Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3](Cl)[CH2:4][CH3:5])[CH3:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Li])=[CH:10][CH:9]=1.ClC1C=CC(Br)=CC=1>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([P:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:10][CH:9]=1
Reactant: [Li]c1ccc(Cl)cc1
Reactant: CCP(Cl)CC
Agent: Clc1ccc(Br)cc1
Solvent: CCOCC
Product: CCP(CC)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A solution of 10 g. (0.08 mole) of diethylphosphinous chloride in 100 ml. of ether was added to a solution of p-chlorophenyllithium [prepared from 15.4 g. (0.08 mole) of p-chlorobromobenzene in 100 ml. of ether and 54 ml. of 1.5M n-butyllithium in hexane] under a nitrogen atmosphere. After 30 minutes, the reaction mixture was quenched with a few drops of ethyl acetate and the solvent was removed at reduced pressure. Distillation of the residual oil gave (p-chlorophenyl)(diethyl)phosphine, b.p. 86°-89° C. at 1.5 mm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH:19]2[CH3:25])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH:19]2[CH3:25])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC1CCCC(C)C1COc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCC(C)C1COc1cc(F)c(C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of tert-butyl 5-chloro-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate (0.21 g, 0.58 mmol) in dichloromethane (2 mL), was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at 0° C. for 1 hour and then concentrated in vacuo. The residue was purified by column chromatography (0 to 30% gradient ethyl acetate in hexanes) to afford the title compound (0.071 g, 38%): MS (ES−) m/z 315.2, 313.2 (M−1).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:7][C@@H:6]1[C:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=4)[O:19][N:18]=3)[CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:33])[CH:9]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[Cl:32][C:24]1[CH:23]=[C:22]([C:20]2[O:19][N:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:11]=3[N:10]([CH3:33])[CH:9]=[C:8]4[C@H:6]3[CH2:7][C@H:5]3[C:3]([OH:4])=[O:2])[N:21]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH:29]([CH3:30])[CH3:31]
Reactant: COC(=O)[C@@H]1C[C@@H]1c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c([C@H]5C[C@H]5C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
To a solution of cis-methyl-2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]cyclopropanecarboxylate (D65) (40 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 60° C. for 4 h. The mixture was cooled to room temperature and acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (25 mL) and water (20 mL). The organic phase was washed with water (25 mL) and saturated brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford cis-2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]cyclopropanecarboxylic acid (E40) (20 mg). δH (DMSO-d6, 400 MHz): 1.31 (1H, m), 1.36 (6H, d), 1.43 (1H, m), 1.72 (1H, m), 2.45 (1H, m), 3.61 (3H, s), 4.88 (1H, m), 7.21 (2H, m), 7.46 (2H, m), 7.82 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d), 12.28 (1H, br s). MS (ES): C24H22ClN3O4 requires 451; found 452.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[C:7]([F:18])[C:8](=[O:17])[N:9]3[CH2:13][C:12]([OH:16])([CH2:14][OH:15])[C:11]=1[C:10]=23.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.O1CCCC1.C([Sn](=O)CCCC)CCC>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:15][CH2:14][C:12]2([OH:16])[C:11]3=[C:2]([F:1])[CH:3]=[N:4][C:5]4[CH:6]=[C:7]([F:18])[C:8](=[O:17])[N:9]([C:10]=43)[CH2:13]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=c1c(F)cc2ncc(F)c3c2n1CC3(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)c(F)cc4ncc(F)c2c43)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.3 %

Procedure:
A solution of 3,8-difluoro-4-hydroxy-4-(hydroxymethyl)-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (710 mg, 2.79 mmol) in dichloromethane (35 ml) and tetrahydrofuran (35 ml) was treated with triethylamine (0.58 ml, 4.19 mmol), para-toluenesulphonyl chloride (586 mg, 3.07 mmol) and dibutyltin oxide (35 mg, 0.14 mmol). After 6 hours stirring at room temperature under argon, the mixture was evaporated and water (200 ml) was added. The aqueous phase was extracted with dichloromethane (3×200 ml) and the combined organic extracts dried over magnesium sulphate and evaporated to give the desired compound (1.2 g, 100%) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21](F)=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)c(F)c2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(F)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-1-(3,4-difluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethylamine. The title compound, ESI MS (m/z): 382 (M+H)+.
Reaction SMILES: Cl[Si:2]([CH3:17])([CH3:16])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:5]=[C:4]1[CH3:15].CCN(CC)CC.C[SiH]([N:28](C1C2C(=C(C)C=C(C)C=2)C(C)=C1C)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)C>CCCCCC>[CH:29]1([NH:28][Si:2]([CH3:17])([CH3:16])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[CH:5]=[C:4]2[CH3:15])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC1=C(C)C(N(C2CCCCC2)[SiH](C)C)c2cc(C)cc(C)c21
Reactant: CC1=Cc2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-s-indacen-1-yl) silane (5.67 g, 0.0216 moles) was stirred in hexane (50 mL) as NEt3 (2.18 g, 0.0216 moles) and cyclohexylamine (2.13 g, 0.0216 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (6.62 g, 94.3 percent).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>ClC(Cl)C.C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)Cl
Product: Oc1ccc(Sc2c(-c3ccc(O)cc3)sc3ccccc23)cc1
Yield: 61 %

Procedure:
A solution of 0.82 g (2.2 mmol) of methyl 4-[[2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]thio]phenyl ether (Part B) in 50 mL of dichloroethane was treated with 1.2 mL (3.3 g; 13 mmol) of BBr3 at 0° C. for 5 h. The reaction was quenched by the careful addition of 15 mL of MeOH. Evaporation of the solvent in vacuo gave a residue which was subjected to flash chromatography (SiO2; 1% MeOH in CHCl3) to afford 0.47 g of the desired product as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([Br:9])[CH:6]=[CH:5][CH:4]=1.[CH2:10]([N:17]=[C:18]=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[Br:9][C:7]1[N:8]=[C:3]([N:2]([CH3:1])[C:18]([NH:17][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19])[CH:4]=[CH:5][CH:6]=1
Reactant: CNc1cccc(Br)n1
Reactant: CCCCCCCN=C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(Br)n1
Temperature: 100 °C
Yield: 71 %

Procedure:
2 g of 6-methylamino-2-bromopyridine (prepared according to the procedure of Example 11, step a) are mixed with 3.0 mL of heptyl isocyanate. The mixture is heated for 12 hours at 100° C. The residue is chromatographed on silica gel (9/1 heptane/ethyl acetate). 2.45 g of 1-(6-bromopyrid-2-yl)-1-methyl-3-heptylurea are obtained. Yield=71%.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1CCO.N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:5]([O:4][CH2:2][CH2:1][CH:9]1[CH2:8][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: OCCC1Cc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCC1Cc2ccccc2C1
Temperature: 20 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Ac2O (47 mL, 505 mmol) in DCM (50 mL) was added over 1 h to a stirred solution of alcohol 149 (54.5 g, 337 mmol), pyridine (52 mL, 981 mmol) and DMAP (1.65 g, 13 mol) in DCM (400 mL) and the resulting solution was stirred at 20° C. for 16 h. H2O (200 mL) was added, and the mixture stirred for 1 h. The organic fraction was washed with aqueous HCl solution (1 M, 100 mL) and H2O (150 mL), dried and the solvent evaporated to give acetate 150 (68.4 g, 99%) as a pale brown oil: 1H NMR δ 7.16-7.19 (m, 2H, Harom), 7.09-7.14 (m, 2H, Harom), 4.16 (t, J=6.8 Hz, 2H, CH2O), 3.04-3.10 (m, 2H, CH2), 2.48-2.66 (m, 3H, CH2, CH), 2.05 (s, 3H, COCH3), 1.85 (q, J=6.8 Hz, 2H, CH2); 13C NMR δ 171.1, 143.0 (2), 126.2 (2), 124.4 (2), 63.5, 39.1 (2), 37.0, 34.3, 21.0. Anal calcd for C13H16O2: C, 76.4; H, 7.9. Found: C, 76.6; H, 7.9%.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH:13][C:14]([CH3:16])=[O:15])=[CH:8][C:7]=1[O:17]C(=O)C)#[N:2].[CH2:22]([NH:24][CH2:25][CH2:26]N)[CH3:23]>C(=S)=S>[CH2:22]([N:24]1[CH2:25][CH2:26][N:2]=[C:1]1[CH2:3][NH:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH:13][C:14]([CH3:16])=[O:15])=[CH:8][C:7]=1[OH:17])[CH3:23]
Reactant: CCNCCN
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)NCC#N)cc1Cl
Solvent: S=C=S
Product: CCN1CCN=C1CNC(=O)c1cc(Cl)c(NC(C)=O)cc1O

Procedure:
143 g of N-(cyanomethyl) 2-acetoxy 4-acetamino 5-chlorobenzamide was introduced into a one liter balloon flask provided with sealed agitator, a reflux condenser on which there was disposed a bubble counter containing vaseline oil, a thermometer and a dropping funnel. Thereafter, 123 g of N-ethyl ethylene diamine were rapidly added dropwise. The reaction was exothermic. The temperature rose to 110° C. and the amount of gas evolved was substantial. A thick solution was obtained. The solution was heated to temperature of 120° and then, after 25 minutes of heating, drops of carbon disulphide were added and the temperature was then maintained at 120° for a further period of 20 minutes until the gas ceased to be evolved.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: BrCCOc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(CCOc3ccccc3)C(C)(C)C2=O)cn1

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and (2-bromoethoxy)benzene. MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.35 μM.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1([C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CO>[ClH:1].[ClH:1].[N:15]1([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCCCC2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCCCC1)N1CCNCC1COc1cccnc1
Reaction time: 12 h
Yield: 100 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(piperidine-1-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (43.0 mg, 0.083 mmol) in MeOH (1 mL). After 12 h, the reaction mixture was concentrated under reduced pressure, yielding 31.3 mg (100%) of the desired product as a white solid. LC-MS: RT=3.34 min, [M+H]+=305.2.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][NH:23][O:24][CH3:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(Cl)Cl>[CH3:25][O:24][N:23]([CH3:22])[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
A solution of 2-phenylamino-6-trifluoromethyl-nicotinic acid (6.2 g, 22.0 mmol), N,O-dimethylhydroxylamine hydrochloride (2.79 g, 28.6 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (13.3 g, 35.2 mmol) in N,N-dimethylformamide (120 mL) was treated with N,N-diisopropylethylamine (8.88 g, 12 mL, 68.7 mmol). The reaction mixture was stirred at 25° C. for 4 h. At this time, the reaction was diluted with methylene chloride (400 mL), washed with a saturated aqueous ammonium chloride solution (1×300 mL), a saturated aqueous sodium bicarbonate solution (1×300 mL), and a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (250 g silica column, 10-35% ethyl acetate/hexanes) afforded N-methoxy-N-methyl-2-phenylamino-6-trifluoromethyl-nicotinamide (6.86 g, 96%) as a brown oil which upon trituration with ether became a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:19])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(S(=O)(=O)n2cccc2)s1
Yield: 74 %

Procedure:
N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C using 2-methoxyphenylboronic acid and N-(5-bromothiophenesulfonyl)pyrrole, 74% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][C:22](=[O:26])[CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].C([C:31]([O:33][CH3:34])=[O:32])#N.C(O)(=O)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[CH2:24][CH2:23][C:22]([OH:26])=[C:21]3[C:31]([O:33][CH3:34])=[O:32])[C:10](=[O:15])[C:11]([F:13])([F:12])[F:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)C#N
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC(=O)C3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)CCc2c1cccc2N(C(=O)C(F)(F)F)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of N-(4-cyanophenyl)-2,2,2-trifluoro-N-(5,6,7,8-tetrahydro-6-oxo-1-naphthyl)acetamide (1.17 g, 3.27 mmol) in THF (15 ml) was added dropwise over a 15 minute period to a stirred suspension of 80% NaH (0.30 g, 10 mmol) (Aldrich) in methyl cyanoformate (1.5 ml, 19 mmol) (Aldrich) and THF (15 ml) under nitrogen. The reaction mixture was stirred 30 minutes at room temperature then quenched with acetic acid (0.7 ml, 12 mmol). The solution was concentrated in vacuo onto silica gel (3 g) and the absorbed material purified by chromatography on silica gel (30 g) eluting with ether:hexane (1:4 to 1:3) to give methyl 5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalene carboxylate (0.64 g). 1H NMR (CDCl3, 200 MHz) δ: 2.5-2.9 (m, 4H, CH2CH2), 3.93 (s, 3H, CH3), 7.10 (d, J=8 Hz, 1H, Ar), 7.32 (t, J=8 Hz, 1H, Ar), 7.39 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 2H, Ar), 7.82 (d, J=8 Hz, 1H, Ar), 13.35 (s, 1H, OH). Anal. Calculated for C21H15F3N2O4 : C, 60.58; H, 3.63; N, 6.73. Found: C, 60.66; H, 3.66; N, 6.68.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]3[CH2:14][CH2:15][CH2:16][C@@H:9]23)=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26])#[CH:18]>>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[C:17]#[C:18][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]3[CH2:14][CH2:15][CH2:16][C@@H:9]23)=[N:6][CH:7]=1
Reactant: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Reactant: C#Cc1cc(F)ccc1F
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(C#Cc2cc(F)ccc2F)cn1
Yield: 98 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 7 using (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydro-cyclopenta[b]pyrrol-2(1H)-one (140 mg, 0.427 mmol) (Example 1, step 6) and 1-ethynyl-2,5-difluorobenzene to yield 142 mg (98%) of the title compound as a viscous light brown oil; MS: m/e=339.5 (M+H+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][C:9]1[N:13]2[C:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:38])=[C:24]([CH:37]=3)[C:25]([N:27]3[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH3+:36])[CH2:29][CH2:28]3)=[O:26])=[CH:15][NH:16][C:17](=[O:18])[C:12]2=[CH:11][C:10]=1[Cl:39].[CH3:40][C:41](OC(C)=O)=[O:42]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:41]([NH:36][CH2:35][CH2:34][NH+:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:25](=[O:26])[C:24]2[CH:37]=[C:20]([CH2:19][C:14]3[N:13]4[C:9]([Cl:8])=[C:10]([Cl:39])[CH:11]=[C:12]4[C:17](=[O:18])[NH:16][CH:15]=3)[CH:21]=[CH:22][C:23]=2[F:38])[CH2:28][CH2:29]1)(=[O:42])[CH3:40]
Reactant: [NH3+]CCN1CCCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)NCC[NH+]1CCCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 20, T1 in pyridine (0.15 M) was added Ac2O (1 eq) and the resulting mixture stirred overnight at RT. The solvent was evaporated under reduced pressure and the residue was purified at the prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column), the desired fractions were lyophilized to afford the titled compound as yellow powder. 1H NMR (300 MHz, DMSO-d6) δ: 10.97 (1H, d, J=5.6 Hz), 9.51 (1H, br. S), 8.22-8.16 (1H, m), 7.37-7.26 (3H, m), 7.20 (1H, s), 6.66-6.61 (1H, m), 4.42 (2H, s), 4.10 (1H, m), 3.63-3.14 (11H, m), 2.11 (1H, m), 1.95-1.88 (4H, m). MS (ES) C24H26Cl2FN5O3 required: 521, found: 522 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:12]=1[O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C1COCC1>[CH3:19][Si:18]([CH3:21])([CH3:20])[C:17]#[C:16][C:10]1[C:11]([C:22]([CH3:25])([CH3:24])[CH3:23])=[C:12]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1OCOCC[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CO)c(C#C[Si](C)(C)C)c(C(C)(C)C)c1OCOCC[Si](C)(C)C
Yield: 189 %

Procedure:
This solution is introduced dropwise into a solution of 15.4 g (42.3 mmol) of 3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzaldehyde in 50 ml of THF at −78° C. The reaction medium is allowed to return to room temperature, poured into aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 18.5 g (95%) of the expected alcohol are obtained in the form of a yellow oil.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[N:17]=[C:4]1[N:8]2[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C@H:7]2[CH2:6][S:5]1
Reactant: Nc1cnccn1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cnccn3)N1C2
Yield: 60 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (16.3 g) and 2-aminopyrazine (8.5 g) as the starting materials, (S)-3-(pyrazin-2-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (7.6 g) is obtained in the form of white crystals, m.p.=140° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.ClC(OCC)=O.[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32])[CH3:25]>C(N(CC)CC)C>[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[O:1][CH2:2][CH2:3][CH2:4]2)=[O:13])[CH3:25]
Reactant: CCN1CCCC1CN
Reactant: O=C(O)c1cccc2c1OCCC2
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cccc2c1OCCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
46 g of chroman-8-carboxylic acid, 188 ml of chloroform and 26 g of triethylamine were introduced into a 1-liter round-bottomed flask. The contents were cooled to 0° C. and 28 g of ethyl chloroformate were then added in small amounts, between 0° and 5° C. The contents were stirred for 30 minutes at 5° C. and 36 g of 1-ethyl-2-aminomethylpyrrolidine were then poured in dropwise, between 5° and 10° C. The contents were then stirred for 1 hour at 10° C. and the temperature was then allowed to rise. The chloroform was distilled off under slight vacuum, the residue was taken up with water and acetic acid was added until a pH of 4 was obtained. The solution obtained was filtered with charcoal and then made alkaline with 20% ammonia until a color change of phenolphthalein was observed.