Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:9]C1C=CC=CC=1)[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6]>C(O)C.Cl.O>[Cl:1][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6]
Reactant: C#CC(C)(C)C(=CCl)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C#CC(C)(C)C(=O)CCl

Procedure:
275 g (1.25 moles) of 1-chloro-3,3-dimethyl-2-phenoxy-pent-1-en-4-ine in 1.25 liters of ethanol and 620 ml of concentrated hydrochloric acid are heated for 5 hours under reflux. The mixture is diluted with water and repeatedly extracted with n-hexane. After drying the extracts and stripping off the solvent, 176 g of crude product remain. Distillation gives 149.9 (that is to say 83% of theory) of 1-chloro-3,3-dimethyl-pent-4-in-2-one of boiling point 67°-70° C./20 mm Hg.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:2][CH2:3][CH2:4][O:5][CH3:6])[CH:11]=[O:12]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: COCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
Commercially available 1-bromo-3-methoxypropane (24.0 g, 157 mmol) was added to a solution of commercially available 3,4-dihydroxybenzaldehyde (21.7 g, 157 mmol) and sodium carbonate (25.0 g, 236 mmol) in N,N-dimethylformamide (50 mL) under nitrogen atmosphere at room temperature. The reaction liquid was stirred at room temperature for 3 days and 4 hours. 2 M hydrochloric acid, ethyl acetate, and water were added to the reaction liquid at 0° C. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed serially with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under vacuum. The insoluble matters were separated by filtration with dichloromethane and the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=17:3-1:1) to obtain the title compound (17.2 g, 52%).
Reaction SMILES: [Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[CH2:32]([CH:35]1[CH2:40][CH2:39][CH:38]([CH:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)[CH2:37][CH2:36]1)[CH2:33][CH3:34]>CCOCC>[CH2:32]([CH:35]1[CH2:40][CH2:39][CH:38]([CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1)[CH2:33][CH3:34]
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC1CCC(C2CCCCC2)CC1
Reaction time: 1 h
Yield: 56 %

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed (2-(1,3-dioxan)-2-yl)ethyl)triphenylphosphonium bromide (12.3 g, 27 mmols), followed by adding tetrahydrofuran (50 ml), suspending, stirring under ice cooling till the liquid temperature reached 10° C. The reaction mixture is added potassium t-butoxide (3.0 g, 27 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (10 ml) solution of 4-(4-propylcyclohexyl)cyclohexanone (15.6 g, 25 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (50 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure, isolating and purifying the resulting pale brown oily substance by means of silica gel column chromatography and recrystallizing from ethanol, to obtain 1-(2-(1,3-dioxin)-2-yl)ethylidene)-4-(4-propylcyclohexyl)cyclohexane (4.5 g, 14 mmols).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C@@H:14]([CH3:15])[CH2:13][CH2:12][CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:10]2(=[O:23])=[O:22])=[C:4]([F:24])[CH:3]=1.Cl.[N:26]1[N:27]=[CH:28][N:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=1.CN(C)CC(O)=O.C([O-])(=O)CC([O-])=O.C([P+](CCCC)(CCCC)CCCC)CCC.C([P+](CCCC)(CCCC)CCCC)CCC>>[F:24][C:4]1[CH:3]=[C:2]([N:34]2[CH2:33][CH2:32][CH:31]([N:29]3[CH:30]=[N:26][N:27]=[CH:28]3)[CH2:36][CH2:35]2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C@@H:14]([CH3:15])[CH2:13][CH2:12][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22]
Reactant: c1nncn1C1CCNCC1
Reactant: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(Br)cc1F
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: CN(C)CC(=O)O
Agent: Cl
Product: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(N2CCC(n3cnnc3)CC2)cc1F
Temperature: 45 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
A vial was charged with (3S)-2-[(4-bromo-2-fluoro-phenyl)methyl]-3-methyl-6-phenyl-thiazinane 1,1-dioxide (250 mg, 0.61 mmol), 4-(1,2,4-triazol-4-yl)piperidine hydrochloride (172 mg, 0.91 mmol), cuprous iodide (35 mg, 0.18 mmol), N,N-dimethylglycine (38 mg, 0.36 mmol) and tetrabutylphosphonium malonate (1.3 g, 1.9 mmol) and the vial was purged with nitrogen for. Dimethyl sulfoxide (3 mL) was then added and the vial was purged with nitrogen for an additional 2 minutes. The reaction mixture was then sonicated for 5 minutes and stirred at 45° C. for 20 hours. The DMSO solution was then directly purified by preparative HPLC to give (3S)-2-[[2-fluoro-4-[4-(1,2,4-triazol-4-yl)-1-piperidyl]phenyl]methyl]-3-methyl-6-phenyl-thiazinane 1,1-dioxide Stereoisomer A (109 mg, 0.23 mmol, 37% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.66-8.62 (s, 2H), 7.49-7.43 (m, 2H), 7.43-7.29 (m, 4H), 6.87-6.82 (m, 1H), 6.80-6.73 (m, 1H), 4.49-4.24 (m, 4H), 4.15-4.04 (m, 1H), 3.90-3.80 (m, 2H), 2.89-2.77 (m, 2H), 2.47-2.35 (m, 1H), 2.15-2.04 (m, 3H), 2.04-1.89 (m, 2H), 1.88-1.74 (m, 1H), 1.70-1.60 (m, 1H), 1.14-1.05 (d, J=6.9 Hz, 3H); LCMS [M+1]+=484.2.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].Cl.[CH2:26]([O:29][NH2:30])[CH:27]=[CH2:28].C([O-])(=O)C.[K+].CO>O>[CH2:26]([O:29][N:30]=[C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:2])[CH:27]=[CH2:28]
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)cccc1C(C)=O
Reactant: C=CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=CCON=C(C)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Reaction time: 5 h
Yield: 46.3 %

Procedure:
1.0 g of methyl 2-acetyl-6-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate, 1.0 g of allyloxyamine hydrochloride and 0.9 g of potassium acetate were added to 30 ml of methanol, and were refluxed with stirring for 5 hours. The reaction mixture was then poured into a cold water, and was extracted with ethyl acetate. The organic layer thus formed was washed with firstly dilute hydrochloric acid, then sodium hydrogencarbonate and water in sequence. The organic layer thus washed was then dried and concentrated. The residue oily product was purified by column chromatography to obtain 0.54 g of the aimed compound (melting point=76° to 78° C.) at a yield of 46% as a colorless transparent crystal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18](O)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:23]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([N:23]2[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24]2)=[O:19])[CH2:15][CH2:16]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C1CCNC1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCN(C(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.6 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 0.30 g, 1.03 mmol), methyl pyrrolidine-3-carboxylate hydrochloride (0.21 g, 1.2 mmol), triethylamine (215 μL, 1.6 mmol), EDCI (0.19 g, 1.2 mmol) and HOBt (0.19 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 85:15 to 35:65) to give the title compound (0.35 g, 85%) as a pale yellow oil.
Reaction SMILES: CS(C)=O.[C:5]([Si:9]([CH3:27])([CH3:26])[O:10][C@H:11]1[CH2:20][CH2:19][CH2:18][C@@:17]2([CH3:21])[C@H:12]1[CH2:13][CH2:14][CH:15]=[C:16]2[C@H:22]([CH3:25])[CH2:23][OH:24])([CH3:8])([CH3:7])[CH3:6].CCN(CC)CC>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[C:5]([Si:9]([CH3:27])([CH3:26])[O:10][C@H:11]1[CH2:20][CH2:19][CH2:18][C@@:17]2([CH3:21])[C@H:12]1[CH2:13][CH2:14][CH:15]=[C:16]2[C@H:22]([CH3:25])[CH:23]=[O:24])([CH3:7])([CH3:8])[CH3:6]
Reactant: C[C@H](CO)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@H](C=O)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reaction time: 0.3 h

Procedure:
Swern reagent was prepared at -78° C. by adding slowly 1.6 ml of abs. DMSO, dissolved in 4 ml of CH2Cl2, to 0.908 ml of oxalylchloride in 26 ml of CH2Cl2.15 minutes later, 3.27 g of (S)-2-[(4aR,5S,8aS)-5-(tert-butyldimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-propan-1-ol (synthesis described in ref. Ex. 12) dissolved in 11 ml of CH2Cl2, were slowly added. After 0.3 h, 4.6 ml of NEt3 were added dropwise and the temperature allowed to reach -15° C. The reaction was quenched by pouring onto crushed ice/NH4Cl, extracted with ether, washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=97/3) yielded (S)-2-[(4aR,5S,8aS)-5-(tert-butyldimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octa-hydro-naphthalen-1-yl]-propionaldehyde in nearly quantitative yield.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][NH2:31])(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:31]([CH2:30][C:21]2[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[CH:10]=1
Reactant: CS(=O)(=O)c1ccc(C(F)(F)F)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(F)(F)F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 62.6 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.69 g), 1-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]methanamine hydrochloride obtained in Step 3 (2.5 g) and potassium carbonate (2.98 g) were stirred in ethanol (30 ml) at 80° C. for 16 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.0 g)
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]3[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[N:16]=3)[C:4]=2[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O.CO>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:12]3[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[N:16]=3)=[O:29])[C:4]=2[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]c(SCc3nccc4sccc34)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S(Cc1nccc2sccc12)c1nc2ccccc2[nH]1
Reaction time: 0.5 h

Procedure:
To a solution of 278.6 mg (0.900 mmol) of 2-[(thieno[3, 2-c]pyridin-4-yl)methylthio]benzimidazole.2/3 H2O (Ia') in 20 ml of CHCl3 and 1 ml of MeOH was added 194.1 mg (0.900 mmol) of 80% mCPBA at -10° to -15° C. and stirred for 30 minutes. To the mixture were added 2.5 ml of saturated aqueous NaHCO3 and 0.5 ml of 10 % aqueous sodium sulfite. After bringing back to room temperature, water was added thereto, and the solution was extracted with CHCl3. After drying CHCl3 layer over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and washed with ether, whereby 274.6 mg (Yield : 92.5%) of the objective compound (Ic'), 2-[(thieno[3, 2-c]pyridin-4-yl)methylsulfinyl]benzimidazole was obtained as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:4].S(Cl)(Cl)=O.[NH3:34]>C1C=CC=CC=1.C(OCC)(=O)C>[C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:7])[NH2:34]
Reactant: N
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a solution of 2-(methoxycarbonyl)-3-[4-[2-(2-naphthoxy)ethoxy]phenyl]propionic acid (2.08 g, 5.29 mmol) in benzene (20 ml) at room temperature is added thionyl chloride (0.76 g, 6.34 mmol). Then the mixture was heated at 80° C. for 90 min. After cooled to room temperature, the solvent is removed under a vacuum. To the residue is added 28% ammonia solution (5.49 ml, 79.30 mmol) at room temperature. The mixture is stirred for 30 min, dissolved in ethyl acetate (20 ml), washed with brine (3×15 ml), dried over sodium sulfate, and concentrated. The crude product is crystallized from ethanol to give title compound (0.98 g, 47%). HRMS calcd for C23H23NO5: 393.4364. Found: 393.4363. MA calcd for C23H23NO5: C, 70.22%; H, 5.89%; N, 3.56%. Found: C, 70.54%; H, 5.87%; N, 3.54%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([CH2:8][C:9]#[N:10])=[O:7].[H-].[Na+].Br.Br[CH2:18][C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:20]>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([CH:8]([CH2:18][C:19](=[O:20])[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:9]#[N:10])=[O:7]
Reactant: COc1cccc(C(=O)CC#N)c1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C(C#N)CC(=O)c2cccnc2)c1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To 1.3 g (7.5 mmol) of 3-methoxybenzoyl acetonitrile in 30 mL of THF, cooled in a wet ice bath, was added 0.3 g (7.5 mmol) of sodium hydride (60% oil dispersion). After 1 h, added 1.0 g (3.6 mmol) of 3-bromoacetylpyridine hydrobromide. After 3 h, poured the reaction mixture into brine, extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure and purified by flash chromatography (gradient elution: 40-100% ethyl acetate/hexane) to give 0.95 g (43%) of 2-(3-methoxybenzoyl)-4-oxo-4-pyridin-3-yl-butyronitrile (MH+=295).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[C:4]([F:21])[CH:3]=1.[CH3:22][N:23](C=O)[CH3:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:23]([CH3:24])[CH3:22])=[O:17])=[CH:18][CH:19]=2)=[C:4]([F:21])[CH:3]=1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 51.1 %

Procedure:
To a solution of 4-[3-(4-bromo-2-fluoro-phenyl)-ureido]-benzoic acid (0.5 g, 0.014 mol) in DMF (5 mL) N,N-dimethylamine hydrochloride (0.14 g, 0.0017 mol), HOBt (0.25 g, 0.0.0018 mol), EDC.HCl (0.41 g, 0.0021 mol) and TEA (0.4 mL, 0.0028 mol) were added. The reaction mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×15 mL). The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound [0.33 g, 65%]; LC-MS (ESI): Calculated mass: 379.0; Observed mass: 382.0 [M+H] (RT: 1.41 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([N:19]2[CH2:28][CH2:27][C:22]3([CH2:25][CH:24]([OH:26])[CH2:23]3)[CH2:21][CH2:20]2)=[N:9][N:8]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([N:19]2[CH2:28][CH2:27][C:22]3([CH2:25][C:24](=[O:26])[CH2:23]3)[CH2:21][CH2:20]2)=[N:9][N:8]=1
Reactant: COc1ccc(CNc2nnc(N3CCC4(CC3)CC(O)C4)c3ccc(C#N)cc23)cc1Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nnc(N3CCC4(CC3)CC(=O)C4)c3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
500 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazine carbonitrile was suspended in 20 ml dichloromethane and 10 ml tetrahydrofuran, then 690 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxsol-3 (1H)-one was added thereto, and the mixture was stirred at room temperature for 15 min. Ethyl acetate, 30 ml saturated aqueous sodium bicarbonate and 2 ml saturated aqueous sodium thiosulfate 5H2O were added thereto. The organic layer was recovered and the aqueous layer was extracted with ethyl acetate. The extracted solutions were combined, washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated and the resulting residue was purified by silica gel column chromatography, crystallized from ethanol, and the resulting crystals were collected filtration by adding hexane thereto to give 420 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-oxo-7-azaspiro[3.5]non-7-yl)-6-phthalazine carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[CH:6]3[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[C:6]3([CH3:24])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC12COCCN1c1nc(Cl)ncc1N(CC(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
To a mixture of 2-chloro-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (768 mg, 2.38 mmol) and iodomethane (0.595 ml, 9.52 mmol) in DMSO (15 ml) at 0° C. was added sodium 2-methylpropan-2-olate (343 mg, 3.57 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water (containing Na2S2O3), dried and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 11:9) to afford 2-chloro-6a-methyl-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (191 mg, 0.566 mmol, 24% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 3 H) 3.17-3.28 (m, 1 H) 3.55 (td, J=12.13, 3.03 Hz, 1 H) 3.68 (d, J=11.62 Hz, 1 H) 3.89-4.07 (m, 3 H) 4.75-5.04 (m, 2 H) 8.31 (s, 1 H). MS [M+H] found 337.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[N:3]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:16]1([CH2:15][NH:14][C:4]2[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[N:3]=2)[CH2:18][CH2:17]1
Reactant: N#Cc1c(Cl)nc(NCC2CC2)nc1NCCO
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCC2CC2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 47b, 4-chloro-2-(cyclopropylmethyl-amino)-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 2-(cyclopropylmethyl-amino)-4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=394.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:18][C:19]([N:21]2C=CN=[CH:22]2)=[O:20])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1.I.NC[CH2:29][C:30]([NH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:31]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:18][C:19](=[O:20])[NH:21][CH2:22][CH2:29][C:30]([NH:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:31])[S:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:11][CH:12]=1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(-n2cccn2)cc1
Reactant: NCCC(=O)Nc1cccnc1
Agent: I
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)NCCC(=O)Nc2cccnc2)sc1-c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of imidazole-1-carboxylic acid [4-methyl-5-(4-pyrazol-1-yl-phenyl)-thiazol-2-yl]-amide (Intermediate A1) (0.1 g, 0.28 mmol) and 3-amino-N-pyridin-3-yl-propionamide hydroiodide (Intermediate B2) (0.083 g, 0.28 mmol) in dry DMF (1 ml) is treated with TEA. After stirring at room temperature for 1 hour, the solvent is removed in vacuo and purification of the crude residue by chromatography on silica eluting with EtOAc/EtOH (10:1 increasing to 5:1) affords a solid which is recrystallised from EtOAc/EtOH to yield the title compound. [MH+ 448.49]