Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([C:26]([O:28]C)=[O:27])[CH:16]=2)=[CH:10][N:9]=1)=[O:7])(C)(C)C.[OH-].[Na+]>CO.C1COCC1>[C:26]([C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)([OH:28])=[O:27]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2c(Oc3ccc(C(=O)O)nc3)cc(C(=O)O)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 124.8 %

Procedure:
To a solution of 5-(6-methoxycarbonyl-2,2-dim ethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester (163a) (110 mg, 0.275 mmol) in 2 mL MeOH and 1 mL THF was added 1N aqueous NaOH (0.55 mL, 0.55 mmol). The mixture was stirred at room temperature overnight, heated at 60° C. for 6 hr, then concentrated, acidified to pH˜3 with 1N aqueous HCl, extracted with 3×EtOAc, dried over Na2SO4, and concentrated to give 113 mg white solid. LCMS for C17H15NO6 m/z 330.00 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].[Br:13][C:14]1[C:15]2[N:16]([C:20](=[O:23])[NH:21][N:22]=2)[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1.C(Cl)Cl>[Br:13][C:14]1[C:15]2[N:16]([C:20](=[O:23])[N:21]([CH2:2][CH2:1][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=c1[nH]nc2c(Br)cccn12
Reactant: C=Cc1ccc2ccccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=c1n(CCc2ccc3ccccc3n2)nc2c(Br)cccn12
Temperature: 160 °C
Yield: 55.6 %

Procedure:
2-Vinylquinoline (1-2) (218 mg, 1.40 mmol) and triazolopyridinone 1-5 (250 mg, 1.17 mmol) were placed in a microwave vial and dissolved in NMP (3 mL). To the mixture was added catalytic powdered KOH (13 mg, 0.234 mmol), and the vial was capped and heated at 160° C. under microwave irradiation for 20 min. After cooling, the mixture was diluted with CH2Cl2 (100 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography (40 g cartridge), eluting with 20-100% EtOAc/hexanes. The fractions containing the desired product (1-6) were pooled, and after solvent removal in vacuo, 240 mg (52%) of a fluffy yellow solid were obtained. 1H NMR (300 MHz, CHCl3-d) δ 8.07 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.77 (app t, J=8.0 Hz, 2H), 7.68 (t, J=7.7 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.38-7.30 (m, 2H), 6.39 (dd, J=7.2, 6.7 Hz, 1H), 4.61 (t, J=7.6 Hz, 2H), 3.57 (t, J=7.6 Hz, 2H); HRMS (ES) 369.0345 (M+H) found, 369.0349 required.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[C:21]([F:25])[CH:22]=[C:23]([F:24])[C:16]=2[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:24][C:23]1[C:16]2[N:15]=[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:18]([CH3:19])[C:17]=2[CH:20]=[C:21]([F:25])[CH:22]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1nc2c(F)cc(F)cc2n1C
Product: Cn1c(CCC#Cc2cccc(CF)n2)nc2c(F)cc(F)cc21

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (109 mg, 0.57 mmol) and 2-(but-3-ynyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (126 mg, 0.57 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: from 100/0 to 99/1 as eluent) to afford 43 mg of a light brown solid. The resulting solid was dissolved in Dioxane and 0.5N HCl in dioxan was added (0.14 mL, 0.07 mmol). A green solid was formed and it was collected by filtration and washed with AcOEt. The chlorhydrate salt was dissolved in MeOH, neutralized by saturated NaHCO3. The aqueous layer was extracted twice with AcOEt. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure to afford 9 mg of 4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole (Yield: 5%) as purple oily solid (Mp=103° C.-104° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[NH2:53][C:54]1[S:55][C:56]([Br:59])=[CH:57][N:58]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:18])[NH:53][C:54]1[S:55][C:56]([Br:59])=[CH:57][N:58]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Br)s1)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (1.44 g, 5.78 mmol), HATU (2.2 g, 5.78 mmol), and DIEA (1.5 mL, 11.6 mmol)in DMF (30 mL) was stirred at room temperature for 1 h. The 2-Amino-5-bromo-thiazole hydrobromide salt (FW=259.95, 1.0 g, 3.85 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered to afford the crude product. The mixture was filtered and separated by reverse phase HPLC (20-100% of buffer B; buffer A: water containing 0.1% TFA; buffer B: MeCN containing 0.1 TFA). The combined fraction was evaporated to dryness to furnish the desired product. MS: 504.1 (M+H+).
Reaction SMILES: [C:1]([CH:4]([C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]N2C3C=CC=CC=3NC2=O)=[CH:8][CH:7]=1)([OH:3])=[O:2].C1(P([C:45]2[CH:50]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:52].CCOC(C)=O.CCCCCC>ClCCl>[Br:52][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH:4]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:1]([O:3][CH2:50][CH3:45])=[O:2])=[CH:7][CH:8]=1
Reactant: O=C(O)C(Oc1ccc(Cn2c(=O)[nH]c3ccccc32)cc1)c1ccc2c(c1)OCO2
Reactant: BrC(Br)(Br)Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)C(Oc1ccc(CBr)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 109.4 %

Procedure:
To a cooled (0°-5° C.), magnetically stirred solution of 0.238 g (0.63 mmol) of the product of step A and 0.197 g (0.75 mmol) of triphenylphosphine dissolved in 3 mL of dichloromethane was added 0.287 g (0.75 mmol) of carbon tetrabromide in several portions. After the addition was complete, the reaction was allowed to warm to room temperature and was stirred 2.5 hours. At this point TLC analysis (50% EtOAc-hexane) indicated that starting material remained, therefore an additional 0.030 g of triphenylphosphine and 0.050 g of carbon tetrabromide were added. After 4 hours, the methylene chloride was removed in vacuo, and the residue was applied to a silica gel flash chromatography column and eluted with 10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.271 g (96%) of the title compound.
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1.CCN(C(C)C)C(C)C.Cl.[CH2:36]([O:38][C:39](=[O:42])[CH2:40][NH2:41])[CH3:37]>ClCCl.O1CCOCC1>[CH2:36]([O:38][C:39](=[O:42])[CH2:40][NH:41][C:2]([NH:25][C:21]1[CH:20]=[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH3:11])[N:24]=[CH:23][N:22]=1)=[O:3])[CH3:37]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)CN
Reactant: COc1ccccc1-c1cc(N)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Nc1cc(-c2ccccc2OC)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenyl chloroformate (0.370 g, 1.98 mmol) was added dropwise to a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (0.25 g, 1.2 mmol) and DIPEA (0.31 g, 2.4 mmol) in dichloromethane (10 ml) at −78° C. and the mixture was allowed to stir overnight at room temperature. Then dichloromethane was evaporated, dry 1,4-dioxane and glycine ethyl ester hydrochloride (0.17 g, 1.2 mmol) and DIPEA (0.31 g, 2.4 mmol) were added and the mixture was heated overnight at 70° C. The solvent was evaporated and the crude product was extracted with ethyl acetate (2×100 ml). The ethyl acetate phase was washed with water (2×50 ml) and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor. The residue was purified by silica gel column chromatography (eluent: 70% ethyl acetate/hexane) giving {3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-acetic acid ethyl ester. Yield: 190 mg, 47.8%.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH3:11])[CH:5]=2)[CH2:3][CH2:2]1.[N:12]([O-])=O.[Na+]>CC(O)=O.O>[CH:1]1([C:4]2[CH:5]=[C:6]3[CH:11]=[N:12][NH:10][C:7]3=[CH:8][N:9]=2)[CH2:3][CH2:2]1
Reactant: O=N[O-]
Reactant: Cc1cc(C2CC2)ncc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1n[nH]c2cnc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 6-cyclopropyl-4-methylpyridin-3-amine (130 mg, 0.88 mmol) in AcOH (10 mL) was treated with a solution of sodium nitrite (61 mg, 0.88 mmol) in water (0.5 mL). The reaction mixture was stirred at RT for 15 min and then was allowed to stand at RT for 24 h. AcOH was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The organic solution was washed with water and brine, then dried (Phase separator) and concentrated under. MS (LC-MS): 160 [M+H]+, tR (HPLC conditions c): 2.07 min.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C[N:23]([CH:25]=O)C.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:33][CH:32]=1)=O>O.CCOC(C)=O>[CH2:9]([C:25]1[N:19]([C:18]2[CH:20]=[CH:21][C:15]([O:14][C:2]3[CH:3]=[CH:4][C:5]4[O:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=3)=[CH:16][CH:17]=2)[CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:33][CH:32]=2)[N:23]=1)[CH2:1][CH2:2][CH3:3]
Reactant: Nc1ccc(Oc2ccc3oc4ccccc4c3c2)cc1
Reactant: CN(C)C=O
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(OCCCN(CC)CC)cc2)cn1-c1ccc(Oc2ccc3oc4ccccc4c3c2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(dibenzofuran-2-yloxy)aniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.3 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:16].[Na+]>CC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][I:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCCCCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCCCCc1ccccc1

Procedure:
A mixture of 8-phenyloctyl chloride (4.4 g), sodium iodide (5.34 g) and acetone (20 ml) was heated under reflux for 20 hours. Evaporated, water (20 ml) added and extracted with diethyl ether (20 ml). The extracts were dried, filtered and evaporated to a pale yellow liquid (5.5 g). Distilled to give 8-phenyloctyl iodide, b.p. 200° C. (air bath temperature) at 0.1 mBar.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C@H:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC(OC1C=CC(C2C=CC(C(OCCCCCCCC)=O)=CC=2)=CC=1)=O>>[CH3:10][C@@H:11]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC[C@H](C)O
Reactant: N#Cc1ccccc1O
Agent: CCCCCCCCOC(=O)c1ccc(-c2ccc(OC(=O)OC)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCC[C@@H](C)Oc1ccccc1C#N

Procedure:
Quantities: 2-(hydroxybenzonitrile (38) (9.17 g, 0.077 mol), (S)-(+)-octan-2-ol (10.00 g, 0.077 mol), DEAD (13.41 g, 0.077 mol), triphenylphosphine (20.20 g, 0.077 mol). The experimental procedure was as described for the preparation of compound 5. The crude product was purified by column chromatography (20% petrol/dichloromethane) to give a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][NH:15][C@H:14](/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1.C(N(CC)CC)C>O1CCCC1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][N:15]([CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[C@H:14](/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Yield: 56.7 %

Procedure:
A mixture of (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine (1.00 g), 3-picolylchloride hydrochloride (509 mg) and triethylamine (0.43 ml) in tetrahydrofuran (25 ml) was refluxed for 48 hours and the solution was diluted with chloroform (40 ml). The solution was washed successively with saturated aqueous sodium bicarbonate and brine, and the organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel (50 g) column with a mixture of chloroform and methanol (100:1) as an eluent to give (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(3-pyridylmethyl)pyrrolidine (700 mg) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:15]([F:21])[C:3]=1[C:4]1[S:24][C:7]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:6]=2[N:5]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(F)c(C(Cl)=Nc2ccnc(Cl)c2F)c(Cl)c1
Reactant: NC(N)=S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N#Cc1cc(F)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A mixture of 2-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-4-cyano-6-fluorobenzimidoyl chloride (0.713 g, 2.05 mmol), thiourea (0.623 g, 8.2 mmol) and pyridine (538 μL, 6.66 mmol) in isopropanol (7 mL) was heated under reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature before adding triethylamine (1.7 mL, 12.3 mmol). The resulting mixture was heated under reflux for a further 3 hours and allowed to cool. The mixture was concentrated under reduced pressure and the residue was partitioned between DCM and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (0-10% EtOAc in pentane) to give the desired compound as an off-white solid (0.356 g, 53% yield). 1H NMR (300 MHz, CDCl3): δ 8.55 (d, J=5.6 Hz, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.72 (t, J=1.4 Hz, 1H), 7.52 (dd, J=8.3, 1.5 Hz, 1H). LCMS (Method D): RT=3.86 min, m/z: 324 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[S:10]([O-:14])([O-:13])(=[O:12])=[O:11].CS[C:17]([NH2:19])=[NH2+:18].CSC(N)=[NH2+]>O>[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:1][C:17]([NH2:19])=[NH:18]
Reactant: CSC(N)=[NH2+]
Reactant: O=S(=O)([O-])[O-]
Reactant: NCCc1ccccn1
Solvent: O
Product: N=C(N)NCCc1ccccn1
Product: O=S(=O)(O)O

Procedure:
A solution of 2-(2-aminoethyl)pyridine (10.0 g) and S-methylthiouronium sulphate (11.39 g) in water (30 ml) is heated under reflux for 2 hours. The crude material, isolated in a manner similar to that described in Example 1, is recrystallized from water, yielding 2-(2-pyridyl)ethylguanidine sulphate, m.p. 264°-266°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][N:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[C:19]([CH:25]=[CH:26][N:27]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
3,4,5-Trimethoxyphenylboronic acid (20.64 g) and ethyl 2-chloroisonicotinate (19.06 g) were suspended in a mixed solvent of toluene (200 mL) and THF (100 mL), and to the suspension 2 M sodium carbonate (200 mL) and tetrakis(triphenylphosphine)palladium(0) (5.93 g) were added. The mixture was stirred overnight at 90° C. under an argon atmosphere. Ethyl acetate was added to the reaction mixture to separate an organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:12])[CH:11]=1)=[O:4].[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C@@H:15]([O:21][C:22]([C:24]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:14]2>C(#N)C>[Cl-:1].[F:12][C:10]1[CH:11]=[C:6]([NH:5][C:3]([CH2:2][N+:13]23[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]2)[C@@H:15]([O:21][C:22]([C:24]2([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH2:14]3)=[O:4])[CH:7]=[N:8][CH:9]=1
Reactant: O=C(CCl)Nc1cncc(F)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1cncc(F)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.5 %

Procedure:
2-Chloro-N-(5-fluoro-pyridin-3-yl)-acetamide (Example 28a) (53 mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e) (84 mg) in acetonitrile (2 mL). The reaction mixture was allowed to stir at room temperature for 24 h. The solid was filtered off and dried under vacuum at 40° C. to give the title compound (47 mg, 35%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[C:10]([O:14][C:15](=[O:24])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22]Cl)[N:21]=1)([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:10]([O:14][C:15](=[O:24])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][S:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[NH2:1])[N:21]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1cc(Cl)ccc1S
Reactant: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(CSc2ccc(Cl)cc2N)cs1
Yield: 100.7 %

Procedure:
Following General Procedure A, the title compound (588 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (376 mg, 2.36 mmol), tert-butyl[4-(chloromethyl)-1,3-thiazol-2-yl]carbamate (391 mg, 1.57 mmol) and K2CO3 (1.08 g, 3.45 mmol) in DMF (10 ml).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]([CH3:19])=[CH:18][C:9]1=2.[CH:39]([C:41]1[S:45][C:44]([C:46]([OH:48])=[O:47])=[CH:43][CH:42]=1)=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:39][C:41]2[S:45][C:44]([C:46]([OH:48])=[O:47])=[CH:43][CH:42]=2)[C:10]2[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([CH3:19])=[CH:18][C:9]1=2
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccc(C(=O)O)s1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1

Procedure:
To a solution of (S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (Example 3, Step 18) (6.10 mmol) in dichloroethane (5 mL), add 5-Formyl-thiophene-2-carboxylic acid (0.4 mmol) followed by acetic acid (cat.). Add NaB(OAc)3H (0.5 mmol) and stir the mixture at room temperature for 14 h. Dilute the reaction with dichloromethane (10 mL) and quench with water (5 mL). Separate the organics and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over Na2SO4, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with MeOH/DCM (1-5%) to provide the title compound as a colorless foam. MS (ES+): 693 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:1]=[C:18]([CH3:25])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCC(CC)COc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(CC)CC)c2c1N

Procedure:
Prepared as in Example Ba from 2-amino-6-(2-ethylbutoxy)benzonitrile (Example Cb) and ethyl 3-oxobutanoate as a white solid (89%). 1H NMR (400 MHz, DMSO-d6) δ 0.90 (t, J=8 Hz, 6H), 1.32 (t, J=8 Hz, 3H), 1.48-1.41 (m, 4H), 1.79-1.73 (m, 1H), 2.54 (s, 3H), 4.08 (d, J=4 Hz, 2H), 4.31 (q, J=8 Hz, 2H), 6.92 (dd, J=2, 8 Hz, 1H), 7.23 (dd, J=2, 8 Hz, 1H), 7.50 (t, J=8 Hz, 1H), 8.04 (brs, 1H). MS 331 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH3:2].C([Li])CCC.CCCCCC.CN([CH:22]=[O:23])C>CCOCC>[CH2:1]([C:3]1[CH:7]=[C:6]([CH:22]=[O:23])[S:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccsc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1csc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-ethylthiophene (2 g, 17.7 mmol) in ether (20 ml) under N2 at room temp is added butyl lithium, 2.5M in hexane solution (8.15 ml, 21.4 mmol) and the resulting straw coloured solution is heated to reflux for 20 minutes. The resulting cloudy solution is then cooled to room temperature before the slow addition of DMF (2 ml) over 2 minutes and the resulting solution is stirred at room temp for 1 hour. The reaction is quenched with aqueous saturated ammonium chloride (100 ml) and extracted with chloroform (100 ml). The organic layer is washed with brine, dried over magnesium sulphate and concentrated to give 4-ethyl thiophene-2-carbaldehyde as a light brown oil (2.48 g).