Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:38][C:39]1([F:45])[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:41]3[CH2:42][CH2:43][CH2:44][C:39]([F:45])([F:38])[CH2:40]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: FC1(F)CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCCC(F)(F)C1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 15.5 %

Procedure:
A cold (0° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (1.0 g, 1.0 eq.) in CH2Cl2 (20 mL) was treated sequentially with EDC HCl (0.656 g, 1.2 eq.), 3,3-difluoropiperidine hydrochloride (0.540 g, 1.2), DIPEA (435 mg, 1.2 eq) and HOBT (25.92 g, 1.2 eq.). The clear reaction mixture was stirred at 0° C. for 1.5-2 h then quenched with 50 mL ice-water slurry and extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 0.70 g of crude compound. No trans compound was formed as confirmed by LCMS and 1H NMR. Purification by column chromatography afforded 0.20 g of material that was further recrystallized/triturated using ether: petroleum ether to remove aliphatic impurity affording 0.180 g (14.1% yield) of desired pure compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:18]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[C:19]#[CH:20].C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:18][C:19]#[C:20][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: C#CCOCCOCCOCCOCCO
Reactant: O=C(OCc1ccccc1)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)c1cccc(C#CCOCCOCCOCCOCCO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of benzyl 3-iodobenzoate (25.68 g, 66.19 mmol, 1.00 equiv) in tetrahydrofuran (300 mL), 2-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethoxy)ethanol (15.36 g, 66.21 mmol, 1.00 equiv), copper(I) iodide (1.26 g, 6.63 mmol, 0.10 equiv), Pd(PPh3)2Cl2 (4.65 g, 6.62 mmol, 0.10 equiv), triethylamine (13.4 g, 132.67 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (1:1). This resulted in 20 g (68%) of benzyl 3-(3-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)prop-1-ynyl)benzoate as a brown oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:28][CH3:29])[C:3]([O:5][CH:6]1[CH:15]2[C:10]([CH:11]=[CH:12][CH:13]([CH3:26])[CH:14]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH:20]([OH:25])[O:19]2)=[CH:9][CH:8]([CH3:27])[CH2:7]1)=[O:4].[C:30](=O)(O)[O-].[Na+]>CO.C(Cl)(=O)C>[CH3:1][CH:2]([CH2:28][CH3:29])[C:3]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:26])[C:14]=2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH:20]([O:25][CH3:30])[O:19]2)[CH:9]=[C:8]([CH3:27])[CH:7]=1)=[O:4]
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CC(O)O3)C21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Product: CCC(C)C(=O)Oc1cc(C)cc2ccc(C)c(CCC3CC(O)CC(OC)O3)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 393.1 %

Procedure:
Acetyl chloride (200 μL, 2.8 mmol) was added to a stirred solution of hemiacetals II (19.0 g, 46.7 mmol) in methanol (100 ml). The solution was stirred for 15 min at ambient temperature. Sodium bicarbonate (1.0 g) was added and the mixture was stirred for another 15 min. The mixture was filtered through a pad of Celite (5.5×1 cm) and washed with toluene. Evaporation of solvent of the filtrate gave crude acetals III (19.4 g, yield 98%) as a colorless syrup (HPLC purity >95%). This was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14].[CH2:17](I)[CH3:18]>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][N:11]=[C:10]1[S:16][CH2:17][CH3:18]
Reactant: NC(=O)CNC(=S)Nc1c(Cl)cccc1Cl
Reactant: CCI
Product: CCSC1=NCC(=O)N1c1c(Cl)cccc1Cl
Yield: 44.3 %

Procedure:
The title compound was prepared by the procedure described in Example 2 using 27.8 g of 2-[3-(2,6-dichlorophenyl)-thioureido]-acetamide and 31.2 g of ethyl iodide. 12.8 g of the title compound was obtained, m.p. 122°-124° C. Anal. Calcd. for. C11H10Cl2N2O S: C, 45.69; H, 3.49; N, 9.69. Found: C, 45.62; H, 3.33; N, 9.43. Mass spectrum (+FAB, [M+H]+) m/z 289/291/293. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.72 (s, 1 H), 7.70 (s, 1 H), 7.58 (t, 1 H), 4.50 (s, 2 H), 3.10 (q, 2 H), and 1.27 ppm (t, 3 H).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:13]([N:15]=[C:16]=NCCCN(C)C)C.[C:24]([O:28][C:29]([N:31]1[CH2:38][C@H:37]([OH:39])[CH2:36][C@H:32]1[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CNC>O1CCCC1>[CH3:13][N:15]([CH3:16])[C:33]([C@@H:32]1[CH2:36][C@@H:37]([OH:39])[CH2:38][N:31]1[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[O:34]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
24.9 g of 1-hydroxybenzotriazole monohydrate and 24.9 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added under ice cooling to a 250 mL tetrahydrofuran solution of 25.1 g of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline and stirred for 15 minutes. 10.7 g of a 50% dimethylamine aqueous solution was added dropwise over a period of 10 minutes to the reaction mixture, and the reaction mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, after which 100 mL of a saturated sodium hydrogencarbonate aqueous solution was added and extraction was performed with chloroform (50 mL×2). The extract was dried with anhydrous sodium sulfate, the drying agent was filtered off, and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: chloroform/methanol=20/1 to 9/1; v/v) to obtain 26.2 g of the titled compound (colorless solid).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([C:41]([F:44])([F:43])[F:42])[CH2:38][C@H:37]([NH:45]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([C:41]([F:44])([F:43])[F:42])[CH2:38][C@H:37]([NH2:45])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[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: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1C[C@@H](N)C[C@@H](C(F)(F)F)C1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.1 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (58.2 mg, 0.163 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (55.3 mg, 0.137 mmol) and HATU (180.9 mg, 0.4758 mmol) was added DMF (2.0 mL) followed by DIPEA (162.2 mg, 1.255 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. To the resulting residue was added DCM (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (9.7 mg, 13%). LCMS calc. for C23H22F5N6O2S (M+H)+: m/z=541.1. found 541.1.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])C=1C#N)#N>CO>[C:1]([O:16][CH3:15])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: COC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) is taken in a round bottom flask and catalytic amount of AMBERLYST® 15 (0.1 g) is added to it. The mixture is stirred for 20 hrs at room temperature. After completion of the reaction (observed by TLC and GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═CH3) is isolated in 98% yield. 1H-NMR (CDCl3, 300 MHz) δ7.56 (1H, d, J=16.55 Hz), 7.34 (2H, m), 7.21 (3H, m), 6.31 (1H, d, J=16.55 Hz), 3.64 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ167.2, 144.7, 134.3, 130.2, 128.8, 128.0, 117.8, 51.5.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].O.[CH2:7]1[CH:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:11]2[CH2:10][CH2:9][NH:8]1>C(O)C>[OH:3][CH:2]([CH2:4][OH:5])[CH2:1][N:8]1[CH2:9][CH2:10][N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[CH:12]2[CH2:7]1
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Reactant: OCC1CO1
Solvent: O
Solvent: CCO
Product: OCC(O)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
A mixture of 0.41 g of glycidol and 0.9 ml of water was added, whilst ice-cooling, to a solution of 1 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine dissolved in 2 ml of ethanol, and the mixture was stirred at room temperature for 5 hours; it was then concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, to afford 0.72 g (yield 56%) of the title compound as a colorless foam.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C(C1C=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]=2[CH:15]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:4]([C:3]1[CH:2]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]=2[CH:15]=1)=[CH2:5]
Reactant: [Li]CCCC
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C=O)cc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=Cc1ccc2c(c1)C(CCCCCCCC)(CCCCCCCC)c1ccccc1-2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (714 mg, 2 mmol) in ether at 0° C. was added dropwise 1.6 M n-BuLi solution in hexane (1.25 mL, 2.00 mmol). The solution was stirred at 0° C. for 40 min and then was warmed to room temperature. A solution of 2-formyl-9,9-dioctylfluorene (585 mg, 1.4 mmol) was then added and reaction mixture was stirred overnight. The reaction mixture was quenched with 20 mL of 1% HCl. The mixture was extracted with ether and the organic layer was washed with NaHCO3 solution, and brine solution, and dried over MgSO4. The solvent was removed in vacuo and the product was purified by column chromatography on silica gel using hexane as the elutant to afford the purified 2-vinyl-9,9-dioctylfluorene (0.2834 g, 49% yield). EI-MS: 416 (M+), 360,192 (100). 1H NMR (CDCl3) δ 7.66 (m, 2H), 7.42-7.32 (m, 5H), 6.83 (dd, 1H), 5.82 (d, 1H), 5.28 (d, 1H), 1.97 (m, 4H), 1.28-1.06 (m, 22H), 0.83 (t, 5H), 0.63 (t, 3H). 13C NMR (CDCl3) δ151.09, 151.00, 141.08, 140.8, 137.51, 136.47, 127.05, 126.77, 125.21, 122.88, 120.54, 119.69 (2C), 112.89, 54.97, 40.39, 31.84, 31.65, 30.09, 29.25, 23.75, 22.65, 14.10
Reaction SMILES: [CH:1]1N=CN(C(N2C=NC=C2)=O)[CH:2]=1.[CH:13]1([N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:35])=[C:23]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)[C:24]=3[F:26])[C:19](=[O:36])[C:18]([C:37]([OH:39])=[O:38])=[CH:17]2)[CH2:15][CH2:14]1>CN(C=O)C.C(O)C>[CH:13]1([N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:35])=[C:23]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)[C:24]=3[F:26])[C:19](=[O:36])[C:18]([C:37]([O:39][CH2:1][CH3:2])=[O:38])=[CH:17]2)[CH2:15][CH2:14]1
Reactant: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)cc(C)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
1,1'-Carbonyldiimidiazole (CDI) (3.9 g, 0.024 mol) was added to a suspension of (6.0 g, 0.016 mol) 1-cyclopropyl-7-(2, 6-dimethyl-4-pyridinyl )-6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, described in U.S. Pat. No. 5,075,319, and incorporated herein by reference, in DMF (40 mL) and the mixture was stirred at 100° C. for 2 hr under a N2 atmosphere. The resulting solution was cooled to 25° C., diluted with and 60 mL ethanol and heated at reflux 17 h. Removal of the solvents in vacuo gave a residue that was stirred in 20 mL ethanol; after cooling in ice a solid separated and was collected (5.5 g, 86%); a 4.5 g portion of this material was recrystallized from ethanol to give 4.25 of ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, mp 193°-195° C.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:30]3[CH2:29][CH2:28][NH:27][CH:26]([CH3:25])[CH2:31]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC1CNCCN1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N2CCNC(C)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 112 mg of 2-methylpiperizine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 422.3 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[S:24][C:25]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[S:24][C:25]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1
Yield: 75 %

Procedure:
Followed the same procedure as that of step 1 in Example 99 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester ((147 mg, 0.5 mmol) and 2,6-dichloro-benzothiazole (102 mg, 0.5 mmol) to yield the title product (172 mg, 75% yield); 1H NMR (400 MHz, DMSO-d6); δ 1.41 (s, 9H), 1.75-2.04 (m, 4H), 3.24-3.35 (m, 2H), 3.89-4.12 (m, 3H), 7.08 (d, J=9.2 Hz, 2H), 7.38 (d, J=9.2 Hz, 2H), 7.45 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:27]([C@@:30]1([CH3:57])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([F:50])[CH:44]=2)[N+:32]2[C@@H:51]([CH:54]3[CH2:56][CH2:55]3)[CH2:52][O:53][C:31]1=2)[CH:28]=[CH2:29]>O1CCCC1>[CH2:27]([C@@:30]1([CH3:57])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([F:50])[CH:44]=2)[N:32]([C@@H:51]([CH:54]2[CH2:55][CH2:56]2)[CH2:52][S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:31]1=[O:53])[CH:28]=[CH2:29]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)c(F)c2)[N+]2=C1OC[C@@H]2C1CC1
Reactant: CC(C)(C)S
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)c(F)c2)N([C@H](CSC(C)(C)C)C2CC2)C1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-2-propanethiol (15.25 mL, 135 mmol, dried over activated 4 Å molecular sieves) was added to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 135 mL, 135 mmol) at room temperature under argon in a 500 mL round-bottomed flask. The reaction mixture was heated to 60° C. After 30 minutes, a solution of (3S,5S,6R,8S)-8-allyl-5-(4-chloro-3-fluorophenyl)-6-(3-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-60 ]pyridin-4-ium 4-methylbenzenesulfonate (78 g, 123 mmol, Example 4, Step H) in anhydrous tetrahydrofuran (100 mL) was added via cannula. The reaction mixture was heated at 60° C. for 3 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organics were pooled, washed with brine, dried over magnesium sulfate, filtered and concentrated under a vacuum to provide a yellow foam. Purification by flash column chromatography (1.5 kg SiO2 column, gradient elution with 5% to 30% ethyl acetate in hexanes provided the title compound as an off-white foam.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[Cl:12][S:13](O)(=[O:15])=[O:14].S(Cl)(Cl)=O>>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: O=C(CCl)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Chloroacetanilide (4.53 g) is slowly added to chlorosulfonic acid (7.5 mL) at a temperature of 5° C. The solution is heated to 65° C. and thionyl chloride (0.78 mL) is added. After 10 minutes of gas evolution the reaction was cooled to room temperature. The mixture is added to ice/water (2.14 g/3.2 mL) and stirred for 30 minutes. The product was filtered, washed with water (60 mL), placed under vacuum at 50° C. and dried to a constant weight. The product is a white powder, yield: 4.81 g (67%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34](S(C)(=O)=O)=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>Cl>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34]([NH:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1cccc(Cl)c1N1Cc2cnc(S(C)(=O)=O)nc2N(c2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C1=O
Agent: Cl
Product: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C1=O
Temperature: 180 °C
Yield: 100 %

Procedure:
A mixture of 1.1 g (1.5 mmol) of 1-[3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenyl]-3-(2-chloro-6-methylphenyl)-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 3 ml of aniline was heated at 180° C. for 20 minutes. The mixture was cooled and added to 50 ml of 2M aqueous hydrochloric acid. The resulting suspension was filtered and the solid washed with water and dried to give 1.2 g (100%) of 1-[3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenyl]-7-anilino-3-(2-chloro-6-methylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a tan solid. [Mass spectrum (ESI) MH+ =724].
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9](C)(C)[CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:15][Si:16](C#C)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][Si:16]([C:10]#[C:9][O:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][CH:2]=[CH:3][CH:4]=1)([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#COC(=O)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture containing 1.31 g of tert.-butyl 4-bromobenzoate, 1.0 g of trimethylsilylacetylene, 10 mg of palladium acetate and 15.6 mg of triphenylphosphine in 15 ml of anhydrous triethylamine is heated in a sealed container at 100° C. for 16 hours. After cooling to room temperature, the reaction mixture is diluted with methylene chloride and extracted with water. The organic solution is dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The dark residue is chromatographed a column of flash silica gel using a 10% ethyl acetate-hexanes mixture as the eluent to give tert.-butyl 4-(trimethylsilylethynylbenzoate as a dark oil: NMR (CDCl3, 300 MHz) delta 0.26 (s, 9H), 1.59 (s, 9H), 7.49 (d, 2H, J=8.23 Hz), 7.91 (d, 2H, J=8.23 Hz). This is dissolved in 20 ml of anhydrous methanol, and then treated with 0.1 g of anhydrous potassium carbonate. The mixture is allowed to stir at room temperature under nitrogen for 3 hours. The reaction mixture is diluted with methylene chloride, extracted with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is distilled under reduced pressure (60°-70° C./0.1 mm to give 0.75 g (73% over 2 steps) of tert.-butyl 4-ethynylbenzoate as a white solid: m.p. 71.5°-72° C.; NMR (CDCl3, 80 MHz) delta 1.62 (s, 9H), 3.23 (s, 1H), 7.55 (d, 2H, J=8.11 Hz), 7.96 (d, 2H, J=8.11 Hz); IR (KBr) 3240, 2970, 2100, 1700, 1600, 1450, 1365, 1300, 1250, 1160, 1115, 1015, 845 and 765 cm-1 ; M/S 202 M+), 187, 157, 146, 129, 101, 75 and 57. Anal. Calcd. for C13H14O2 : C, 77.20; H, 6.98 Found: C, 76.86; H, 6.79.