Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([CH3:19])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH:14]([CH3:16])[CH3:15])[CH:8]=2)=[C:4]([CH3:20])[CH:3]=1.[N:21]([O-])=O.[Na+].[CH3:25][CH2:26][O:27][C:28]([CH:30]([C:32](C)=O)C)=[O:29]>C(O)C.Cl.O.[OH-].[Na+]>[CH2:26]([O:27][C:28](=[O:29])[C:30](=[N:21][NH:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH:14]([CH3:16])[CH3:15])[CH:8]=2)=[C:17]([CH3:19])[CH:18]=1)[CH3:32])[CH3:25]
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)=NNc1cc(C)c(Oc2ccc(O)c(C(C)C)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 4-(4-amino-2,6-dimethyl-phenoxy)-2-isopropyl-phenol (136 mg, 0.50 mmol) in a mixture of ethanol (2 mL) and hydrochloric acid (12M, 0.17 mL) at 0° C. was added slowly a solution of sodium nitrite (45 mg, 0.65 mmol) in water (0.5 mL). After stirring at 0° C. for 30 minutes, the diazonium solution was added dropwise into a solution of ethyl-2-methyl acetoacetate (87 mg, 0.60 mmol) in ethanol (1 mL) and 1N sodium hydroxide (2.26 mL) at 0° C. The resulting mixture was warmed to room temperature, stirred for 1 hour, then diluted with water (10 mL) and 1M hydrochloric acid (1 mL), and extracted with ethyl acetate (15 mL). The organic layer was separated, washed with 1M hydrochloric acid (15 mL), brine (15 mL), dried (Na2SO4), filtered, and concentrated to give the title compound (193 mg) which was used in the next step without further purification. MS (APCI−) Calc: 384.2, Found: 383.3 (M−1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cccc(O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc(C(C)C)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 3-isopropyl-phenol (5.00 g, 36.2 mmols) in 50 mL of acetone was added K2CO3 (7.50 g, 54.3 mmols) and iodomethane (10.3 g, 72.5 mmols). The resulting solution was heated to 50° C. and stirred for 18 hours, cooled to room temperature, and concentrated under reduced pressure. The residual oil was dissolved in Et2O and washed with H2O saturated aqueous NaHCO3, and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The crude methyl ether was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([C:18]([OH:20])=O)=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)=[C:5]([F:21])[CH:4]=1)[CH3:2].FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.N1C=CC=CC=1.[NH2:46][CH2:47][CH2:48][OH:49]>CN(C=O)C>[OH:49][CH2:48][CH2:47][NH:46][C:18]([C:11]1[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[F:21])=[CH:15][C:14](=[O:16])[N:13]([CH3:17])[CH:12]=1)=[O:20]
Reactant: CCc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Reactant: NCCO
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCc1ccc(Nc2cc(=O)n(C)cc2C(=O)NCCO)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
4-(4-Ethyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.50 g, 1.72 mmol) was reacted with pentafluorophenyl trifluoroacetate (0.92 mL, 5.20 mmol) in the presence of pyridine (0.45 mL) in DMF (15 mL). The solution was allowed to stir at room temperature for 15 hours and then treated with 2-Amino-ethanol (0.50 mL, 8.60 mmol) as in example 75 to afford the 4-(4-Ethyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-hydroxy-ethyl)-amide (0.47 g, 82%). 1H NMR [400 MHz, (CD3)2SO] δ 9.82 (s, 1H), 8.35 (t, J=5.4 Hz, 1H), 8.20 (s, 1H), 7.27 (t, J=8.4 Hz, 1H), 7.12 (d, J=11.8 Hz, 1H), 7.06 (d, J=7.7 Hz, 1H), 5.38 (s, 1H), 4.72 (t, J=5.1 Hz, 1 H, OH), 3.44 (t, J=11.5, 6.2 Hz, 2H), 3.35 (s, 3H), 3.22 (t, J=12.8, 6.8 Hz, 2H), 2.58 (q, J=7.1 Hz, 2H), 1.14 (t, J=7.1 Hz, 3H). (APCI+) calcd for C17H20FN3O3 333.36 (M+1), found 334.1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].N1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>ClCCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: O=C(Cl)CCCl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(CCCl)Nc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of 4-bromo-3-chloroaniline (6.0 g, 29.1 mmol) and pyridine (3.45 g, 43.6 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (5.53 g, 43.6 mmol) drop wise at 15° C. After stirring for 2 hr at room temperature, the mixture was washed with water and then 2 N aq. hydrochloric acid. The organic layer was dried over anhy. Na2SO4, and after filtration, the solvent was removed under reduced pressure. The product N-(4-bromo-3-chloro-phenyl)-3-chloro-propionamide (8.20 g, 95% yield) was obtained as oil. MS: 298.0 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1.[I:19]N1C(=O)CCC1=O>C(OCC)(=O)C>[I:19][C:10]1[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][O:13][C:9]=1[CH3:8]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(C)on1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc(C)c1I
Temperature: 65 °C
Yield: 71.2 %

Procedure:
To a 25 mL RB flask fitted with a magnetic stirrer was charged with 1 mL of TFA. To the stirred solvent were added ethyl 5-methyl-1,2-oxazole-3-carboxylate (0.1 g, 0.6 mmol) and N-iodosuccinimide (0.289 g, 1.2 mmol). After addition, the reaction mixture was heated at 65° C. for 3 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL), the organic layer was washed with saturated NaHCO3 solution (10 mL), thiosulfate solution (10 mL), water (25 mL) and finally with brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as a brown liquid (0.12 g, yield: 66.2%). 1H NMR (300 MHz, CDCl3): δ 4.36-4.43 (q, 2H), 2.49 (s, 3H), 1.34-1.39 (t, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([C:15]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)([CH:18]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][C:23]=1[OH:32])[CH2:19][CH:20]=[CH2:21])[CH2:16]O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1(C)C=CC=CC=1.O1CCOCC1>[CH2:13]([C:15]1([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=2)[CH:18]([CH2:19][CH:20]=[CH2:21])[C:22]2[C:23](=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=2)[O:32][CH2:16]1)[CH3:14]
Reactant: C=CCC(c1ccc(OCOC)cc1O)C(CC)(CO)c1ccc(OCOC)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC1c2ccc(OCOC)cc2OCC1(CC)c1ccc(OCOC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
A 40% solution of diethyl azodicarboxylate in toluene (21.9 ml) was added dropwise to an ice-cold solution of (2RS,3RS)-2-ethyl-3-(2-hydroxy-4-methoxymethoxyphenyl)-2-(4-methoxymethoxy-phenyl)-5-hexenol (9.5 g) and triphenylphosphine (15.0 g) in dry 1,4-dioxane (150 ml) over 25 minutes under nitrogen atmosphere. The reaction mixture was stirred for 10 minutes on ice and for 30 minutes at room temperature. Under ice-cooling, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and then concentrated to give a crude product, which was then purified by flash column chromatography (silica gel: Merck Kieselgel 60, eluent: hexane/ethyl acetate=50/1→20/1→10/1) to give (3RS,4RS)-3-ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman (8.4 g, Yield 92.6%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH2:36]([N:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][NH2:42])[CH3:37]>C1COCC1>[CH2:36]([N:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][NH:42][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH3:37]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CCN(CC)CCCN
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 75.1 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (18 mg, 0.04 mmol) in THF (3 mL) was added N,N-diethyl-1,3-propanediamine (0.028 mL, 0.18 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (17 mg, 83%). LC-MS m/z 566 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 6H), 1.27 (d, 6H), 1.55 (m, 2H), 2.30 (s, 3H), 2.40 (m, 2H), 2.52 (m, 4H), 3.07 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](OCC)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH4-].[Na+]>C1COCC1.C(O)(C)(C)C>[Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cnc(CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a suspension of ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate (4.0 g, 8.9 mmol) in THF:t-butanol (1:1) (10 mL) was added NaBH4 (0.46 g, 12.4 mmol). The reaction stirred at room temperature under argon overnight. The reaction mixture was quenched with acetic acid (2 mL) and the solvent was removed in vacuo. The residue was triturated with water and filtered. The solid was washed with fresh water followed by ethanol. The solid was purified by flash column chromatography (100% ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired compound (1.58 g, 44%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.59 (s, 1H), 8.56 (s, 1H), 7.52 (m, 1H), 7.01 (m, 2H), 6.55 (m, 1H), 5.45 (s, 2H), 5.29 (s, 2H), 4.71 (2H), 2.54 (s, 3H); ES-HRMS m/z 408.0940 (M+H calculated for C19H17N3O3ClF2 requires 408.0921).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[NH:21][CH2:20][CH2:19][C:12]3(C(=O)CCC3=O)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.[OH-:25].[Na+]>Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[CH2:11][C:12](=[O:25])[CH2:19][CH2:20][NH:21]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [OH-]
Reactant: O=C1CCC(=O)C12CCNC(Cc1ccc(F)c(F)c1)C2
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCNC(Cc2ccc(F)c(F)c2)C1
Temperature: 75 °C

Procedure:
A mixture of intermediate 12 (0.032 mol) in HCl, (6N; 90 ml) was stirred at 75° C., then cooled. CH2Cl2 was added and the mixture was alkalized with NaOH at a temperature below 20° C. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was dried, yielding 7.2 g of 2-[(3,4-difluorophenyl)methyl]-4-piperidinone (intermediate 13).
Reaction SMILES: [CH2:1]([N:8]1[C:12](I)=[C:11]([CH:14]=[O:15])[CH:10]=[C:9]1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([OH:29])[C:27]#[CH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:28]#[C:27][C:26]([OH:29])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:11]([CH:14]=[O:15])[CH:10]=[C:9]1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C=O)c(I)n1Cc1ccccc1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=O)c(C#CC(O)(c2ccccc2)c2ccccc2)n1Cc1ccccc1
Yield: 83.9 %

Procedure:
A solution of 5 (0.47 g, 1.3 mmol), 1,1-diphenylprop-2-yn-1-ol (0.66 g, 3.2 mmol), CuI (0.05 g, 0.3 mmol), Pd(PPh3)2Cl2 (0.18 g, 0.3 mmol), PPh3 (0.07 g, 0.3 mmol), and Et3N (4 mL) in anhydrous DMF (4 mL) was stirred for 16 hours at 70° C. under N2 atmosphere. The reaction mixture was then partitioned between water and EtOAc. The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. MPLC purification (Hexanes:EtOAc/80:20) of the residue gave 6 as a pale yellow solid (0.49 g, 87%). 1H NMR (CDCl3) δ 9.88 (s, 1H), 7.50-7.52 (m, 4H), 7.36 (s, 1H), 7.24-7.30 (m, 8H), 7.04 (m, 2H), 5.69 (s, 2H), 3.80 (s, 3H), and 3.65 (s, 1H); 13C NMR (CDCl3) δ 185.16, 160.72, 144.07, 136.84, 128.91, 128.72, 128.33, 127.91, 127.79, 127.05, 126.23, 124.96, 116.97, 103.35, 75.37, 75.27, 52.15, and 50.38.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:24]=[CH:23][C:11]([C:12]([N:14]3[CH2:19][CH2:18][C:17]4[O:20][CH:21]=[CH:22][C:16]=4[CH2:15]3)=[O:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:21]1[O:20][C:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C:11]3[CH:23]=[CH:24][C:8]([C:6](=[O:7])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=4)=[CH:9][CH:10]=3)[CH2:15][C:16]=2[CH:22]=1)[CH3:29]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)N2CCc3occc3C2)cc1
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccc(C(=O)c3ccc(Cl)cc3)cc1)C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 0.300 g (0.820 mmol) of 5-[4-(4-chlorobenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.11 ml (1.23 mmol) of 50% aqueous dimethylamine and 0.10 ml (1.23 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 120 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: BrCC[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1F.[C:15]([Cu])#[N:16]>CN(C=O)C.O>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:15]#[N:16]
Reactant: N#C[Cu]
Reactant: N#Cc1ccc(OCCCBr)c(F)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1C#N
Temperature: 120 °C
Reaction time: 15 h
Yield: 47.8 %

Procedure:
2,4-Dibromo-1-methoxybenzene (25 g, 0.094 mol; see step (i) above) was dissolved in dry DMF (50 mL). CuCN (25.3 g, 0.283 mol) was then added and the resulting mixture was stirred at 120° C. for 15 h, before being cooled to RT. The crude mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, using 25% ethyl acetate in petroleum ether as eluent, to yield the sub-title compound (7.1 g, 24%) as pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[CH2:28]([O:27][C:25](=[O:26])[CH:24]([O:23][CH2:21][CH3:22])[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[O:17][CH:18]([CH3:20])[CH3:19])[OH:14])[CH3:29]
Reactant: CCOCC(=O)OCC
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Product: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1OC(C)C

Procedure:
In analogy to the procedure described in example 47 a], 4-benzyloxy-2-isopropoxy-benzaldehyde [Chemical & Pharmaceutical Bulletin (1998), 46(2), 222-230] was reacted with the enolate of ethyl ethoxyacetate, to yield [rac]-3-(4-benzyloxy-2-isopropoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester as a mixture of diastereomers in form of a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=3[CH:14]=2)[O:4][N:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[N:25]([CH3:26])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:23][N:22]=1>>[ClH:16].[CH3:1][C:2]1[C:15]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][CH2:19][S:20][C:21]4[N:25]([CH3:26])[C:24]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=5)=[N:23][N:22]=4)[CH2:10][CH2:9][C:8]=3[CH:14]=2)[O:4][N:3]=1
Reactant: Cc1noc2cc3c(cc12)CCNCC3
Reactant: Cn1c(SCCCCl)nnc1-c1ccc(C(F)(F)F)cc1
Product: Cc1noc2cc3c(cc12)CCN(CCCSc1nnc(-c2ccc(C(F)(F)F)cc2)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 3-methyl-6,7,8,9-tetrahydro-5H-isoxazolo[4,5-h][3]benzazepine (0.12 mmol) and 3-[(3-chloropropyl)thio]-4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole (0.14 mmol) and was obtained as a faint yellow slightly hygroscopic solid (0.01 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(F)c4)n3n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of trans-N1-(3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (180 mg, 0.55 mmol) and DIPEA (213.2 mg, 1.65 mol) in DMSO (2.8 mL) was added dropwise MeSO2Cl (63.4 mg, 0.55 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed most of starting material was converted. The mixture was partitioned between brine (100 mL) and EtOAc (50 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-89 (13 mg, 6%) as a brown solid.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:24]([CH:29]([CH2:32]O)[CH2:30][OH:31])[CH2:25][CH2:26][CH2:27][CH3:28].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[CH2:24]([C@@H:29]1[CH2:30][O:31][C@@H:20]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][CH2:12][C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:23][CH:22]=2)[O:21][CH2:32]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC(CO)CO
Reactant: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C=O)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc([C@H]3OC[C@H](CCCCC)CO3)cc2)CC1

Procedure:
A solution of 2.1 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzaldehyde and 1.2 g of 2-pentyl-1,3-propanediol in 50 ml of toluene was treated with 2 drops of 10% (vol., sulfuric acid. The mixture was heated to boiling for 2.5 hours, with the resulting water being distilled off simultaneously. Then, 4 drops of triethylamine were added to the reaction mixture. After cooling the mixture was washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time, dried over sodium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene gave 0.6 g of trans-5-pentyl-2-(4-[3-(trans-4-pentylcyciohexyl)-1-propyloxy]phenyl)-1,3-dioxane. M.p. (C-SB) 65° C. transition SB -N 73° C., cl.p (N-I) 128° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[Cl:4][C:5]1[N:6]=[C:7]([N:2]([CH3:3])[CH3:1])[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1
Reactant: Clc1nc(Cl)c2cscc2n1
Reactant: CNC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1nc(Cl)nc2cscc12
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.13 g) in ethanol (5 mL) were added 2,4-dichlorothieno[3,4-d]pyrimidine (0.20 g) and triethylamine (0.10 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine, then the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized with diethyl ether to obtain 2-chloro-N,N-dimethylthieno[3,4-d]pyrimidin-4-amine (0.16 g). (2) To a mixture of 2-chloro-N,N-dimethylthieno[3,4-d]pyrimidin-4-amine (0.156 g), Pd2(dba)3 (0.033 g), (±)-BINAP (0.068 g), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.27 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.21 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain light yellow amorphous 1-((3R,4R)-3-(4-dimethylaminothieno[3,4-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.037 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[CH3:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=2[CH:6]=1
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
To a stirred suspension of 2-hydroxy-5-methylbenzaldehyde (5 g, 36.7 mmol) and K2CO3 (12.7 g, 91.8 mmol) in DMF (30 mL), ethyl bromoacetate (4.07 ml, 36.7 mmol) was added drop-wise. This mixture was allowed to stir for two hours under nitrogen at room temperature, and was then heated to 80° C. and stirred overnight. The reaction was quenched with H2O to form a precipitate which was collected by filtration and purified by flash chromatography (eluent 5% EtOAc in hexane) to give the title compound 25 (2.30 g, 31%). 1H-NMR (CDCl3) δ: 1.45 (t, J=7.0 Hz, 3H); 2.47 (s, 3H); 4.45 (q, J=7.0 Hz, 2H); 7.26 (m, 1H); 7.46 (m, 3H).