Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[CH:7]([CH3:8])[O:6][CH2:5][S:4]1)[OH:2].[CH3:9][N:10]=[C:11]=[O:12].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C(OCC)C>[CH3:9][NH:10][C:11]([O:2][N:1]=[C:3]1[CH:7]([CH3:8])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CC1OCSC1=NO
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Product: CNC(=O)ON=C1SCOC1C

Procedure:
A quantity of 4.3 grams of 4-oximino-5-methyl-1,3-oxathiolane was caused to react with 3.5 ml of methylisocyanate in the presence of dibutyltin diacetate in ethyl ether and worked up as described in Example I to give 6 grams of crude 4-(methylcarbamoyloximino)-5-methyl-1,3-oxathiolane. Recrystallization from isopropyl ether/ethyl acetate afforded pure syn isomer, mp 70.0°-71.5°; structure confirmed by spectral analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4][C:3]1=2.[Br:19]Br>>[Br:19][C:7]1[C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:18])([CH3:1])[C:3]=2[CH:4]=[C:5]([C:15]([OH:17])=[O:16])[C:6]=1[OH:14]
Reactant: BrBr
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)c(O)cc21
Product: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br

Procedure:
3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound L, 155 mg, 0.62 mmol) was dissolved in 1 ml of HOAC. To this solution was added Br2 (0.033 ml, 0.62 mmol). The reaction mixture was left at room temperature for over night. A stream of air was passed through the reaction mixture to remove the unreacted Br2. The remaining solid was dissolved in small amount of THF and purified by column chromatography (ethyl acetate/hexane 1/1) to yield the desired product as a cream colored solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][C:5](C(O)=O)=[C:4]([OH:13])[CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:9][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1cc(C(=O)O)c(O)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Product: N#Cc1ccc(O)cc1N
Temperature: 160 °C
Yield: 76 %

Procedure:
4-Amino-5-cyano-2-hydroxybenzoic acid (2.1 g, 11.79 mmol) is added to a quinoline solution already heated to 160° C. (12 ml) and the reaction solution is stirred at 180° C. for a further hour. After cooling, it is diluted with about 50 ml of a 1N sodium hydroxide solution. The mixture is extracted with dichloromethane. Subsequently, the aqueous phase is adjusted to pH 6.5 with hydrochloric acid and extracted with ethyl acetate and methanol (as a solubilizer). The combined organic phases are dried over sodium sulphate. The desired product is obtained after concentrating the solvents in 76% yield (1.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[NH:26][CH:25]=[N:24][CH:23]=1>>[NH:24]1[C:23]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:22][N:26]=[CH:25]1
Reactant: Ic1cnc[nH]1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cnc[nH]2)c1)c1ccccc1
Yield: 46 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 5-iodo-1H-imidazole were reacted to give the title compound as a white foam (24 mg, 46%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]=2[CH:11]=[C:12]([Cl:14])[CH:13]=1)=O.CC(C[AlH]CC(C)C)C>O1CCCC1>[C:18]([O:17][C:15]([N:9]1[C:10]2[C:6](=[C:5]([CH2:3][OH:2])[CH:13]=[C:12]([Cl:14])[CH:11]=2)[CH:7]=[CH:8]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1cc(Cl)cc2c1ccn2C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2c(CO)cc(Cl)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-indole-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester 13.2 g (42 mmol) is dissolved in 200 mL of dry tetrahydrofuran and cooled to −78° C. The reaction is equipped with a dropping funnel and the reaction purged with nitrogen. DIBAL-H (85 mL, 1.5 M/L 128 mmol) is added via a syringe to the dropping funnel and the reagent added over the course of 10 minutes. The reaction is stirred for 30 minutes then tested via LC/MS for completion. An additional two equivalents of DIBAL-H is added to the reaction via syringe and the reaction stirred for an additional hour. After 1 hour, the reaction is quenched by the slow addition of 500 mL of saturated Rochelle's salt, and slowly warmed to room temperature with stirring overnight. The resulting biphasic mixture is separated and the water layer extracted with DCM. The combined organic layers were dried (MgSO4) filtered and evaporated in vacuo to give the title compound that is purified on silica gel with hexanes ethyl acetate as the eluent (9.5 g 34 mmol, 80%). LCMS (ESMS): m/z 282.9 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:10]([NH2:18])[C:9]=3[N:19]=[C:6]2[CH2:5][O:4][CH2:3]1.C(Cl)(Cl)Cl>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[N:11]=[C:10]([NH2:18])[C:9]=3[N:19]=[C:6]2[CH2:5][O:4][CH2:3]1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1COCc2nc3c(N)nc4c(c3n21)CCCC4
Reaction time: 48 h
Yield: 49.6 %

Procedure:
(11S)-11-Methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (1.13 g, 4.45 mmol) was dissolved in 20 mL of trifluoroacetic acid and the solution was placed in a pressure bottle. Platinum oxide (1.34 g) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 2 days, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1,2-dichloroethane and the combined filtrates were concentrated under reduced pressure to give a peach colored oil. The oil was partitioned between dilute NH4OH solution and CH2Cl2. The layers were separated and the organic portion was washed successively with dilute NH4OH solution and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a white foam. Chromatography (SiO2, 10-30% CMA/CHCl3) gave (11S)-11-methyl-2,3,4,8,10,11-hexahydro-1H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (0.57 g) as a white solid, mp 209-211° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][CH2:17][CH3:18])[C:7](=[CH:14][NH2:15])[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:19]N1C(=O)CCC1=O>N1C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:16][CH2:17][CH3:18])[C:7](=[CH:14][NH2:15])[C:8]2[CH:13]=[C:12]([Cl:19])[S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCC1=Nc2sccc2C(=CN)N1CCC
Solvent: c1ccncc1
Product: CCCCC1=Nc2sc(Cl)cc2C(=CN)N1CCC
Temperature: 70 °C

Procedure:
In a sulfonation flask, 0.92 g (3.5 mmol) (2-butyl-3-propyl-3H-thieno [2,3-d] pyrimidine-4-ylidene)methylamine are dissolved in 10 ml of absolute pyridine and heated up to 70° C. Then 0.71 g (5.3 mmol) N-chlorosuccinimide are added and the resulting mixture is heated for 1 h at 70° C. After completion of the reaction, pyridine is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed several times with water and after drying of the organic phase with Na2SO4, the solvent is removed in vacuum. The raw material is purified by column chromatography over silica gel (eluant: hexane/THF 2:1). Yield: 0.95 g of (2-butyl-6-chloro-3-propyl-3H-thieno [2,3-d]pyrimidin-4-ylidene) methylamine in the form of a brown oil (1H-NMR-data see table 5).
Reaction SMILES: ON1C=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](C)[CH2:3]1.[H-].[Na+].CI.[CH3:16][N:17]([CH:19]=[O:20])[CH3:18]>>[CH3:16][N:17]1[CH:18]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:3])[C:19]1=[O:20]
Reactant: CC1=CC([N+](=O)[O-])=CN(O)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cc1cc([N+](=O)[O-])cn(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1 g (6.49 mmol) 1-hydroxy-3-methyl-5-nitropyridine, 0.197 g (7.8 mmol) NaH and 0.61 ml (9.73 mmol) MeI in 20 ml DMF is stirred at room temperature for 20 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound as off-white crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:21][CH3:22])([CH2:18][O:19][CH3:20])[CH2:13]1.[CH2:23](Br)[CH:24]=C>>[CH2:20]([O:19][CH2:18][C:14]1([CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)[CH2:13]1)[CH:23]=[CH2:24]
Reactant: CCC1(COC)CCCN(CC2COc3ccccc3O2)C1
Reactant: C=CCBr
Product: C=CCOCC1(CC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
The procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-3-methoxymethylpiperidine was repeated except that allyl bromide was used instead of methyl iodide.
Reaction SMILES: C([N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH2:14]Br)[NH:6][C:5]1=[O:16])(=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(O)C.O.C(O)C>[ClH:17].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:25][CH2:26][N:27]([CH2:14][C:7]3[NH:6][C:5](=[O:16])[NH:4][C:8]=3[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CCOC(=O)c1c(CBr)[nH]c(=O)n1C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1[nH]c(=O)[nH]c1CN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4.1 g (14.2 mmole) of ethyl 3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate, 3.0 g (14.2 mmole) of 4-(4-chlorophenyl)-4-hydroxypiperidine, 2.0 g (14.2 mmole) of potassium carbonate and 75 ml of ethanol is stirred under argon for 16 hours at 25° C. Water (100 ml) is added and the precipitate which forms is collected and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added. The resulting solid is separated and recrystallized twice from a mixture of 2-propanol and water to give ethyl 5-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate hydrochloride.
Reaction SMILES: [CH3:1][C:2]([CH3:40])([CH3:39])[C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:15][CH:14]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[C:35]([CH3:37])[N:36]=[C:6]12.Cl.[NH2:42][O:43][CH3:44].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:44][O:43]/[N:42]=[C:3](/[C:2]([CH3:39])([CH3:1])[CH3:40])\[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:17][CH:18]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[C:35]([CH3:37])[N:36]=[C:6]12
Reactant: CON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(C)(C)C)c2nc(C)nn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N\OC)C(C)(C)C)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
A mixture of 4-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.3 g), (aminooxy)methane hydrochloride (0.93 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.16 g, 49%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:30].Cl>CCOC(C)=O.C(OCC)C.CC(=O)CC>[ClH:25].[F:37][C:34]1[CH:33]=[CH:32][C:31]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:15]2[CH2:16][CH:13]([CH2:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:14]2)=[CH:36][CH:35]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C(CCCN1CC(CS(=O)(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Yield: 6.6 %

Procedure:
A stirred mixture of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (150 mg, 0.56 mmol), 2-butanone (5 mL), potassium carbonate (0.25 g, 1.81 mmol), sodium iodide (20 mg, 0.13 mmol) and 4-chloro-1-(4-fluorophenyl)butan-1-one (115 μL, 0.68 mmol) was heated at reflux for 5 h under an inert atmosphere. The cooled reaction mixture was partitioned between EtOAc and water. The EtOAc extracts were washed with water and saturated brine then dried (MgSO4), filtered and concentrated in vacuo. The resultant material was purified by column chromatography on silica eluted with a gradient of 0–15% MeOH-EtOAc to give the free base. This was dissolved in EtOAc and treated with 1M HCl in diethyl ether. The solvents was removed in vacuo to give 1-(4-fluorophenyl)-4-(3-{[(4-fluorophenyl)sulfonyl]methyl}azetidin-1-yl)butan-1-one hydrochloride as a white solid (16 mg). 1H NMR (400 MHz, CD3OD) δ 1.90–1.99 (2H, m), 3.17 (2H, t, J=6.6 Hz), 3.25–3.35 (3H, m), 3.68 (2H, d, J=7.3 Hz), 4.0–4.2 (2H, br s), 4.2–4.4 (2H, br s), 7.20–7.27 (2H, m), 7.39–7.46 (2H, m), 7.98–8.04 (2H, m), 8.05–8.10 (2H, m). m/z (ES+) 394 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:23]([OH:25])=O)=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[S:11][C:5]=2[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]1=[O:30].C(Cl)(=O)[C:32]([Cl:34])=O>ClCCl.CN(C)C=O>[Cl:34][CH2:32][C:23]([C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:21])([F:22])[F:20])=[O:25]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3ccccc3C(F)(F)F)sc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)CCl)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid, (prepared by the method of Example 8a) (3.665 g) was suspended in dichloromethane (70 ml) containing dimethyl formamide (1 drop) and treated with oxalyl chloride (1.47 ml). 1 hr after gas evolution ceased the reaction was concentrated in vacuo and stored under high vacuum for 1 h. The residue was redissolved in dichloromethane (50 ml) and treated with triethylamine (1 ml). To this solution was added trimethylsilyldiazomethane (7 mls of 2M solution in tetrahydrofuran) and the reaction was stirred at room temperature under an atmosphere of nitrogen for 4 hrs before HCl (8 ml, 4M in dioxane) was added. The reaction was stirred for 18 hrs before being concentrated in vacuo and the residue was purified by chromatography eluting with 2:1 isohexane:diethyl ether. The product was recrystallised from ethyl acetate and isohexane to yield the subtitle compound as white needles(4.616 g)
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Br:9][C:10]1[CH:11]=[C:12]([C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:16](=[O:24])/[C:17](/[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:3]/[N:4]([CH3:5])[CH3:6])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cc1ccncc1)c1cccc(Br)c1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CN(C)/C=C(/C(=O)c1cccc(Br)c1)c1ccncc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
Dimethylformamide dimethylacetal (15 mL) were added to a solution of 7.2 g (0.026 ol) of 1-(3-bromophenyl)-2-pyridin-4-ylethanone in 15 ml of dry tetrahydrofuran. After stirring at 65° C. for 6 hours, the solvent was removed under reduced pressure. 8 g (93% yield) of the title compound as an oil were obtained and employed in the next step without any further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][N:17]1[C:22]([NH:23][CH2:24][CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][C:20](=[O:37])[N:19]([CH3:38])[C:18]1=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:16][N:17]1[C:22]([NH:23][CH2:24][CH2:25][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[CH:21][C:20](=[O:37])[N:19]([CH3:38])[C:18]1=[O:39]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCNc2cc(=O)n(C)c(=O)n2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)c1ccc(N2CCN(CCNc3cc(=O)n(C)c(=O)n3C)CC2)cc1
Temperature: 80 °C
Yield: 41.7 %

Procedure:
A mixture of 1.6 g of 1-(4-acetylphenyl)piperazine and 1.1 g of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)-ethylamino]-2,4(1H,3H)-pyrimidinedione was heated at 80° C. for 6 hours, and after standing for cooling, the reaction solution was poured into a 5% aqueous sodium carbonate solution, stirred and then extracted with chloroform. The chloroform solution was washed with water and then concentrated, and the resultant residue was purified through a silica gel column chromatograph (chloroform/methanol=50/1 in volume ratio), thereby obtaining 0.5 g of 1,3-dimethyl-6-[2-(4-[4-acetylphenyl]piperazin-1-yl)ethylamino]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)([CH2:17][CH2:18][CH:19]=[CH2:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C(OCC)C>[C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:26][C:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[O:29]1)([CH2:17][CH2:18][CH:19]=[CH2:20])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
While under an atmosphere of argon, a solution of tert-butyl 2-(tert-butoxycarbonylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate (1.35 g, 2.89 mmol) in freshly distilled (THF 5 mL) was cooled to 0° C. and treated with sodium bis(trimethylsilyl)amide (6 mL, 1.0 M in THF) under argon. After stirring for 10 min, iodomethane (2.04 g, 14.4 mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. After being complete by TLC, the reaction mixture was cooled to 0° C., diluted with ethyl ether and washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 8 CV) gave tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate as a colorless oil (1.27 g, 91%). Rf 0.35 (20% ethyl acetate in heptane). ESI MS found for C26H48BNO6 m/z [482.3 (M+1)].
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[C:25](Cl)=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=2)[CH2:9]1
Reactant: CCOC(=O)c1cnc(N[C@@H]2CCCN(Cc3ccccc3)C2)c(Cl)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1ccc(N[C@@H]2CCCNC2)nc1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of ethyl 6-{[(3R)-1-benzyl-3-piperidinyl]amino}-5-chloronicotinate (6.75 g, 18.1 mmol) in ethanol (200 mL) were added ammonium formate (6.83 g, 108 mmol) and 10% Pd/C (20% w/w, 1.2 g) at ambient temperature and the mixture was heated to reflux with stirring for 8 hrs. After cooling, the catalyst in the reaction mixture was removed by filtration. The solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (NH, CHCl3 only-CHCl3:MeOH/50:1˜25:1) to give ethyl 6-[(3R)-3-piperidinylamino]nicotinate (4.5 g, 100%) as an oil.
Reaction SMILES: O=[C:2]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1>C1COCC1>[N:18]1([CH2:2][CH2:3][O:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCCCC2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCCN2CCCCC2)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 101.7 %

Procedure:
Tert-butyl 4-(2-oxo-2-(piperidin-1-yl)ethoxy)piperidine-1-carboxylate (111) (7.5 g, 22.98 mmol) was dissolved in dry THF (100 mL), to this was added borane-methyl sulfide complex (17.23 mL, 34.46 mmol) and the reaction was stirred at 40° C. for 3 hours then at ambient temperature overnight. The gummy mixture was evaporated and was quenched with 2.0 N sodium carbonate (50 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(2-(piperidin-1-yl)ethoxy)piperidine-1-carboxylate (7.3 g, 95% yield) as a colourless liquid and used without further purification.