Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)C.CC[O-].[Na+]>C(O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([C:9]2[N:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[NH:13][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCc2nc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
2.4 g 3-[3-Amino-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-propionic acid ethyl ester were dissolved in 200 ml ethanol. 2.41 g sodium ethylate were added and the reaction mixture stirred at room temperature for ten minutes and then at 60° C. for 1.5 hours. The cooled reaction mixture was evaporated in vacuo and the residue dissolved in 100 ml ethyl acetate and 200 ml 4M HCl were added. The mixture was vigorously stirred at room temperature. The organic lay was separated and washed with 100 ml 4M HCl. The combined aqueous layers were neutralized with NaOH. The precipitate was filtered, washed with water and dried under vacuo to obtain 1.87 g 6-(4-Trifluoromethyl-phenyl)-3,4-dihydro-1H-[1,5]naphthyridin-2-one.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[C:9]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)([CH2:12][CH3:13])([CH3:10])[CH3:11]
Reactant: CCC(C)(C)c1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(C)(C)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-methoxy-3-tert-pentylbenzene (3.22 g, 18.1 mmoles) in 100 mL of DCM stirring in −78° C. bath was added dropwise 2.14 mL (5.68 g) of BBr3. The mixture was stirred while warming to room temperature. After 3 h, ice was added, and the organic layer separated, dried over Na2SO4, filtered and evaporated affording 3-tert-pentylphenol, 2.77 g, as an oil.
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12]>C(O)C>[C:1]([NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])(=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: CCOC(=O)C(C)O
Reactant: CC(C)(N)CO
Solvent: CCO
Product: CC(O)C(=O)NC(C)(C)CO
Temperature: 112.5 °C

Procedure:
15 g of ethyl lactate and 10 g of 2-amino-2-methyl-1-propanol were mixed and subsequently heated to 110-115° C. for 3.5 hours. During the reaction, the ethanol formed was distilled off. After the reaction, the excess of ethyl lactate was removed by vacuum distillation (bottom temperature: 160° C., 7 mbar), using a vigreux column. 15.5 g of residual brown viscous liquid was collected, which was confirmed to be pure N-lactoyl 2-amino-2-methylpropanol by NMR analysis.
Reaction SMILES: C(Cl)(Cl)Cl.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([O:25][C@@H:26]([C:35]([F:38])([F:37])[F:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])=[O:24])[CH2:17][CH2:16]2)C1C=CC=CC=1.I[Si](C)(C)C>CO>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([O:25][C@@H:26]([C:35]([F:36])([F:37])[F:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])=[O:24])[CH2:17][CH2:16]2
Reactant: CCOCCCCC[C@@H](OC(=O)C1=Cc2ccc(OCc3ccccc3)cc2CC1)C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOCCCCC[C@@H](OC(=O)C1=Cc2ccc(O)cc2CC1)C(F)(F)F
Yield: 414.1 %

Procedure:
To 10 ml of a chloroform solution of 0.19 g (0.4 mmol) of the (R)1-trifluoromethyl-6-ethoxyhexyl 6-benzyloxy-3,4-dihydro-2-naphthalenecarboxylate obtained in the first step was added 0.1 ml (0.4 mmol) of iodotrimethylsilane in a nitrogen atmosphere with stirring, and the mixture was reacted at room temperature for two and a half hours with stirring. Then, 8 ml of methanol was added, and the mixture was rapidly concentrated at room temperature under reduced pressure. The concentrate was separated by column chromatography, to obtain 0.64 g of (R)1-trifluoromethyl-6-ethoxyhexyl 6-hydroxy-3,4-dihydro-2-naphthalenecarboxylate as a crude product. The 1H-NMR data of this compound are described below. 1H-NMR (CDCl3), δ (ppm)
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([Br:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([Br:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc2cc(Br)ccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2ccc(Br)cc2n1
Yield: 89.5 %

Procedure:
A mixture of 3.00 g (12.00 mM) of 2-chloro-4-methyl-7-bromoquinoline and 0.63 g (12.00 mM) of sodium methoxide was heated to reflux in 30 mL of dry methanol for 48 h. The methanol was then removed in vacuo, and the resultant concentrate was taken up in methylene chloride. This methylene chloride solution was washed repeatedly with saturated sodium chloride. After drying (MgSO4), solvent removal, and recrystallisation from toluene, 2.63 g (87%) of the product was obtained as white crystals: mp 58°-60° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:34][CH:33]=1.[Br-]>CN(C)C=O>[C:44]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][CH2:20][C@@H:14]([NH:13][C:11](=[O:12])[CH2:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:27])[CH3:26])[C:15]2=[O:25])=[CH:37][CH:36]=1)#[N:45]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 0.83 g (2.21 mmol) of 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) in 6 mL of dry dimethylformamide at room temperature under nitrogen was added 97 mg of 60% sodium hydride dispersion in oil (58 mg NaH, 2.43 mmol, 1.1 eq). After stirring for 1 hour, a solution of 780 mg (2.88 mmol, 1.3 eq) of 4'-bromomethyl-1,1'-biphenyl-2-nitrile (Step C) in 2.0 mL of dimethylformamide was added via cannula. The flask which originally contained the bromide was washed with 1 mL of dry dimethylformamide which was then added to the reaction mixture via cannula. After stirring at room temperature for 3 hours, the reaction was diluted with 200mL of ethyl acetate, washed with 50 mL of water and 50 mL of brine. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate/hexane (6:4), to afford 1.13 g (90%) of the product as a white foam. 1H NMR (200MHz,CDCl3); 1.32 (s,3H), 1.40 (s,12H), 1.85 (m,1H), 2.35-2.70 (m,5H), 4.52 (m,1H), 4.90 (d,12Hz,1H), 5.21 (d,12Hz,1H), 6.70 (d,5Hz,1H), 7.10-7.65 (m,12H), 7.72 (d,6Hz,1H). FAB-MS: calculated for C34H38N4O4 566; found 567 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:12][CH:11]=3.[O:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[O:29]1[CH2:30][CH:31]=[C:32]([C:2]2[N:7]=[C:6]([F:8])[C:5]3[O:9][C:10]4[C:15]([C@@:16]5([CH2:20][O:19][C:18]([NH2:21])=[N:17]5)[C:4]=3[CH:3]=2)=[CH:14][C:13]([C:22]2[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:12][CH:11]=4)[CH2:33][CH2:34]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(Cl)nc1F
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(C2=CCOCC2)nc1F
Temperature: 135 °C

Procedure:
A reaction vessel charged with (S)-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (95 mg, 0.237 mmol; prepared as described in Method BB33) 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.474 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (8.39 mg, 0.012 mmol) and potassium phosphate (111 mg, 0.522 mmol) in 1.5 ml of a 2:1 mixture of dioxane and was heated at 135° C. microwave for 25 minutes. The reaction mixture was loaded directly onto a silica gel column and purified (CH2Cl2 to CH2Cl2/ethyl acetate=3:1 to 2:1 to 1:1 to 100% ethyl acetate to ethyl acetate/MeOH=100:5) to provide (S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as a off-white solid. MS m/z=449.0 [M+H]+. Calculated for C24H18F2N4O3: 448.42.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>C(#N)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCBr
Solvent: CC#N
Product: O=C(Cl)CCCCCCCBr
Temperature: 95 °C

Procedure:
A mixture of 8-bromooctanoic acid (26.4 g), thionyl chloride (40 ml) and acetonitrile (40 ml) was heated at 95° C. for 3 hours. The solvent was removed by distillation under vacuum and the residue purified by azeotropic distillation, using acetonitrile, to give 8-bromooctanoyl chloride.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]([O:14][CH2:15][CH3:16])(=[O:13])/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C1C=CC=CC=1>[C:8]([O:10][CH2:11][CH3:12])(=[O:9])[C@@H:7]1[CH2:4][CH:3]=[CH:2][CH2:1][C@H:6]1[C:5]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=CC=C
Reactant: CCOC(=O)/C=C/C(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1CC=CC[C@H]1C(=O)OCC
Temperature: 50 °C

Procedure:
One hundred (100) parts by weight of a butadiene is dissolved into a solution of 153 parts of diethyl fumarate in 650 parts of benzene at 0° C. The reaction solution is then heated in a bomb at 50° C. for 24 hours. The solvent is removed by a distillation and the liquid crude product is purified by a fractional distillation under vacuum (b.p.: 102-105° C. at 2 mm);
Reaction SMILES: [CH3:1][NH2:2].CO[C:5](=[O:24])[C@H:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:7][C:8]([NH:10][C:11]1[S:12][C:13](=[S:16])[NH:14][N:15]=1)=[O:9]>C(O)C>[S:16]=[C:13]1[S:12][C:11]([NH:10][C:8]([NH:7][C@@H:6]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]([NH:2][CH3:1])=[O:24])=[O:9])=[N:15][NH:14]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1n[nH]c(=S)s1
Reactant: CN
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1n[nH]c(=S)s1

Procedure:
A saturated solution of methylamine in ethanol (50 mL) and N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-L-phenylalanine methyl ester (EXAMPLE 1; 0.770 g, 2.28 mmol) is stirred at room temperature for 6 days. The solution is concentrated, diluted with water, and acidified with 1N HCl. The resultant solids are filtered and dried to give 576 mg of the amide. Recrystallization from hot EtOAc/CH2 Cl2 /MeOH gives 390 mg (51%) of the desired product as a white solid (mp 234°-236° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1.CCOCC>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Br[Mg]CCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Oc1ccc(C(O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of p-hydroxybenzaldehyde (1.50 g) in THF (30 mL) was added dropwise a solution of 2-phenylethyl magnesium bromide in ether (15.2 mL, 1.7M) at 0°. After being stirred overnight at room temperature (RT) using a mechanical stirrer, it was poured onto a buffer (pH 7), extracted with ethyl acetate and the organic phase was dried and evaporated. The title compound was obtained after crystallization from ethyl acetate/hexane and was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:16][C@H:17]4[CH2:22][CH2:21][C@H:20]([N:23]([CH3:24])[CH3:25])[CH2:19][CH2:18]4)[C:6]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][N:8]=3)[N:3]=2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, trans-N1-(6-chloro-3-(methylsulfonyl)-1,5-naphthyridin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine (28 mg, 0.073 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) followed by formation of the dihydrochloride salt to afford the desired product (30 mg, 72%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.92 (s, 1H), 8.51 (d, J=9.0 Hz, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.02 (t, J=1.7 Hz, 1H), 7.92 (dd, J=11.5, 2.2 Hz, 1H), 5.64 (br s, 1H), 3.52-3.42 (m, 1H), 3.39 (s, 3H), 2.91 (s, 6H), 2.65-2.55 (m, 2H), 2.33-2.26 (m, 2H), 1.88-1.72 (m, 4H); ESI MS m/z 493 [M+H]+; HPLC 98.3% (AUC), tR=9.62 min.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=O.Cl.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C(O)C>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:5]3[N:32]([C:29]4[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=4)[N:33]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=3)[S:8][C:9]=2[CH:15]=1
Reactant: COc1ccc2nc(C(=O)CC(=O)C(F)(F)F)sc2c1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2c1
Yield: 77.2 %

Procedure:
The mixture of 4,4,4-trifluoro-1-(6-methoxybenzothiazol-2-yl)butane-1,3-dione (300 mg, 1.0 mmol) and 4-methylsulfonyl-phenylhydrazine hydrochloride (260 mg, 1.1 mmol) was heated under reflux in ethanol (50 ml) for 3.5 hours, and then allowed to cool. The precipitated crystals were collected and subjected to recrystallization from ethanol and ethyl acetate-isooctane to afford 6-methoxy-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzothiazole (350 mg, 77%). NMR(CDCl3) δ: 3.11 (3H, s), 3.89 (3H, s), 7.11 (1H, dd, J=2.3 Hz, 8.6 Hz), 7.20 (1H, s), 7.32 (1H, d, J=2.3 Hz), 7.75 (2H, d, J=8.6 Hz), 7.82 (1H, d, J=8.6 Hz), 8.04 (2H, d, J=8.6 Hz); mp 217-218° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[C:18]([N:22]=[C:23]=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][C:23]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: CC(C)(C)N=C=O
Product: CN1C(=O)N2C(=NC1(C)C)N(C(=O)NC(C)(C)C)c1ccccc12

Procedure:
The procedure of Example 10 was used to prepare the title compound from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one and tert-butyl isocyanate. The white solid product melted at 209° C. with decomposition. The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [O-]CC.[Na+].O[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C.C(OCC)C>[O:8]=[C:7]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[O:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C(CO)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2ccccc2o1
Yield: 82.9 %

Procedure:
A 2,68 M sodium ethoxide solution in ethanol (21,9 ml) was added slowly to a solution of 2-hydroxyacetophenone (1.76 ml, 14.7 mmol) and diethyl oxalate (3.98 ml, 29.4 mmol) in a mixture of dry ethyl ether (20 ml) and absolute ethanol (20 ml). The mixture was stirred under reflux for 3 h. Afterwards it was diluted with ethyl ether (40 ml), added with 1M HCl (25 ml) and extracted with ethyl ether (3×40 ml). The combined ether phases were dried and the solvents were removed by evaporation under reduced pressure. The obtained residue was dissolved in absolute ethanol (60 ml) and 0.380 ml of concentrated hydrochloric acid were added. The resulting mixture was left under stirring at 75° C. for 1 h. After this time, 50 ml of water were poured on the mixture which was extracted with ethyl acetate (3×50 ml). The organic phase was washed successively with a sodium bicarbonate saturated solution and a NaCl saturated solution, dried and the solvents were evaporated off under reduced pressure, to obtain a crude which was purified by crystallization in ethyl ether, thereby obtaining 2.660 g of the title product (83% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[S:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[S:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(N2CCCCC2)sc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(CO)ccc1OCc1nc(N2CCCCC2)sc1C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde (0.50 g) in tetrahydrofuran (5 mL)-ethanol (5 mL) was gradually added sodium borohydride (0.05 g) at room temperature. After stirring for 1 hr, water was added to the reaction mixture and the precipitated crystals were collected by filtration to give {3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as colorless crystals (0.44 g, yield 90%). melting point: 92-93° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[S:7])[NH:4][C:3]1=[O:8].Cl.[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.O.[OH-].[Na+]>CS(C)=O>[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][S:7][C:5]1[NH:6][C:2]([CH3:9])([CH3:1])[C:3](=[O:8])[N:4]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: CC1(C)NC(=S)NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)c1ccccc1CSC1=NC(=O)C(C)(C)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, 1 g of 5,5-dimethyl-2-thiohydantoin was dissolved in 20 mL of dimethylsulfoxide, and 1.7 g of 2-dimethylaminobenzylchloride hydrochloride was added to the solution. The reaction mixture was stirred at the room temperature for one hour, and poured into 50 mL of water. The pH value of the solution was adjusted to 7-8 with diluted aqueous solution of 2N sodium hydroxide (NaOH). A precipitated sediment was extracted from the liquid, two times, using 50 mL of ethyl acetate (AcOEt). The AcOEt layer was successively washed with 50 mL of water and 50 mL of brine, dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The thus obtained residue was purified by column chromatography [developing solvent=CHCl3 :MeOH=20:1 (volume ratio, v/v)]. Recrystallized from diethyl ether gave the desired compound in the form of needle-like crystal. The yield of the compound was 1.2 g with a yield ratio of 62.4%, and its melting point was 113°-115° C.
Reaction SMILES: Cl.C([O:6][C:7](=O)[NH:8][CH2:9][CH2:10][C:11]([NH2:14])([CH3:13])[CH3:12])(C)(C)C.CC([O-])(C)C.[K+]>C1COCC1>[CH3:12][C:11]1([CH3:13])[CH2:10][CH2:9][NH:8][C:7](=[O:6])[NH:14]1
Reactant: CC(C)(N)CCNC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CCNC(=O)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
(3.4 g, 14.3 mmol) (3-Amino-3-methyl-butyl)-carbamic acid tert-butyl ester hydrochloride was dissolved in THF (60 ml) and KOtBu (6.4 g, 57.1 mmol, 4 equiv.) was added. The mixture was stirred for 16 hours at 60° C. and evaporated then with isolute to dryness. The crude product was purified by flash chromatography by directly loading the residue onto a silica gel column and eluting with an ethyl acetate:methanol gradient 100:0 to 70:30. The desired 4,4-dimethyl-tetrahydro-pyrimidin-2-one (1.65 g, 90% yield) was obtained as a light yellow solid, MS: m/e=129.1 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13](=O)[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)CC12CC2
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN2CCC3(CC3)C2)cc1

Procedure:
5-benzyl-5-azaspiro[2.4]heptan-7-one (300 mg) was mixed with hydrazine (600 mg) and NaOH (300 mg) in H2O (2 ml). The mixture was refluxed for overnight and purified by column chromatography to give 5-benzyl-5-azaspiro[2.4]heptane that was hydrogenated at 50 psi with Pd—C (10%, 80 mg) in EtOH (15 ml) for overnight followed by filtration through Celite to give 5-azaspiro[2.4]heptane. This product was mixed with 2-Bromoethanol and K2CO3 in Acetonitrile. The reaction was refluxed overnight and filtered, the filtrate was evaporated and purified on silica gel column to give the titled product. Mass: (M+1), 142
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][C:12]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[CH:14][C:13]=1[NH:27][C:28]([C:30]1[S:34][C:33]2[CH2:35][CH2:36][CH2:37][CH2:38][C:32]=2[CH:31]=1)=[O:29].BrC1C(=O)N(C)C=C(Br)C=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:10][C:4]1[CH:3]=[C:2]([C:17]2[C:12]([CH3:11])=[C:13]([NH:27][C:28]([C:30]3[S:34][C:33]4[CH2:35][CH2:36][CH2:37][CH2:38][C:32]=4[CH:31]=3)=[O:29])[CH:14]=[CH:15][CH:16]=2)[CH:7]=[N:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ncc(Br)cc1N
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cn1cc(Br)cc(Br)c1=O
Solvent: COCCOC
Product: COc1ncc(-c2cccc(NC(=O)c3cc4c(s3)CCCC4)c2C)cc1N
Temperature: 95 °C
Yield: 65 %

Procedure:
In a 48 mL sealed tube equipped with a magnetic stirring bar was placed 5-bromo-2-methoxypyridin-3-amine (16) (1.0 g, 4.0 mmol), N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (1(2.4 g, 6.7 mmol), and Pd(PPh3)4 (0.30 g, 0.20 mmol) in DME/1N Na2CO3 (10 mL, 1/1). After the reaction mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the mixture was cooled to room temperature and diluted with dichloromethane (10 mL) and H2O (10 mL), and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-25% MeOH in dichloromethane, to afford 1.0 g (65%) of N-(3-(5-amino-6-methoxypyridin-3-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (17) as a solid.