Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:24]Br.CS(C)=[O:28]>CC(=O)OCC.O>[Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:28]
Reactant: CS(C)=O
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(CBr)c(Br)sc21
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Temperature: 50 °C
Yield: 33.8 %

Procedure:
To a solution of 6-bromo-5-(bromomethyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl) thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.7 g, 3.43 mmol) in DMSO (20 mL) was added IBX (1.92 g, 6.85 mmol). The reaction was heated at 50° C. for 2 h, cooled to RT then diluted with EA (80 mL) and water (50 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1) to give 6-bromo-1-methyl-2,4-dioxo-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (500 mg, 33.8% yield) as a yellow oil. LCMS: MH+ 431 and TR=1.313 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21]O)[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].C([N:32](C(C)C)[CH:33]([CH3:35])[CH3:34])C.CS(Cl)(=O)=O.C(N)(C)C>C(Cl)Cl.C(#N)C.CCOC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[CH2:21][NH:32][CH:33]([CH3:35])[CH3:34])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: COCc1cc(-c2nc(-c3cccc(CO)c3)no2)ccc1-c1ccccc1C
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC(C)N
Solvent: CCOC(C)=O
Product: COCc1cc(-c2nc(-c3cccc(CNC(C)C)c3)no2)ccc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)methanol (100 mg, 0.26 mmol) was dissolved in DCM (2 mL). N-ethyldiisopropylamine (0.090 mL, 0.52 mmol) was added and the mixture was cooled to 0° C. Methanesulfonyl chloride (22 μl, 0.29 mmol) was added and the resulting mixture was stirred at 0° C. for 10 minutes, and then at RT for 2 hours. The reaction mixture was then poured into a solution of isopropylamine (223 μl, 2.60 mmol) in ACN (2 mL) and stirred at RT for 15 hours. It was diluted with EtOAc, washed with water and brine and dried over MgSO4. After concentration under vacuum, the crude product was purified by flash chromatography (silica, cHex/EtOAc containing 1% of TEA) to give the title compound as a colorless oil. HPLC (Method A) Rt 4.25 min (Purity: 97.1%).
Reaction SMILES: [Na+].[CH:2]1([CH2:7][CH2:8][S:9]([O-:12])(=O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:15])=O>CN(C)C=O>[CH:2]1([CH2:7][CH2:8][S:9]([Cl:15])(=[O:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(=O)([O-])CCC1CCCC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCC1CCCC1
Temperature: 25 °C

Procedure:
Dimethylformamide (5 drops) was added over 1 minute to a stirred solution of 2-(cyclopentyl)ethylsulfonic acid sodium salt (1 5.5 g, 87.5 mmol) in thionyl chloride (60 ml) under a nitrogen atmosphere. The reaction mixture was stirred under reflux for 5 hours and was then cooled to room temperature and concentrated under vacuum. The residue was suspended in toluene (100 ml) and then concentrated under vacuum. The residue was dissolved in a mixture of ethyl acetate (150 ml) and water (150 ml) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 ml) and the combined organic extracts were washed with brine (3×100 ml), dried (magnesium sulfate) and evaporated to give the title compound as a brown oil (14.1 g), Rf 0.5 (pentane/ethyl acetate 95:5).
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](Cl)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([OH:27])=[CH:22]2>>[Br:1][C:2]1[C:7]2[NH:8][C:9]([NH:16][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][C:21]([OH:27])=[CH:22]4)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2[nH]c(Cl)nc2c1
Reactant: Nc1cccc2cc(O)ccc12
Product: Oc1ccc2c(Nc3nc4cc(C(F)(F)F)cc(Br)c4[nH]3)cccc2c1
Yield: 57 %

Procedure:
The reaction of 7-bromo-2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (240 mg, 0.8 mmol, prepared according to the procedure described in WO 2004/035549 A1) with 5-amino-2-naphthol (64 mg, 0.4 mmol, TCI-US) under the condition of Example 2 afforded the title compound (57%) as an amorphous solid. MS (ESI, pos. ion) m/z: 423 (M+1).
Reaction SMILES: [C:1]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)(=O)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>C(OCC)C.O1CCCC1.O>[CH2:1]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)[CH2:2][CH3:3]
Reactant: CCC(=O)NC1CNc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCCNC1CNc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
To a ice-cooled solution of 3.2 g (15.6 mmol) 3-(N-propionyl)amino-l,2,3,4-tetrahydroquinoline in 50 ml dry diethyl ether and 80 ml dry tetrahydrofurane was 3.0 g (79 mmol) lithium aluminum hydride added. The mixture was gently heated to reflux and kept that way for 5 days. Ethyl acetate (4.5 ml), 3.0 ml water,3.0 ml 15% sodium hydroxide and 9 ml water was added consecutively. The precipitate appearing after 5 minutes was filtered off and washed with diethyl ether. Evaporation of the etheric solution yielded 2.66 g (89%) of the desired product.: 13C NMR () d 11 (76), 23.46, 33.71, 46.41, 48.98, 50.43, 113.79, 117.29, 119.37, 126.87, 130.06, 144.09; MS m/e 190 (M+, 17), 132 (100), 130 (32), 72 (22), 118 (17), 131 (17).
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([CH3:18])[C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])C1C=CC=CC=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.CCO.[Pd]>[CH2:19]([C:10]1[C:9](=[O:8])[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[N:12]([OH:34])[C:11]=1[CH3:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCc1c(C)nc(C)c(OC)c1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCc1c(C)n(O)c(C)c(OC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 (19 mg, 0.66 mmol) and mCPBA (125 mg, 0.72 mmol) in anhydrous CH2Cl2 (2 mL) was stirred at 0° C. for 1 hr under argon atmosphere, the solution was washed with aqueous NaHCO3 dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. The residue was dissolved in EtOH, Pd/C was added and after applying an H2 atmosphere (1 bar), the solution was stirred at room temp for 30 min, After filtration through celite, which was thoroughly washed with EtOH, the filtrate was concentrated under diminished pressure and purified by chromatography on a silica gel column. Elution with 20:1 ethyl acetate/methanol gave 3-heptyl-1-hydroxy-5-methoxy-2,6-dimethylpyridin-4(1H)-one (CPD-5) as a light yellow oil; yield 9 mg (61%); silica gel TLC Rf 0.25 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3) δ 0.84-0.89 (m, 3H), 1.24-1.35 (m, 10H), 2.45 (s, 3H), 2.50 (s, 3H) 2.63-2.67 (m, 2H) and 3.74 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([B:23]([OH:24])[OH:22])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Br)cc1C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1C(C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a mixture of 2-(t-butyl)-4-bromoanisole (23.07 g, 0.0949 mol) in THF (238 mL) cooled to −75° C. under an atmosphere of argon was added n-BuLi (65.3 mL, 1.6 M, 0.1044 mol) dropwise maintaining a temperature below −70° C. The resulting suspension was stirred for 30 minutes and triisopropylborate (34.2 mL, 27.87 g, 0.148 mol) was added dropwise. The mixture was allowed to warm to RT overnight. The resulting mixture was cooled to 0° C. and 1.0 N HCl (150 mL) was slowly added. After warming to RT the mixture was diluted with ether and the layers separated, the aqueous layer was extracted ether (3×) and the organic layers combined. The resulting organic layer was washed with water, brine and dried (Mg2SO4). The mixture was filtered, evaporated and the resulting yellowish residue solidified overnight. The solid was collected and washed with hexane and dried under high vacuum to afford 12.68 g of 3-(t-butyl)-4-methoxyphenyl boronic acid (64%). 1H NMR (300 MHz; DMSO-d6): δ 1.33 (s, 9H), 3.81 (s, 3H), 6.91 (d, J=7.8 Hz, 1H), 7.62–7.79 (m, 2H), 7.78 (brs, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[C:18]([S:19](Cl)(=[O:21])=[O:20])=[C:17]([CH3:23])[O:16][N:15]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[S:19]([C:18]1[C:14]([CH3:13])=[N:15][O:16][C:17]=1[CH3:23])(=[O:21])=[O:20]
Reactant: CNCCC#Cc1ccccn1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Product: Cc1noc(C)c1S(=O)(=O)N(C)CCC#Cc1ccccn1
Yield: 17.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3,5-dimethylisoxazole-4-sulfonyl chloride (79 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 17 mg of N,3,5-trimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)isoxazole-4-sulfonamide as a brown oil (Yield: 17%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)=[CH:6][N+:7]=1[O-].[OH-].[Na+].P(Cl)(Cl)([Cl:26])=O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)=[C:6]([Cl:26])[N:7]=1
Reactant: CC(C)n1nc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide 4-oxide (1.65 g) in DMF (33 ml), phosphorous oxychloride (1.59 ml) was added below −30° C. and the mixture was stirred at 0-5° C. for one hour. The reaction mixture was poured into ice-water (132 ml), stirred at 40-50° C. for 2 hours, adjusted to pH 8 with 30% aq. NaOH solution under ice-cooling and a precipitate was collected by filtration. The precipitate was purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (2:98 v/v) to give 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide as a solid (682 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]Br>ClCCl>[Br:10][C:5]1[C:6]([Cl:8])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:9]
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1nc(N)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
To a mixture of the 2-amino-4-chloro-6-methylpyrimidine (5.00 g, 34.8 mmol) in dichloromethane (240 mL) was added bromine (1.88 mL, 36.6 mmol). The resulting suspension was stirred at room temperature for 1.5 hours. The mixture was diluted with dichloromethane (1.3 L) and washed with saturated sodium bicarbonate (2×200 mL) and brine (200 mL), dried (MgSO4), filtered and concentrated to afford 5-bromo-4-chloro-6-methylpyrimidin-2-amine (7.5 g, 97%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[CH3:12][O:13][CH2:14][CH2:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O.[NH4+].[Cl-]>C1COCC1>[Br:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:39]([CH:40]=[CH:16][CH2:15][CH2:14][O:13][CH3:12])[CH:38]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COCCC=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of NaHMDS (9.02 g, 49.2 mmol) in THF (50 mL) under nitrogen atmosphere is added drop wise at 0° C. a THF solution (50 mL) of the title A compound, (3-methoxy-propyl)-triphenyl-phosphonium bromide (20.4 g, 49.2 mmol). The resulting mixture is stirred for 1 h at 0° C. before the addition of a THF solution (50 mL) of m-bromobenzaldehyde (7 g, 37.8 mmol). The reaction mixture is further stirred for 2 h at room temperature and poured into a saturated NH4Cl aqueous solution, the aqueous layer is extracted twice with EtOAc. The combined organic extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is taken up into ether and the triphenylphosphine oxide precipitate is filtered off through a pad of celite. The filtrate is concentrate and the residual material purified by flash column chromatography on silica gel (hexane/EtOAc 95/5) to afford the title compound (as a mixture Z and E stereoisomers) as a yellow oil: Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 6.30 min.
Reaction SMILES: [OH-].[K+].[CH:3]1([C:9]2[CH:27]=[CH:26][C:12]([O:13][CH:14]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:15]([OH:17])=[O:16])=[CH:26][CH:27]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)C(Oc1ccc(C2CCCCC2)cc1)C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(Oc1ccc(C2CCCCC2)cc1)C1CCCCC1
Yield: 43.2 %

Procedure:
Into 15 ml of ethanol, 430 mg of potassium hydroxide was dissolved and 1.7 g (0.00512 mole) of ethyl α-(p-cyclohexylphenoxy)α-cyclohexylacetate was added. The mixture was heated on a water bath at 65° to 70° C. for 90 minutes and then ethanol was distilled off under a reduced pressure and the residue was admixed with water and washed twice with benzene. The water layer was acidified with 10% HCl aq.sol. to precipitate a precipitate. The precipitate was filtrated and washed with water and dried. The product was recrystallized from n-hexane to obtain 0.7 g of α-(p-cyclohexylphenoxy)α-cyclohexylacetic acid (yield: 44.9%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:18][CH:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.C1C(=O)N([Br:40])C(=O)C1>C(Cl)Cl>[Br:40][C:19]1[CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[O:16][C:15]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2ccc(-c3ccccn3)o2)cc1OC1CCCC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1ccc(-c2oc(-c3ccccn3)cc2Br)cc1OC1CCCC1
Yield: 63 %

Procedure:
A mixture of 2-(3-cyclopentyloxy-4-methoxyphenyl)-5-(2-pyridyl)furan, (0.5 g) example 2, in CH2Cl2 (3 ml) and diisopropylamine(21 ul) and NBS (0.320 g) were stirred for 20 mins. at room temperature. The reaction mixture was quenched with Na2CO3, extracted with CH2Cl2 dried with sodium sulfate and evaporated in vacuo to afford the title compound as a beige solid in 63% yield. 1H NMR (300 MHz, CDCl3): δ 1.6 (m, 2H), 2.0-1.8 (m, 6H), 3.90 (s, 3H), 4.95 (m, 1H), 7.05 (dd, 1H), 7.23 (m, 2H), 7.43 (m, 2H), 7.85 (dd, 2H), 8.5 (dd, 1H).
Reaction SMILES: [CH2:1]=[O:2].[CH:3](=[O:7])[CH:4]([CH3:6])[CH3:5].CN(C)C>C(O)=O>[OH:7][CH2:3][C:4]([CH3:1])([CH3:6])[C:5]([O:2][CH2:1][C:4]([CH3:6])([CH3:5])[CH2:3][OH:7])=[O:2]
Reactant: C=O
Reactant: CC(C)C=O
Agent: CN(C)C
Solvent: O=CO
Product: CC(C)(CO)COC(=O)C(C)(C)CO
Temperature: 60 °C

Procedure:
101 g (1.25 mol) of 37% strength aqueous formaldehyde solution and 99 g (1.37 mol) of isobutyraldehyde were mixed at 40° C. under nitrogen with 4.2 g (0.03 mol) of 40% strength aqueous trimethylamine solution by stirring. The temperature of the mixture rose to 93° to 94° in the course of from 15 to 20 minutes. The mixture was stirred at that temperature for a further 10 minutes, and the trimethylamine, excess isobutyraldehyde and 58 g of water were then distilled off under reduced pressure. The remaining solution of hydroxypivalinaldehyde was then cooled down to 60° C., and 1.9 g (0.025 mol) of finely pulverulent calcium hydroxide were then added with vigorous stirring. After the exothermic reaction had ceased and a further, short period of stirring, 2.5 g (0.054 mol) of 100% strength formic acid were added at 70° C., and the mixture was stirred 70° C. for 10 minutes. The aqueous phase was then separated off, and the organic phase was subjected to fractional distillation. 110 g (0.54 mol) were isolated of 2,2-dimethyl-1,3-propanediol hydroxypivalate, corresponding to 86.5% of theory, based on starting formaldehyde.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[C:13]([Cu])#[N:14].O>CN1C(=O)CCC1>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:13]#[N:14])=[C:3]([CH3:12])[CH:4]=[CH:5]2)=[N:9]1
Reactant: N#C[Cu]
Reactant: Cc1ccc2cn(C)nc2c1Br
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2cn(C)nc2c1C#N
Temperature: 130 °C
Yield: 40 %

Procedure:
To a solution of 7-bromo-2,6-dimethyl-2H-indazole (1 equiv.) in NMP, was added CuCN (2 equiv.) and heated at 130° C. for 16 h. On completion, water was added to quench the reaction, solid precipitated was filtered and purified by column chromatography to afford the title compound (40-60% yield)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([OH:21])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(#N)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:19])[CH3:20])[N:11]=[C:10]([O:21][S:33]([CH3:32])(=[O:35])=[O:34])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(C)(=O)=O)nc1C(C)C
Temperature: 2.5 °C
Yield: 89.2 %

Procedure:
In a 100 mL-volume glass flask were placed 10.0 g (34.4 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 5.22 g (58.5 mmol.) of triethylamine, and 34 mL of acetonitrile. The mixture in the flask was chilled to 0-5° C. in an ice bath. To the chilled mixture was slowly added 5.12 g (44.7 mmol.) of methanesulfonyl chloride, and the resulting mixture was subjected to reaction at 20-25° C. for 2 hours. After the reaction was complete, to the reaction mixture was added 60 mL of water. The aqueous reaction mixture was extracted with toluene and the toluene portion was separated. The toluene portion was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The dried mixture was filtered and concentrated under reduced pressure. The residue was crystallized from methanol, to give 11.3 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine as a colorless crystalline product having the below-mentioned characteristics. The yield was 89% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][C:21](=[O:27])[NH:22]3)[CH2:9][CH2:8]1)(=O)C.Cl>CO>[OH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][C:21](=[O:27])[NH:22]3)[CH2:9][CH2:8]1
Reactant: CC(=O)OCCN1CCN(CCCOc2cccc3c2CCC(=O)N3)CC1
Agent: Cl
Solvent: CO
Product: O=C1CCc2c(cccc2OCCCN2CCN(CCO)CC2)N1

Procedure:
2.0 grams of 5-{3-[4-(2-acetyloxyethyl)-piperazinyl]propoxy}-3,4-dihydrocarbostyril are mixed with 30 ml of methanol and 5 ml of concentrated hydrochloric acid and heated for 2 hours under refluxing conditions. The reaction mixture is concentrated under reduced pressure to dryness. The residue is recrystallized from water to obtain 5-{3-[4-(2-hydroxyethyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless flake-like crystals with a melting point of 158°-159° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:36]>C(OCC)(=O)C>[NH2:1][C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:36]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1)C(N)=O
Yield: 82 %

Procedure:
Condensation of BocDPheOH (2.65 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 2.98 g.) by the mixed anhydride method using isobutyl chloroformate gave BocDPhe-Leu-MetNH2 in 57% yield. De-t-butoxycarbonylation of BocDPhe-Leu-MetNH2 (2.7 g.) using hydrogen chloride in ethyl acetate gave HDPhe-Leu-MetNH2 hydrochloride salt in 82% yield.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.O.C(O)C.C([O-])(=O)C.[Na+]>C(O)C.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH:18][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1C=C(NNc2ccc(F)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
The title compound was prepared by a modification of a published procedure (Brueckner R. et al., European Patent EP 1 424 337 A1 (2004)). To a stirred solution of cyclohexane-1,3-dione (10 g, 0.089 mol) in ethanol (50 mL) and water (150 mL) was added portionwise under nitrogen over 15 minutes 4-fluorophenyl hydrazine hydrochloride (14.5 g, 0.089 mol). After 10 minutes 120 mL of 3:1 (v/v) water/ethanol was added in three portions. Solid sodium acetate (7.2 g) was then added portionwise over 45 minutes. The mixture was stirred for another 30 minutes at room temperature. The brown solid was collected, washed with 2×30 mL of 3:1 (v/v) water/ethanol and water, and dried in vacuo overnight to provide the title compound (16.48 g). MS (ES): [M+H]+ @m/z 221.1.