Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[O:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=3)=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)([OH:37])N.Cl([O-])=O.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:12][CH2:13][CH:14]([CH2:17][C:18]([C:20]3[O:24][C:23]([C:25]([OH:37])=[O:26])=[CH:22][CH:21]=3)=[O:19])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)o1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)o1
Temperature: 25 °C

Procedure:
To a solution of the product from Example 139 (29 mg, 0.057 mmol) in dichloromethane (2 mL) and water (1 mL) cooled to 0° C. was added sulfamic acid followed by sodium chlorite. The reaction was left to stir, warming to room temperature over 2.5 hours. The layers were separated and the aqueous layer extracted further with dichloromethane. The combined organic layers were dried (MgSO4) and evaporated to a cream foam, which was purified by column chromatography on silica (50% ethyl acetate/49% dichloromethane/1% acetic acid) to obtain a white solid (10 mg).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:6][C:7]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:8]([C:10]2[N:11]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[CH:26]=[CH:25]4)[C:12]([NH:15][C:16]3[CH:21]=CC=CC=3)=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].CN(C)C=[O:51].C(C1NC=CN=1)(=O)C>C(OCC)(=O)C>[CH2:33]([O:32][C:7]1[CH:6]=[C:5]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][C:8]=1[C:10]1[N:11]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[CH:26]=[CH:25]3)[C:12]([NH:15][C:16](=[O:51])[CH3:21])=[N:13][N:14]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)C=O
Reactant: CC(C)c1cc(-c2nnc(Nc3ccccc3)n2-c2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(=O)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nnc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)n1-c1ccc2c(ccn2C)c1
Temperature: 75 °C

Procedure:
A flask was charged with [5-(5-Isopropyl-2,4-dibenzyloxy-phenyl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-phenyl-amine (0.25 mmol, 136 mg.), dimethylformamide (2 mL), and acetylimidazole (2 eq., 90 mg.), and the reaction was heated at 75° C. for 16 hours. The solution was diluted with ethyl acetate (20 mL) and washed with water (3×10 mL), dried and the product was purified by column chromatography to give N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C1COCC1.[Br-].[CH2:36]([Zn+])[CH:37]([CH3:39])[CH3:38]>O.CCOC(C)=O>[CH2:36]([C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2)[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)C[Zn+]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CC(C)C)cc(C)c32)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (Example 47-D) (2.7 g, 6.2 mmol) in isobutylzinc(II) bromide in THF (0.5 M, 24.9 mL, 12.4 mmol) was added Pd[(t-Bu)3P]2 (0.5 g, 0.98 mmol), and then the mixture was stirred at 70° C. for 14 h. The mixture was then stirred under reflux for 7 h. The reaction was then diluted with H2O and EtOAc. The mixture was then filtered through a Celite® pad. The filtrate was partitioned. The organic phase was washed with H2O, and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by SiO2 column chromatography (heptane/EtOAc=88/12) to afford the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.74 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.59 Hz, 2H), 7.31 (d, J=8.60 Hz, 2H), 6.86-6.94 (m, 2H), 4.90 (d, J=11.12 Hz, 1H), 4.64 (d, J=11.12 Hz, 1H), 4.60-4.64 (m, 1H), 3.81-3.91 (m, 1H), 3.45-3.54 (m, 1H), 2.57 (d, J=7.33 Hz, 2H), 2.52 (s, 3H), 2.35 (s, 3H), 1.79-1.88 (m, 1H), 1.56-1.75 (m, 2H), 1.39-1.55 (m, 4H), 0.84-0.89 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][NH:12]2)[CH2:9]1)=[O:7].C(N(CC)CC)C.N1C=CC=CC=1.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][N:12]2[S:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:41])=[O:40])[CH2:9]1)=[O:7]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CNC2C1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CN(S(=O)(=O)c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of rac-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide (150 mg, 270 μmol) in dichloromethane (6 mL) were added triethylamine (82 mg, 810 μmol), pyridine (1 mL) and benzenesulfonyl chloride (52 mg, 297 μmol). The reaction mixture was stirred at ambient temperature overnight before concentrating in vacuo. Purification by chromatography (SiO2; dichloromethane:methanol 1:0 to 19:1) afforded the title compound (56 mg, 47%) as a colorless solid. MS (EI) m/e: 440.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si](OC)(OC)OC.[CH2:12]([C:15]1C=CC=C[C:16]=1[OH:21])[CH:13]=[CH2:14]>C1(C)C=CC=CC=1>[O:21]1[C:16]2[CH:15]=[CH:12][CH:13]=[CH:14][C:4]=2[CH:3]=[CH:2][NH:1]1
Reactant: C=CCc1ccccc1O
Reactant: CO[Si](CCCN)(OC)OC
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 94 %

Procedure:
This compound was prepared according to the method described in the previous examples using 3-aminopropyltrimethoxysilane (17.9 g, 100 mmole), paraformaldehade (6.3 g, 210 mmole), 2-allyl-phenol (13.4 g, 0.1 mmole), and toluene (200 ml). The final product was obtained as a slightly yellow, mobile liquid. The yield was 94% of theory.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[N:14][C:15]([NH:18][C:19]3[N:20]=[CH:21][C:22]4[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[N:25]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:23]=4[N:24]=3)=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)[CH3:5].[Li+].[OH-]>C1COCC1.O>[CH:33]1([N:25]2[C:23]3[N:24]=[C:19]([NH:18][C:15]4[N:14]=[CH:13][C:12]([N:9]5[CH2:8][CH2:7][N:6]([CH:4]([CH3:5])[C:3]([OH:38])=[O:2])[CH2:11][CH2:10]5)=[CH:17][CH:16]=4)[N:20]=[CH:21][C:22]=3[CH:27]=[C:26]2[C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COC(=O)C(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
To a solution of 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid methyl ester (250 mg, 0.48 mmol) in 10 mL of THF is added a solution of LiOH (19 mg, 48 mmol) in 10 mL of H2O. After 18 h stirring at room temperature, the resulting mixture is concentrated and diluted with H2O and adjusted to pH=6 with 1 N HCl. Ished with dichloromethane then solids precipitated and collected to give 2-{4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid (225 mg, 94%). MS (EST) m/z 507.3 (M+H)+
Reaction SMILES: C([Li])CCC.CC1CCCN(C)C1(C)C.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][N:18]=1.CN(C=[O:30])C.C1[CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:16][C:17]1[CH:25]=[C:24]([C:20]([CH:21]=[O:23])=[CH:19][N:18]=1)[C:35]([O:34][CH2:33][CH3:32])=[O:30]
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]CCCC
Product: CCOC(=O)c1cc(Cl)ncc1C=O
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of 51 ml (128 mmol) of 2.5 N n-butyllithium in hexanes was added slowly to a THF solution of 16 ml (95 mmol) of tetramethylpiperidine cooled in a dry ice-acetone bath. The solution was warmed to −30° C. and cooled to −60° C. before 5.0 g (32 mmol) of 6-chloronicotinic acid was added portion wise. The mixture was warmed to −25° C. and stirred for 30 min. It was then cooled to −70° C. and 10 ml (129 mmol) DMF was added quickly. After quenching with 1N HCl, the solution was warmed to room temperature. The pH was brought to about 4 with additional 1N HCl and the solution was continuously extracted with EtOAc overnight. The EtOAc was dried (MgSO4) and concentrated. The residue was dissolved in 100 ml EtOH and 2 ml concentrated H2SO4 was added. The solution was heated at reflux for 24 h. The mixture was brought to about pH=4 with 50% NaOH and was extracted twice with ether. The ether was dried (MgSO4) and concentrated to gave an oil that was chromatographed on silica gel (50% hexanes in CH2Cl2 with gradient elution to 100% CH2Cl2) to afford 1 g of product as an oil that slowly solidified. NMR (CDCl3): 1.4 (t, 3H), 4.5 (q, 2H), 7.7 (s, 1H), 9.1 (s, 1H), 10.7 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13][NH:27][CH:24]1[CH2:26][CH2:25]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(Cl)c1F
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)c(F)c(F)c(Cl)c1F
Yield: 110.4 %

Procedure:
Employing ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-3-ethoxyacrylate (360 mg) and cyclopropylamine (60 mg), the procedure of Reference Example 21 is repeated to give ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-3-cyclopropylaminoacrylate (410 mg), as brown oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[N:8]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][NH:9]1.N1C=CC=CC=1>O1CCCC1>[N:9]1([C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3])[CH2:10][CH2:11][CH:12]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)C1CCNN1C(=O)OC(C)(C)C
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCC(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
Allyl chloroformate (0.488 ml, 4.59 mmol) was added dropwise to the solution of di-tert-butyl pyrazolidine-1,5-dicarboxylate (1 g, 3.67 mmol) and pyridine (0.371 ml, 4.59 mmol) in tetrahydrofuran (THF) (1.79 ml) at 0° C. The resulting solution was allowed to warm up to ambient temperature and stirred for 30 min. The reaction was filtered, and to the filtrate was added EtOAc. The solution was washed with brine. The organic layers were separated and dried over anhydrous Na2SO4. The crude product was purified by RP-HPLC to give 2,3-bis(1,1-dimethylethyl) 1-(2-propen-1-yl) 1,2,3-pyrazolidinetricarboxylate (749 mg, 2.101 mmol, 57% yield). MS (ES+) m/z 357.3 (MH+).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][Cl:21])[OH:19])[CH3:9].[C:22]([N:27]=[C:28]=[O:29])(=[O:26])[C:23]([CH3:25])=[CH2:24]>>[C:22]([NH:27][C:28]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][Cl:21])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])=[O:29])(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)N=C=O
Reactant: COC1C(O)CCC(O)(CCl)C1C1(C)OC1CC=C(C)C
Product: C=C(C)C(=O)NC(=O)OC1CCC(O)(CCl)C(C2(C)OC2CC=C(C)C)C1OC
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
As in Example 2, a mixture of 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (1.13 g) and methacryloylisocyanate (800 mg) was stirred for 30 minutes at room temperatures. The reaction mixture was purified by means of a silica gel column chromatography (carrier 50 g, developing solvent:hexane-ethyl acetate=3:1) to afford 4-O-(methacryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (520 mg, yield 34%) as colorless crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1.[CH2:12]([Li])CCC.IC>CCCCCC.O1CCCC1>[CH3:12][C:5]1[O:4][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:7][C:6]=1[CH:8]=[O:9]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)c1cc(C=O)co1
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1oc([Si](C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
D-Butyl lithium (a 1.6 M solution in hexane; 2.04 ml, 3.28 mmol) was added dropwise to a solution of N,N'N'-trimethylethylenediamine (0.46 ml, 3.56 mmol) in tetrahydrofuran (7 ml) at -78 degrees under argon. After 15 minutes, a solution of 2-trimethylsilyl-4-furaldehyde (0.5 g, 2.98 mmol) in tetrahydrofuran (2 ml) was added, followed by n-butyl lithium (3.72 ml, 5.94 mmol) after 15 minutes. Iodomethane (1.12 ml, 17.9 mmol) was then added and the mixture was allowed to warm to room temperature gradually over 1/2 hour. The mixture was quenched with brine and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by flash chromatography using 10% ethyl ether/hexane. Fractions with Rf of about 0.22 on evaporation afforded the title methylfuran as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[N:15]1([CH2:2][C:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)=[O:4])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C(CBr)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Cn1nnc2ccccc21)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-1-(naphthalen-1-yl)ethanone (1 g, 4.02 mmol), benzotriazole (530 mg, 4.42 mmol) and K2CO3 (560 mg, 4.02 mmol) in toluene (100 mL) was heated at reflux for 16 hours. The reaction was cooled to room temperature, washed with water, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (100% DCM) afforded 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-(naphthalen-1-yl)ethanone as a tan solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:6]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:32]=[CH:33][S:34][CH:35]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:5]4[CH:6]=[C:2]([C:31]5[N:32]=[CH:33][S:34][CH:35]=5)[N:3]=[CH:4]4)[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(Br)c3)nc2N1C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(-c4cscn4)c3)nc2N1C1CCCC1
Temperature: 100 °C
Reaction time: 19 h
Yield: 18.7 %

Procedure:
(R)-2-(4-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 43, 0.11 g, 0.271 mmol), 4-(tributylstannyl)thiazole (0.10 g, 0.271 mmol, see Example 355) and Pd(PPh3)4 (31 mg, 0.0271) were dissolved in DMF in a screw cap vial and a stream of nitrogen was bubbled through the mixture for 2 minutes. The vial was sealed and the resulting solution was stirred at 100° C. for 19 h. The reaction mixture was diluted with brine, extracted with EtOAc, dried with Na2SO4 then purified by flash chromatography with a silica gel column by eluting with a mixture of Hexane:EtOAc and then further purified by preparative HPLC to give the title compound (20.7 mg). LCMS: 410.1 m/z (M+H)+; ret. Time: 3.94 (Analytical Method A).
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH:22]1([C:27]2[CH2:28][CH:29]3[CH:32]([CH:33]=2)[C:31](=O)[CH2:30]3)[CH2:26][CH2:25][CH2:24][CH2:23]1>O>[CH:22]1([C:27]2[CH2:33][C@@H:32]3[C@H:29]([CH:28]=2)[C:30](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:31]3)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C1CC2CC(C3CCCC3)=CC12
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C=C1C[C@@H]2CC(C3CCCC3)=C[C@H]12
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.21 g, 14.4 mmol) was added dropwise at 0° C. over 15 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.59 g, 63%, 15.7 mmol), and the mixture was stirred at 0° C. for 25 minutes. To this solution, a tetrahydrofuran (15 mL) solution of 3-cyclopentylbicyclo[3.2.0]hept-3-en-6-one (2.30 g, 13.1 mmol) was added dropwise at 0° C. over 10 minutes, and the mixture was stirred at room temperature for 16 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (3.30 g, 92%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CN=C(N)C=1C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C.ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
The compound (3R)-1-benzyl-pyrrolidin-3-ol (1.0 g, 5.65 mM) was dissolved in triethylamine (2.0 ml, 14.3 mM), and dimethyl amino pyridine (DMAP) (0.002 g), dichloromethane (20.0 ml) and methanesulfonyl chloride (0.9 ml, 11.7 mM) was added dropwise at 0-5° C. The reaction mixture was maintained at the same temperature for about half an hour. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50.0 ml), washed with saturated sodium bicarbonate and brine solution. It was further dried over anhydrous sodium sulphate and concentrated to get the title compound as oil. Yield=95% (1.2 g, 5.38 mM). This material was used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>O.COCCOC>[NH2:14][C:15]1[CH:22]=[CH:21][C:20]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(Br)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 250 ml of water and 500 ml of 1,2-dimethoxyethane, was mixed 26.5 g of 4-(trifluoromethyl)benzeneboronic acid, 25 g of 2-amino-5-bromo-benzonitrile and 57.9 g of potassium carbonate. The mixture was bobbled through with nitrogen for 10 minutes, then 1 g of bis(triphenylphosphine)palladium(II) choride was added and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, added 700 ml of water and extracted with 800 ml of ethyl acetate. The organic phase was washed first with 300 ml of saturated sodium chloride, then 300 ml of 2 M calcium chloride and at last with 300 ml of water. The organic phase was dried with magnesium sulfate, evaporated to an oil and trituated with ether. Yield 30.5 g (92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH3:12][Mg]Br>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: C[Mg]Br
Reactant: O=C1CCc2cc(F)ccc21
Solvent: C1CCOC1
Product: CC1C=Cc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of 5-fluoro-1-indanone (25 g, 0.17 mol) in dry THF (100 ml) was added dropwise to a solution of methyl magnesium bromide (70 ml of 3N in diethyl ether, 0.21 mol) in dry THF (50 ml) at 0° C. The mixture was stirred at RT overnight. The reaction mixture was quenched with aq. HCl to pH 1 and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give the title compound as an oil (22.3 g, 91%).
Reaction SMILES: C[O-].[Na+:3].[O-:4][CH2:5][CH3:6].[Na+].[CH3:8][CH:9]([CH3:11])[O-:10].[Na+].[Na]>>[O-:4][CH2:5][CH2:6][CH2:8][CH3:9].[CH3:8][C:9]([CH3:5])([O-:10])[CH3:11].[Na+:3]
Reactant: CC(C)[O-]
Reactant: CC[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Product: CC(C)(C)[O-]
Product: CCCC[O-]

Procedure:
Employing the procedure substantially as described in Example 1, Step E, but substituting for the sodium methoxide used therein, an equimolecular amount of sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium sec.-butoxide, or sodium t-butoxide, there is produced respectively (-)-3-ethoxycyproheptadine, (-)-3-n-propoxycyproheptadine, (-)-3-isopropoxycyproheptadine, (-)-3-n-butoxycyproheptadine, (-)-3-sec.-butoxycyproheptadine, or (-)-3-t-butoxycyproheptadine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[CH2:31][CH2:32]2)=[O:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(Cc3ccccn3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.100 g (0.29 mmol) of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolved in 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 51 mg (0.29 mmol) of 1-Pyridin-2-ylmethyl-piperazine and 0.098 g (0.3 mmol) of TOTU. The solution was stirred for 1 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in DCM and the solution was washed three times with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), ethyl acetate, and ethyl acetate/MeOH (10/1).