Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([OH:18])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]2[C:23](=[O:24])[C:22]3[CH2:25][CH2:26][CH2:27][CH2:28][C:21]=3[C:20]2=[O:29])=[C:4]([F:30])[CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C1C=CC=CC=1>[C:38]([O:18][CH:17]1[CH2:16][O:15][CH2:14][CH:13]1[O:12][C:10]([CH2:9][O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:30])=[C:5]([N:19]2[C:20](=[O:29])[C:21]3[CH2:28][CH2:27][CH2:26][CH2:25][C:22]=3[C:23]2=[O:24])[CH:6]=1)=[O:11])(=[O:40])[CH3:39]
Reactant: O=C(COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl)OC1COCC1O
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OC1COCC1OC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
In 15 ml of benzene were dissolved 0.66 g of N-(4-chloro-2-fluoro-5-(4-hydroxytetrahydrofuran-3-yloxycarbonylmethoxy)phenyl)-3,4,5,6tetrahydrophthalimide and 0.20 g of triethylamine, followed by dropwise addition of a solution of 0.14 g of acetyl chloride in benzene. After stirring at room temperature for 4 hours, the reaction mixture was washed with water and subsequently with aqueous saturated sodium chloride solution, and 'dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 0.55 g of a compound described in Table 1 (No.3) (76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([Cl:18])=[O:16])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Solvent: c1ccccc1
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)Cl

Procedure:
A mixture of 4-chloro-α-methoxy-5-nitro-o-toluic acid (3.6 g.) and phosphorus pentachloride (3.0 g.) in 120 ml of benzene is refluxed for thirty minutes. The mixture is then concentrated in vacuo and the residue boiled with 200 ml of hexane and filtered hot. The filtrate is partially concentrated and chilled to give 2.5 g. of white solid with mp 63°-65°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13](C#N)=[CH:12]1.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[N:18]=2)[CH:13]=[CH:12]1
Reactant: Cc1ccc2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Agent: O=S(=O)(O)O
Product: Cc1ccc2ccn(-c3ccc(C(C)C)cc3Br)c2n1

Procedure:
Material from Example 72 was treated with 65% sulfuric acid as described in Example 65 to give the desired product as a viscous oil. TLC on silica gel with 70:30 hexane-ethyl acetate showed Rf=0.57. Mass spec. (m+H)+ =329.0641; calcd., 329.0653 (79Br).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([NH2:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[C:27](O)=[O:28])=[O:20])([CH3:17])([CH3:16])[CH3:15].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)C>[NH2:11][C:9](=[O:10])[C@@H:7]([NH:8][C:27]([C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:28])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
4-Iodo-(L)-phenylalaninamide (2 g), (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (2.4 g) and disopropylethylamine (3 mL) were dissolved in DMF (10 mL) and to the solution was added 2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.3 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether (200 mL) then washed with water (250 mL) and brine (4×250 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Crude product was purified by flash silica chromatography eluting with ethyl acetate to give the sub-title compound (2.88 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)(=[O:24])=[O:23]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][CH:5]=[C:4]([NH:31][CH:28]2[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26][CH2:27]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1ccc(F)c(F)c1C(=O)c1ccc(Cl)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 39) and 1-methanesulfonyl-piperidin-4-ylamine (Step A. Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 441.1407, Calcd for (M+H)+: 441.1403. Ki for cdk4=0.017 μM, cdk1=0.060 μM, cdk2=0.054 and IC50 for HCT116 cell line=2.6 μM.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[CH2:26]([O:28][NH2:29])[CH3:27].C(N(CC)CC)C>CO>[CH2:26]([O:28]/[N:29]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)=[CH:14][N:15]=2)[N:18]=1)\[CH3:23])[CH3:27]
Reactant: CCON
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCO/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone (50 mg, 0.16 mmol) in methanol (10 mL) was added O-ethylhydroxylamine hydrochloride (46 mg, 0.47 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at rt overnight. The solution was concentrated under reduced pressure and the residue was purified by prep-HPLC to afford 30 mg (53%) of the title compound as a white solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.82 (dd, 1H), 8.30 (d, 1H), 7.93 (m, 2H), 7.85 (d, 1H), 7.70 (d, 1H), 7.66 (s, 1H), 7.49 (q, 1H), 4.62 (s, 2H), 4.31 (q, 2H), 2.27 (s, 3H), 1.36 (t, 3H). LCMS (method C): [MH]+=364, tR=4.71 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=[C:9]2[C:17]([OH:19])=[O:18])([O-:3])=[O:2].[CH2:20](O)[CH3:21]>Cl>[CH2:20]([O:18][C:17]([C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)=[O:19])[CH3:21]
Reactant: O=C(O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12

Procedure:
52 parts of 8-nitro-naphthalene-1,4-dicarboxylic acid are dissolved in 700 parts of absolute ethyl alcohol and the solution is boiled under reflux for 12 hours whilst continuously passing in hydrogen chloride gas. The resulting solution is evaporated in vacuo. The 4-ethoxycarbonyl-8-nitro-naphthalene-1-carboxylic acid of the formula ##STR27## which is obtained in this way, melts at 178° to 180°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[CH3:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:30]([C:28]2[S:29][C:25]([CH3:24])=[CH:26][CH:27]=2)=[O:31])[S:3][CH:4]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Product: Cc1ccc(C(=O)Nc2nc(CC(=O)N3CCN(CC(=O)N4CCCC4)CC3)cs2)s1

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with 5-methylthiophene-2-carboxylic acid, using general method D, to give 5-methyl-thiophene-2-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Light yellow solid. MS 462.3 ([M+H]+)
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[C:35]1([CH:34]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCC=Cc1ccccc1
Yield: 44.3 %

Procedure:
This compound was synthesized from 10-carboxydecyltriphenylphosphonium bromide (10.55 g, 20 mmol) and benzaldehyde (2.12 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation (bp 152-155° C./0.03 torr) and crystallization afforded the product (2.43 g, 44%) as white crystals (mp 27-27.5° C.). IR: 3400-2500, 1720, 700 cm-1 ; 1H-NMR: 1.30 (m, 10H), 1.40 (m, 2H), 1.62 (m, 2H), 2.35 (m, 4H), 5.65 (m, 1H), 6.40 (m, 1H), 7.25 (m, 5H), 10.40 (bs, 1H). Anal. Calcd. for C18H26O2 : C, 78.79, H, 9.55%; Found: C, 78.66, H, 9.60%. Z:E=93:7.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([NH2:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[N:12]=2)=[CH:6][CH:5]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH2:26][C:27](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3=[N:12][C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]3[N:17]=[C:27]2[CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][N:22]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c(N)c(Nc2ccc(CCCl)cc2)n1
Reactant: O=C(O)CCc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)c2nc(CCc3nccs3)n(-c3ccc(CCCl)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a mixture of N2-[4-(2-chloroethyl)phenyl]-4,6-dimethyl-2,3-pyridinediamine (step 2, 276 mg, 1.0 mmol) and 3-(1,3-thiazol-2-yl)propanoic acid (157 mg, 1.0 mmol) in dichloromethane (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (WSC) (192 mg, 1.0 mmol) in one portion. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene (20 mL) and heated at 150° C. for 5 h. The reaction mixture was poured into water (50 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (50 mL) and dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 210 mg (53%) of the title compound: MS (EI) m/z 396 (M+); 1H-NMR (CDCl3) δ 7.63 (1H, d, J=3.4 Hz), 7.39 (2H, d, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz), 7.15 (1H, d, J=3.4 Hz), 6.93 (1H, s), 3.78 (2H, t, J=7.4 Hz), 3.69-3.50 (2H, m), 3.39-3.20 (2H, m), 3.15 (2H, t, J=7.4 Hz), 2.66 (3H, s), 2.53 (3H, s).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C@H:5]1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C@H:5]1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N
Temperature: 70 °C
Yield: 99.8 %

Procedure:
To a stirred mixture of Compound 264B (530 mg, 1.50 mmoL) in 6 mL of THF and 1 mL of water was added Ph3P (900 mg, 3.43 mmoL). The reaction mixture was heated at 70° C. for 15 h and cooled to room temperature. This mixture was concentrated in vacuo, diluted with 15 mL of 2N HCl solution, and then washed with CHCl3 (3×20 mL). The aqueous was basified to pH 12 by the addition of 50% NaOH solution, saturated with NaCl, and then extracted with EtOAc (3×25 mL). The combined EtOAc extracts were washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo to give 490 mg (yield: 100%) of Compound 264C. It had an analytical HPLC retention time=1.67 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=328.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([NH:20][CH2:21][CH2:22][NH:23][C:2](=[O:3])[NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)NCCN
Reactant: O=C=Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Solvent: CN(C)C=O
Product: CC(=O)NCCNC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
In a manner similar to Example 13b, 5-[4-(isocyanato)phenyl]-2(1H)-pyrazinone is reacted with 2-acetamidoethylamine (1 g) in dimethylformamide (5 ml) for 17 hours at room temperature to form the title compound, m.p. 238°-44° C.; δ(DMSO-d6) 1.80 (s, 3H, COCH3), 7.94, 8.08 (2s, 2H, pyrazinone H's).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:70]1([C@H:76]([NH2:78])[CH3:77])[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:78][C@@H:76]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH3:77])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: C[C@@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@H](C)c3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [(1R)-1-phenylethyl]amine (12.9 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 45%). LC-MS m/z 625 (M+H)+.
Reaction SMILES: [CH2:1]([NH+:3]1[CH2:8][CH2:7][C:6](O)(O)[C:5]([F:12])([F:11])[CH2:4]1)[CH3:2].[NH2:13][OH:14]>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[N:13][OH:14])[C:5]([F:12])([F:11])[CH2:4]1)[CH3:2]
Reactant: CC[NH+]1CCC(O)(O)C(F)(F)C1
Reactant: NO
Solvent: CCO
Product: CCN1CCC(=NO)C(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A suspension of 1-ethyl-3,3-difluoro-4,4-dihydroxy-piperidinium (10.213 g, 46.93 mmol) in ethanol (80 ml) was charged with aqueous hydroxylamine solution (50% by weight, 3.58 ml, 58.4 mmol) and left to stand overnight. The thick precipitate was dissolved with the addition of ethanol (20 ml) and heating. The solution was then cooled to room temperature before being place over ice. The precipitated solid was then collected by filtration and dried over vacuum to yield 8.27 g 1-ethyl-3,3-difluoro-piperidin-4-one oxime (99%) LCMS (Method F): RT=0.14 min, m+H=179.0 1H NMR (400 MHz, D2O) δ 4.07-3.82 (m, 2H), 3.53 (s, 2H), 3.38 (q, J=7.3 Hz, 2H), 3.13 (s, 2H), 1.38 (t, J=7.3 Hz, 3H).
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[CH:18][C:19]([O:23]C)=[C:20]([O:21]C)[C:15]=4[CH2:14][CH2:13][N:12]([CH3:25])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.B(Br)(Br)Br>ClCCl>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[CH:18][C:19]([OH:23])=[C:20]([OH:21])[C:15]=4[CH2:14][CH2:13][N:12]([CH3:25])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COc1ccc2c(c1OC)CCN(C)CC2c1cccc2ccoc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCc2c(ccc(O)c2O)C(c2cccc3ccoc23)C1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
1.10 g (0.0033 mol) 1 -(benzofuran-7-yl)-6,7-dimethoxy-3-methyl-2,3,4,5-tetrahydro-1-H-3-benzazepine was dissolved in 25 ml dry dichloromethane. The solution was cooled to -60° C. and 0.93 (0.0098 mol) boron tribromide was slowly added. The reaction mixture was stirred at -60° C. for 15 min., allowed to warm up to 0° C. and stirred for 1 h. Evaporation in vacuo left a brown residue, which was redissolved in dichloromethane. The solution was stirred in an ice bath and 5 ml methanol was added dropwise. The solution was again concentrated in vacuo, the residue was dissolved in 6N HCl and refluxed for 30 min. Then pH was adjusted to 8 with 2N NaOH-solution and the product extracted with ethylacetate. The organic layer was washed with water and brine and concentrated in vacuo. 1-(Benzofuran-7-yl)-6,7-dihydroxy-3-methyl-2,3,4,5,-tetrahydro-1H-3-benzazepine was obtained as an offwhite powder.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[OH:14])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[CH:13]([C:11]4[O:12][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:9][N:10]=4)[OH:14])=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (5-benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][CH:17]=[C:18]([C:20](=[O:22])[NH2:21])[N:19]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:20]([C:18]1[N:19]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]2)[S:16][CH:17]=1)(=[O:22])[NH2:21]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2nc(C(N)=O)cs2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NC(=O)c1csc(N2CCC(O)CC2)n1
Yield: 100.5 %

Procedure:
To a solution of 4-t-butyidimethylsilyloxy-1-(4-carbamoyl-1,3-thiazol-2-yl)piperidine (1.226 g, 3.59 mmol) (obtained as described in Reference Example 15(1)) in anhydrous tetrahydrofuran (30 ml) were added acetic acid (1.85 ml) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (32.3 ml, 32.3 mmol) in an ice bath, and the mixture was stirred for 24 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column to afford 1-(4-carbamoyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (0.82 g, yield 100%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[C:8]([NH:15][CH2:16][CH2:17][CH2:18]Br)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[NH:1]=[C:2]1[N:6]([CH2:18][CH2:17][CH2:16][NH:15][C:8](=[O:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:7])[S:3]1
Reactant: Cc1cnc(N)s1
Reactant: CC(C)(C)OC(=O)NCCCBr
Product: Cc1cn(CCCNC(=O)OC(C)(C)C)c(=N)s1
Temperature: 85 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of 2-amino-5-methylthiazole (0.58 g, 5.0 mmol) and 3-(Boc-amino)propyl bromide (1.2 g, 5.0 mmol) was warmed to 85° C. and was allowed to stir for 4 h. The mixture was cooled to ambient temperature and was purified via column chromatography (SiO2, 9:1:0.1 CH2Cl2:methanol:ammonium hydroxide) to give the title compound (0.96 g, 3.5 mmol, 70% yield). MS (DCI/NH3) m/z 272 (M+H)+.
Reaction SMILES: BrC1C=CC(C([O:8][C@@H:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)[C:12]=3[C@H:11]([CH3:31])[CH2:10]2)=O)=CC=1.O.O.[OH-].[Li+]>C1COCC1>[OH:8][C@@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1
Reactant: C[C@@H]1C[C@H](OC(=O)c2ccc(Br)cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
Lithium hydroxide hydrate (0.779 mL, 28.0 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (5.8 g, 11.2 mmol) in THF:H2O (150 mL, 2:1) at 0° C. The mixture was allowed to warm to room temperature and stirred at for 1 hour. The mixture was concentrated in vacuo, taken up into saturated sodium bicarbonate (100 mL) and extracted into EtOAc (2×200 mL). The reaction was dried over Na2SO4 and concentrated in vacuo to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (3.8 g, 11.4 mmol, 100% yield) as a foam. Similarly, tert-butyl 4-((5R,7S)-7-(4-bromobenzoyloxy)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.29 g, 2.49 mmol) was dissolved in THF:H2O (10 mL, 2:1), cooled to 0° C. and then treated with solid lithium hydroxide hydrate. The solution was stirred at ambient temperature for 16 hours. The reaction was quenched with saturated NH4Cl and concentrated in vacuo. The resulting residue was diluted with ethyl acetate and a small amount of water. The layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 (2×), saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The resulting residue was dried under high vacuum to give tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as a foam (0.843 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([OH:20])([C:18]#[CH:19])[CH3:17]>C(#N)C.C(N(CC)CC)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>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:19]#[C:18][C:16]([CH3:17])([OH:20])[CH3:15])=[CH:9][CH:8]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(O)C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 71.1 %

Procedure:
257.1 g of 4-Bromobenzoic acid tert.-butyl ester, 168 g of 2-methyl-3-butyn-2-ol and 15.6 g of (Ph3P)2PdCl2 in 1.5 l of absolute acetonitrile and 480 ml of triethylamine are stirred together at reflux for 6 hours under nitrogen. The product is then concentrated by evaporation and worked up with toluene/H2O to yield 185 g of an oil which slowly crystallises.