Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=3)=[C:11]([F:22])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:23][C:24](C)([O-])C.[K+].O.Cl>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]([CH:20]=[CH:23][CH3:24])=[CH:17][CH:16]=3)=[C:11]([F:22])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCc1ccc(-c2ccc(-c3ccc(C=O)s3)c(F)c2)cc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC=Cc1ccc(-c2ccc(-c3ccc(CC)cc3)cc2F)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
26.0 g (70.0 mmol) of ethyltriphenylphosphonium bromide are initially introduced in 400 ml of THF together with 20.0 g (62.6 mmol) of 5-(4′-ethyl-3-fluorobiphenyl-4-yl)thiophene-2-carbaldehyde, and a solution of 7.86 g (70.0 mmol) of potassium tert-butoxide in 100 ml of THF is added with ice-cooling. The mixture is stirred at room temperature for 20 h. Water and 2 N hydrochloric acid are added, and the batch is extracted with MTBE. The organic phase is washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is evaporated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene 9:1→toluene).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.CN(C)[CH:17]=[O:18].O>O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: COc1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of butyllithium in hexanes (2.5 M; 15.9 ml) was added to a stirring solution of 3-fluoroanisole (5.0 g) in dry tetrahydrofuran (100 ml) at -78° C. and the mixture stirred at that temperature for 30 min. Dry dimethylformamide (3.1 ml) was added and the mixture stirred and allowed to warm to ambient temperature during one hour. Water (150 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulphate, and the solvent removed in vacuo. Distillation of the residue under reduced pressure gave 2-fluoro-6-methoxybenzaldehyde (4.6 g) as an oil b.p. 120° C. at 10.66 mbar.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=O)[CH2:10][S:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][NH:12][CH2:11][CH2:10][S:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(C2CNC(=O)CS2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1ccc(C2CNCCS2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To the solution of 6-(4-aminophenyl)-thiomorpholin-3-one (0.26 g, 1.25 mmol) in anhydrous tetrahydrofuran (6.7 mL) was added lithium aluminium hydride (0.16 g, 4.27 mmol) in several portions and the mixture was stirred at 60° C. for 2 h. Na2SO4×10H2O (2.00 g) was added in small portions until the complex was decomposed. The suspension was filtered, the solids were washed with tetrahydrofuran (2×3 mL) and the combined filtrates were evaporated. The title compound was obtained as a viscous oil (0.25 g, 1.26 mmol, 100%). ESMS m/z 195 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([O:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C.C(O)C.CO>ClC1C=CC(Cl)=CC=1Cl>[O:9]=[C:10]1[N:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][CH:17]=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1nccs1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1cnc2sccn2c1=O

Procedure:
A solution of 2-aminothiazole (10g., 100mM) and diethyl ethoxymethylenemalonate (21.6g., 100mM) in 1,2,4-trichlorobenzene (100ml) was heated at 150° C for 4 hours with collection of evolved ethanol. The reaction mixture was cooled and the required product filtered off and recrystallised from ethanol in 75.9% weight yield (17.0g). δ (CDCl3), 8.98 (1H,s, H5), 8.33 (1H,d, H1, J = 5.0Hz), 7.40 (1H,d, H2, J = 5.0Hz), 4.47 (2H,q, --CH2CH3), 1.41 (3H,t, --CH2CH3); λmax (MeOH) 235nm (εm 5000), 258nm (εm 4,550) and 346nm (εm 13,500); (Found: C, 47.84; H, 3,42; N, 12.19; S, 14.54%. C9H8N2O3S requires C, 48.22; H, 3.60; N, 12.50; S, 14.28%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[Cl:15])(=O)C.[CH3:16][NH:17][CH3:18].Cl.CO>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:17]([CH3:18])[CH3:16])(=[O:13])=[O:12])=[CH:7][C:6]=1[Cl:15]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CNC
Agent: Cl
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 15.8 %

Procedure:
A suspension of 4-acetamido-3-chlorobenzene-1-sulfonyl chloride (0.96 g, 3.58 mmol) in a dimethylamine solution (2M in MeOH, 5.37 mL, 10.7 mmol) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was then redissolved in MeOH (17.9 mL). A 1M HCl solution in MeOH (5.37 mL, 5.37 mmol) was added and the reaction mixture was refluxed for 6 hours before being concentrated under reduced pressure. The residue was purified via Biotage silica gel column chromatography eluting with (cyclohexane/EtOAc 80/20 to 60/40) to afford the title product as a white solid (133 mg, 16%). 1H NMR (500 MHz, CDCl3) d 2.70 (s, 6H), 4.54 (br s, 2H), 6.83 (d, J=8.5 Hz, 1H), 7.48 (dd, J=8.5, 2.1 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([Si:27]([CH3:41])([CH3:40])[O:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][OH:39])=[CH:33][CH:32]=1)([CH3:26])([CH3:25])[CH3:24].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Si:27]([O:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH:38]=[O:39])=[CH:35][CH:36]=1)([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(CCO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CC=O)cc1
Reaction time: 0.5 h

Procedure:
Dess-Martin periodinane (0.38 g) was added to a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethyl)phenyl)ethanol (example 5, step b) (0.21 g) in dichloromethane (5 mL) and the resulting mixture stirred for 30 min. A mixture of saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (25 mL) were added and the resulting mixture stirred for 10 min. The organic phase was separated and washed with saturated sodium bicarbonate solution (2×10 mL) and brine (10 mL), then dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a clear oil which was used immediately. Yield 0.20 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25]Cl)(=[O:22])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[CH3:35][NH:36][CH3:37]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:36]([CH3:37])[CH3:35])(=[O:22])=[O:21])[CH2:16][CH2:15]1
Reactant: CNC
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 60 °C
Reaction time: 0.02 h
Yield: 49 %

Procedure:
To a solution of 5-bromo-3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-1H-indazole-7-carboxamide (Intermediate 7) (200 mg, 0.432 mmol) in DMF (5 mL) was added K2CO3 (250 mg), sodium iodide (10 mg), and 2M dimethyl amine in DMF (1 mL) The reaction mixture was heated to 60° C. overnight. The solution was filtered. The filtrate was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 40% B to 80% B in 3.2 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (100 mg, 49%)
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN.[CH3:23][C:24]1[N:29]=[C:28]([C@H:30]2[CH2:34][CH2:33][C@@:32]3([CH2:38][CH2:37][N:36](COCC[Si](C)(C)C)[C:35]3=[O:47])[NH:31]2)[CH:27]=[C:26]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[CH:25]=1.[ClH:58].CCOCC>C1COCC1.C(Cl)Cl>[ClH:58].[CH3:23][C:24]1[N:29]=[C:28]([C@H:30]2[CH2:34][CH2:33][C@@:32]3([CH2:38][CH2:37][NH:36][C:35]3=[O:47])[NH:31]2)[CH:27]=[C:26]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:50][CH:49]=2)[CH:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc([C@H]2CC[C@@]3(CCN(COCC[Si](C)(C)C)C3=O)N2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: NCCN
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc([C@H]2CC[C@@]3(CCNC3=O)N2)n1
Temperature: 120 °C

Procedure:
1 M tetra-n-butylammonium fluoride in THF (1.43 mL, 1.43 mmol) then ethylenediamine (0.19 mL, 2.87 mmol) were successively added to a stirred solution of (2R,5S)-2-[6-methyl-4-[4-(trifluoromethyl)-phenyl]-2-pyridyl]-7-(2-trimethylsilylethoxymethyl)-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 45) (145 mg, 0.2900 mmol) in dry THF (4 mL) in a 20 mL microwave vial. It was then sealed under N2 and heated in a microwave reactor at 120° C. for 0.5 hours (3 bar pressure recorded). Further 1 M tetra-n-butylammonium fluoride in THF (1.43 mL, 1.43 mmol) was added and the solution microwaved for a further 0.5 hours at 120° C. More 1 M tetra-n-butylammonium fluoride in THF (1.43 mL, 1.43 mmol) was added and the solution microwaved for a further 0.5 hours at 120° C. More 1 M tetra-n-butylammonium fluoride in THF (1.43 mL, 1.43 mmol) was added and the solution microwaved for a further 0.5 hours at 120° C. The reaction mixture was evaporated to a residue which was dissolved in EtOAc (25 mL) and the solution washed with water (2×20 mL). The latter was re-extracted with EtOAc (2×20 mL) and the combined organic extracts were dried (MgSO4) and evaporated to an oil, which was dried at room temperature under vaccum overnight. The oil separated into a colourless mobile phase and a light yellow, viscous, immobile oil. The former was removed to leave the viscous oil. This was purified by silica gel column chromatography. The oil was dissolved in DCM (3 mL) and the solution applied to a 10 g cartridge which was eluted on a Biotage SP4 system with a gradient of solvent A:DCM (0-80%) where solvent A=MeOH/DCM/1 M NH3-MeOH (10:90:4). Relevant fractions were pooled and evaporated to a light yellow oil which was stirred with iso-hexane (2×2 mL), which was decanted leaving an insoluble oil. This was dissolved in DCM (2 mL) and 1 M HCl in Et2O (190 μL, 1.05 equivalent) was added. The solution was evaporated to a foam. To the foam was added Et2O (2 mL) and the mixture was stirred for 2 hours until a cream solid was obtained. The supernatant was decanted off and the solid was dried at room temperature under vacuum overnight to form (2R,5S)-2-[6-methyl-4-[4-(trifluoro-methyl)phenyl]-2-pyridyl]-1,7-diazaspiro-[4.4]nonan-6-one hydrochloride (E94) (50 mg);
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=2[Cl:1])[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Oc1cccc(C(F)(F)F)c1Cl)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(F)(F)F)c2Cl)CC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
An intermediate, 1-(2-Chloro-3-trifluoromethyl-phenyl)-piperazine was produced as follows: To a stirred solution of trifluoro-methanesulfonic acid 2-chloro-3-trifluoromethyl-phenyl ester (5.0 g, 15.20 mmol) in toluene (50 mL) at room temperature, was added 1-boc-piperazine (3.39 g, 18.20 mmol), tris-(dibenzylideneacetone)di-palladium(0) (Pd2(dba)3) (3.49 g, 38.10 mmol), tert-2,2′-bis(diphenyl)phosphino-1,1′-binaphthyl (BINAP) (4.27 g, 68.60 mmol) and sodium tert-butoxide (2.04 g, 21.30 mmol). The mixture was degassed, filled with N2, degassed and heated at 80° C. for 1.5 h. The mixture was diluted with ethyl acetate, celite was added and the mixture was stirred at room temperature for 15 min. It was filtered through a pad of silica gel and the pad was washed with additional amounts of ethyl acetate, The combined solvent was removed in vacuo and the residue was purified on a silica gel column using hexanes-ethyl acetate (5:1) as eluent to give 4-(2-chloro-3-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.30 g, 42%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.35 (m, 2H), 7.22 (d, 1H), 3.62 (br s, 4H), 3.05 (br s, 4H), 1.55 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][N:16]=2)[CH2:12][CH2:13]1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(NC2CCNCC2)nc1

Procedure:
4-(5-Trifluoromethyl-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (460 mg; 1.33 mmol, prepared in accordance with Example 49) is dissolved in dichloromethane (6 mL) and trifluoroacetic acid (1 mL) is added under stirring. After 30 minutes reaction time, the solution is concentrated under reduced pressure and the residue obtained is co-evaporated with dichloromethane (5 mL). The product isolated is dissolved in dioxane (2 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added. The precipitate formed is filtered, rapidly rinsed with a small amount of dioxane and is dried under high vacuum to afford the desired product as hydrochloride (352 mg; 1.25 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][C:5]([CH3:18])=[C:4]([C:19](O)=[O:20])[C:3]1=[O:22].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][C:5]([CH3:18])=[C:4]([C:19]([N:44]2[CH2:45][CH2:46][CH:41]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:42][CH2:43]2)=[O:20])[C:3]1=[O:22]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)n(C)c(=O)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)n(C)c(=O)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A solution of 0.16 g (0.5 mmol) of 1,4-dimethyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid (intermediate 5) in 5 ml of CH2Cl2 was treated at RT with two drops of DMF; then, 0.05 ml=0.074 g (0.6 mmol) of oxalyl chloride was added and the reaction mixture was stirred for 30 min at RT. After removal of the solvents by evaporation in a high vacuum, the residue was dissolved again in 10 ml of CH2Cl2 and the solution was cooled down to 0° C.; then, 0.29 ml=0.21 g (2.1 mmol) of Et3N was added while stirring, followed by 0.081 g (0.5 mmol) of 4-pyrrolidin-1-yl-piperidine. The reaction mixture was subsequently warmed up to RT. After 3 hours, it was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 95:5) to give 0.20 g (85%) of the title compound as light yellow solid. MS: 448.2 (MH+).
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:30]=[CH:31]/[C:32]([OH:34])=O)[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1.[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([C:42]2[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=2)[C:37]1=[O:49].O>CN(C=O)C.C(OCC)(=O)C>[Br:48][C:45]1[CH:44]=[CH:43][C:42]([CH:38]2[CH2:39][CH2:40][CH2:41][N:36]([NH:35][C:32](=[O:34])/[CH:31]=[CH:30]/[C:20]3[CH:21]=[CH:22][C:23]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:18]([O:17][CH3:16])[CH:19]=3)[C:37]2=[O:49])=[CH:47][CH:46]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN1CCCC(c2ccc(Br)cc2)C1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)NN2CCCC(c3ccc(Br)cc3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
BOPCl (1.18 g) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (800 mg), 1-amino-3-(4-bromophenyl)piperidin-2-one (898 mg) and TEA (0.9 mL) in DMF (20 mL), and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 1.484 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[CH:20][N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[CH:20][N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(N)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.32 g, 1.0 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (1.22 mL, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and the mixture was extracted with aqueous 1N HCl solution (three times). The combined extract was neutralized with solid NaHCO3 and extracted with dichloromethane (two times). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give the desired product (0.17 g, 58%). LCMS calculated for C14H13FN3OS (M+H)+: m/z=290.1. Found: 290.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CC(C)([O-])C.[K+]>O1CCCC1.O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: OCc1ccccn1
Reactant: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OCc2ccccn2)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 95) 356 mg and 2-hydroxymethylpyridine 109 mg in anhydrous tetrahydrofuran 4.5 ml is added potassium tert-butoxide 112 mg under ice cooling, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with water, extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (silica gel 10 g, solvent; chloroform:ethyl acetate=5:1→2:1) and concentrated in vacuo to give 2-(2-pyridylmethoxy)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (the compound prepared in Example 67-(3)) as a colorless caramel, 338 mg, which is crystallized on standing at room temperature overnight. mp 90–92° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5](=[O:9])[CH2:6][C:7]#[N:8].[OH-].[Na+].S(O)(O)(=O)=O.O[NH2:20].Cl>O>[CH3:1][O:2][CH2:3][C:4]([C:5]1[O:9][N:8]=[C:7]([NH2:20])[CH:6]=1)([CH3:11])[CH3:10]
Reactant: COCC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COCC(C)(C)c1cc(N)no1
Temperature: 100 °C
Yield: 93.6 %

Procedure:
To a stirred solution of 1.68 g (10.8 mmol) of 5-methoxy-4,4-dimethyl-3-oxo-pentanenitrile and 0.49 g (11.9 mmol) of sodium hydroxide in water (13 mL) is added a solution of 0.98 g (5.9 mmol) of hydroxyamine sulfate in water (4 mL). The reaction mixture is heated to 100° C. for 1.5 h. After this time, the reaction mixture is cooled to room temperature and 0.8 mL (9.7 mmol) of 37% aqueous HCl solution is added. The reaction is heated to 100° C. for 0.5 h. After cooling, the pH of the reaction mixture is adjusted to pH˜12 by addition of 1M aqueous NaOH solution and extracted with DCM (3×20 mL). The organic layers are combined and washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residual brown oil is purified by column chromatography (Biotage, eluent DCM, MeOH) to yield 0.94 g of 5-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-3-ylamine as a yellow oil. Yield 51%; m/z 171 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (6H, s), 3.22 (3H, s), 3.26 (2H, s), 5.40 (2H, m) 5.53 (1H, s).
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:17]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.C(O)(=O)C.O1CCCC1>[OH:4][C:3]1[CH2:5][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[O:24][C:1](=[O:6])[CH:2]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(c1ccccc1)c1ccncc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2ccccc2)(c2ccncc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 90 mmol of ethyl acetoacetate, 99 mmol of NaH 30 60% dispersion in oil, 95 mmol of 1.6 M n-butyl lithium in hexane and 90 mmol of 4-benzoylpyridine and 250 mL of tetrahydrofuran. The reaction mixture was acidified with acetic acid and the crude solid was washed with ice water (m.p. 148-150° C.).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>>[C:1]1([C@H:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:9][NH2:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc([C@@H]2CN2)cc1
Reactant: c1c[nH]cn1
Product: NC[C@H](c1ccccc1)n1ccnc1

Procedure:
1 g of (R)(-)-2-phenyl-aziridine and 1.14 g of imidazole are heated at 120° for 24 hours. After cooling the reaction mixture can be used for the acylating step without further purification. An analytical sample can be obtained by chromatography over silica gel;