Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:20]N1C(=O)CCC1=O>ClCCl.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[S:12][C:13]([I:20])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccsc1NC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cc(I)sc1NC(=O)OCc1ccccc1

Procedure:
To a solution of benzyl[3-(aminocarbonyl)-2-thienyl]carbamate (4.39 g, 15.88 mmol) in dichloromethane (440 mL) was added N-iodosuccinimide (3.57 g, 15.88 mmol). An additional amount of N-iodosuccinimide (1.07 g) was added in 3 portions over the next 60 min to drive the reaction to completion. The dark reaction mixture was diluted with ethyl acetate (700 mL), hexanes (100 mL), aqueous sodium thiosulfate (1 M, 150 mL), and aqueous sodium hydroxide (1 M, 300 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound as a solid.
Reaction SMILES: I[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: OB(O)c1ccccc1Cl
Product: COc1ccc(-c2ccccc2Cl)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 80 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid [7-(2-chloro-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and 2-chlorophenylboronic acid (54 mg, 0.35 mmol) using the general procedure A as a light yellow solid in 80% yield. MS: m/e=415 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11](C(O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([N:19](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([NH2:19])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ncccc2Cl)cc1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
The product from Example 24A (104 mg, 0.444 mmol) and triethylamine (0.095 mL, 0.68 mmol) were combined in DMF (3 mL) and treated with diphenylphosphoryl azide (0.14 mL, 0.65 mmol). After stirring for 4 hours, the mixture was treated with water (0.30 mL) and heated at 65° C. for 1 hour. The mixture was allowed to cool to room temperature, diluted with water (7 mL), and extracted with diethyl ether (7 mL). The organic layer was washed with brine (7 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (50% ethyl acetate in hexanes) to provide the title compound.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][N:22]=N1)([C:14]1[CH:19]=[CH:18][CH:17]=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:25]([C:29]1N=C(Cl)N(CC2C=CC(C3C(C(O)=O)=CC=CC=3)=CC=2)N=1)[CH2:26][CH2:27]C>>[CH2:29]([C:24]1[N:20]=[C:1]([CH2:14][CH2:19][CH2:18][CH3:17])[NH:22][N:23]=1)[CH2:25][CH2:26][CH3:27]
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnnn2)cc1
Reactant: CCCCc1nc(Cl)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)n1
Product: CCCCc1n[nH]c(CCCC)n1

Procedure:
A solution of 64.5 g (0.50 mol) of ethyl iminovalerate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. France, 2997 (1964)] in 100 mL of methanol was added slowly to 58.0 g (0.50 mol) of valeric acid hydrazide (Lancaster Synthesis) in 400 mL of methanol at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to warm to ambient temperature and then stir at reflux for 2 days. The solvent was removed in vacuo; purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (80:20) gave 78.9 g (93%) of a colorless solid: mp 50.5°-51.5° C.; NMR (CDCl3) δ 0.88 (t, J=7 Hz, 6H), 1.28-1.33 (m, 4H), 1.63-1.77 (m, 4H), 2.72 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 183 (12%), 182 (100), 181 (3), 180 (6), 152 (8), 139 (4); HRMS. Calcd for M+H: 182.1657. Found: 182.1661.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:14](=[CH:17][C:18]4[O:19][CH2:20][O:21][C:22]=4[C:23]=3[CH2:24][N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:14](=[CH:17][C:18]4[O:19][CH2:20][O:21][C:22]=4[C:23]=3[CH2:24][N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c3c(cc4c2O/C(=C\c2n[nH]c5ccccc25)C4=O)OCO3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1cc1c(c2CN2CCNCC2)OCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A solution of tert-butyl (Z)-4-({6-[(1H-indazol-3-yl)methylene]-7-oxo-6,7-dihydrobenzofuro[5,6-d][1,3]dioxol-4-yl}methyl)piperazine-1-carboxylate (0.019 g, 0.038 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped with toluene under reduced pressure to remove the solvent and hydrogen chloride. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (99:1→95:5)) to obtain (Z)-6-[(1H-indazol-3-yl)methylene]-4-(piperazin-1-ylmethyl)benzofuro[5,6-d][1,3]dioxol-7(6H)-one (0.005 g, 33%).
Reaction SMILES: I.CS[C:4]([C:6]1[S:7][C:8]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)=[NH:5].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](OCC)(OCC)[CH:32]([NH2:42])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].B(F)(F)F.CCOCC>O1CCCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]2[N:5]=[C:4]([C:6]3[S:7][C:8]4[C:14]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=4[N:10]=3)[NH:42][C:32]=2[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=N)SC)nc12
Reactant: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1N
Agent: FB(F)F
Agent: I
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CN(C(=O)OC(C)(C)C)CC4)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.5 %

Procedure:
To a suspension of 0.50 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboximidothioic acid methyl ester hydroiodide in 33 ml tetrahydrofurane was added 1.34 g 3-amino-4,4-diethoxy-piperidine-1-carboxylic acid tert-butyl ester and the mixture was stirred at room temperature for two days. Then 0.2 ml boron trifluoride etherate was added and the solvent was distilled off under vacuum. Again 0.2 ml boron trifluoride etherate was added and the mixture was dissolved in 30 ml dimethylformamide and heated for 10 minutes at 125° C. The solvent was distilled off and the residue was dissolved in dichloromethane and extracted with water. The organic layer was dried with sodium sulfate, filtered and the solvent was evaporated. Chromatography on silicagel with ethylacatate/hexane 1:1 followed by chromatography on aluminiumoxide with ethylacatate/hexane 1:1 yielded 0.18 g (35%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester as an amorphous solid; m/e=472 (M+H+).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, light brown solid (79 mg, 66%), MS (ISP) m/z=481.3 [(M+H)+], mp 149° C., was prepared in accordance with the general method of example 36 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and p-toluenesulfonyl chloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].N1C(C)=CC=CC=1C.O([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH:29]([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[O:1][CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9])([CH3:31])[CH3:30]
Reactant: COC(=O)c1nnsc1CO
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution of methyl 5-(hydroxymethyl)-1,2,3-thiadiazole-4-carboxylate (1.22 g, 0.007 mol) in DCM (20 mL) at 0° C. was added 2,6-lutidine (2.0 mL, 0.018 mol) followed by triisopropylsilyl triflate (2.4 mL, 0.0091 mol). The solution was stirred at 0° C. for 5 minutes. The reaction was then concentrated and purified by flash chromatography to give the desired product (2.0 g, 87%). 1H NMR (400 MHz, CDCl3): δ□; MF=C14H26N2O3SSi; LCMS calculated for C14H27N2O3SSi (M+H)+: m/z 331.1.
Reaction SMILES: CCO.[CH3:4][NH:5][NH2:6].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24](Cl)[C:23]([C:27]([O:29]CC)=O)=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24]3[NH:6][N:5]([CH3:4])[C:27](=[O:29])[C:23]3=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1Cl
Reactant: CNN
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cn1[nH]c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Yield: 63 %

Procedure:
Added at room temperature (about 20° C.) to an EtOH solution (20 ml) of 2.0 g of 2-methylhydrazine was a chloroform solution (12 ml) of 5.3 g of the ethyl 2-(4-benzylpiperazino)-4-chloropyrimidine-5-carboxylate synthesized in Referential Example 63. The resultant mixture was stirred for 3 hours. The solvent was distilled off and ethyl acetate was added to the resultant solid. After thoroughly mixing the thus-obtained mixture, 3 g of crystals were collected by filtration (yield: 63%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21]>CN(C)C=O.Cl[Cu]>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[C:14]=1[F:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cccc(F)c1F
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
Into a 500 mL, 4-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of sodium hydride (6.8 g, 170.00 mmol, 1.70 equiv, 60%) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14.1 g, 99.93 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 0° C. in 15 min. The resulting solution was stirred for 2 h at room temperature. CuCl (10 g, 101.01 mmol, 1.00 equiv) was added and a solution of 2,3-difluorophenol (15.6 g, 119.91 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100° C. in an oil bath. The resulting solution was extracted with ether and the organic layers combined. The organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8) to give 21.2 g (84%) of 1,2-difluoro-3-(4-nitrophenoxy)benzene as a brown solid.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10]N2CCCC2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:18][N:19]([CH3:31])[CH2:20]CCOC1C=CC(N)=CC=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:18][N:19]([CH3:31])[CH3:20])=[CH:16][CH:17]=1)=[C:2]=[S:3]
Reactant: CN(C)CCCOc1ccc(N)cc1
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Product: CN(C)CCCOc1ccc(N=C=S)cc1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4 isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-(3-dimethylamino-propoxy)-phenylamine. Title compound: ES-MS: 237.1 [M+H]+; single peak at tR=6.91 min (System 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=1.[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:35]([O:34][C:32]([N:26]1[CH2:31][CH2:30][N:29]([CH2:20][C:11]2[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[N:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:10]=2)[CH2:28][CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O

Procedure:
Following the procedure of Example 1(10), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a slightly yellow oil (yield: 97.5%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:17]2[C:18]3[O:23][C@@H:22]([CH2:24][OH:25])[CH2:21][O:20][C:19]=3[CH:26]=[CH:27][C:16]=2[S:15][CH:14]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:25][CH2:24][C@@H:22]2[CH2:21][O:20][C:19]3[CH:26]=[CH:27][C:16]4[S:15][CH:14]=[C:13]([Cl:12])[C:17]=4[C:18]=3[O:23]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1COc2ccc3scc(Cl)c3c2O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc4scc(Cl)c4c3O2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
4-Dimethylaminopyridine (0.26 g) then 4-toluenesulphonyl chloride (0.40 g) were added to a stirred solution of (S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-f][1,4]-benzodioxin (0.49 g) in dichloromethane (20 ml), and the mixture then stirred at ambient temperature for 24 hours. The resulting solution was poured into water (100 ml) and extracted with dichloromethane (150 ml). The resulting organic solution was then washed successively with saturated copper sulphate solution (2×100 ml) and water (100 ml). The solution was dried over sodium sulphate and the solvent evaporated under reduced pressure to give (S)-9-chloro-2,3-dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl 4-toluene-sulphonate (0.7 g) as a white solid m.p. 169-70° C.
Reaction SMILES: [CH2:1]([C:8](=[CH2:16])[C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([NH2:19])[CH3:18]>N1C=CC=CC=1>[CH2:1]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9](=[O:10])[CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][NH:19][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: C=C(Cc1ccccc1)C(=O)NCC(=O)O
Solvent: c1ccncc1
Product: CCNCC(Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 120 °C

Procedure:
4 g (13 mmoles) of N-(2-benzyl propenoyl)-glycine p.fluorobenzyl ester, 14, are dissolved in 15 ml of pyridine. 1.02 g (13 mmoles) of ethylamine in solution in the pyridine are added. The solution is heated to 120° C. for 2 hours. At the end of the reaction, the solution is concentrated to 5 ml, and 50 ml of ether are added. A white product precipitates. It is filtered, washed with water, and then with ether. It is recrystallized in a 50/50 CH3OH/H2O mixture. White crystals are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([CH2:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][C:17]1([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: NCC1(c2cccnc2)CCCC1
Product: Cc1ccccc1C(=O)NCC1(c2cccnc2)CCCC1

Procedure:
From 2-methylbenzoic acid and C-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH+): m/z=357.0, tR (minutes, Method B)=1.16
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][NH:32]3)O1>>[NH:32]1[C:33]2[C:29](=[C:28]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=4[N:7]=3)[CH:36]=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Yield: 28 %

Procedure:
1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 55 from Example 11a was reacted with 0.18 g (1.3 eq) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure A to give 18 mg of 389 after RP-HPLC purification (28% yield). MS (Q1) 381.2 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)[NH2:5].Cl[C:11]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1.C(O)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Nc1cc(Br)cc(Br)c1
Reactant: Cc1ccnc(Cl)n1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1ccnc(Nc2cc(Br)cc(Br)c2)n1
Temperature: 120 °C
Yield: 85.4 %

Procedure:
A solution of 3,5-dibromoaniline (2.93 g, 11.67 mmol), 2-chloro-4-methylpyrimidine (1.5 g, 11.67 mmol), and acetic acid (0.701 mL, 12.25 mmol) in 1,4-dioxane (23.5 mL) was sealed in a pressure vessel under an argon atmosphere and heated at 120° C. for 17 hours. After being cooled to room temperature, the reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (40 mL). The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Silica gel flash chromatography (10% to 30% ethyl acetate/hexanes) afforded N-(3,5-dibromophenyl)-4-methylpyrimidin-2-amine (3.6 g, 9.97 mmol, 85% yield, 95% purity) as a light yellow solid. MS ESI: [M+H]+ m/z 343.8.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2[C:12]([C@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3C(OCC3C=CC=CC=3)=O)=[N:13][N:14]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1>C(O)(C(F)(F)F)=O>[NH:21]1[CH2:22][CH2:23][CH2:24][C@@H:20]1[C:12]1[C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:2](=[O:1])[NH:3][C:4]=2[N:14]([CH2:15][C:16]([F:19])([F:18])[F:17])[N:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1c1nn(CC(F)(F)F)c2[nH]c(=O)c3c(c12)CCCC3
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2c(c([C@H]3CCCN3)nn2CC(F)(F)F)c2c1CCCC2

Procedure:
A solution of Example 69D (0.55 g, 1.16 mmol) in TFA (10 ml) was heated at 50° C. for 6 h. Volatile were removed and the residual was purified by HPLC (C-18, 0-100% gradient CH3CN with 0.1% TFA in water with 0.1% TFA) to provide Example 69E. MS (DCI): m/z 341 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)=[O:4].[CH3:18][S:19]([NH:22][C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[N:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[N:12]([CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17]1)[C:34](=[O:35])[CH2:33][C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:31])(=[O:32])[N:29]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NCCC1CC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C1CCCCCC1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude cis-2-(2-cyclopropyl-ethylamino)-cycloheptanecarboxylic acid methyl ester (260.5 mg, 1.09 mmol) was mixed with (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 399 mg, 1.2 mmol) and dissolved in N,N-dimethylformamide (9 mL). N-Methylmorpholine (264 μL, 2.4 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol). The resulting mixture was shaken at 25° C. overnight. A 1.0 M aqueous hydrochloric acid solution (11 mL) was added (pH=2) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further dried in vacuo for 5.5 h to afford the crude product, 2-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cycloheptanecarboxylic acid methyl ester, containing 2-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetylamino]-cycloheptanecarboxylic acid methyl ester as a side product, as a brown oil. This crude product was directly used in the next step without further purification. LC-MS (ESI) calcd for C24H34N4O7S2 554.19, found 555.3 [M+H+] and LC-MS (ESI) calcd for C19H26N4O7S2 486.12, found 487.3 [M+H+]+.