of palladium(II)acetate and the mixture was stirred for 72 h at 22° C. under nitrogen. The solution was transferred into a pressure flask, 10 mL of methanol was added and the mixture was treated with carbon monoxide at 40 psi for 24 h. After addition of 175 μL (1.26 mmol) of triethylamine, the mixture was filtered through a pad of celite and evaporated to give a crude mixture of 3au and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile. In order to afford purification, a solution of 57 mg of the crude product was dissolved in 1 mL of methanol and treated with 63 μL of 10 N NaOH. After stirring for 1 h at 22° C., an additional 1264 of 10 N NaOH and 2 mL of methanol was added. The solution was heated to 50° C. then cooled to 22° C., evaporated and partitioned between ether and 0.5 N NaOH. The aqueous layer was acidified to about pH 6 with 12 N HCl then extracted with ethyl acetate (3×). The combined organic layers were dried (Na2SO4) and evaporated to give 2-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoic acid. The carboxylic acid was esterified by treating with 44 mg (0.24 mmol) of carbonyldiimidazole in 1 mL of THF for 3 h at 22° C. followed by addition of 8 mL of methanol and continued stirring for about 16 hours at 22° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with dichloromethane and then gradually increasing to 3% methanol/dichloromethane to give 3au. MS found M+H=453. Substitution of the ester group in the indicated ortho-position of the phenyl ring was confirmed by 1H NMR analysis.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[CH2:19][C:18]2=[O:37])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH2:38]([O:41][C:42](OC1C=CC([N+]([O-])=O)=CC=1)=[O:43])[CH2:39][CH3:40].C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>CN(C=O)C>[Cl:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:23]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:4]3([NH:3][C:42]([O:41][CH2:38][CH2:39][CH3:40])=[O:43])[CH2:9][CH2:8][N:7]([C:10]4[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=4)[CH2:6][CH2:5]3)[C:18](=[O:37])[CH2:19]1)(=[O:24])=[O:25])[CH:35]=[CH:34]2
Reactant: CCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Yield: 47.4 %

Procedure:
A solution of 1-[4-amino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone dihydrochloride (235 mg), O-propoxycarbonyl-4-nitrophenol (270 mg) and N-ethyldiisopropylamine (0.348 ml) in DMF (5 ml) was stirred at 80° C. overnight. To the reaction solution was added ethyl acetate, the mixture was washed successively with a 10% aqueous sodium carbonate solution, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:10% aqueous ammonia-containing methanol=90:10→80:20), and crystallized from a mixed solution of acetone and ethyl acetate to obtain the pale brown crystalline title compound (114 mg).
Reaction SMILES: C(#N)C.[CH2:4]([CH:6]([CH2:23][CH3:24])[C@H:7]([NH:10][S:11]([C:14]1[S:15][C:16]([Sn](C)(C)C)=[CH:17][CH:18]=1)(=[O:13])=[O:12])[CH2:8][OH:9])[CH3:5].[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(OCC)(=O)C>[CH2:23]([CH:6]([CH2:4][CH3:5])[C@H:7]([NH:10][S:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:13])[CH2:8][OH:9])[CH3:24]
Reactant: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc([Sn](C)(C)C)s1
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1cccs1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of anhydrous acetonitrile (6 mL) and N-[(1S)-2-ethyl-1-(hydroxymethyl)butyl]-5-(trimethylstannyl)thiophene-2-sulfonamide (0.24 g, 0.56 mmol) was added Selectfluor (Aldrich) (0.204 g, 0.57 mmol) all at once. The mixture was heated to 75° C. under a nitrogen atmosphere, stirred 16 h and then cooled to 25° C. and filtered. Evaporation of the solvent produced a crude solid that was taken up in ethyl acetate and again filtered to remove insoluble solids. Evaporation of the remaining solvent produced an oil that was purified by flash chromatography using hexane-ethyl acetate 2-1 as eluant, producing the title compound as the major product (0.051 g, 33%). MS (−ESI) 276.20 ([M−H]−).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=2)=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(Cl)c3)cnc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(Cl)c3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-((5-chloropyridin-3-yl)oxy)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (40 mg, 0.078 mmol) in THF (6 mL) and water (6 mL) was added LiOH.H2O (6.51 mg, 0.156 mmol) at 20° C. The reaction was stirred at RT for 30 min. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-((5-chloropyridin-3-yl)oxy)-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 21.2% yield) as a white solid. 1H NMR (CDCl3) δ: 8.52 (s, 1H), 8.39 (d, J=3.0 Hz, 1H), 8.10 (s, 1H), 7.71 (d, J=3.0 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 4.24 (t, J=6.1 Hz, 2H), 4.19 (s, 2H), 3.72 (s, 3H), 3.57 (d, J=5.0 Hz, 2H), 2.99 (s, 1H), 2.00-1.85 (m, 2H). LCMS MH+ 487 and TR=2.436 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH3:11][NH2:12].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:12][CH3:11])[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(C#N)cc1Cl
Temperature: 65 °C
Yield: 95 %

Procedure:
A mixture of 3-chloro-4-fluorobenzonitrile (5.2 g, 33 mmol), THF (55 mL), and 40% methylamine in water (25 mL, 290 mmol) in a sealed tube was heated to 65° C. for 1.5 hours, cooled to room temperature. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The resulting solid was dried for about 16 hours under high vacuum in the presence of P2O5 to provide 6.3 g (95%) of the desired product. MS (DCI/NH3) m/z 184, 186 (M+H+NH3)+; 1H NMR (DMSO-d6) δ 7.72 (d, 1H), 7.55 (dd, 1H), 6.70 (d, 1H), 6.52 (br q, 1H), 2.80 (d, 3H).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:5]2.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(#N)C.O>[OH:1][C@H:2]1[C@H:6]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](Oc2ccccc2)C1

Procedure:
21.9 g (0.1 mol) of 3,4-epoxy-1-carbobenzyloxypyrrolidine [S. Oida et al., Chem. Pharm. Bull., 18 (12), 2478 (1970)] are dissolved, together with 18.8 g (0.2 mol) of phenol and 100 ml of 2 N sodium hydroxide solution (0.2 mol) in 300 ml of acetonitrile. The reaction mixture is heated under reflux for 5 hours and after cooling is diluted with 600 ml of water and extracted by shaking with methylene chloride. The organic phase is washed with 2 N sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum and trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-pyrrolidine is obtained in the form of a pale yellow oil.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH2:6]([S:8][CH:9]([CH2:14][CH3:15])[CH2:10][N+:11]([O-:13])=[O:12])[CH3:7].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:6]([S:8][C:9]([CH2:14][CH3:15])=[CH:10][N+:11]([O-:13])=[O:12])[CH3:7]
Reactant: CCSC(CC)C[N+](=O)[O-]
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSC(=C[N+](=O)[O-])CC
Reaction time: 0.25 h
Yield: 13 %

Procedure:
2-Ethylthio-1-nitrobutene was prepared by adding a solution of sulfuryl chloride (20.16 g., 0.149 mol) in methylene chloride (30 ml.) to a stirred solution of 2-ethylthio-1-nitrobutane (23.02 g., 0.141 mol) in methylene chloride (100 ml.) at 0° C. The resulting solution was stirred for 15 minutes after addition was complete, and the volatile components were removed under reduced pressure. The residue was dissolved in methylene chloride (100 ml.) and a solution of triethylamine (14.27 g., 0.141 mol) in methylene chloride (30 ml.) was added at 0C. Once addition was complete, the solution was stirred for 15 minutes, and then was poured into dilute aqueous hydrochloric acid solution (400 ml.). The organics were separated and washed with deionized water (2×75 ml.), dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography(10:1 hexanes/ethyl acetate) yielded the product as a yellow oil, 2.85 g., 13% yield. 1H-NMR (CDCl3): δ 1.26, m, 3H, --CH3 ; 1.36, m, 3H, --CH3 ; 2.55, q, 2H, --CH2 --; 2.92, q, 2H, SCH2 --; 7.2, s, 1H, olefinic H.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[CH:3]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,3′]bipyridinyl (example E.24) (0.15 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.092 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.085 g, 54%). MS (ISP) 407.2 [(M+H)+]; mp 161-177° C.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7].CN(C)C=O.N1C=CN=C1.Cl[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>O>[CH2:21]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[O:1][CH2:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7])[CH3:22]
Reactant: CCCCC(=O)CO
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)CO[Si](CC)(CC)CC

Procedure:
To a solution of the crude 1-hydroxy-hexan-2-one (prepared in Example 1) in 80 ml. of dimethylformamide at 0° C. is added with stirring, 40.8 g. of imidazole and 45.21 g. of chlorotriethylsilane. The mixture is stirred at 0° C. for 5 minutes and then at room temperature overnight, then poured into cold water and extracted with petroleum ether. The petroleum ether solution is washed with water, then saturated sodium bicarbonate solution and then dried over magnesium sulfate. The solvent is removed and the residue is distilled. The fraction boiling at 95°-103° C. (0.7 mm.) is collected giving the desired product as a cloudy colorless liquid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[N:17]4[CH:18]=[C:19]([CH2:21][OH:22])[N:20]=[C:16]4[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[H-].[Na+].Cl[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.O>CN(C=O)C>[NH:1]1[C:5]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[N:17]4[CH:18]=[C:19]([CH2:21][O:22][C:32]5[CH:41]=[CH:40][C:39]6[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=6)[N:33]=5)[N:20]=[C:16]4[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCc1cn2c(-c3ccc(-c4nnn[nH]4)nc3)cnc(N3CCOCC3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2nc(OCc3cn4c(-c5ccc(-c6nnn[nH]6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a solution of compound 1h (187 mg, 0.510 mmol) in DMF (2 mL) was added sodium hydride (49.0 mg, 2.04 mmol) in portions at 0° C. The mixture was stirred for 15 min before the addition of 2-chloroquinoline (125 mg, 0.765 mmol). The reaction mixture was stirred at 70° C. overnight. Water was added, and the resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with EtOAc/petroleum ether (1:3 v/v) to obtain the title compound 97 as a yellow solid (27.6 mg, 11% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.23-8.28 (m, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.23-8.15 (m, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.68 (t, J=7.2 Hz, 1H), 7.63-7.55 (m, 1H), 7.44 (t, J=7.2 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 7.03-7.00 (m, 1H), 5.59 (s, 2H), 4.35-4.20 (m, 4H), 3.85-3.69 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H22N10O2: 507.2 (M+H). Found 507.2.