Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=O)[CH:10]=[C:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][CH2:13][CH2:14][O:15]C1CCCCO1.O.[NH2:30][NH2:31].[C:32](Cl)(=[O:34])[CH3:33].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[C:32]([N:30]1[C:11]([CH2:12][CH2:13][CH2:14][OH:15])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:10][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[N:31]1)(=[O:34])[CH3:33]
Reactant: O=C(C=C(CCCOC1CCCCO1)c1ccccc1)c1cc(F)ccc1F
Reactant: NN
Reactant: CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1N=C(c2cc(F)ccc2F)CC1(CCCO)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 16.0 g (41.4 mmol) of 1-4 in 150 mL of pyridine was added 3.0 mL (62.1 mmol) of hydrazine hydrate, and the resulting mixture was heated at 90° C. for 45 min. After cooling to room temperature, the reaction was placed in an ice bath and 14.7 mL (207 mmol) of acetyl chloride was added dropwise. The bath was removed and the reaction was stirred overnight at room temperature before being dumped into a separatory funnel containing EtOAc and brine. The layers were separated, the organic was washed twice with 1M HCl, once with brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was twice resuspended in toluene and concentrated to azeotrope off any remaining pyridine. The residue was dissolved in 200 mL of MeOH and 8.0 g (42 mmol) of p-toluenesulfonic acid monohydrate was added. After stirring for 2 h at room temperature, most of the solvent was removed by rotary evaporation and the residue partitioned between saturated aqueous NaHCO3 and EtOAc. After separating the layers, the organic was washed again with bicarbonate, then brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was triturated with Et2O and the solid material was collected by filtration to provide racemic 1-5 as a white solid. Data for racemic 1-5: 1HNMR (500 MHz, CDCl3) δ 7.7 (m, 1H), 7.4-7.0 (m, 7H), 3.8-3.65 (m, 2H), 3.6 (m, 1H), 3.5 (m, 1H), 2.9 (m, 1H), 2.4 (s, 3H), 2.3 (m, 1H), 1.7-1.5 (m, 2H) ppm. HRMS (ES) calc'd M+H for C20H20F2N2O3: 359.1566. Found: 359.1557
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[O:10][CH:11]=1)(=O)=O.C[Sn](C)(C)[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:26][CH:25]=1.[Li+].[Cl-]>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>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:9]2[O:10][CH:11]=[C:7]([C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:28][CH:29]=3)[N:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)co2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc([Sn](C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cccc(-c2nc(-c3ccc(NC(=O)OC(C)(C)C)cc3)co2)c1
Temperature: 100 °C
Yield: 73 %

Procedure:
In a sealable tube, 17 (436 mg, 1 eq), tert-butyl 4-(trimethylstannyl)phenylcarbamate (600 mg, 1.25 eq), LiCl (280 mg, 4 eq), Pd(PPh3)4 (77 mg, 5%) were mixed in 10 ml of dioxane. The tube was sealed and heated for 1 night at 100° C., cooled to RT, evaporated and purified by flash chromatography (SiO2, hexane/AcOEt, 85/15) giving 18 as a white solid in 73% yield.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([CH:11]1[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)=O.FC(F)(F)C([O-])=O.[NH4+:31].O>C(Cl)Cl>[C:18]1([CH2:17][N:13]2[CH2:14][CH2:15][O:16][CH:11]([C:9]3[NH:8][C:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=4[N:31]=3)[CH2:12]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [NH4+]
Reactant: O=C(N[C@@H]1CCCCC1=O)C1CN(Cc2ccccc2)CCO1
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: c1ccc(CN2CCOC(c3nc4c([nH]3)CCCC4)C2)cc1
Temperature: 150 °C
Yield: 75.4 %

Procedure:
A mixture of N-[(1R)-2-oxocyclohexyl]-4-(phenylmethyl)-2-morpholinecarboxamide (1.1 g, 3.48 mmol) and ammonium trifluoroacetate (2.069 g, 17.38 mmol) was heated at 150° C. for 20 minutes. After cooling, to the mixture was added water (30 mL) and CH2Cl2 (50 mL). The organic layer was separated and washed with brine, dried (MgSO4), and concentrated to afford the crude title compound (0.78 g). LC-MS (ES) m/z=298 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][S:8][C@H:3]12.Cl.[CH2:37]([O:39][N:40]=[C:41]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:42](Cl)=[O:43])[CH3:38].C(OCC)(=O)C>O1CCCC1>[CH2:37]([O:39][N:40]=[C:41]([C:45]1[N:49]=[C:48]([NH2:50])[S:47][N:46]=1)[C:42]([NH:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][S:8][C@H:3]12)=[O:43])[CH3:38]
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS[C@H]12)c1nsc(N)n1
Yield: 74.1 %

Procedure:
To a solution of benzhydryl 7-amino-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (trans isomer) (3 g) in tetrahydrofuran (30 ml) containing monotrimethylsilyl acetamide (5 g) was added 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (1.8 g) under stirring at -10°-0° C. The reaction mixture was stirred at the same temperature for 30 minutes. After addition of ethyl acetate (150 ml) and a small amount of water, the separated organic layer was washed in turn with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate. The solvent was evaporated in vacuo to give benzhydryl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (3.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:34][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=1[O:30][CH3:29])=[O:27]
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1CN
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OC)c(OC)c1
Product: COc1ccc2c(c1)CCN(CC(=O)NCc1ccccc1OC)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxybenzylamine
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].O=[C:15]1[CH2:23][CH:22]2[CH:17]3[CH2:18][CH:19]4[CH:21]2[CH:20]4[CH:16]13.O>O1CCCC1.CS(C)=O>[C:3]([CH:5]=[C:15]1[CH2:23][CH:22]2[CH:17]3[CH2:18][CH:19]4[CH:21]2[CH:20]4[CH:16]13)#[N:4]
Reactant: O=C1CC2C3CC4C2C4C13
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#CC=C1CC2C3CC4C2C4C13
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.4 g. washed free of oil) was treated with dimethyl sulphoxide (100 ml.) and warmed under nitrogen to 75°-80° C. for 35 minutes. The mixture was cooled to ambient temperature and a solution of diethyl cyanomethylphosphonate (17.7 g.) in dry tetrahydrofuran (100 ml.) added dropwise. The mixture was stirred for 30 minutes. A solution of the above ketone (13.4 g.) in a mixture of dimethyl sulphoxide (100 ml.) and tetrahydrofuran (100 ml.) was then added dropwise and stirred for 16 hours at room temperature. The product was poured into water (1000 ml.) and the mixture extracted with ether (5×100 ml.). The combined extracts were washed with saturated brine, dried over potassium carbonate, filtered and evaporated. Distilled in vacuo gave 8-cyanomethylenetetracyclo-[4,3,0,02,4,03,7 ]nonane, b.p. 138°-140° C./18 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.[CH3:11][N:12]([CH2:16][CH2:17]O)[CH2:13][CH2:14]O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([B:8]2[O:10][CH2:17][CH2:16][N:12]([CH3:11])[CH2:13][CH2:14][O:9]2)[CH:5]=[N:4][CH:3]=1
Reactant: CN(CCO)CCO
Reactant: OB(O)c1cncc(Br)c1
Solvent: Cc1ccccc1
Product: CN1CCOB(c2cncc(Br)c2)OCC1
Temperature: 23 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
Step 1) A mixture of 3-bromopyridine-5-boronic acid [CAS-no. 452972-09-7] (10 g, 50 mmol) and N-methyldiethanolamine (5.9 g, 50 mmol) in toluene (50 mL) was stirred at 23° C. for 24 h, then totally evaporated, triturated with heptane to give 2-(5-bromo-pyridin-3-yl)-6-methyl-[1,3,6,2]dioxazaborocane (14.1 g, 100%) as an off-white solid. MS (ISP) 285.0 [(M+H)+].
Reaction SMILES: [Br:1][CH:2]1[CH:6]2[O:7][CH:8]([OH:11])[CH:9]3[CH2:10][CH:3]1[CH2:4][CH:5]23.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1.C[N:24]([CH3:27])C=O>C(Cl)Cl>[Br:1][CH:2]1[CH:6]2[O:7][C@H:8]([O:11][C@@H:22]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:7][C:6]4[CH:2]=[CH:3][CH:10]=[CH:9][CH:5]=4)[CH:13]=3)[C:27]#[N:24])[CH:9]3[CH2:10][CH:3]1[CH2:4][CH:5]23
Reactant: CN(C)C=O
Reactant: OC1OC2C(Br)C3CC1C2C3
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: N#C[C@@H](O[C@H]1OC2C(Br)C3CC2C1C3)c1cccc(Oc2ccccc2)c1

Procedure:
A solution of 2.19 g of the product of Step B in 50 ml of methylene chloride was added to a refluxing mixture of 2.93 g of (R,S)α-cyano-3-phenoxy-benzyl alcohol, 100 ml of methylene chloride and 300 mg of p-toluene sulfonic acid and the mixture was refluxed for another 15 minutes and then returned to room temperature. The mixture was washed with water, dried, vacuum filtered and evaporated to dryness under reduced pressure. The 4.34 g of the (R,S)α-[(2S)(6-bromohexahydro-3,5-methano-2H-cyclopenta[b]furan-2-yl)-oxy]-3-phenoxy-benzene acetonitrile were chromatographed over silica gel and eluted with a 9-1 hexane-ethyl acetate mixture to obtain the (S)α-isomer melting at 65° C. and having a specific rotation of [α]D20 =+110° (c=0.5% in dimethylformamide) and the (R)α-isomer with a specific rotation of [α]D20 =+108.5° (c=0.4% in dimethylformamide).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:24]=[C:7]2[N:8]=[C:9]([C:16]3[C:17]([CH3:23])=[N:18][N:19]([CH2:21]C)[CH:20]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:6]2[N:5]=1.Cl>C(O)C>[Br:3][C:4]1[CH:24]=[C:7]2[NH:8][CH:9]([C:16]3[C:17]([CH3:23])=[N:18][N:19]([CH3:21])[CH:20]=3)[CH2:10][CH:11]([C:12]([F:13])([F:14])[F:15])[N:6]2[N:5]=1
Reactant: CCn1cc(-c2cc(C(F)(F)F)n3nc(Br)cc3n2)c(C)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)cc1C1CC(C(F)(F)F)n2nc(Br)cc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
Sodium tetrahydroborate (472 mg) was slowly added to a suspension of 2-bromo-5-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (Preparation 7, 1.8 g) in Ethanol (20 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was then very slowly added to ice cooled 1N HCl until a pH=2.0 was achieved to quench any remaining sodium tetrahydroborate. The solution was then concentrated under high vacuum to remove the majority of ethanol. Saturated sodium bicarbonate aqueous solution was then slowly added to the acidic solution until a neutral pH (7.0) was achieved and a white precipitate forms. The precipitate was filtered off and washed with water (200 mL) and ether (20 mL). The white precipitate was collected and dried in vacuo to afford the title compound as a white powder (1.36 g, 74.7%). 1H NMR (400 MHz, DMSO-d6) δ: 2.00, (m, 1H), 2.09, (s, 3H), 2.30, (m, 1H), 3.67, (s, 3H), 4.34, (m, 1H), 5.15, (m, 1H), 5.31, (s, 1H), 6.69, (s, 1H), 7.63, (s, 1H).
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)[Cl:8].[CH2:11]1[C:15]2([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12]1>ClCCl>[Cl:8][C:18]1[CH2:19][CH2:20][C:15]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16][C:17]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCC2(CCCC2)CC1
Solvent: ClCCl
Product: O=CC1=C(Cl)CCC2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N,N-dimethylformamide (2.81 mL) in dichloromethane (40 mL) was added dropwise POCl3 (2.78 mL) at 0° C. The reaction mixture was warmed up to room temperature and spiro[4.5]decan-8-one (3.95 g) in dichloromethane (5 mL) was added dropwise. The mixture was stirred overnight. The reaction was quenched with cold aqueous sodium acetate and the resulting mixture was extracted with ether and the organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].CI.O.[C:19](OCC)(=O)C>O1CCCC1>[CH3:19][N:4]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)[C:1](=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc2c(c1)CCCC2=O
Temperature: 40 °C
Reaction time: 15 h

Procedure:
6-Acetamido-1-tetralone (13.7 g, 67.4 mmol) was dissolved in tetrahydrofuran (40 ml). Sodium hydride(oil)(2.40 g, 101 mmol) was added to the solution, which was refluxed with heating for 2.5 hours. After cooling, methyl iodide(20 ml)was added to the reaction mixture, which was stirred at 40° C. for 15 hours. The reaction mixture was poured into a cold water, and extraction was conducted using ethyl acetate. The extract was washed with 1N hydrochloric acid and 1 N aqueous sodium hydroxide solution. The ethyl acetate layer was concentrated. The residue was purified by alumina column chromatography (development solvent; ethyl acetate:n-hexane=50:50 ˜100:0). The eluent was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-diisopropyl ether, to give the titled compound(8.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].Cl>CCOC(C)=O>[ClH:1].[C:18]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4]3[C:3]=2[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=3)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CC(=O)N1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2nc(C)[nH]c3cc(-c4ccccc4)nc2-3)CC1
Temperature: 180 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (500 mg, 2.05 mmol) and 1-acetyl-piperazine (Aldrich Chemical Company) (525 mg, 4.10 mmol). The flask was purged with N2 and the mixture was heated to 180° C. for 30 min. The reaction was allowed to cool to room temperature and the crude material was purified by flash chromatography on silica gel with 10% MeOH/EtOAc as eluant to give 600 mg (87% yield) of an off white solid. The free base (400 mg, 1.2 mmol) was dissolved in hot EtOAc (10 mL) and anhydrous ethereal HCl (1.2 mL, of a 1.0 M soln, 1.2 mmol) was added dropwise. The mixture was stirred for 2 h and allowed to cool to room temperature. The resulting solid was filtered and dried under high vacuum to give 205 mg (96% yield) of the title compound as a light yellow solid. Mp: 282-283° C. 1H NMR (DMSO-d6; 400 MHz): d 2.09 (s, 3), 2.61 (s, 3), 3.7 (s, 4), 4.14 (dt, J=5.3, 14), 6.95 (s, 1), 7.54 (m, 3), 8.00 (d, 2, J=6.88). MS m/z: 366 (M+1); 364 (M−1). Anal. Calcd for C19H21N5O.HCl.: C, 60.76; H, 5.95; N, 18.65; O, 4.45; Cl, 10.19. Found: C, 60.76; H, 5.90; N, 18.64; Cl, 10.15.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][C@@H:18]([S:20]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:19])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:40])[N:4]([CH3:41])[C:3]1=[O:42].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[SH:20][C@@H:18]([CH3:19])[CH2:17][N:9]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]2[C:7]([N:2]([CH3:1])[C:3](=[O:42])[N:4]([CH3:41])[C:5]2=[O:40])=[CH:8]1
Reactant: C[C@@H](Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](S)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To crude (S)-1,3-dimethyl-5-phenyl-6-(2-(tritylthio)propyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 3)(1.35 mg, 1.06 mmol) in DCM (30 ml) was added TFA (4.09 ml, 53.1 mmol) and triethylsilane (1.7 ml, 10.6 mmol) giving a yellow solution. The mixture was stirred at RT overnight. The reaction mixture was evaporated under vacuum. The residue was partitioned between DCM/water and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. The solid was dissolved in a minimal volume of DCM and purified via ISCO column chromatography, 40 g silica, liquid load, 0-60% iso-hexane:EtOAc, product eluting at 50% affording 7 pure fractions. Corresponding fractions were reduced in vacuo to yield the title compound as a white solid.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C[O:10][C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1)=O.Cl>O1CCCC1.O>[C:1]([CH2:2][C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14]1)=[O:10])#[N:3]
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To a solution of acetonitrile (708 μL, 13.5 mmol) in tetrahydrofuran (30 mL) was added n-butyl lithium (1.6 M solution in hexane, 7.75 mL, 12.4 mmol) at −78° C. The solution was stirred at −78° C. for 10 minutes and a solution of EXAMPLE 24A (3.0 g, 11.34 mmol) in 10 mL of tetrahydrofuran was added. The mixture was stirred at −78° C. for 1 hour and was warmed up to −20° C. over 3 hours. Water was added and the mixture acidified to pH 3 with 2N hydrochloric acid. The mixture was partitioned between ethyl acetate and brine and the organic phase concentrated. The residue was purified by flash chromatography on silica gel using 30-80% ethyl acetate in hexane to give the title compound (1.91 g, 61%). MS(DCI): m/z 273 (M+1)+.
Reaction SMILES: C[O-].[Na+].[Cl:4][CH2:5][C:6]#[N:7].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1.Cl>CO>[ClH:4].[Cl:4][CH2:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=[NH:7]
Reactant: N#CCCl
Reactant: NC1Cc2ccccc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(CCl)NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.54 g. (0.01 mole) of sodium methoxide in 100 ml. methanol was added 7.6 g. (0.1 mole) chloroacetonitrile with cooling. The solution was stirred at room temperature for 1 1/2 hours. Then there was added a solution of 10.9 g. (0.1 mole) of 2-aminoindane in 50 ml. of methanol and 16.66 ml. of 6N ethanolic hydrochloric acid (0.1 mole). The solution was stirred at room temperature for 4 hours and concentrated to dryness at room temperature under high vacuum. The product was recrystallized from isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:15](Cl)(=O)=O)[CH:11]=2)[O:6]1)=[O:4].COC(C1C=CC2C=C(SCC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)C=CC=2O1)=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([SH:15])[CH:11]=2)[O:6]1)=[O:4]
Reactant: COC(=O)C1CCc2cc(S(=O)(=O)Cl)ccc2O1
Agent: COC(=O)C1C=Cc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc2O1
Product: COC(=O)C1CCc2cc(S)ccc2O1

Procedure:
Compound 3C was prepared according to the method of Example 1 utilizing compound 3B. Compound 3C was prepared in 67% yield. MS: 223 (M−1)+. Preparation of 6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-1-benzopyran-2-carboxylic acid methyl ester (Compound 3D)
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:10][C:3]1[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Cc1cc(C)c(Br)cc1C
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cc1cc(C)c(N2CCNCC2)cc1C

Procedure:
A target compound (1.03 g, 5.041 mmol, 40.2%) was yielded in the same manner as Reference Example 10 by reacting 5-bromo-1,2,4-trimethylbenzene (2.5 g, 12.556 mmol) with piperazine (4.32 g, 50.224 mmol), sodium t-butoxide (1.75 g, 18.206 mmol) and dichlorobis(tri-o-tolylphosphine)palladium(II) (295.5 mg, 0.37 mmol) and purifying by separation through column chromatography (CH2Cl2/MeOH, 1:1).
Reaction SMILES: [CH2:1]([C:9]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21]2[CH:20]=[C:19]([C:22](O)=[O:23])[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:35])=O>>[CH2:1]([C:9]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21]2[CH:20]=[C:19]([C:22]([Cl:35])=[O:23])[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)O)cc21
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)Cl)cc21

Procedure:
9,9-Dioctyl-9H-fluorene-2-carboxylic acid (32.36 g, 74.5 mmole) was refluxed in thionyl chloride (93 g, 782 mmole) for 8 hrs. Unreacted thionyl chloride was distilled off and the residue material used without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]2[CH2:21][CH:20]2[CH2:22][OH:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(Cl)(Cl)Cl.C(#N)C.I([O-])(=O)(=O)=[O:35].[Na+]>O.[Ru](Cl)(Cl)Cl.O>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]2[CH2:21][CH:20]2[C:22]([OH:35])=[O:23])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=S(=O)(Oc1ccccc1C1CC1CO)c1ccc(C(F)(F)F)cc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(O)C1CC1c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 2-[2-(hydroxymethyl)cyclopropyl]phenyl 4-(trifluoromethyl)-benzenesulfonate (0.70 g, 1.9 mmol), carbon tetrachloride (2.5 mL), acetonitrile (2.5 mL), water (3.8 mL), sodium periodate (1.8 g, 8.4 mmol) and ruthenium choride hydrate (75 mg, 0.4 mmol) is stirred at room temperature overnight. The reaction is partitioned between ethyl acetate and dilute HCl. The organic layer is filtered through anhydrous sodium sulfate, evaporated and purified on silica gel in ethyl acetate-methylene chloride-acetic acid mixtures. The product, 2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)phenyl]cyclopropanecarboxylic acid, is obtained as a mixture of isomers. A yield of 95% is obtained.