Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH:11]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12]1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:38])[CH2:36]Br)=[CH:31][C:30]=1[S:39]([NH2:42])(=[O:41])=[O:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(C(C)=O)C>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:38])[CH2:36][N:8]([CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH3:10])[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:31][C:30]=1[S:39]([NH2:42])(=[O:41])=[O:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(NCc1ccccc1)C1COc2ccccc2O1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: CCC(C)=O
Product: CC(C1COc2ccccc2O1)N(CC(=O)c1ccc(OCc2ccccc2)c(S(N)(=O)=O)c1)Cc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 10.76 g (0.04 mole) of N-benzyl-1-(1,4-benzodioxan-2-yl)ethylamine (i1 '), 7.68 g (0.02 mole) of 2-benzyloxy-5-bromoacetylbenzenesulfonamide, and 50 ml of methyl ethyl ketone was reluxed for 2 hours with stirring and then methyl ethyl ketone was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted using a mixture of chloroform and ethyl acetate of 2:1 by volume ratio to provide 9.6 g of the isomer (i1 ') of crude 2-benzyloxy-5-[N-benzyl-1-(1,4-benzodioxan-2-yl)ethylaminoacetyl]benzenesulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.[CH2:19]([N:26]([CH2:32]OC)[CH2:27][Si](C)(C)C)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([N:26]1[CH2:32][CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=Cc1ccc([N+](=O)[O-])cn1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C2CCN(Cc3ccccc3)C2)nc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
0.15 g of 5-nitro-2-vinyl-pyridine were dissolved in 2.5 ml of dichloromethane, 0.149 g of trifluoroacetic acid (1.31 mmol) were added, followed by slow addition of 0.928 g of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (3.91 mmol). Stirring was continued at room temperature for 1 h, before the reaction mixture was washed with aqueous sodium hydrogencarbonate, the aqueous layer reextracted with dichloromethane, the organic layers combined, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with ethyl acetate. Fractions containing the product were combined, the solvent evaporated to yield 0.186 g of the desired product.
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CC(C1C=CC([Cl:36])=CC=1)=O>O1CCCC1.CCCCCC>[Cl:36][C:5]1[CH:6]=[CH:7][C:2]([C:8]([CH3:15])=[CH2:9])=[CH:3][CH:4]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C)c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a slurry of triphenylmethylphosphonium bromide (71.4 grams (g), 200 millimole (mmole)) in 500 milliliters (ml) dry tetrahydrofuran (THF) (distilled from sodium/benzophenone), were slowly added dropwise 129 ml (200 mmole) 1.55 molar (M) n-butyllithium in hexane. The reaction mixture was stirred for 30 minutes at -10° C. whereafter a solution of 30.92 g (200 mmol) 4-chloroacetophenone in 100 ml dry THF was slowly added dropwise. The reaction mixture was then stirred for one hour at -10° C., slowly warmed to ambient temperature (about 23° C.) and stirring continued overnight. The mixture was thereafter filtered and the solvent removed by distillation at atmospheric pressure. Distillation, using a water aspirator, yielded 16.5 g (54.2% yield) of p-chloro-α-methylstyrene, boiling point (bp) 82°-86° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10]N(C=O)C.[H-].[Li+].IC>COCCOC>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=c1[nH]c(Cl)ncc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li+]
Solvent: CI
Solvent: COCCOC
Product: Cn1c(Cl)ncc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidin-4(3H)-one (1.00 g, 4.78 mmol) in DME (12 mL)/DMF (3 mL) under N2 at 0° C. was added LiH (0.044 g, 5.25 mmol), and the reaction mixture was stirred for 15 minutes at room temperature. Iodomethane (0.589 mL, 9.45 mmol) was then added and the reaction mixture was stirred at room temperature for 30 minutes and then at 60° C. for 1.5 hours. The reaction mixture was quenched with H2O and then partitioned between EtOAc and saturated aqueous NaCl. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude yellow oil. The crude product was purified by flash column chromatography, eluting with 25:1 dichloromethane/EtOAc. The desired product (0.764 g, 72%) was obtained as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 3.59 (s, 3H). LRMS (ESI pos) m/e 223, 225 (M+1, Br pattern).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([CH2:48][O:47][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=c1[nH]nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.552 g of 6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 3 ml of N,N-dimethylformamide; 0.200 g of potassium carbonate and 0.209 ml of chloromethyl pivalate were added, followed by stirring at room temperature for 20 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (185:15:2). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with siethyl ether-hexane (1:1), and dried, to yield 0.515 g of the title compound.
Reaction SMILES: C(C[C@H](O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]Br)=[CH:9][CH:8]=1)C)C.[CH3:16][C@H:17]([NH2:26])[C@H:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:8]([CH2:9][C@H:10]([CH2:13][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:26][C@@H:17]([CH3:16])[C@H:18]([OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH:12]=1)[CH3:11])[CH3:7]
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: CCC[C@@H](C)Oc1ccc(CCBr)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@@H](C)Cc1ccc(CCN[C@@H](C)[C@H](O)c2ccccc2)cc1

Procedure:
A compound ethyl(R)-2-[4-(2-bromoethyl)phenoxy]propane (450 mg, 1.5 mM) and (1R,2S)-Norephedrine in DMF (5 ml) it is maintained in agitation in nitrogen atmosphere at a temperature of 70° C. for 72 hours. Then the reaction mixture is diluted with ethyl acetate, washed with a saturated solution of NaCl and dried with anhydrous Na2SO4. The solvent is removed at reduced pressure and the product is isolated from the residue by column chromatography (silica gel; mobile phase: dichloromethane/ethanol=40:1). 145 mg of ethyl (R)-2-[4-[2-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl-amino)ethyl]benzyl]propane is obtained as clear yellow oil (52% of yield). [α]D=−0.6 (c 1.1, CH Cl3). FT-IR (neat): 3262, 3055, 2986, 2930, 1748, 1613, 1559, 1511, 1451, 1270, 1241, 1196, 1136, 1098, 1051, 1016, 743, 703 cm−1. 1NMRs (500 MHz, CDCl3, δ): 7.32-7.22 (m, 5H, aromatic protons); 7.11-7.09 (2H, aromatic protons); 6.80-6.78 (2H, aromatic protons); 5.15-5.14 (d, 1H, J=4.0 Hz, CHOH); 4.76 (bs, 2H, OH and NH: exchanged with D2O); 4.71-4.67 (q, 1H, J=6.7 Hz, CH3CHCO); 4.22-4.18 (q, 1H, J=7.2 Hz, CH2CH3); 3.71-3.67 (q, 1H, J=7.0 Hz, CH3CHNH); 3.20-2.91 (m, 4H, CH2CH2); 1.60-1.59 (d, 3H, J=6.7 Hz, OCHCH3); 1.25-1.20 (m, 3H, CH3CH2); 0.96-0.94 (m, 3H, J=7.0 Hz, CH3CHNH). 13C NMRs (125 MHz CDCl3, δ): 172.23, 161.34, 156.25, 129.69, 128.13, 127.60, 127.17, 126.10, 125.88, 115.22, 75.80, 72.62, 72.40, 61.23, 58.98, 49.72, 48.09, 34.28, 18.51, 14.08. MS-ESI m/z (%): 372 [M+H]+(100). MS-MS (372): 354 (100), 221 (55), 147 (24), 121 (7).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30][NH:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:39](=O)[CH3:40].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[CH2:30][N:31]([CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH2:39][CH3:40])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC=O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CNC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCN(Cc1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)C1CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[(cyclobutylamino)methyl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (3.6 mg, 6.50×10−3 mmol) in dichloroethane (300 μL) was added acetaldehyde (40 μL, 0.709 mmol) and NaBH(OAc)3 (excess). The reaction was stirred at room temperature for 2 hours and then diluted with EtOAc (10 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-{[cyclobutyl(ethyl)amino]methyl}-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.69 (25% EtOAc/hexanes). LCMS=583.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.90 (s, 1H), 7.80 (s, 2H), 7.54-7.52 (m, 3H), 5.74 (d, J=8.0 Hz, 1H), 4.99 (d, J=16.1 Hz, 1H), 4.65 (d, J=16.2 Hz, 1H), 4.04-3.98 (m, 1H), 3.64 (d, J=13.9 Hz, 1H), 3.47 (d, J=13.9 Hz, 1H), 3.18-3.12 (m, 1H), 2.48-2.39 (m, 2H), 1.98-1.92 (m, 2H), 1.87-1.74 (m, 2H), 1.67-1.58 (m, 2H), 0.90 (t, J=7.2 Hz, 3H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][CH:47]1[CH2:50][CH2:49][O:48]1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[N:13]([CH2:46][CH:47]2[CH2:50][CH2:49][O:48]2)[C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Reactant: BrCC1CCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(CC3CCO3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
500 mg (0.980 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.270 mmol) of cesium carbonate and 150 mg (1.08 mmol) of 2-(bromomethyl)oxetane were added and the mixture was stirred at RT for 18 h, at 40° C. for 18 h and at 100° C. for 4 h. After cooling, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum. 581 mg (53% of theory, purity 63%) of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH:12]([CH3:14])[CH3:13].C(O)C.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.[OH-].[K+]>O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C1C(=O)Nc2ccc(O)cc21
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C1C(=O)Nc2ccc(OCC3CO3)cc21
Yield: 50 %

Procedure:
18 g. 5-Hydroxy-3-isopropylindolinone are dissolved in 150 ml. ethanol, 22 ml. epichlorohydrin are added thereto, the mixture is mixed with 5.3 g. potassium hydroxide in 5 ml. water and the reaction mixture is stirred for 2 days at ambient temperature. After the addition of 200 ml. water, the reaction mixture is extracted with ethyl acetate and the extract purified over a column of silica gel with methylene chloride/methanol (95:5 v/v). There are obtained 11 g. of the title compound; yield 50% of theory; m.p. 122°-125° C., after recrystallisation from diethyl ether.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][C:6]=1[F:16])=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]3[CH:2]=2)=[C:6]([F:16])[CH:7]=1
Reactant: O=C(CBr)c1ccc(OCCCCl)cc1F
Reactant: Cc1ccnc(N)c1
Solvent: CCO
Product: Cc1ccn2cc(-c3ccc(OCCCCl)cc3F)nc2c1
Temperature: 25 °C

Procedure:
A solution of the product of Step B (1.0 g) and 2-amino-4-picoline (0.357 g) in ethanol (4 mL) was heated at 73° C. for 18 hours. The reaction mixture was cooled to ambient temperature and the solvent evaporated in vacuo. A portion of the residue was purified via silica gel chromatography (ethyl acetate/hexane) directly. The remainder of the residue was dissolved in methanol/dichloromethane and treated with Dowex® 550A basic resin (Aldrich, Milwaukee, Wis.) for 10 minutes. The resin was removed via filtration and the filtrate evaporated prior to silica gel chromatography (ethyl acetate/hexane). The combined material (0.42 g) containing the title compound was used without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[F:23][C:24]([F:29])([F:28])[C:25]([CH3:27])=[O:26]>O1CCCC1>[F:23][C:24]([F:29])([F:28])[C:25]([OH:26])([CH3:27])[C:17]#[C:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: CC(=O)C(F)(F)F
Reactant: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
To a cooled (-78° C.) solution of 4-phenylsulfonylphenylethyne (66 mg, 0.27 mmol) in freshly distilled tetrahydrofuran (2.5 mL) was added n-BuLi (109 mL, 2.5M solution in hexanes, 0.27 mmol). The solution was stirred for 10 minutes at -78° C. at which time 1,1,1-trifluoroacetone (272 mL, 1.0M solution in tetrahydrofuran, 0.27 mmol) was added. The reaction mixture was kept at -78° C. for five minutes before quenching with 2N HCl . Diethyl ether was added, and the aqueous layer extracted further with diethyl ether. The combined organic layers were dried, evaporated and the product purified by chromatography, with ethyl acetate:hexanes as eluent (1:4) to yield the title butyne as a white solid (72 mg, 75%); mp 94.8°-95.3° C.; 250 MHz NMR (CDCl3): 1.72 (s,3, CH3), 3.08 (s,1, OH), 7.48-7.60 (m,5, Ar), 7.87-7.94 (m,4, Ar); MS: m/z=355(M+ 1). Analysis for C17H13F3O3S: Calculated: C, 57.62; H, 3.70; Found: C, 57.46; H, 3.65.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=2[CH:28]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=2[CH:28]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Into a solution of crude methyl 7-[[2-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate in THF-methanol (10-5 ml) was added at room temperature an aqueous solution (2.1 ml) of potassium carbonate (622 mg), and the resulting mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain 7-[[2-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (136 mg) as a yellow amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([S:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[C:2]1[CH3:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1[nH]c2ccccc2c1Sc1cccc(CC(=O)O)c1
Reactant: BrCc1ccccc1
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccccc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: [3-(2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and benzyl bromide.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]>CN(C=O)C>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1ccccc1CBr
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1Cn1c(C)cc2c1ccc1nnc(C)n12
Reaction time: 0.17 h

Procedure:
To a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (15.0 mg, 0.0806 mmol, from Example 2, Step 5) in DMF (2.2 mL) was added sodium hydride (0.0098 g, 0.24 mmol, 60% in mineral oil). After stirring for 10 minutes, 1-(bromomethyl)-2-methylbenzene (0.015 g, 0.080 mmol, Aldrich) was added. After stirring for 45 minutes, the reaction was quenched by the addition of water and diluted to 5 mL volume with MeCN. The solution was filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (9 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Oc1ccc(N)cn1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2)cn1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
2-(4-Chloro-2-methyl-phenoxy)-5-aminopyridine (211 mg, 0.90 mmol) was dissolved in methylene chloride (2.7 mL) then treated with triethylamine (0.19 mL, 1.35 mmol) followed by benzoyl chloride (0.13 mL, 1.12 mmol). The reaction mixture was stirred for 3 hours at 22° C. then saturated aqueous NaHCO3 was added and the mixture was stirred for another hour. The organic layer was separated and washed 2× with 6% aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent. The product was recovered as a white solid. MS (m/z): 338/340 (M+H)+ ; C19H15N2O2Cl requires 338.8.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[NH2:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:29][C@H:30]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31]4)=[O:27])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1S,3S)-3-aminocyclopentyl]carbamate hydrochloride (example C6) the title compound is obtained as pale yellow foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)[CH:22]=2)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1>>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:29]2[N:28]=[C:27]([C:23]3[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=3)[CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH:32]=[CH:31][N:30]=2)=[CH:38][CH:39]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)CC1CCNCC1

Procedure:
Intermediate 34 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 496. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 2H), 8.1 (d, 1H) 7.6 (d, 1H) 7.5 (t, 1H), 7.3 (d, 1H), 7.1 (d, 2H), 6.7 (d, 2H), δ 4.5 (s, 2H), 3.3-3.2 (m, 6H), δ 3.0 (s, 3H), 2.9 (t, 2H), δ 2.7 (t, 2H), δ 1.6 (m, 1H), δ 1.2 (m, 4H).