Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][NH2:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:19][CH2:20]O>>[ClH:1].[CH2:19]([NH:15][CH2:14][C@H:13]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([I:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[C:16]([OH:18])=[O:17])[CH3:20]
Reactant: NC[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCNC[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
HCl gas was rapidly bubbled through a suspension of acid 8-3 (4.0 g, 10.81 mmol) in EtOH (50 ml) at 0° C. for 10 minutes. The cooling bath was removed and the reaction was heated to 60° C. After 18 h, the reaction was concentrated to provide ester 8-4 as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.C[Si]([C:13]#[N:14])(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: [O-][n+]1ccc(Br)cc1
Reactant: C[Si](C)(C)C#N
Product: N#Cc1cc(Br)ccn1

Procedure:
The title compound was prepared from 4-bromo-pyridine-1-oxide (Rec. Trav. chime, 1951, 70, 581) and trimethylsilyl cyanide, using the procedure described in Chem. Pharm. Bull., 1985, 33, 565, and obtained as a solid (49% yield), m.p. 88°-93° C. Rf 0.53 (SS 11). Found: C,39.15; H,1.50; N,15.07. C6H3BrN2 requires C,39.37; H,1.65; N,15.30%.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[O:13][CH:12]([CH2:15][NH2:16])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>O1CCCC1>[CH2:30]([O:29][C:27](=[O:28])[NH:16][CH2:15][CH:12]1[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:14]=2[O:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(C3CCCC3)c2O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(C3CCCC3)c2O1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
To a suspension of (7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.4 g, 9.46 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was added diisopropylethylamine (2.14 g, 16.58 mmol) followed by benzyl chloroformate (2.08 g, 12.19 mmol) and the reaction mixture was allowed to stir for 15 min. The reaction mixture was quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 2.52 g (76%) of (±)-benzyl(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a yellow oil. Rf=0.21 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C22H25NO3 C, 75.19; H, 7.17; N, 3.99. Found C, 74.74; H, 7.02; N, 3.85. Chiral HPLC separation of (±)-benzyl(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=9.678 min, Chiralcel OJ, ethanol:hexane 1:1); Fraction 2 (Rt=12.824 min, Chiralcel OJ, ethanol:hexane 1:1).
Reaction SMILES: C1OC1.P(Cl)(Cl)Cl.[Cl:8][CH2:9][CH2:10]O.[P:12]([O:21][CH2:22][CH2:23][Cl:24])([O:17][CH2:18][CH2:19][Cl:20])[O:13]CCCl.C(O)(=O)C=C.COC1C=CC(O)=CC=1>>[Cl:8][CH2:9][CH2:10][P:12](=[O:13])([O:17][CH2:18][CH2:19][Cl:20])[O:21][CH2:22][CH2:23][Cl:24]
Reactant: OCCCl
Reactant: ClCCOP(OCCCl)OCCCl
Agent: C=CC(=O)O
Agent: COc1ccc(O)cc1
Solvent: C1CO1
Solvent: ClP(Cl)Cl
Product: O=P(CCCl)(OCCCl)OCCCl
Reaction time: 3.25 h

Procedure:
Ethylene oxide, 816 g. (18.5 m) is added subsurface to a stirred solution of 824 g. (6.0 m) of phosphorus trichloride and 8.2 g. of 2-chloroethanol in 2.75 hr with cooling at 15°-20° C. The resulting reaction mixture consists of about 90% tris(2-chloroethyl) phosphite, the remainder being a mixture of phosphonates, is warmed to 80°, and 389 g. (5.4 m.) of acrylic acid containing 100 ppm of hydroquinone monomethyl ether is added in 1.2 hr with cooling at 80°-85°. The reaction mixture is warmed to 130° in 0.5 hr and kept at 130°-140° for 3.25 hr. Stripping to 165°/1 mm leaves 1881 g. of yellow liquid which is a mixture of 2-chloroethyl phosphonates, acidity 9.7 meq/100 g. Washing of a 622 g. portion with 5% sodium carbonate solution, followed by stripping at reduced pressure, gives 590 g. acidity 3.7 meq./100 g. Distillation of a portion of the washed material gives bis(2-chloroethyl) 2-chloroethylphosphonate, b.p. 148°-151°/0.5 mm., and 2-chloroethyl 3-[bis(2-chloroethoxy)phosphinyl]propionate, b.p. 189°-191°/0.1 mm, leaving a mixture containing higher molecular weight 2-chloroethyl phosphonates as undistilled residue.
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].C[O-].[Na+].[N+]([CH:12]1[CH:17]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[NH:16][C:15](=[O:23])[CH2:14][CH2:13]1)([O-])=O>Cl.CO.[Cl-].[Cl-].[Cl-].[Ti+3]>[O:23]=[C:15]1[CH2:14][CH2:13][C:12](=[O:3])[CH:17]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[NH:16]1
Reactant: CC(=O)[O-]
Reactant: O=C1CCC([N+](=O)[O-])C(c2cccs2)N1
Agent: [Ti+3]
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: O=C1CCC(=O)C(c2cccs2)N1
Reaction time: 0.33 h

Procedure:
A 13% solution of titanium trichloride in 20% hydrochloric acid (173 ml) was added to a degassed solution of ammonium acetate (100 g) in methanol (300 ml) at 0° C. under nitrogen over 20 min. A solution of sodium methoxide (1.49 g) in methanol (60 ml) was added to a suspension of 5-nitro-2-oxo-6-thienylpiperidine (5 g, Example 25a) in methanol (75 ml) and the mixture stirred for 20 min. This solution was then added dropwise to the titanium trichloride/buffer solution at 0° C. under nitrogen. The reaction was stirred at 0° C. for 30 min and at 23° C. for 30 min. Methanol was removed in vacuo and ethyl acetate was added to the residue. The emulsion was filtered through Hi-flo and then shaken with brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The material was chromatographed on silica using (1:1 then 9:1) ethyl acetate in petroleum ether (60-80) as eluant to give 2,5-dioxo-6-thienylpiperidine. m/z (CI+) m/z 105 (MH, 53%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Br-].[CH2:10]([Zn+])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:10]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: Brc1cncc(Cc2ccccc2)c1
Temperature: 50 °C
Yield: 56.7 %

Procedure:
To a solution of 3,5-dibromopyridine (XXXIV) (1.03 g, 4.36 mmol) in THF (7 mL) under argon was added CuI (50 mg, 0.26 mmol) and PdCl2(dppf)2 (178 mg, 0.22 mmol). Benzylzinc(II) bromide (XXXV) (0.5M in THF) (13.09 mL, 6.55 mmol) was slowly added by syringe. The reaction was heated at 50° C. over the weekend. The reaction was quenched with water and extracted with EtOAc. The EtOAc was separated, washed with water, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% hexanes 5:95 EtOAc:hexanes) to afford 3-benzyl-5-bromopyridine (XXXVI) (0.614 g, 2.47 mmol, 57% yield) as a light brown oil. 1H NMR (DMSO-d6) δ ppm 3.98 (s, 2H), 7.19-7.23 (m, 1H), 7.27-7.32 (m, 4H), 7.92-7.93 (m, 1H), 8.51 (d, J=2 Hz, 1H), 8.54 (d, J=3 Hz, 1H); ESIMS found for C12H10BrN m/z 248 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1F.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.N1C=CC=CC=1>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(F)c(F)c1
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CCC(=O)CCC(=O)c1ccc(-n2ccnc2)c(F)c1
Yield: 68.5 %

Procedure:
Ethyl 7-(3,4-difluorophenyl)-4,7-dioxoheptanoate (351 mg) was treated with imidazole (241 mg) and pyridine (395 mg) in DMSO (3 mL) at 150° C. over 7 h with a micro-wave heating. The resultant mixture was diluted with water (12 mL) and was extracted with EtOAc (20 mL×3). After removal the solvents, the mixture was purified by flash silica gel chromatography, eluting with EtOAc, to afford the desired product -ethyl 7-(3-fluoro-4-(1H-imidazol-1-yl)phenyl)-4,7-dioxoheptanoate (279 mg, 68%) as light brown solids.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:14]=[C:15]([CH2:17][CH3:18])[N:16]=[C:4]2[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([C:15]1[N:16]=[C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][N:5]2[N:14]=1)[CH3:18]
Reactant: CCc1nc2nc(Cl)c(-c3ccccc3)cn2n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CCc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Temperature: 90 °C

Procedure:
To a mixture of 3.90 g of the crude product obtained in step 3 and 3.00 g 4-formylphenylboronic acid in 180 ml 1,2-dimethoxyethane are added 0.55 g dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) and 25 ml of a 10% w/w sodium carbonate solution. The resulting mixture is heated to 90° C. under an inert gas atmosphere for 20 h. The work up is performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers are dried over sodium sulphate, the solvent is evaporated and the residue is suspended in ethyl acetate. The crude product is isolated by filtration, witch is purified on silica gel (dichloromethane/methanol).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](O)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH2:13]>>[C:1]1([N:7]2[C:10](=[O:18])[C:11]3[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:13][C:8]2=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccccc1C(=O)O
Product: O=c1c2ccccc2[nH]c(=S)n1-c1ccccc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Phenyl isothiocyanate (28.3 g) was added to anthranilic acid (28.7 g) in absolute alcohol (250 ml) and heated at reflux for 4.5 hours. The mixture was cooled to room temperature and the solid removed by filtration to give 32.5 g of 3-phenyl-2,3-dihydro-2-thioxoquinazolin-4(1H)-one, mp 287°-291° C. Sulphuryl chloride (5.4 ml) was added dropwise at room temperature to a suspension of this product (32.5 g) in chloroform (250 ml). The mixture was heated at reflux for 4 hours. When cool it was poured into water (400 ml), filtered and the solid washed with dichloromethane. The organic layer was separated from the filtrate, dried and concentrated in vacuo. The residue was extracted with ether, filtered and the filtrate concentrated in vacuo to give an oil which solidified on standing. This was recrystallised from cyclohexane to give crude 2-chloro-3-phenylquinazolin-4(3H)-one, mp 102°-5° C. (shown to be 90% pure by high pressure liquid phase chromatography (hplc). A mixture of this product (3.85 g), imidazole (1.02 g) and potassium carbonate (2.07 g) in acetonitrile (60 ml) was heated at reflux for 4 hours. The mixture was cooled to room temperature, and concentrated in vacuo. The residue was chromatographed on silica using light petroleum (bp 60°-80° C.)/ethyl acetate (1:1) as eluant. The resulting solid was recrystallised from cyclohexane to give 0.8 g of 3-phenyl-2-(imidazol-1-yl)-quinazolin-4(3H)-one, mp 163°-5° C. (Compound 1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.Cl[Si:10]([CH3:13])([CH3:12])[CH3:11].[Mg].II.[Cl-].[NH4+]>CCOCC>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1
Reactant: Cc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cccc([Si](C)(C)C)c1
Yield: 53.6 %

Procedure:
A mixture of 9.2 g (50 mmol) of 3-bromo-toluene and 5.84 g (50 mmol) of chlorotrimethylsilane in 100 ml of dry ether are added dropwise to 1.2 g (50 mmol) of magnesium turnings in a few milliliters of ether, some crystals of iodine are added to start the reaction. The reaction mixture is refluxed for 20 hours after the end of the addition and then poured into a saturated solution of ammonium chloride (200 ml). The aqueous solution is further extracted with ether, the ethereal extracts are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4.4 g of a yellowish liquid. Flash chromatography ona silica gel column and elution with petroleum ether give 2.3 g (30%) of the expected 1-methyl-3-trimethylsilyl-benzene as a colorless liquid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:24]1[S:28][N:27]=[CH:26][N:25]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O.CO.[OH-].[Li+]>C(Cl)Cl.C1COCC1.O>[S:28]1[C:24]([NH:6][S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13]3)(=[O:8])=[O:9])=[N:25][CH:26]=[N:27]1
Reactant: COC(=O)c1cccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ncns3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-naphthoate (7.10 g, 14.21 mmol) was dissolved in 100 mL of DCM and TFA (10.95 ml, 142 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The material was concentrated, dissolved in methanol, and re-concentrated to afford a light yellow solid. The solid was dissolved in THF (47.4 ml), methanol (47.4 ml), and water (47.4 ml). Lithium hydroxide (1.021 g, 42.6 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was concentrated and dissolved in concentrated HCl solution. The solution was stirred for 5 minutes and filtered. The resulting white solid was washed with water, dried under a nitrogen blanket, and collected to afford 6-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1-naphthoic acid (Intermediate MM) as an off-white solid. m/z (ESI) 336.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[CH2:11][CH:12]([OH:35])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(Cl)Cl>CN(C=O)C.CCCCC>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH:12]([OH:35])[CH2:11][S:3][C:4]3[N:9]=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:19][CH2:18]2)=[CH:22][CH:23]=1
Reactant: Sc1ncccn1
Reactant: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OC(CSc1ncccn1)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
To NaH (240 mg, 5 mmol, 50% in oil, prewashed with pentane) in DMF (5 mL) was added 2-mercaptopyrimidine (5 mmol, 560 mg) in portions over 5 minutes at 0° C. After 30 minutes, 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4,4'-diflurobenzhydryl)piperazine (1.9 g, 5 mmol) in DMF (15 mL) was added over 10 minutes under nitrogen. After 12 days, the sodium chloride was removed by filtration and the DMF was removed in vacuo (~0.5 mm Hg, ~50° C.) to give the crude (1.82 g). Flash column chromatography over silica gel using 2% methanol:methylene chloride (2×) and subsequent washings of the product with pentane gave the pure product (380 mg, 16.7%) as a white solid, mp 75°-76° C.; DCI/MS (M+1)=456; (400 MHz) 1H NMR (CDCl3)δ: 8.55 (s, 1H), 8.50 (s, 1H), 7.35 (m, 4H), 7.0 (m, 4H), 4.2 (s, 1H) , 4.0 (m, 1H), 3.3 (m, 2H), 2.65 (m, 2H), 2.4 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I.[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([O:24][CH3:27])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc([C@@H](C)O)nc3N21
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CO[C@H](C)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.75 g (2.25 mmol) (4R,9aR)-6-(1-(R)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 5 ml N,N-dimethylformamide was added 0.12 g (2.70 mmol) sodium hydride (55–65% dispersion in oil). After 30 min, 0.28 ml (0.64 g, 4.50 mmol) methyl iodide was added and the reaction mixture was stirred at 50 deg C. for 2 h. After cooling to room temperature the reaction mixture, was poured onto 10% aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-heptane (1:2) as eluant.
Reaction SMILES: [CH2:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH:2]=[CH2:3].C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)CCC>CN(C=O)C>[CH2:1]([C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[N:6][C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:2]=[CH2:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: C=CCc1c(Cl)ncnc1Cl
Solvent: CN(C)C=O
Product: C=CCc1c(Cl)ncnc1-c1ccccn1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
The 5-allyl-4,6-dichloropyrimidine (2 g) and 2-(tributylstannyl) pyridine (6.1 g) were dissolved in dry DMF (1.0 mL). The reaction mixture was degassed with nitrogen for 30 minute and Pd(PPh3)4 (615 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes before being irradiated under microwave at 160° C. for 30 minutes. The reaction mixture was cooled to room temperature, filtered through a celite pad and washed with ethyl acetate (2×50 mL). The combined filtrate was washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by column chromatography using EtOAc/hexane (0.4:9.6) as eluent to afford 5-allyl-4-chloro-6-(pyridin-2-yl)pyrimidine (1 g) as off white solid. 1H NMR (DMSO-d6): δ 3.80-3.82 (d, 2H), 4.83-4.89 (dd, 1H), 4.90-5.00 (dd, 1H), 5.82-5.88 (m, 1H), 7.53-7.57 (m, 1H), 7.90-8.04 (m, 2H), 8.69-8.71 (d, 1H), 9.0 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.ClCCl.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C>CCOC(C)=O.[Pd].O>[C:13]([CH2:12][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:14]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1cc(CC#N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CC#N)ccc1NC(=O)c1cccc(C(F)(F)F)c1

Procedure:
Compound 19.2 (0.096 mmol), and catalytic Pd/C in EtOAc (2 mL) were placed under an atmosphere of hydrogen for 3 hours. The reaction mixture was filtered, concentrated and taken on crude to the next reaction. The crude compound (0.096 mmol), dichloromethane (0.5 mL), 3-(trifluoromethyl)benzoyl chloride (1.05 mmol) and DIEA (1.10 mmol) was stirred at room temperature for 10 minutes. Water was added after which the mixture partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel using a gradient of EtOAc/hexanes provided N-(4-cyanomethyl-2-methoxy-phenyl)-3-trifluoromethyl-benzamide (compound 19.3) in 71%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:16]=3[S:17][C:18]=2Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:46])(=O)=O)=CC=1.[Na+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:16]=3[S:17][C:18]=2[F:46])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)sc3cc(F)ccc23)CC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)sc3cc(F)ccc23)CC1
Temperature: -65 °C
Yield: 82.7 %

Procedure:
At a temperature of −65° C. stir, under nitrogen, a solution of the 4-(2-bromo-6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 28b) (15.59 g, 37.55 mmol) in anhydrous THF (247 mL) and add, dropwise, n-butyllithium in hexane (2.5M, 19.53 mL, 48.82 mmol). Stir for 30 min and then add, dropwise, N-fluorobenzenesulfonimide (17.76 g, 56.33 mmol) dissolved in anhydrous THF. Stir overnight at ambient temperature, cool the reaction to 0° C., add saturated NaCl solution and then water. Extract the mixture with EtOAc (3×'s), combine the extracts and wash with water and brine. Dry the extract (MgSO4), and concentrate to obtain 11.0 g of oil. Chromatograph the oil over silica gel (ether/pet. ether, 9:1) and obtain 6.28 g (52%) of red oil, MS, m/z, 354 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8](O)[C:9](=[S:13])[N:10]([CH3:12])[CH3:11])[CH:7]=1.[OH-].[Na+]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[F:1][C:2]1[C:7]2[S:13][C:9]([N:10]([CH3:12])[CH3:11])=[CH:8][C:6]=2[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)cc1C(O)C(=S)N(C)C
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: COc1ccc(F)c2sc(N(C)C)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
A solution of 2-(5-fluoro-2-methoxyphenyl)-2-hydroxy-N,N-dimethylethanethioamide (0.5 g, 2.1 mmol) in Eaton's reagent (5 mL) were combined and heated rapidly to 60° C. and left for 1 h. After cooling to room temperature over 2 hours the mixture was dropwise addition into prechilled aqueous sodium hydroxide (2 N, 16.25 mL) with constant stirring. This solution was then extracted with methyl tert-butyl ether (5×20 mL) and the combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give a yellow solid. This was purified by flash chromatography with a gradient of 0–2% diethyl ether in hexane and gave 0.2 g of yellow solid containing an impurity, this was triturated with hexane to leave a colourless solid (0.155 g, 34%) of the title compound; δH (300 MHz, CDCl3) 6.70–6.52 (2H, m, ArH), 6.12–6.10 (1H, m, ArH) 3.90 (3H, s, OCH3) and 3.2 (6H, s, N(CH3)2), M+H=226.1.