Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]12[CH2:19][CH:18]=[CH:17][CH2:16][C@:15]1([CH3:20])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9]([Br:21])=[CH:8][CH2:7]3)[CH2:4][C@H:3]2O.CS([Cl:27])(=O)=O>N1C=CC=CC=1>[OH:1][C@:2]12[CH2:19][CH:18]=[CH:17][CH2:16][C@:15]1([CH3:20])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9]([Br:21])=[CH:8][CH2:7]3)[CH2:4][C@H:3]2[Cl:27]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H](O)[C@@]4(O)CC=CC[C@]34C)[C@@H]1CC=C2Br
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H](Cl)[C@@]4(O)CC=CC[C@]34C)[C@@H]1CC=C2Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
95 g (0.258 mole) of 5α,6β-dihydroxy-17-bromo-androsta-2,16-diene are dissolved in 950 ml of anhydrous pyridine, and 21 ml (0.276 mole) of methanesulfonic acid chloride are added under stirring at room temperature to the solution. The reaction mixture is allowed to stand for 16 hours and then poured under vigorous stirring into 9 liters of ice water. The precipitating difficulty separable substance is extracted with 1600 ml of dichloro methane. The dichloro methane extract is washed with aqueous 10% hydrochloric acid solution to remove the pyridine and then with water until neutral, dried over sodium sulfate and evaporated to dryness. The evaporation residue, which is a mixture of 5α-hydroxy-6β-chloro-17-bromo-androsta-2,16-diene and 5α,6β-epoxy-17-bromo-androsta-2,16-diene, is dissolved in diethyl ether and etheral hydrochloric acid solution is added thereto until pH = 2 to 3. The so obtained 5α-hydroxy-6β-chloro-17-bromo-androsta-2,16-diene is separated and purified by mixing it with 10-fold amount of petroleum ether. 79.0 g of 5α-hydroxy-6β-chloro-17 -bromo-androsta-2,16-diene (79.0%) are obtained; m.p. 125°-126° C; [α]D25 = + 3.8° (c = 1 in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].B1([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)OC(C)(C)C(C)(C)O1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(-c3ccc(O)cc3)n2)cc(OC)c1OC
Yield: 25.3 %

Procedure:
Using Method B with 275 mg (0.93 mmol) 2a and 242 mg (1.10 mmol) 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenol, 83 mg pure title compound (59.7%) were obtained after purification by preparative HPLC (eluent:AcOEt). Reaction time: 48 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.CC(=O)OCC>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)nc(-c2ccccc2)n1

Procedure:
2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester (930 mg), phenylboronic acid (610 mg), tetrakis(triphenylphosphine)palladium (265 mg) and potassium phosphate (2.12 g) were dissolved in anhydrous dioxane (25 ml) under argon. The mixture was refluxed overnight and worked up with water/EA. The org. phases were dried (Na2SO4) and evaporated off. Column chromatography (EA/Hept 1/5) offered 875 mg of the desired compound.
Reaction SMILES: [IH:1].CS[C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[F:9][C:10]([F:15])([F:14])[CH2:11][NH:12][NH2:13]>C(O)C>[IH:1].[F:9][C:10]([F:15])([F:14])[CH2:11][NH:12][NH:13][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1
Reactant: CSC1=NCCN1
Reactant: NNCC(F)(F)F
Agent: I
Solvent: CCO
Product: FC(F)(F)CNNC1=NCCN1
Reaction time: 0.5 h

Procedure:
To a solution of 12.2 g of 2-methylthioimidazoline, hydroiodide in 30 ml of ethanol was slowly added 12.6 g of 2,2,2-trifluoroethyl hydrazine, dropwise over 30 minutes. This mixture was refluxed overnight, then evaporated to an oil which crystallized on standing, giving 4,5-dihydro-2-[2-(2,2,2-trifluoroethyl)hydrazino]-1H-imidazole, hydroiodide, a one gram portion of which was reacted as described in Example 33, giving 1.0 g of the desired product, mp>290° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]=[N+:29]=[N-:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:31]1([CH2:37][C:38]#[CH:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]4[CH:39]=[C:38]([CH2:37][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:30]=[N:29]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C#CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN=[N+]=[N-])cc3)cc2)CC1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(Cc5ccccc5)nn4)cc3)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-[4′-(4-azidomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.183 g, 0.45 mmol) in tBuOH (1.5 mL) and H2O (1.5 mL) was added 3-phenyl-1-propyne (0.053 g, 0.45 mmol), followed by sodium ascorbate (0.009 g, 0.045 mmol) and copper(II) sulfate pentahydrate (0.001 g, 0.005 mmol), and the reaction was stirred overnight. After aqueous workup, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [FH:1].[CH2:2]([O:4][SiH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH3:3]>>[F:1][Si:5]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[O:4][CH2:2][CH3:3]
Reactant: CCO[SiH](OCC)OCC
Reactant: F
Product: CCO[Si](F)(OCC)OCC

Procedure:
According to the present invention, silicon hydride substrates, such as, for example, alkyl, cycloalkyl, alkoxy, aryl, aryloxy or siloxy silanes containing at least one silicon hydride bond, are treated with hydrogen fluoride to give high yields of the corresponding silicon fluorides with the concomitant generation of hydrogen. In one embodiment of the invention hydrogen fluoride is contacted with triethoxysilane to give a near quantitative yield of fluorotriethoxysilane, with surprisingly little contamination of the desired product by material formed by substitution of fluoride for ethoxy.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([CH3:20])([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH3:20][C:10]1([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC1(C(=O)N2CCCC2)CCNC1
Yield: 79.3 %

Procedure:
A solution of 3-methyl-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (330 mg, 1.17 mmol) in TFA (5 mL), DCM (5 mL) and water (0.1 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was taken up in MeOH and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed to give (3-Methylpyrrolidin-3-yl)pyrrolidin-1-ylmethanone as a white solid (169 mg, 79%). 1H NMR (400 MHz, CHCl3-d): δ 3.55-3.40 (m, 5 H); 3.06-2.92 (m, 2 H); 2.32-2.20 (m, 2 H); 2.01-1.82 (m, 5 H); 1.71 (m, 1 H); 1.33 (s, 3 H).
Reaction SMILES: I(O)(=O)(=O)=O.C[S:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])=O.S(Cl)(Cl)=O>>[S:7]1[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](=[O:12])[NH:13]1
Reactant: CS(=O)c1ccccc1C(N)=O
Agent: [O-][I+3]([O-])([O-])O
Solvent: O=S(Cl)Cl
Product: O=c1[nH]sc2ccccc12

Procedure:
In the above method, 2-(methylthio)benzamide is produced from 2-(methylthio)benzoylchloride; oxidized with periodic acid to 2-(methylsulfinyl)benzamide; and cyclized in the presence of thionyl chloride to yield a 1,2-benzisothiazol-3-one.
Reaction SMILES: Cl[C:2]1[N:37]=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[C:9]([O:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:8]=1)=[O:5].[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>CCOC(C)=O.O>[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:2]2[N:37]=[CH:36][CH:35]=[CH:34][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[C:9]([O:20][CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:8]=2)=[O:5])=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Reactant: NCc1ccc(F)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2NCc2ccc(F)cc2)ccc1C(F)(F)C(F)(F)F
Temperature: 130 °C

Procedure:
2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide (442.8 mg) DIEA (351 μL) and 4-fluorobenzylamine (322 μL) were combined in a sealed tube and heated to 130° C. for 3 h. The mixture was diluted with EtOAc and H2O, the layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (1% MeOH/CH2Cl2) to obtain an off-white solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][CH3:34])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:43])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][CH3:34])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: CCCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCn1nc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a solution of 2-(6-chloro-1-propyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (38 mg, 0.06 mmol) in CH2Cl2 (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 10% MeOH/CH2Cl2 to afford 10 mg (32%) of 2-[6-chloro-1-propyl-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid. MS: (M+Na)+=513; mp=219-221° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.93 (s, 1H), 9.13 (s, 1H), 8.71 (d, J=9.1 Hz, 1H), 8.46 (dd, J=7.6, 2.6 Hz, 2H), 8.03 (s, 1H), 7.25 (d, J=9.1 Hz, 1H), 4.43-4.78 (m, 5H), 4.16-4.27 (m, 1H), 4.05-4.13 (m, 1H), 3.78-3.91 (m, 1H), 1.86-1.96 (m, 2H), 1.39 (dd, J=6.6, 4.3 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([CH3:11])([N+:8]([O-:10])=[O:9])[CH2:5][O:4]C1.[ClH:12]>C(O)C.O>[ClH:12].[CH3:11][C:6]([N+:8]([O-:10])=[O:9])([CH2:7][NH:2][CH3:1])[CH2:5][OH:4]
Reactant: CN1COCC(C)([N+](=O)[O-])C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNCC(C)(CO)[N+](=O)[O-]

Procedure:
A solution of 3,5-dimethyl-5-nitro-1,3-oxazinane (11.5 g, 71.8 mmol) in 280 ml ethanol, 50 ml water, and 12 ml of concentrated hydrochloric acid was equipped with a dean stark trap and heated at reflux temperature. To the refluxing reaction was slowly added a solution of 280 ml ethanol and 50 ml water. The rate of addition of the solution was matched to the rate of distillation and removal of an equal volume of solvent over the course of ca. 2 hours. After 4 hours at reflux temperature, the remaining solvent was distilled off and the crude residue was lyophilized from water to give 14.1 g of white solid, which was used directly in the next step without further purification. 1H NMR (400 MHz, D2O) δ 1.53 (s, 3H), 2.74 (s, 3H), 3.62-3.66 (d, J=14.6 Hz, 1H), 3.68-3.72 (d, J=14.6 Hz, 1H), 3.84-3.87 (d, J=12.5 Hz, 1H), 4.10-4.13 (d, J=12.5 Hz, 1H). 13C NMR (100 MHz, D2O) δ 18.9, 34.4, 52.8, 66.2, 88.9. LRMS (ESI/APCI):149 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:18])[N:9]2[CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[N:4][CH:3]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)(Cl)Cl>O1CCOCC1.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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[CH2:12][N:9]1[C:8](=[O:18])[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]([NH:20][C:19](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][C:10]1=2
Reactant: O=c1ccc2ncc(Br)cc2n1CC1OCCO1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Temperature: 92.5 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To a suspension of 0.40 g of 7-bromo-1-((1,3-dioxolan-2-yl)methyl)-1,5-naphthyridin-2(1H)-one in 4 mL of dioxane, 0.18 g of tert-butyl carbamate, 0.59 g of cesium carbonate, 22 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and 18 mg of tris(dibenzylideneacetone)dipalladium(0) were added at room temperature, and the mixture was stirred at 90 to 95° C. for 4 hour 15 minutes. After cooling to the room temperature, chloroform and water were added to the reaction mixture, the organic layer was separated, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, diethyl ether was added to the resultant residue and the solid was filtered off to obtain 0.29 g of tert-butyl (5-(1,3-dioxolan-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)carbamate as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCCc1ccc(C(=O)O)c(F)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1ccc(C(=O)Cl)c(F)c1

Procedure:
First, 1.1 g (6.1 mmol) of 2-fluoro-4-propylbenzoic acid was mixed with 1.1 g (9.1 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 80° C. for 2 hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude 2-fluoro-4-propylbenzoyl chloride.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](Cl)=[O:31]>>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19])=[O:31]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc2ccccc2c1

Procedure:
The procedure of Example 134 was carried out using 3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg, 0.156 mmole) in place of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 2-naphthoyl chloride (29.7 mg, 0.156 mmole) in place of p-trifluoromethylbenzoyl chloride. The product was chromatographed on silica gel (15% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized from CH2Cl2 /EtOAc to give the title compound which was dried in vacuo at 82° C.: (m.p. 293°-294° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N:12]1([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccnc(N2CCNCC2)n1
Yield: 57.9 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyrimidine (2.0 g, 11 mmol), piperazine (2.8 g, 33 mmol) and triethylamine (3.0 mL, 22 mmol) in DMF (40 mL) was stirred at 100° C. in a sealed tube overnight. After removal of most of the solvent, the residue was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH/NEt3 9/1/0.5) to give 1.48 g (56%) of desired product. MS calculated for C9H11F3N4: (M+H) 233; found 233.1.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Mg].Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1.Cl>C(OCC)C>[CH2:1]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCBr
Reactant: Brc1ccsc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCc1ccsc1
Temperature: 0 °C
Yield: 65 %

Procedure:
0.125 mole of n-hexylbromide was dissolved in 40 ml of ethyl ether. Then, 10 ml of ethyl ether was added in drops and also 0.13 mole of magnesium chip was added. The mixture was refluxed for 5 to 6 hours and the Grignard agent was obtained. The Grignard reagent was added to a solution consisting of 70 mg of NiDPPPCl2 and 0.106 mole of 3-bromo thiophene in drops at 0° c, then the mixture was refluxed for 12 to 15 hours. After that, the mixture was hydrolyzed with 40 ml of 1 N hydrochloric acid and 150 ml of ice water. Then, ethyl ether was used to extract the mixture for a few times, and the mixture was washed with water until the solution was neutral. The extract was dried by sodium sulfate to remove the solvent. The product of 3-hexylthiophene was obtained with a yield of 65% after distillation under reduced pressure.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[C:7]([OH:9])=[O:8].C[C:12](C)(C)[C:13]([O-])([O-:15])[O-:14].C(O)(=O)CCCCC>C1C2C(CCCC2)CCC1>[C:13]([CH2:12][C:3]1[CH:4]=[CH:5][O:1][C:2]=1[CH2:6][C:7]([OH:9])=[O:8])([OH:15])=[O:14]
Reactant: O=C(O)C(O)c1ccco1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Solvent: CCCCCC(=O)O
Solvent: C1CCC2CCCCC2C1
Product: O=C(O)Cc1ccoc1CC(=O)O
Temperature: 180 °C
Reaction time: 12 h
Yield: 54 %

Procedure:
A solution of the product from step b.) (10.9 g, 64 mmol) in decalin (193 ml) was treated with trimethylorthoacetate (48.2 ml, 384 mmol) and hexanoic acid (2.0 ml). Next, the reaction mixture was fitted with a Vigreaux column and heated to 180° C. for 18 hours. Additional hexanoic acid (3×1.5 ml) aliquots of hexanoic acid were added every 2 hours for the first 6 hours of reaction time. Next, the reaction was cooled to 22° C. and extracted with MeOH providing 27 g of a crude mixture of the diester and decalin. This mixture was dissolved in MeOH (250 ml), cooled to 0° C., and treated with 2 M NaOH (150 ml). After 12 hours, the solvent was evaporated and the residue was taken up in 2 N NaOH (100 ml) and washed with ether (2×150 ml). The basic layer was acidified with 4 M HCl to pH 1 and back extracted with EtOAc (4×100 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated providing 6.4 g (54%) of the above subtitle compound.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=[O:18])[C:11]([C:16]#[N:17])=[C:12](SC)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[CH2:1]([C:8]1[NH:9][C:10](=[O:18])[C:11]([C:16]#[N:17])=[C:12]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CSc1nc(Cc2ccccc2)[nH]c(=O)c1C#N
Solvent: CC#N
Product: N#Cc1c(N2CCCCC2)nc(Cc2ccccc2)[nH]c1=O

Procedure:
43 mg (0.17 mmol) of 2-benzyl-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are suspended in 0.3 ml of acetonitrile and stirred with 42.7 mg (0.50 mmol) of piperidine at 85° C. for 16 h. The resulting crude product is then purified by preparative HPLC. 11 mg (22% of theory) of the title compound are obtained.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])[CH:42]=[CH:41][C:40]=1[F:51]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:41]1[CH:42]=[C:43]([S:45]([CH:48]([CH3:49])[CH3:50])(=[O:46])=[O:47])[CH:44]=[CH:39][C:40]=1[F:51])([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(F)c(Br)c1
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)S(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-bromo-1-fluoro-4-(isopropylsulfonyl)benzene (Intermediate 128), the title compound was obtained as a white solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][CH2:9][CH:10]1[S:15][C:14]2[S:16][CH:17]=[CH:18][C:13]=2[CH:12]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:11]1.[CH3:26][O:27][CH2:28][CH2:29]Br>O>[CH3:26][O:27][CH2:28][CH2:29][O:8][CH2:9][CH:10]1[S:15][C:14]2[S:16][CH:17]=[CH:18][C:13]=2[CH:12]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:11]1
Reactant: COCCBr
Reactant: COCCOCOC1CC(CO)Sc2sccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOC1CC(COCCOC)Sc2sccc21
Temperature: 25 °C
Yield: 86.1 %

Procedure:
Under N2, a suspension of 60% NaH (20 g, 0.5 mol), DMF (350 ml) and 7 (38.3 g, 0.13 mol) was stirred at ambient temperature. After 2.5 h. the reaction was cooled to 0°-4° C. and 2-methoxyethylbromide (71 g, 0.51 mol) was added dropwise. After complete addition, the reaction was allowed to stir to room temperature overnight. The solution was then poured into H2O and the aqueous layer was extracted with EtOAc (3x). The organic layer was washed with saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column with silica gel and the product eluted with 20% EtOAc-hexane to yield 39 g (84%) of 8.