Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:13])([O:6][CH2:7][C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)OC(Cl)C.[NH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O.[Na+].[Cl-]>C1COCC1.C(=O)([O-])[O-].[K+].[K+]>[CH2:7]([O:6][C:1]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CN
Reactant: CC(Cl)OC(=O)OCc1ccco1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)OCc1ccco1
Reaction time: 18 h
Yield: 66 %

Procedure:
2.05 g (10 mmol) of α-chloroethyl furfuryl carbonate are added to a solution of 1.03 g (10 mmol) of ethyl glycinate in 6 ml of THF and 4 ml of 0.5M potassium carbonate solution maintained at between 5° and 10° C. The mixture is allowed to come to room temperature and is stirred for 18 hours. 50 ml of water saturated with NaCl are added and the mixture is extracted with 3×40 ml of ethyl ether. The organic phases are combined and dried over magnesium sulphate. After removal of the solvent and distillation, 1.5 g (66% yield) of the expected product is collected.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[O:28]1[C:32]2([CH2:37][CH2:36][C:35](B(O)O)=[CH:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:35]2[CH2:36][CH2:37][C:32]3([O:31][CH2:30][CH2:29][O:28]3)[CH2:33][CH:34]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: OB(O)C1=CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C2=CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1.312 g, 2.86 mmol) and 1,4-dioxaspiro[4,5]dec-7-en-8-boronic acid (1.066 g, 4.01 mmol) in DMF (12 mL) was added 2M solution of Na2CO3 (6 mL), and the mixture was deoxygenated by bubbling nitrogen through solution for 10 min. Then Pd(PPh3)4 was added to the mixture, and it was heated at 100° C. for 40 min. The mixture was brought to room temperature, diluted with CH2Cl2, acidified with 3N HCl till pH 2-3, and extracted with EtOAc. Organic fraction was washed with NaHCO3 and brine, dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using hexanes-EtOAc gradient to afford 1.368 g (92%) of 5-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid.
Reaction SMILES: N1C2C3C(CNCC=3C=CC=2)=[CH:2]1.[CH2:13]([N:16]1[C:26]2[C:27]3[C:18]([CH2:19][NH:20][CH2:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)=[CH:17]1)[CH2:14][CH3:15]>>[CH3:2][N:20]1[CH2:19][C:18]2=[CH:17][N:16]([CH2:13][CH2:14][CH3:15])[C:26]3[C:27]2=[C:22]([CH:23]=[CH:24][CH:25]=3)[CH2:21]1
Reactant: c1cc2c3c(c[nH]c3c1)CNC2
Reactant: CCCn1cc2c3c(cccc31)CNC2
Product: CCCn1cc2c3c(cccc31)CN(C)C2

Procedure:
By following the procedure of Example 7 but replacing 1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline with an equivalent amount of 1,3,4,5-tetrahydro-1-propylpyrrolo[4,3,2-de]isoquinoline, described in Example 6, 1,3,4,5-tetrahydro-4-methyl-1-propylpyrrolo[4,3,2-de]isoquinoline is obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.[CH2:18](Br)[C:19]#[CH:20].O>CN(C)C=O>[F:3][C:4]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:7]2[N:8]([CH2:20][C:19]#[CH:18])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: C#CCBr
Reactant: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 69.9 %

Procedure:
A suspension of sodium hydride (0.06 g) in N,N-dimethylformamide (3 ml) was cooled to 0° C. 7-Fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (0.57 g) was added thereto at 0° to 5° C., and the resultant mixture was stirred for 30 minutes. Propargyl bromide (0.35 g) was added to the mixture, which was gradually heated to room temperature, and the reaction was continued for 6 hours. After addition of water, the resultant mixture was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and n-hexane (1:1) as an eluent to give 7-fluoro-6-nitro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.47 g). m.p., 109.1° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[C:14]([F:24])[CH:13]=[CH:12][CH:11]=2)=[O:7])(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].ClCCl>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[F:24][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[C:8]([C:6]([OH:7])=[O:5])[NH:9]2
Reactant: CC(C)(C)OC(=O)c1[nH]c2cccc(F)c2c1Nc1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1[nH]c2cccc(F)c2c1Nc1ccncc1
Temperature: 25 °C
Yield: 88 %

Procedure:
Stir at ambient temperature for 3 h a solution of 4-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic tert-butyl ester (Example 17, 0.15 g, 0.458 mmol) in 35% trifluoroacetic acid/dichloromethane. Concentrate the reaction under vacuum to obtain a gray solid. Dry the solid at 40° C. under vacuum and then triturate with hot ethyl acetate. Allow to cool to ambient temperature and collect a light gray powder. Dry the powder at 45° C. under vacuum for 2 h and obtain 0.15 g (88%) of the title compound: MS 272(M+H), m.p. 231–234° C. (dec.)
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH2:17])[CH2:5]1)(=O)C.[OH-].[K+].O>CCO>[NH2:17][C:6]1[CH:5]=[N:4][C:13]2[C:8]([CH:7]=1)=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2
Reactant: CC(=O)N1CC(N)=Cc2c1cccc2[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cnc2cccc([N+](=O)[O-])c2c1

Procedure:
N-Acetyl-3-amino-5-nitroquinoline, as described above in Step B, (5.89 g, 25.5 mmol) was dissolved in EtOH (200 mL) and KOH (2 N aqueous solution, 19.2 mL, 38.4 mmol) was added. The reaction mixture was heated to reflux for 48 hours, cooled, poured into water, and concentrated to in vacuo to remove the EtOH. The resulting solid was collected by filtration and dried to afford the desired product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.C([O-])(O)=O.[Na+]>CO.O.CCOC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([NH2:10])=[O:9])[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: NC(=O)[C@@H]1CCCC[C@@H]1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (±)-cis-2-aminocyclohexanecarboxamide (28 mg, 0.20 mmol), 2,4,5-trichloropyrimidine (37 mg, 0.20 mmol, 1 equiv.) and NaHCO3 (17 mg, 0.20 mmol, 1 equiv.) in a mixture of MeOH (1.0 mL) and H2O (0.5 mL) is stirred at room temperature for 12 h. The reaction is diluted with EtOAc and washed with water (2×), dried over Na2SO4 and concentrated in vacuo to generate the product (±)-cis-2-(2,5-dichloropyrimidin-4-ylamino)cyclohexanecarboxamide; ESMS m/z 289.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12]([CH3:19])=[N+:13]([O-])[CH:14]=[C:15]([CH3:17])[N:16]=1.O=P(Cl)(Cl)[Cl:22]>CN(C=O)C>[Cl:22][C:14]1[C:15]([CH3:17])=[N:16][C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[C:12]([CH3:19])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2nc(C)c[n+]([O-])c2C)c(OC)c1
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C)c(Cl)nc2C)c(OC)c1

Procedure:
The product from step 2 (444 mg) is dissolved in POCl3 (1 mL) and DMF (N,N-dimethylformamide, 15 mL), and the resulting solution is stirred at 60° C. for 5 hours. The reaction mixture is cooled, and the volatiles removed under reduced pressure. Flash chromatography (30% ethyl acetate in hexanes) affords 2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-dimethyl-pyrazine as a clear oil. MS: 279.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.B([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([OH:43])=[O:42])(O)O.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.O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:38]4[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=4)[C:41]([OH:43])=[O:42])=[CH:32][C:17]=3[C:18]=2[C:28](=[O:31])[NH:29][CH3:30])=[CH:22][CH:23]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (3.5 g, 10.7 mmol) was added to Pd(Ph3P)4 (108 mg, 0.093 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (3.0 g, 7.19 mmol), 3-boronobenzoic acid (1.97 g, 11.86 mmol). Dioxane (60 ml) and water (12 ml) was added at rt. The reaction was degassed 3× and then heated to 95° C. and allowed to stir overnight. It was allowed to cool to rt. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The precipitate that formed was filtered and dried overnight at 55° C. under vacuum. The remaining organic phase was concentrated and triturated with DCM, followed by hot DCE and finally hot MeOH to afford the titled compound which was combined with the previously collected precipitate (2.4 g, 87%). LC-MS retention time: 1.19 min; m/z (MH+): 390. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(O[C:5](=[O:16])[NH:6][C:7]1[CH:8]([O:13][CH2:14][CH3:15])[O:9][C:10](=[O:12])[CH:11]=1)C=C.[C:17]([NH:25][CH2:26][C:27]1[CH2:33][N:32]([CH2:34]C(O)=O)[C:31](=[O:38])[CH:30]([NH:39][C:40]([C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=[CH:44][N:43]=2)=[O:41])[CH2:29][CH:28]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.C(Cl)Cl.CN(C=O)C.CCOC(C)=O.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:17]([NH:25][CH2:26][C:27]1[CH2:33][N:32]([CH2:34][C:5](=[O:16])[NH:6][CH:7]2[CH2:11][C:10](=[O:12])[O:9][CH:8]2[O:13][CH2:14][CH3:15])[C:31](=[O:38])[CH:30]([NH:39][C:40]([C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=[CH:44][N:43]=2)=[O:41])[CH2:29][CH:28]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CCOC(=O)NC1=CC(=O)OC1OCC
Reactant: O=C(O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC1OC(=O)CC1NC(=O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A catalytic amount of Pd(Ph3P)4 is added to a solution of (2-ethoxy-5-oxo-furan-3-yl)-carbamic acid allyl ester (100 mg, 0.43 mmol) and N,N-dimethylbarbituric acid (135 mg, 0.86 mmol) in CH2Cl2 (5 mL). The solution is stirred at room temperature for 15 minutes then {6-(benzoylamino-methyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid, 31, prepared in the previous step, is dissolved in CH2Cl2/DMF (2 mL of 1:1) and added. HOBt (54 mg, 0.40 mmol) and EDCl (77 mg, 0.40 mmol) are added and the solution stirred for 5 hours after which time it is diluted with EtOAc, washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. The resulting residue is purified over silica (EtOAc/hexane) to afford the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1.Cl>CCO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CCO
Product: COCCCn1c([C@@H]2CCCNC2)nc2ccccc21
Yield: 98.8 %

Procedure:
(R)-tert-Butyl 3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (4.82 mmol; 1.8 g) was added to a 100 mL round-bottomed flask equipped with a reflux condenser and stirring under nitrogen. EtOH (15 mL) and HCl (8 M in H2O; 4 mL) were then added and the solution was heated to reflux for 10 min. Analysis of the reaction mixture by LC/MS indicated that the reaction was complete. The solvent was then removed in-vacuo. The resultant oil was then extracted with EtOAc and a 10% aqueous K2CO3 solution. The organic layer was collected and dried with Na2SO4, and was then filtered. The filtrate was concentrated and dried in-vacuo affording (R)-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (7D) as a brown oil (4.76 mmol, 1.3 g, 99% yield). ESI-MS: m/z 274.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]([CH:12]=O)[CH3:11].B>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]([CH3:11])[CH3:12]
Reactant: Cc1ccsc1C(Cc1ccccc1N)N(C)C=O
Agent: B
Solvent: C1CCOC1
Product: Cc1ccsc1C(Cc1ccccc1N)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A stirred solution of 5.79 g of 2-amino-N-formyl-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine in 400 ml of tetrahydrofuran was treated dropwise under nitrogen with 90 ml of a 1M solution of borane in tetrahydrofuran. The solution was stirred overnight at room temperature and then quenched with 60 ml of a 10% sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane (2×100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was treated with 15 ml of glacial acetic acid and 35 ml of concentrated hydrochloric acid. After stirring at room temperature overnight, the solution was decanted over 200 g of ice, basified with 20 ml of 50% aqueous sodium hydroxide, and extracted with dichloromethane (3×100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purification was accomplished by means of HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). Concentration of the appropriate fraction afforded a solid which was recrystallized from diethyl ether to afford 3.7 g of 2-amino-N,N-dimethyl-α-(3-methyl-2-thienyl)benzenethanamine, mp 75°-77° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:5]=1[CH2:6][C@@H:7]([CH:22]=[CH2:23])[C@@H:8]([OH:21])[C@@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:10].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:29]([O:21][C@@H:8]([C@@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:10])[C@H:7]([CH:22]=[CH2:23])[CH2:6][C:5]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:4]=1[F:3])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: C=C[C@H](Cc1ccc(F)cc1F)[C@@H](O)[C@H](C)OCc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@H](Cc1ccc(F)cc1F)[C@@H](OCc1ccccc1)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
An oven-dried 100 mL Schlenk flask was cooled under nitrogen and was then charged with NaH (60% dispersion in mineral oil, 1.24 g, 31.0 mmol) and anhydrous DMF (50 mL). A solution of (2S,3R,4S)-4-(2,4-difluorobenzyl)-2-((4-methoxybenzyl)oxy)hex-5-en-3-ol (8.06 g, 22.2 mmol) in anhydrous DMF (10 mL) was added via canula over a period of 6 min followed by an anhydrous DMF rinse (5 mL) of the source flask and needle. Gas evolution was observed, and the resulting white suspension was stirred at room temperature for 90 min, at which point the reaction color had turned red. Benzyl bromide (4.23 mL, 35.6 mmol) was added and the reaction was heated to 40° C. After stirring for 3 hours, the heat source was removed and the reaction was cooled to room temperature. Saturated aqueous NH4Cl solution (20 mL) was added, and the mixture was allowed to stir for 30 min, at which point gas evolution had ceased. The crude mixture was then diluted with H2O (50 mL) and extracted with Et2O (100 mL×3). The combined organic extracts were washed with saturated aqueous NH4Cl solution (100 mL), dried over anhydrous MgSO4, filtered, concentrated, and the residue was purified by column chromatography on SiO2 (0%→10% methyl tert-butylether (MTBE)/hexane gradient) to furnish the title product as white solid (90% Pure, 8.47 g, 84%): mp 141-144° C.; 1H NMR (400 MHz, CDCl3) δ 7.41-7.30 (m, 4H), 7.30-7.24 (m, 3H), 7.05-6.96 (m, 1H), 6.90-6.84 (m, 2H), 6.76-6.67 (m, 2H), 5.57 (dddd, J=17.1, 10.3, 9.0, 1.3 Hz, 1H), 4.88 (dd, J=10.2, 1.9 Hz, 1H), 4.87 (d, J=11.4 Hz, 1H), 4.72 (ddd, J=17.2, 1.8, 0.5 Hz, 1H), 4.63 (d, J=11.4 Hz, 1H), 4.53 (d, J=11.3 Hz, 1H), 4.40 (d, J=11.3 Hz, 1H), 3.79 (s, 3H), 3.70 (qd, J=6.2, 3.8 Hz, 1H), 3.52 (dd, J=6.9, 3.9 Hz, 1H), 3.09 (d, J=10.4 Hz, 1H), 2.59-2.44 (m, 2H), 1.25 (d, J=6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 161.24 (dd, J=245.7, 11.9 Hz), 161.09 (dd, J=247.0, 11.6 Hz), 159.11, 138.90, 138.24, 132.05 (dd, J=9.4, 6.7 Hz), 130.92, 129.17, 128.33, 127.97, 127.53, 123.45 (dd, J=15.9, 3.7 Hz), 116.95, 113.78, 110.59 (dd, J=20.8, 3.7 Hz), 103.33 (dd, J=26.5, 25.0 Hz), 83.67, 76.56, 74.18, 70.41, 55.28, 47.98, 29.75, 14.24; 19F NMR (376 MHz, CDCl3) δ −113.06 (d, J=6.8 Hz), −113.95 (d, J=6.4 Hz); ESIMS: m/z 475 ([M+Na]+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[C:15](#[N:18])[CH:16]=[CH2:17].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:17][CH2:16][C:15]#[N:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: C=CC#N
Reactant: OCCc1ccc2sccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCCOCCc1ccc2sccc2c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To 2.00 g of 2-(1-benzothiophen-5-yl)-1-ethanol were added 13 mg of potassium hydroxide, 36 mg of tetra-n-butylammonium bromide and 1.11 mL of acrylonitrile, and the resulting mixture was stirred at 45° C. for 3 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 2 mol/L hydrochloric acid. The insoluble materials were removed and then the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; hexane:ethyl acetate=3:1) to obtain 2.46 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]propiono-nitrile as a colorless oil.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:35]([F:38])([F:37])[F:36])[C:31]([NH2:34])=[N:32][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:2]2[N:9]3[C:5]([S:6][C:7]([C:10]4[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=4)=[N:8]3)=[N:4][CH:3]=2)=[CH:29][C:30]=1[C:35]([F:38])([F:36])[F:37]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: CC(=O)Nc1cccc(-c2nn3c(I)cnc3s2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 110 °C
Yield: 4 %

Procedure:
A mixture of N-[3-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-phenyl]-acetamide (0.16 g, 0.416 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (0.12 g, 0.416 mmol, 1 eq), 2M aq Na2CO3 (0.9 mL) and PdCl2(PPh3)2 (60 mg, 0.083 mmol, 0.2 eq) in dioxane (5 mL) was heated at 110° C. for 90 min. The solvent was removed under reduced pressure and the residue was redissolved in DCM and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography (DCM: MeOH, 5 to 15%) and by HPLC to afford the desired product (7 mg, 4%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.74 min, [M+H]+ m/z 419.1; 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 8.89 (s, 1H), 8.32 (m, 2H), 7.81 (m, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 6.75 (s, 2H), 2.09 (s, 3H).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:31][OH:32])[CH:24]=[CH:23]1>ClCCl>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[CH:31]=[O:32])[CH:24]=[CH:23]1
Reactant: OCc1cccc2cc[nH]c12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cccc2cc[nH]c12
Reaction time: 2 h

Procedure:
Solid pyridinium dichromate (1.77 g, 5.1 mmol) is added in portions over 3 hours to a stirred solution of 7-indolemethanol (0.5 g, 3.4 mmol) in dichloromethane (50 ml). The mixture is stirred for a further 2 hours then filtered through a pad of Celite filter aid. The filtrate is evaporated and the residue purified by chromatography on silica in ethyl acetate-hexane (1:3)