Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:23]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([O:8][CH:9]([C:18]([F:19])([F:21])[F:20])[CH2:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1ccccn1)C(F)(F)F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccn1
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 88.5 %

Procedure:
A solution of 810 mg (2.54 mmol) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluorobutyl]pyridine in 8 mL of THF was treated with 2.54 mL (3.81 mmol, 1.5 eq.) of LDA (1.5 M solution in cyclohexane) at −75° C. After stirring at −75° C. for 45 minutes, 474 μL (7.61 mmol, 3.0 eq.) of methyl iodide was added at −75° C. The resulting mixture was stirred at this temperature for 10 minutes and quenched with saturated NH4Cl solution. The product was extracted into ether. The ethereal layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 750 mg (89%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1-methylbutyl]pyridine (a mixture of two diastereomers) as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: COc1ccc(CCN)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCNCc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
0.39 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.230 ml 2-(4-methoxy-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1) to give 430 mg colorless viscous oil (96%). MS (ISP) 298.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(Br)c(F)c1

Procedure:
To 1-bromo-2-fluoro-4-hydroxybenzene (100 g, 0.52 mol) and K2CO3 (179.4 g, 1.3 mol) in 1300 mL acetone was added dimethyl sulfate (98.38 g, 0.78 mol). After refluxing overnight, the reaction mixture was cooled, filtered and dried over Na2SO4, and the filtrate was concentrated to afford 1-bromo-2-fluoro-4-methoxybenzene as a brown oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[ClH:19].[NH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2O[Si](C(C)(C)C)(C)C)[N:22]=1.C1C[O:48]CC1>>[ClH:19].[NH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]([C:31]2[CH:36]=[CH:35][C:34]([OH:48])=[CH:33][CH:32]=2)[N:22]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1C1Cc2ccccc2C(N)=N1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: NC1=NC(c2ccc(O)cc2)Cc2ccccc21
Reaction time: 0.25 h

Procedure:
Tetra-n-butylammonium fluoride (1.0M in THF, 3.3 ml) was added to a stirred solution of 1-amino-3-(tert-butyldimethylsilyloxyphenyl)-3,4-dihydroisoquinoline hydrochloride (638 mg, 1.11 mmol) in THF (10 ml). After 15 min., the mixture was evaporated and the residue purified by flash chromatography on untreated neutral alumina, eluting with 5% methanol in dichloromethane, increasing the gradient to 40% methanol in dichloromethane to give a colourless solid (172 mg). This was recrystallised from methanol/dichloromethane (1:2) to give the product as a white powder. M+ 239; 360 MHz 1H n.m.r (d6 -DMSO) 9.65 (1H, br.s), 8.15 (1H, d, J 7.8 Hz), 7.69 (1H, t, J 7.5 Hz), 7.52 (1H, t, J 7.6 Hz), 7.45 (1H, d, J 7.5 Hz), 7.19 (2H, d, J 8.6 Hz), 6.77 (2H, d, J 8.6 Hz), 4.87 (1H, t, J 7.3 Hz), 3.25 (2H, d, J 7.3 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:16]=[C:15]([C:26]([OH:28])=O)[CH:14]=1)#[N:2].Cl.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@H:37]([NH2:39])[CH3:38])[CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:16]=[C:15]([C:26]([NH:39][C@H:37]([CH3:38])[CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)=[O:28])[CH:14]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cc(C(F)(F)F)ccc3C#N)c2)nc1
Reactant: C[C@@H](N)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3cc(C(F)(F)F)ccc3C#N)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 2′-cyano-5-(5-methylpyridin-2-yl)-5′-(trifluoromethyl)biphenyl-3-carboxylic acid (30 mg, 0.078 mmol), (R)-1-morpholinopropan-2-amine hydrochloride (33 mg, 0.18 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (145 mg, 0.38 mmol), N,N-diisopropylethylamine (106 μL, 0.61 mmol), N,N-dimethylformamide (0.5 mL) and the reaction was stirred overnight at room temperature. The mixture was purified by HPLC to afford the title compound as a light orange solid.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].[S:2]([O-:5])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
Methanesulfonic acid (0.65 ml, dissolved in 35 ml of 2-propanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 182.2° C.
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[C:12]([CH:13]=O)=[C:11]([OH:15])[C:10]([O:16][CH3:17])=[CH:9][CH:8]=1.Cl.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:6][C:7]1[C:12]([CH:13]=[CH2:1])=[C:11]([OH:15])[C:10]([O:16][CH3:17])=[CH:9][CH:8]=1
Reactant: COc1ccc(F)c(C=O)c1O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1c(F)ccc(OC)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 50 g of methyltriphenylphosphonium bromide in 300 ml of toluene there was added dropwise 45 ml of n-butyllithium (2.55 M, hexane solution) at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours and allowed to stand. Next, 150 ml of the supernatant was added to a solution of 5 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No. 457628-15-8] in 90 ml of toluene. The mixture was stirred at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 3-fluoro-6-methoxy-2-vinylphenol (4.33 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.F[C:10]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:11]=1[C:12]([C:14](=[CH2:18])[C:15]([O-:17])=[O:16])=[O:13]>C(O)C>[F:25][C:20]1[CH:19]=[C:11]2[C:10](=[C:22]([F:23])[C:21]=1[F:24])[N:6]([C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:12]2=[O:13]
Reactant: C=C(C(=O)[O-])C(=O)c1cc(F)c(F)c(F)c1F
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C

Procedure:
5.7 g of 4-fluoroaniline are added dropwise to a solution of 16 g of ethyl 3-ethoxy-2-(2,3,4,5-tetra-fluorobenzoyl-acrylate (5) (X1 -X4 =F) (Appln. Ser. No. 756,469, filed July 18, 1985, now U.S. Pat. No. 4,952,695) in 50 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 50 ml of ice-water are added and the precipitate is filtered off cold with suction, rinsed with water and dried at 50° C. over calcium chloride in vacuo. 16.5 g of (6) (R=4-fluorophenyl, X1 -X4 =F) of melting point 93°-95° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:23])=O)[NH:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:33])[NH2:23])[NH:6]2
Reactant: CN(c1ccc(Cl)c2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CN(c1ccc(Cl)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A mixture of 4-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.54 g), Lawesson's reagent (0.59 g) and tetrahydrofuran (20 mL) was stirred at 60° C. for 3 hr. The reaction mixture was concentrated, toluene was added, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (0.51 g, yield 87%) as yellow crystals. melting point>248° C. (decomposition).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([CH3:23])[C:20]([C:24]([OH:26])=O)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1.[N+:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([NH2:39])[CH:34]=[CH:33]2)([O-:29])=[O:28].CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([NH:39][C:24]([C:20]1[C:21]([CH3:23])=[N:22][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=3)=[N:18][CH:19]=1)=[O:26])[CH:34]=[CH:33]2)([O-:29])=[O:28]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Nn1ccc2cc([N+](=O)[O-])ccc21
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 85 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
DIPEA (12.65 mmol) is added a solution of 2-(3-fluoro-phenyl) -4-methyl-pyrimidine-5-carboxylic acid (4.22 mmol), 5-nitro-indole-1-ylamine (4.22 mmol) and HOTT (S-(1-oxido-2-pyridyl)-thio-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (7.6 mmol) in anhydrous DMF (15 mL) and the mixture is heated at 80-90° C. overnight. After evaporation of solvent, the residue is dissolved in EtOAc (150 mL), washed with water (20 mL), 5% sodium sulfate (20 mL), water (mL) and brine (20 mL). The organic layer is dried (Na2SO4), filtered and concentrated. The residue is kept at rt overnight to yield 4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-nitro-indol-1-yl)-amide (730 mg, 44%) as a solid. MS: 392 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.78(s, 3H), 6.88(d, H), 7.38-7.53(m, H), 7.57-7.76(m, 2H), 7.81(d, H), 8.06-8.32(m, 2H), 8.34(d, H), 8.65(d, H), 9.27(s, 2H).
Reaction SMILES: [CH2:1](OC(C1OC2C=CC=C(C(=O)N)C=2C=1C)=O)C.[H-].[Na+].IC.[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:41])[NH:39][CH3:40])[C:31]=2[C:32]=1[CH3:33])=[O:27])[CH3:24]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:41])[N:39]([CH3:1])[CH3:40])[C:31]=2[C:32]=1[CH3:33])=[O:27])[CH3:24]
Reactant: CCOC(=O)c1oc2cccc(C(=O)NC)c2c1C
Reactant: CCOC(=O)c1oc2cccc(C(N)=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(C(=O)N(C)C)c2c1C
Temperature: 50 °C

Procedure:
To 200 mg of 4-carbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.81 mmol, 1 eq.) in 5 mL of DMF was added 50 mg of NaH (60% in mineral oil, 1.25 mmol, 1.5 eq) under nitrogen. After 30 min of reaction, iodomethane (0.053 mL, 0.85 mmol, 1 eq) was added to the reaction. The mixture was then heated to 50° C. for 12 h. After work up and column chromatography, a mixture of 3-methyl-4-methylcarbamoyl-benzofuran-2-carboxylic acid ethyl ester and 4-dimethylcarbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained (76 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.8 (d, J=4.5 Hz, 6 H) 4.4 (q, J=7.2 Hz, 2 H) 7.3 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (dd, J=8.3, 7.3 Hz, 1 H) 7.8 (dd, J=8.5, 0.9 Hz, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:37])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:37])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(F)(F)F)c3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(C(F)(F)F)c3)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-5-methyl-2-{3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M244) (0.26 g, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (200 mg, 98%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:23])=[C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:12]#[N:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>ClCCl>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([O:23][S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:12]#[N:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(O)=C(C#N)c2nc3ccccc3s2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C(OS(=O)(=O)c2ccc(C)cc2)=C(C#N)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.9 %

Procedure:
To a solution of the above prepared 3-(1-acetylpiperidin-4-yl)-2-benzothiazol-2-yl-3-hydroxyacrylonitrile (415 mg, 1.27 mmol) in anhydrous dichloromethane (20 mL) at room temperature under argon were added triethylamine (193 mg, 1.9 mmol) and tosyl chloride (303 mg, 1.59 mmol) in small portions. The resulting mixture was stirred at room temperature for 6 hrs. The reaction mixture was diluted with dichloromethane. The organic phase was washed with 1% HCl, 0.5% NaOH, water, brine, and dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting crude product was purified by flash column chromatography eluting with CH2Cl2:MeOH=20:1 to yield 140 mg (23%) of toluene-4-sulfonic acid 1-(1-acetylpiperidin-4-yl)-2-benzothiazol-2-yl-2-cyanovinyl ester. MS (m/z, ES+): 482.1 (M+1, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30]
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(F)cc1F
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(F)cc2F)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:13][C:12](=[O:14])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.IC.[C:23](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:23])[C:12](=[O:14])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CC2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 1.00 g (0.0034 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-spiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VI-53) in 40 mL of dimethylformamide was added 1.47 g (0.0104 mole) of iodomethane and 1.68 g (0.00575 mole) of cesium carbonate. The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.957 g of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8]N)=[N:6][CH:7]=1.[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH2:11][CH3:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]([CH3:12])=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(=O)c1ccccc1
Reactant: NNc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)[nH]c2ncc(Br)cc12

Procedure:
5-Bromo-2-hydrazinopyridine (15.6 g, 0.083 mol) and propiophenone (11.1 ml) was heated at 90° C. (steam bath) for 30 min. Then toluene (100 ml) was added and the resulting solution was refluxed for 2 h to remove water by azeotropic distillation (Dean Stark apparatus). Evaporation of solvent gave 26.4 g of crude product, assumed to be the desired hydrazone. Crude hydrazone (3.02 g) was dissolved in diethylene glycol (30 ml) and heated at 245° C. under argon for 24 h. The reaction mixture was poored crushed ice and extracted with methylene chloride. Drying over MgSO4 and evaporation of solvent left a tary residue which was triturated with diethyl ether to produce 0.84 g (30%) of a brownish, semi-crystalline product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1([P:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17]C)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClC1C=CC=CC=1Cl>[C:10]1([P:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:2]2[N:7]=[C:6]([P:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:17])[CH:5]=[C:4]([P:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])[N:3]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COP(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1cc(P(=O)(c2ccccc2)c2ccccc2)nc(P(=O)(c2ccccc2)c2ccccc2)n1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred, refluxing mixture of 5.00 g of 2,4,6-trichloropyrimidine in 100 ml of o-dichlorobenzene under nitrogen was added dropwise 26.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 6.5 hours and then allowed to stand overnight at room temperature. The next day a small amount of the solvent was removed by boiling, and the solution was allowed to stand again overnight. The next day the resulting solid was separated by filtration, washed twice with benzene and three times with hexane, recrystallized from 650 ml of toluene, and dried at 100° C./0.1 mm (13 Pa) to give 11.35 g of 2,4,6-tris(diphenylphosphinyl)pyrimidine (shown by formula in Claim 10) as a white solid, mp 235°-236° C. Anal. Calcd for C40H31N2O3P3 : C, 70.59; H, 4.59; N, 4.12; P, 13.65. Found: C, 70.72; H, 4.90; N, 3.92; P, 13.61.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: OCc1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(CO)cc1
Reaction time: 18 h
Yield: 28.3 %

Procedure:
To a solution of 4-hydroxybenzyl alcohol (7.5 g, 60 mmol) and 8.4 mL of triethylamine (8.4 mL, 60 mmol) in 100 mL of ethyl acetate, cooled in an ice bath, was added, via canula over 15 min, a solution of acetyl chloride (4.7 mL, 66 mmol) in 50 mL of ethyl acetate. The mixture was stirred in the same bath, which was left to come to room temperature on its own. After 18 h, the precipitate was removed by filtration. It was rinsed with 50 mL of ethyl acetate in small portions. The combined filtrates were concentrated in vacuo and purified by flash chromatography on silica gel, using 3:2 hexanes:ethyl acetate as the eluent, to afford 60 (2.853 g, 17 mmol, 29%) as an oil. 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 4.69 (d, J=5.8 Hz, 2H), 7.08 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.Br[CH2:35][F:36].[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][O:17][CH2:35][F:36])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Reactant: FCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=COCF)c2ccc3c(c2)CCCC3)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
0.76 g (2.0 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide and 8ml of anhydrous N,N-dimethylformamide were mixed and 0.5 ml of bromofluoromethane was added thereto at −15° C. 88 mg (2.2 mmol) of 60% sodium hydride was added and stirred at −15° C. for 30 minutes and then stirred at approximately 0° C. for 1.5 hours. Water was added to the reaction mixture, followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel preparative thin layer chromatography (eluent, hexane:ethyl acetate=1:1) to give 0.68 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide(the present compound 1103).