Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O.O>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (1.56 g, 6.2 mmol) is treated with 248 mg (6.2 mmol) of 60% NaH/mineral oil in dimethylformamide and the mixture stirred for 0.67 hours. 0.6 mL(6.2 mmol) of methyl bromoacetate is added and the mixture stirred for 17 hours. The reaction mixture is diluted with water and then extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried, and concentrated at reduced pressure. The product is purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1.37 g (69% yield) of [[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, 89-92° C.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].O[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1.O>[C:18]([C:17]1[CH:20]=[CH:21][C:22]([O:1][CH:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])=[CH:15][CH:16]=1)#[N:19]
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: N#Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccc(C#N)cc2)cc1
Yield: 43.8 %

Procedure:
Methyl 4-(1-hydroxyethyl)benzoate (540 mg, 3 mmol), 3-hydroxybenzonitrile (360 mg, 3 mmol), triphenylphosphine (1.04 mg, 4 mmol), azodicarboxylic acid diisopropyl ester (800 mg, 4 mmol) in tetrahydrofuran (130 mL) were stirred at 20° C. for 12 hours. Water was added and the mixture was extracted with ethyl acetate (150 mL×3), the combined organic phase was dried by sodium sulfate, then filtered. The filtrate was evaporated in vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give methyl 4-(1-(4-cyanophenoxy)ethyl)benzoate (370 mg, 45%) as colorless oil. LRMS (M+H+) m/z: calcd 281.11. found 281.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:28])[CH:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:25]1[CH2:26][CH2:27][CH:22]([CH:20]([N:19]([CH3:18])[CH3:28])[CH3:21])[CH2:23][CH2:24]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C1CCNCC1)N(C)C
Product: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1)N(C)C
Yield: 63.6 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (300 mg, 0.965 mmol) was reacted with N,N-dimethyl-1-(piperidin-4-yl)ethanamine (332 mg, 1.45 mmol) to afford the desired product (264 mg, 63%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 8.78 (s, 1H), 8.32 (s, 1H), 7.95-7.80 (m, 2H), 3.57-3.39 (m, 2H), 3.21 3.05 (m, 2H), 2.59-2.42 (m, 2H), 2.31 (s, 6H), 2.11-1.97 (m, 1H), 1.89 (d, J=12.4 Hz, 1H), 1.80-1.67 (m, 1H), 1.68-1.49 (m, 2H), 1.36-1.16 (m, 4H), 1.06 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:35]=[CH:34][N:33]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2ccnc(Cl)c2)CC1
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16](O)[CH3:17])=[CH:12][C:11]=2[C:19]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3C2CCCCO2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:47][S:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])=[O:49].[OH-].[Na+].Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([C:19]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][NH:23]4)=[CH:12][C:13]([CH:16]([N:54]3[CH2:55][CH2:56][N:51]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:52][CH2:53]3)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(C)O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2ncc(C(C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
Separately, 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethanol (231 mg, 0.501 mmol) was dissolved in DCM (10 mL) and triethylamine (Aldrich 99.5%, 0.28 ml, 2.0 mmol) was added. The reaction was cooled in an ice water bath, and methanesulfonyl chloride (0.15 mL, 1.9 mmol) was added. The reaction was stirred at 0° C. for 15 min, and then 1-methanesulfonylpiperazine (474.4 mg, 2.89 mmol) was added, causing precipitation. The reaction was warmed to room temperature and stirring was continued. After 2 h, the reaction was diluted with MeOH (10 mL) and 5 N HCl (2.0 mL) was added. Stirring was continued at room temperature. After another hour, this reaction was combined with the other reaction, treated with 5 N NaOH and 5 N HCl to adjust the pH to around 6, and allowed to stand at room temperature over the weekend. The resultant suspension was filtered, and the solid was washed with DCM and MeOH. The filtrate was concentrated and treated with water and filtered. The solid was washed with water. The filtrate was discarded. The solid was collected and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min.) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-amine (81.0 mg, 24% yield) as a TFA salt. 1H NMR (d6-DMSO, 400 MHz) δ 12.61 (br s, 1H), 9.78 (s, 1H), 8.67 (s, 1H), 8.54 (d, J=2.54 Hz, 1H), 8.40 (d, J=2.35 Hz, 1H), 8.16 (dd, J=9.0 Hz, 2.74 Hz, 1H), 6.87 (d, J=8.80 Hz, 1H), 4.69 (br, s, 1H), 3.85 (s, 3H), 3.45-3.00 (m, 6H), 2.98 (s, 3H), 2.86 (s, 3H), 1.76 (d, J=7.04 Hz, 3H). m/z (ESI, pos. ion) 524 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][CH:11]1[CH2:13][NH:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH2:13][CH:11]2[CH3:10])=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CC1CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CN1Cc1ccc(Cl)nc1
Temperature: 60 °C
Yield: 16.7 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (352 mg, 2.17 mmole) in 4 mL of dry acetonitrile is 0.4 mL (4.34 mmol) of 2-methyl-aziridine followed by 300 mg (2.17 mmol) of potassium carbonate. The reaction is heated at 60° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 66 mg (17% yield) of 2-Chloro-5-(2-methyl-aziridin-1-ylmethyl)-pyridine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.15 (d, 3H, J=5.4 Hz), 1.34 (d, 1H, J=6.6 Hz), 1.47–1.55 (m, 2H), 3.35 (abq, 2H, J=5.8 Hz), 7.25 (d, 1H, J=6.3 Hz), 7.65 (dd, 1H, J=8.3 and 2.5 hz), 8.27 (d, 1H, J=1.7 Hz); MS 183.2 (M+H).
Reaction SMILES: S(Cl)(Cl)=O.O[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][NH:8][C:9]1[NH:10][CH2:11][CH2:12][N:13]=1>>[C:14]1([CH:6]2[N:13]3[CH2:12][CH2:11][NH:10][C:9]3=[N:8][CH2:7]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC(CNC1=NCCN1)c1ccccc1
Solvent: O=S(Cl)Cl
Product: c1ccc(C2CN=C3NCCN32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 80 parts thionylchloride (previously cooled to 0°C.) are added 10.15 parts 2-(β -hydroxy-phenethyl-amino)-2-imidazoline. After the addition is complete, the whole is stirred for 30 minutes at room temperature and further stirred and refluxed for 15 minutes. The solvent is evaporated. The residue is dissolved in 40 parts toluene and evaporated again. This treatment is repeated by using 40 parts methanol. The residue is then dissolved in 40 parts 2-propanol. To this solution is added a solution of 1.15 parts sodium metal in 40 parts 2-propanol. The whole is stirred and refluxed for one hour. The solvent is evaporated. The residue is dissolved in 150parts water. The solution is filtered. The filtrate is alkalized with ammonium hydroxide and extracted three times with 40 parts ether and three times with 75 parts chloroform. The combined extracts are dried over potassium carbonate and evaporated. The solid residue is recrystallized from a mixture of 16 parts acetone and 16 parts 4 -methyl-2-pentanone, yielding 2,3,5,6-tetrahydro-5-phenyl-1H-imidazo[1,2-a]imidazole; m.p. 167°-169.5°C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].O.[NH2:13][NH2:14].O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:13][NH2:14])=[O:6]
Reactant: NN
Reactant: COC(=O)c1cccc(I)c1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(I)c1
Temperature: 25 °C

Procedure:
To Methyl 3-iodobenzoate (25.0 g, 95.41 mmol) in ethanol (120.0 ml) was added hydrazine hydrate (50.0 ml). The reaction mixture was reflux for 18 hours. Heating was stopped and then water (300.0 ml) was added. After cooling down to room temperature, white solid was appeared. The white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white pure product was obtained in 23.0 g (92.0%). 1H NMR (400 MHz, DMSO-d6, δ): 9.85 (s, br, 1H, NH), 8.14 (t, J=1.6 Hz, 1H), 7.85 (m, 1H), 7.82 (m, 1H), 7.25 (t, J=8.0 Hz, 1H), 4.50 (s, 2H, NH2). 13C NMR (100 MHz, CDCl3) δ: 168.54, 155.38, 129.54, 126.72, 125.57, 34.90, 31.07.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH:33]([CH3:35])[CH3:34])[NH:25][CH:24]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:23]=2)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH:33]([CH3:34])[CH3:35])[N:25]=[C:24]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:23]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1=C(C(C)C)NC(c2ccccc2)N=C1c1ccc(F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nc(-c2ccccc2)nc1C(C)C
Temperature: 50 °C

Procedure:
2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) (7.69 gm, 34 mmol) was added to a solution of 4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenyl-5-ethoxycarbonyl-1,2-dihydropyrimidine obtained in step (i) above (10.200 gm, 28 mmol) in toluene (200 ml). The red solution was then heated at 50° C. for 3 hours. The solution was cooled to room temperature, then passed through a silica gel plug which was washed with 10% EtOAc in hexane. The filtrate was concentrated to give an amber oil. The oil was purified by flash chromatography on Merck silica gel in 15% EtOAc in hexane. Fractions containing the desired product were pooled and concentrated to give a clear oil which solidified to afford the title compound as a white, crystalline solid (8.800 gm, 87%) (mp 97°-99° C.).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: NO
Reactant: Cc1cnc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: Cc1cnc(NC(=O)[C@H](CC2CCC(=NO)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 244.4 %

Procedure:
A solution of hydroxylamine hydrochloride (17.0 mg, 0.24 mmol) in methanol (0.5 mL) and 2,6-lutidine (0.5 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 62, 34 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 65/35 hexanes/ethyl acetate to ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-N-(5-methyl-pyrazin-2-yl)-propionamide (75 mg, 100%) was a white foam: [α]23589=−30.0° (c=0.32 chloroform); EI-HRMS m/e calcd for C21H25ClN4O4S (M+H)+ 465.1358, found 465.1365.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[S:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](O)[C:10]=2[CH:9]=1)[CH3:7]>O1CCOCC1>[Cl:3][C:15]1[C:10]2[CH:9]=[C:8]([CH2:6][CH3:7])[S:17][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCc1cc2c(O)ncnc2s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CCc1cc2c(Cl)ncnc2s1
Temperature: 25 °C
Yield: 42 %

Procedure:
Phosphoryl trichloride (2.3 mL, 3.00 equiv) was added to a solution of 6-ethylthieno[2,3-d]pyrimidin-4-ol (1.5 g, 8.32 mmol, 1.00 equiv) in dioxane (15 mL) dropwise with stirring at room temperature. The resulting solution was stirred overnight at 110° C. in an oil bath. The resulting solution was cooled and quenched by the addition of 100 mL of water and ice mixture. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10) to yield 700 mg (42%) of 4-chloro-6-ethylthieno[2,3-d]pyrimidine as a yellow solid. MS: m/z 199 (M+H)+.
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH:7]=[O:8])=O.C(=O)(O)[O-].[Na+].O1CCCC1>O>[OH:3][CH2:4][CH2:5][N:6]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH:7]=[O:8]
Reactant: O=COCCN(C=O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=CN(CCO)c1cccnc1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A mixture of 3-[N-(2-formyloxyethyl)formamido]-pyridine (7.01 g) and sodium bicarbonate (3.04 g) in a mixed solution of tetrahydrofuran (60 ml) and water (110 ml) was stirred for 8 hours at 45° to 46° C. The reaction mixture was extracted with a mixed solvent of chloroform and ethanol (1:1) and the extract was evaporated. The residue was dissolved in a mixed solvent of chloroform and ethanol (4:1) and subjected to column chromatography on silica gel (150 g). The elution was carried out with the same solvent and the fractions containing an object compound were collected and evaporated to give 3-[N-(2-hydroxyethyl)formamido]pyridine (4.60 g) as an oil.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.[SH:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24].O>CN(C)C=O.C(OCC)(=O)C>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([CH2:9][S:20][C:21]2[C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=[CH:28][N:29]=2)=[CH:11][CH:12]=1
Reactant: ClCc1ccnc2ccccc12
Reactant: O=C(O)c1cccnc1S
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccnc1SCc1ccnc2ccccc12
Yield: 59 %

Procedure:
Triethylamine (33 mL, 240 mmol) was added to a suspension of a mixture containing 4-(chloromethyl) quinoline (Reference Compound No. 5-1, 17.0 g) and 2-mercaptonicotinic acid (13 g, 86 mmol) in anhydrous N,N-dimethylformamide (200 mL) at room temperature, and the mixture was stirred for 48 hours. Water (700 mL) and ethyl acetate (400 mL) were added thereto. After the mixture was separated into the organic layer and the aqueous layer, 1N hydrochloric acid (50 mL) was added to the aqueous layer. The precipitated solid was filtered off and dried under reduced pressure at 60° C. to give 15 g of the title Reference Compound as a yellow solid (Yield: 59%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:12]
Reactant: CCOC(=O)CC1CCCCN1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCN1CCCCC1CC(=O)OCC
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A stirred solution of ethyl piperidin-2-ylacetate (8.0 g, 0.047 mole) and ethyl 4-bromobutyrate (6.7 ml, 0.047 mole) in acetone (100 ml) was treated with potassium carbonate (13 g, 0.094 mole) and heated under reflux for 32 h. A further 1.5 ml of ethyl 4-bromobutyrate and 3 g of potassium carbonate was added and reflux continued for 16 h. The mixture was concentrated in vacuo and the residue treated with water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with ether/petrol (60-80) to afford the title compound as a pale yellow oil (11.5 g, 86%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:14]=[C:15](O)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.C1C[N:34]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)C>CN(C=O)C>[CH2:33]([NH:34][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[C:13]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[N:14]=1)[CH3:32]
Reactant: NS(=O)(=O)c1ccc(CNc2nc(O)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(NCc2ccc(S(N)(=O)=O)cc2)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
4-{[6-(4-Fluoro-phenyl)-4-hydroxy-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide (100 mg, 0.23 mmol) and PyBOP (119 mg, 0.23 mmol) were taken up in DMF (2 mL) and DIEA (0.07 mL, 0.46 mmol) was added, followed by ethylamine (2.0M in THF) (0.115 mL, 0.23 mmol) This solution was stirred at room temperature overnight. The DMF was removed in vacuo and the residue diluted with ethyl acetate (2 mL) and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to afford an oily residue. The residue was purified by RP HPLC using a C18 column with a 0-60% gradient of 0.1% TFA-H2O/0.1% TFA-acetonitrile to afford 55 mg (52%) of Example 297. MS (m/z) 453.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH2:30]([O:37][C:38]([NH:40][NH:41][CH3:42])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.O>[CH2:30]([O:37][C:38]([NH:40][N:41]([C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9])[CH3:42])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CNNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC(=O)N(C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
2.1 g of (tert-butoxycarbonyl-methyl-amino)-acetic acid was dissolved in 150 mL of tetrahydrofuran, and 4.64 mL of triethylamine and 1.51 mL of isobutyl chloroformate were added under stirring at ice-cooling. After stirring at room temperature for 10 minutes, N′-methyl-hydrazine carboxylic acid benzyl ester hydrochloride was added and stirred at room temperature for 50 minutes. The reaction solution was added with water, extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, followed by purification by silica gel column chromatography (ethyl acetate:n-hexane=1:1), to afford 3.2 g of N′-[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-N′-methyl-hydrazine carboxylic acid benzyl ester. Subsequently, by conducting catalytic hydrogen reduction in accordance with Production example 365, 1.9 g of the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O>CO.[Pd]>[NH2:15][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]=2[C:2]=1[OH:1]
Reactant: O=[N+]([O-])c1ccc2c(c1O)Cc1ccccc1-2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1O)Cc1ccccc1-2
Yield: 70.5 %

Procedure:
To a solution of 1-hydroxy-2-nitrofluorene(250 mg, 1.23 mmol) in methanol(250 mL) was added 10% Pd/C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/CH2Cl2) gave the desired product(171 mg, 81.2%). 1H NMR (CD3OD): δ 7.60 (d, 1H), 7.47 (d, 1H), 7.28 (t, 1H), 7.18 (m, 2H), 6.82 (d, 1H), 3.76 (s, 2H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: Cc1ccccc1CN
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cc1ccccc1CNC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2-methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as an off-white solid (34.1 mg, 88.6% yield). 1HNMR (500 MHz, CDCl3) δ: 12.38 (1H, s), 7.63 (1H, br s), 7.51–7.45 (1H, m), 7.26–7.16 (4H, m), 7.04 (2H, dd, J=8.54, 7.32 Hz), 4.59 (2H, d, J=5.79 Hz), 3.40 (3H, s), 2.33 (3H, s). HRMS (ESI) calcd for C20H16F2N3O3 (M−H): 384.1160; found: 384.1171.