Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.0585 g, 52%). MP: 219° C. (dec.). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.27-8.22 (m, 1H), 8.13-8.10 (m, 1H), 8.02 (d, 1H, J=1.3 Hz), 7.53 (s, 1H), 7.43 (s, 1H), 6.63 (s, 1H), 6.56-6.53 (m, 1H), 6.52-6.47 (m, 1H), 6.07-5.75 (m, 1H), 3.92 (s, 3H), 3.91-3.87 (m, 4H), 3.86 (s, 3H), 3.18-3.12 (m, 4H), 2.97-2.75 (m, 10H). MS: 575 (MH)+.
Reaction SMILES: Br[CH:2]([CH3:13])[CH2:3][NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17]>[I-].[K+].Cl>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[NH:4][CH2:3][CH:2]([NH:17][C:16]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:15]=1[CH3:14])[CH3:13]
Reactant: Cc1cccc(C)c1N
Reactant: Cc1cccc(C)c1NCC(C)Br
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: Cc1cccc(C)c1NCC(C)Nc1c(C)cccc1C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A mixture of 106.8 g (0.441 moles) of N-(β-bromopropyl)-2,6-dimethyl-aniline, obtained as described in point (a) above, 110 ml (107.4 g, 0.88 moles) of 2,6-dimethyl-aniline and 1.6 g (10 mmoles) of potassium iodide is stirred at 100° to 105° C. for 3 hours under nitrogen atmosphere. The mixture is allowed to cool, 600 ml of 10% aqueous hydrochloric acid are added, and the resulting mixture is allowed to stand at room temperature overnight. The separated precipitate, which is a mixture of the hydrochloride and the hydrobromide of the expected product, is filtered off, washed with water, dried, and then treated as described in point (b) of Method (b) above in order to liberate the base. In this way 93.8 g (75.3%) of 1,2-bis(2',6'-dimethylphenyl-amino)-propane are obtained; m.p.: 54°-56° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])OC(C)(C)C)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:29]=1)C(O)=O.[CH3:36][C:37]1[N:38]=[CH:39][S:40][C:41]=1[CH2:42][CH2:43]O>>[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH:29]=1)[C:13]([NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][CH2:43][CH2:42][C:41]2[S:40][CH:39]=[N:38][C:37]=2[CH3:36])=[CH:3][CH:4]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Reactant: Cc1ncsc1CCO
Product: Cc1ncsc1CCOc1ccc(NC(=O)c2cc(F)cc(N3CCCCC3)c2)c2ccccc12

Procedure:
Compound is prepared from tert-butyl (4-hydroxy-1-naphthyl)carbamate, 3-fluoro-5-piperidin-1-yl-benzoic acid and 2-(4-methylthiazol-5-yl)-ethanol according to conditions described in general procedure D. A pink solid is produced (12 mg). Mp: 221-222° C.; 1H NMR (300 MHz, CDCl3) δ 1.62-1.69 (m, 6H), 2.50 (s, 3H), 3.20-3.27 (m, 5H), 3.40 (t, J=6.3 Hz, 1H), 4.34 (t, J=6.0 Hz, 1H), 4.46 (t, J=6.6 Hz, 1H), 6.73-6.82 (m, 2H), 6.98 (d, J=8.1Hz, 1H), 7.06-7.10 (m, 1H), 7.31-7.35 (m, 1H), 7.50-7.59 (m, 2H), 7.73 (d, J=9.3 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.93 (s, 1H), 8.32-8.35 (m, 1H), 8.60-8.62 (m, 1H); MS 490 (M+1).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27])=O)(=O)OC.O.[NH2:31][NH2:32]>>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([C:17]2[N:31]=[N:32][C:2]3[CH:1]4[CH2:7][CH:4]([C:3]=3[CH:16]=2)[CH2:5][CH2:6]4)[CH:24]=1
Reactant: COP(=O)(CC(=O)c1cc(Cl)ccc1C(F)(F)F)OC
Reactant: O=C1C(=O)C2CCC1C2
Reactant: NN
Solvent: O
Product: FC(F)(F)c1ccc(Cl)cc1-c1cc2c(nn1)C1CCC2C1

Procedure:
yellow gum. MS (EI): 324.1 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(5-Chloro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine mono hydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.[CH2:28]([N:30](CC)CC)C.CN.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([NH:30][CH3:28])=[O:26])=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Reactant: CCN(CC)CC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-nicotinic acid (75 mg, 0.19 mmol, 1 eq) in DMF (2 ml) was added triethylamine (30 μl, 0.21 mmol, 1.1 eq) followed by methylamine (1.17 ml, 3.89 mmol, 2M solution in THF, 20 eq). To the suspension was added a solution of PyBrOP (100 mg, 0.21 mmol, 1.2 eq) in DMF (1 ml) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (5% MeOH in CHCl3) to afford 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-N-methyl nicotinamide, 44 (20 mg, 26%) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17].II.[NH4+].[OH-].CN([CH:26]=[O:27])C>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:17][C:16]([NH:18][CH:26]=[O:27])=[N:15][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: NC(N)=S
Reactant: O=C(Cc1ccco1)c1ccccc1
Agent: II
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=CNc1nc(-c2ccccc2)c(-c2ccco2)s1
Temperature: 100 °C

Procedure:
2-Furan-2-yl-1-phenyl-ethanone (14.0 g, 75 mmol) and thiourea (11.5 g, 150 mmol) was dissolved in DMF (30 mL) and iodine (19.1 g, 75 mmol) was added. The reaction mixture was heated at 100° C. overnight, then diluted with water, made alkaline with saturated aqueous NH4OH, and extracted with ether. The organic phases were washed with water, dried over sodium sulfate, filtered, concentrated and purified by flash column chromatography using 1% ethyl acetate in hexane as eluent. Yield: 9.2 g, 45%
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][CH2:23][CH2:24][CH2:25]Br>CC(C)=O>[Br:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccc(O)cc2)CCCCC1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CC1(c2ccc(OCCCBr)cc2)CCCCC1
Temperature: 70 °C
Yield: 86.9 %

Procedure:
1-(4-Hydroxyphenyl)cyclohexanecarbonitrile (2.0 g, 10 mmol) was taken in acetone (150 mL) and then Cs2CO3 (8.1 g, 25 mmol) was added followed by dropwise addition of 1,3 dibromopropane (5.1 mL, 50 mmol). The mixture was heated for 3 h at 70° C. After cooling and filtration, the mixture was concentrated and the residue was purified by flash chromatography (50 g silica gel, DCM) to provide the title compound (2.8 g, 87%). Note: presence of allyl derivative as impurity.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>Br.ClCCl>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cccc(C2CCCN2CCN2CCOCC2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(C2CCCN2CCN2CCOCC2)c1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
1-[2-(4-Morpholinyl)ethyl]-2-(3-methoxyphenyl) pyrrolidine (3.6 g) in 48% hydrobromic acid (50 ml) was heated at 100° C. for 8.5 hrs. The reaction mixture was cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution and diluted with dichloromethane. The layers were separated and the aqueous phase was extracted with dichloromethane (3 times). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, ether). The appropriate fractions were collected and concentrated to give 2.0 g (59%) of 3-{1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinyl}phenol.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH2:11](Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:2][P:1]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: CCOP([O-])OCC
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(CCc1ccccc1)OCC
Temperature: -15 °C
Yield: 51.6 %

Procedure:
Diethyl phosphite (27.64 g, 200 m mole) was dissolved in DMF (200 ml), and to the solution at nitrogen atmosphere while stirring and -15° C., sodium hydride (60% in oil, 9.6 g, 220 m mole) was added. The mixture was stirred for 1 hour at not more than 0° C. To the solution phenethyl bromide (37.0 g, 200 m mole) was dropwise added and further the mixture was stirred overnight at room temperature. The DMF solution was distilled under reduced pressure leaving a residue, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated and the thus obtained oily product was distilled under reduced pressure to obtain diethylphenethylphosphonate (25.0 g, yield: 51.6%) of boiling point 136.5°~137.5° C./3 mmHg.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25](=[N:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[C:39]([F:45])[CH:38]=1)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1>CN(C=O)C>[C:43]([C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH:25]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:24]2[NH:23][C:22](=[O:21])[N:2]([C:4]3[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=3[C:6]([OH:8])=[O:7])[N:3]=2)=[CH:38][C:39]=1[F:45])#[N:44]
Reactant: NNc1ccccc1C(=O)O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(F)c1)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(Nc2ccc(C#N)c(F)c2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
After adding 55 mg of 2-hydrazinobenzoic acid hydrochloride and 101 μl of triethylamine to a solution of 120 mg of [2-(4-cyano-3-fluorophenylimino)-2-(3,4-dimethoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of a methanol:THF=1:1 mixed solvent. After adding 58 μl of acetic acid and 91 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 15 hours. Ethyl acetate was then added to the reaction mixture. The organic layer was washed with dilute hydrochloric acid and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (100 mg) as a light yellow solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[S:13]1[C:17]2[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH2:27].C(OC(=O)C)C>C1COCC1.CCCCCC>[S:13]1[C:17]2[CH:18]=[C:19]([NH:22][C:2]([NH:27][CH2:26][CH:25]([O:28][CH3:29])[O:24][CH3:23])=[O:4])[CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: Nc1ccc2ncsc2c1
Reactant: COC(CN)OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(CNC(=O)Nc1ccc2ncsc2c1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 228.8 %

Procedure:
TEA (185 mL, 1.3315 mmol) and triphosgene (138 mg, 0.4660 mmol) were added to a solution of benzothiazol-6-ylamine (200 mg, 1.3315 mmol) in THF (20 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours. This was followed by the addition of 2,2-dimethoxy-ethylamine (173 mL, 1.5978 mmol) in THF and TEA (185 mL, 1.3315 mmol) and the stirring was continued for a further 18 hours at room temperature. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was concentrated and the concentrate was partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (100% ethylacetate) afforded 300 mg of 1-Benzothiazol-6-yl-3-(2,2-dimethoxy-ethyl)-urea (80.21% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][CH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:40])[CH3:41]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OC[C@@H]1CCCN1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Temperature: 60 °C
Yield: 28 %

Procedure:
To a solution of Intermediate A (50 mg, 0.309 mmol) in DMF (2 mL) was added NaH (60% in oil, 33 mg, 0.80 mmol) and the mixture stirred at RT for 20 min, before Intermediate 28b (110 mg, 0.280 mmol) was added. This mixture was heated at 60° C. in the microwave for 1.25 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-7% [2M NH3 in MeOH] in DCM gave the title compound as a viscous yellow oil (42 mg, 28%). LCMS (Method 4): Rt 2.55 min, m/z 536 [MH+].
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:14]OS(C3C=CC(C)=CC=3)(=O)=O)[O:13][C:9]=2[CH:8]=[C:7]([C:26](=[O:34])[NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)[CH:6]=1)([CH3:3])[CH3:2].Cl.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C>C1COCC1>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:26]([C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[C:10]3[CH2:11][CH:12]([CH2:14][N:37]([CH3:38])[CH3:36])[O:13][C:9]=3[CH:8]=2)=[O:34])=[N:29]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(OC(C)C)cc(C(=O)Nc4ccn(C)n4)cc3O2)cc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CN(C)C)O2
Temperature: 50 °C
Yield: 9.8 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in THF (2 mL) was added dimethyl amine hydrochloride (190 mg) and triethylamine (0.4 mL). The mixture was heated at 50° C. for 2 days, then concentrated, and purified by reverse phase HPLC to give a white solid (6 mg, 10% yield). 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1 H) 7.25-7.32 (m, 1 H) 7.04 (s, 1 H) 6.90 (d, J=1.01 Hz, 1 H) 6.84 (d, J=2.27 Hz, 1 H) 5.03-5.14 (m, 1 H) 4.61-4.71 (m, 1 H) 3.81 (s, 3 H) 3.29 (dd, J=16.42, 9.35 Hz, 1 H) 2.75-2.92 (m, 2 H) 2.60-2.70 (m, 1 H) 2.47 (s, 6 H) 1.34 (d, J=6.06 Hz, 6 H); LCMS for C19H26N4O3 m/z 359.20 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Br)[CH:10]([CH3:12])[CH3:11].FC(F)(F)S(OCC(F)(F)F)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: CC(C)CBr
Reactant: Oc1cccc(F)c1
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: CC(C)COc1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure described in Step 7 of EXAMPLE 7 using 3-fluorophenol and isobutyl bromide instead of methyl 4-[(4-{2-[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]ethyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate and 2,2,2-trifluoroethyl trifluoromethanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20](O)=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl.[CH3:24][O:25][NH:26][CH3:27].O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C(N=C=NCCCN(C)C)C>C1COCC1>[NH2:1][C:2]1[C:3]([C:20]([N:26]([O:25][CH3:24])[CH3:27])=[O:21])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CNOC
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Temperature: 0 °C
Yield: 77.6 %

Procedure:
3-Amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carboxylic acid (10 g, 31.12 mmol) was dissolved in THF (80 mL) and cooled to 0° C. N-methoxymethanamine hydrochloride (3.642 g, 37.34 mmol), 1-hydroxybenzotriazole hydrate (5.242 g, 34.23 mmol), DIPEA (8.044 g, 10.84 mL, 62.24 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (5.314 g, 34.23 mmol) was added and the reaction mixture allowed to warm to ambient temperature over 15 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc. The organic layer was washed water (×2), saturated aqueous NaHCO3 (×2) and brine (×1). The organic layer was dried (MgSO4), filtered and concentrated in vacuo and the residue purified by column chromatography (eluting with 30% EtOAc/petroleum ether) to give the sub-title compound as an off-white solid (8.8 g, 78% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 3.42 (s, 3H), 3.44 (sept, 1H), 3.67 (s, 3H), 6.95 (br s, 2H), 7.90 (d, 2H), 8.22 (d, 2H) and 8.82 (s, 1H) ppm; (ES+) 366.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]([O:49][C:50]([NH:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[NH:58][C:57]([C:62](O)=[O:63])=[CH:56]2)=[O:51])([CH3:48])[CH3:47].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:62]([C:57]2[NH:58][C:59]3[C:55]([CH:56]=2)=[CH:54][C:53]([NH:52][C:50](=[O:51])[O:49][C:46]([CH3:47])([CH3:45])[CH3:48])=[CH:61][CH:60]=3)=[O:63])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
HATU (2.75 g, 7.23 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.50 g, 4.82 mmol), 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (1.33 g, 4.82 mmol) and diisopropylethylamine (1.26 mL, 7.23 mmol) in DMF (10 mL). The mixture was stirred at RT overnight. The reaction mixture was extracted with EtOAc and water and the organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography (5-50% EtOAc:hexane) to give an off-white solid which was triturated with EtOAc:hexane, filtered and dried to afford the title compound (1.36 g, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 9.07 (br. s., 1H), 8.95 (t, 1H), 7.78 (s, 1H), 7.71 (br. s., 1H), 7.41-7.55 (m, 3H), 7.36 (t, 1H), 7.21-7.30 (m, 1H), 7.15 (d, 1H), 7.03 (s, 1H), 4.37-4.68 (m, 2H), 1.44 (s, 9H). ES-LCMS: m/z 569 (M+H).
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].Cl.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH2:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>CO>[CH3:6][S:3]([CH2:1][CH2:2][N:15]([CH2:16][CH2:17][NH2:18])[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: C=CS(C)(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCN)CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
Methyl vinyl sulfone (0.42 mL, 4.8 mmol) was added dropwise to a cooled solution of N-tert-butyloxycarbonyl-1,2-ethylenediamine hydrochloride (1.00 g, 5.1 mmol) and triethylamine (1.4 mL, 10.7 mmol) in methanol (20 mL). The reaction was stirred at room temperature for 18 h and concentrated. Purification of the crude residue by chromatography over silica gel using 0-5% methanol in methylene chloride gave 2-(N-tert-butyloxycarbonyl-2-aminoethylamino)ethyl methyl sulfone (1.05 g, 77%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:3].[OH-].[Na+].O.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCCC1.CCOCC>[CH2:25]([O:24][C:22]([N:15]1[CH2:14][CH2:13][CH:12]([S:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=2)[CH2:17][CH2:16]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)Cc1ccc(SC2CCNCC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(SC2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
250 mg (1 mmol) of 4-[4-(dimethylaminomethyl)phenylthio]piperidine in 20 ml tetrahydrofuran are combined with 2 ml 2N sodium hydroxide solution and 5 ml water. At ambient temperature 200 mg (1.2 mmol) of benzyl chloroformate in 5 ml tetrahydrofuran are slowly added dropwise. After 1.5 hours at ambient temperature some benzyl chloroformate and sodium hydroxide solution are again added. After the addition of 100 ml ether the mixture is washed with saturated saline solution, the organic phase is dried with magnesium sulphate and concentrated by evaporation. The product obtained after purification by column chromatography (aluminium oxide, petroleum ether/ethyl acetate=4:1, v:v) is converted into the hydrochloride with ethereal hydrochloric acid. 190 mg (45.1% of theory) of the title compound are obtained as a colourless powder, melting point 144° C.