Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[N:4][N:5]([CH2:7][CH:8]([F:10])[F:9])[CH:6]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].Cl.CN(C)CCCN=C=NCC>>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH2:7][CH:8]([F:10])[F:9])[N:4]=1)=[O:13]
Reactant: O=C(O)c1nn(CC(F)F)cc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CON(C)C(=O)c1nn(CC(F)F)cc1Cl
Yield: 98 %

Procedure:
In a manner analogous to that described in Example 1d), the condensation of 4-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxylic acid and N,O-dimethylhydroxylamine hydrochloride by N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride yielded the title compound (98% yield) as a colorless oil. MS (ISP): m/z=254.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12].[CH:13]1([NH2:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:9]([NH:19][CH:16]3[CH2:17][CH2:18][CH:13]([NH2:20])[CH2:14][CH2:15]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12]
Reactant: NC1CCC(N)CC1
Reactant: Cc1sc2ncnc(Cl)c2c1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1sc2ncnc(NC3CCC(N)CC3)c2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of 5-bromo-4-chloro-6-methylthieno[2,3-d]pyrimidine (79 mg, 0.30 mmol, 1.00 equiv) in anhydrous DMF (5 mL) was added cyclohexane-1,4-diamine (171 mg, 1.50 mmol, 5.00 equiv) and triethylamine (91 mg, 0.90 mmol, 3.00 equiv) successively at room temperature. The resulting solution was stirred overnight at ambient temperature and then quenched with water. The resulting solution was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to provide the resulted 1-N-[5-bromo-6-methylthieno[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine (90 mg, 88%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]2[C:17]([C:18]3[CH:34]=[CH:33][O:32][C:19]=3[C:20](=[O:31])[O:21]2)=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[C:22]2[C:17]([C:18]3[CH:34]=[CH:33][O:32][C:19]=3[C:20](=[O:31])[O:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)c1c(N)ccc2c1oc(=O)c1occc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1oc(=O)c1occc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.229 g) was added to a solution of tert-butyl 7-amino-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 57, 0.210 g) and pyridine (1.13 mL) in DCM (20 mL) and the mixture was stirred at room temperature overnight. The mixture was reduced to half volume in vacuo and the resultant mixture was stirred and heated at 35° C. for 6 hours. Further 2-bromo-4-fluorobenzenesulfonyl chloride (0.572 g) was added and the reaction mixture was heated at 35° C. overnight. The mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with ethyl acetate and cyclohexane, with a gradient of 5-20% to give tert-butyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (0.329 g) as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH2:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH2:24][CH2:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CCCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: CCCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 33.8 %

Procedure:
Using cyclohexyl{3-propyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.65 g) synthesized in Example 5(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.44 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.34 g, 34%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[C:33]1=[O:41].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:34]5[C:33](=[O:41])[N:32]([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[CH3:25])[CH:37]=[CH:36][CH:35]=5)=[O:39])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccccc1-n1cccc(C(=O)O)c1=O
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
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: Cc1ccccc1-n1cccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c1=O
Yield: 53.7 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.613 mmol), 1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (169 mg, 0.735 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (211 μL, 1.23 mmol) and HATU (280 mg, 0.735 mmol) and in the same manner as in Example 24, the title compound (177 mg, 54%) was obtained as pale-yellow crystals.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][CH2:19][CH2:20]O)=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>O>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][CH2:19][CH2:20][Br:1])=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: Br
Reactant: OCCNc1ccnc2cc(Cl)ccc12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1ccc2c(NCCBr)ccnc2c1
Temperature: 165 °C
Yield: 55 %

Procedure:
Hydrobromic acid (22.5 ml, 414 mmol) and then sulphuric acid (7.5 ml, 140 mmol) are added dropwise onto the 7-chloro-4-(β-hydroxyethylamino)quinoline 5 (15 g, 67 mmol), the reaction medium being refrigerated using a bath of cold water. The reaction medium is then heated at 165° C. for 3 h 30 min, and then poured into 300 ml of cold water. The pH is then adjusted by adding NaHCO3 (pH approximately 9) and the medium is then extracted at the reflux of toluene (300 ml) for 15 min. The organic phase is then collected and the product 6 is obtained by crystallization at −18° C. overnight, filtration, and then drying under vacuum: 10.55 g (yield=55%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:21][C:22]1[C:28]([OH:29])=[CH:27][C:25]([NH2:26])=[C:24]([F:30])[CH:23]=1>>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:26][C:25]3[CH:27]=[C:28]([OH:29])[C:22]([Cl:21])=[CH:23][C:24]=3[F:30])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Agent: Cl
Product: Oc1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)c(F)cc1Cl
Yield: 94.2 %

Procedure:
Using an analogous procedure to that described in Example 70, 7-benzyloxy-4-chloroquinazoline hydrochloride (307 mg, 1 mmol), (prepared as described for the starting material in Example 70), was treated with 4-chloro-2-fluoro-5-hydroxyaniline (193 mg, 1.2 mmol), (EP 061741 A2), to give 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinazoline hydrochloride (407 mg, 94%). m.p. 253-257° C. 1H NMR Spectrum: (DMSOd6) 5.37(s, 2H); 7.16(d, 1H); 7.32-7.5(m, 4H); 7.54(s, 1H); 7.56(d, 2H); 7.59(dd, 1H); 8.73(d, 1H); 8.86(s, 1H); 10.63(br s, 1H); 11.6(br s, 1H) MS-ESI: 396 [MH]+
Reaction SMILES: [CH3:1][C:2]([NH2:8])([C:6]#[N:7])[CH:3]([CH3:5])[CH3:4].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:23])[C:18]=1[O:19][CH2:20][C:21]#[CH:22])[C:13](Cl)=[O:14]>>[CH3:1][C:2]([NH:8][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([F:23])[C:18]([O:19][CH2:20][C:21]#[CH:22])=[C:10]([F:9])[CH:11]=1)([C:6]#[N:7])[CH:3]([CH3:5])[CH3:4]
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Reactant: CC(C)C(C)(N)C#N
Product: C#CCOc1c(F)cc(C(=O)NC(C)(C#N)C(C)C)cc1F

Procedure:
According to the same method as that of Production Example 1, 1,2-dimethyl-1-cyanopropylamine was used in place of 2,2-dimethylpropylamine, 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1,2-dimethyl-1-cyanopropyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 53 of the present invention) represented by the formula:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([NH2:62])[CH:57]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:62][C:58]3[CH:59]=[CH:60][CH:61]=[C:56]([O:55][CH3:54])[CH:57]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: COc1cccc(N)c1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[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: COc1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (63 mg, 0.165 mmol) in 1.5 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 10 minutes meta-anisidine (0.025 mL, 0.225 mmol) was added and the reaction continued at room temperature for 4 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an acetone/hexane mixture to give the title compound as a light beige solid (41 mg, 73%). 1H NMR (DMSO-d6) δ: 10.13 (s, 1H), 8.13 (s, 1H), 7.46-7.51 (m, 2H), 7.31-7.41 (m, 3H), 7.19-7.28 (m, 2H), 6.68 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.75 (s, 3H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][OH:34]>>[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:34][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Reactant: OCc1cccc(F)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2cccc(F)c2)n1
Yield: 57 %

Procedure:
As described for Example 157, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 3-fluorobenzyl alcohol instead of 3-chlorobenzyl alcohol, was converted to the title compound (70 mg, 57%) which was obtained as a light yellow solid. MS: m/e=485.5 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[N:10][C:11]([NH2:19])=[N:12][C:13]=2[C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:25][CH2:26][CH3:27])[CH:7]=2)=[C:13]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:12]=[C:11]([NH2:19])[N:10]=1
Reactant: CCCN
Reactant: Nc1nc(-c2ccco2)c(-c2ccnc(F)c2)c(-c2ccco2)n1
Product: CCCNc1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccn1
Temperature: 120 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
In a reaction vessel, 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (200 mg, 0.621 mmol) and n-propylamine (5 ml) were mixed together and the mixture was stirred at 120° C. After 18 hours, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over anhydrous sodium sulfate and then the filtrate was concentrated. The resulting solid was suspended in ethanol, collected by filtration and washed with ethanol, to give the title compound (64%,72 mg) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:17][CH2:16][C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: OCCc1cccs1
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1c(=O)c(Br)nn(CCc2cccs2)c1=O
Temperature: 70 °C
Yield: 78.3 %

Procedure:
0.4 g (1.94 mmol) of intermediate 2a are placed in the presence of 0.24 mL (2.14 mmol) of 2-thiophen-2-yl-ethanol, 0.61 g (2.33 mmol) of triphenylphosphine in 4 mL of THF. At 0° C., 0.54 mL (2.33 mmol) of DEAD in solution in toluene are added dropwise. The reaction medium is heated for 7 h at 70° C. After concentration, the obtained residue is taken up with ethyl acetate and washed with water. After drying on MgSO4, the organic phase is dry concentrated. The obtained residue is purified by flash chromatography on silica (CH2Cl2/MeOH, gradient 100/0 to 97/3 over 30 min). 0.48 g of crystals corresponding to the compound 4k are obtained (yield: 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[S:5][CH:6]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([N:17]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11])[S:5][CH:6]=1
Reactant: CC(C)CCNC(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1)S(=O)(=O)c1ccccc1
Temperature: 75 °C

Procedure:
N-[1-(4-bromothiophen-2-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-3-methylbutan-1-amine (248 mg, 0.610 mmol) and DMAP (3.7 mg, 0.031 mmol) were dissolved in 2 mL pyridine and benzenesulfonyl chloride (234 μl, 1.830 mmol) was added. The resulting mixture was heated at 75° C. overnight, after which the mixture was cooled to room temperature, toluene was added and the mixture was concentrated in vacuo. The title compound was purified on silica gel (EtOAc/hexanes).
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:23][C:24](=O)[CH2:25][C:26](=O)[CH3:27]>>[CH3:23][C:24]1[CH:25]=[C:26]([CH3:27])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[N:4]=2)[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(NN)nc21
Product: Cc1cc(C)n(-c2nc(Nc3ccc([N+](=O)[O-])cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-(4-nitro-phenyl)-amine and 2,4-pentanedione.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[N:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([O:39]C)=[O:38])#[N:2].O[Li].O.O.Cl>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=4)[N:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:37]([OH:39])=[O:38])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)n4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)n2)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.1 %

Procedure:
A mixture of methyl 6-cyano-7-(4-(6-(3,4-dimethylphenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (51.1 mg, 0.096 mmol), LiOH—H2O-1M−H2O (191.5 μL, 0.1915 mmol), and THF (1.5 mL) was stirred at ambient temperature for 3 days. The mixture was quenched with HCl (4M in dioxane) (71.83 μL, 0.287 mmol). The crude material was purified by silica gel column chromatography to provide the desired product (0.027 g). MS (APCI)=520.2 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1COCC1>[CH2:10]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([S:36]([C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)(=[O:37])=[O:38])[CH2:22][CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Diisopropylethylamine (1.04 ml, 7.0 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid benzyl ester (0.74 g, 3.1 mmol) in THF (10 ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (0.77 g, 3.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the solvent was removed under vacuum and the resulting residue was partitioned between ethyl acetate (50 ml) and HCl (50 ml, 1M solution), the organic layer was separated and washed with brine (50 ml) before being dried (MgSO4), filtered and concentrated under vacuum. The resulting white solid was suspended in heptane and collected by filtration, washed with water (50 ml), heptane (50 ml) and TBME (50 ml) before being dried under vacuum to afford the title compound (1.3 g, 100% yield) as a white solid. Tr=2.09 min m/z (ES+) (M+H+) 420.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:18][CH2:19][O:20][CH3:21])=[C:7](B(O)O)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33](I)[C:27]=2[CH:26]=1)(=[O:24])[CH3:23].C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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:22]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:7]3[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=3[O:18][CH2:19][O:20][CH3:21])[C:27]=2[CH:26]=1)(=[O:24])[CH3:23]
Reactant: COCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Reactant: CC(=O)c1cc2c(I)cccc2s1
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: CCO
Solvent: Cc1ccccc1
Product: COCOc1c(-c2cccc3sc(C(C)=O)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 70 %

Procedure:
A mixture of 620 mg (2.1 mmol) 3,5-di-tert-butyl-2-methoxymethoxy phenylboronic acid, 377 mg (1.24 mmol) of 2-acetyl-4-iodo benzo[b]thiophene, 72 mg (0.105 mmol, 5%) Pd(PPh3)4 6 mL of ethanol, 1.25 mL of Na2CO3 in 8 mL of toluene was heated to reflux for 12 hours. After cooling and work-up, the crude product was purified over a short silica gel plug (eluent: ethyl acetate/hexane: 10/90) to give 368.6 mg (0.868 mmol, yield: 70%) of pure 2-acetyl-4-(2-methoxymethoxy-3,5-di-tert-butylphenyl)benzo[b]thiophene as a clear oil. 1H-NMR (CDCl3), δ: 7.84 (d, J=7.9 Hz, 1H), 7.79 (s, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.46 (d, J=2.6 Hz, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 4.47 (d, J=4.5 Hz, 1H), 4.06 (dd, J=14.2, 7.0 Hz, 2H), 2.81 (s, 3H), 2.54 (s, 3H), 2.02 (s, 3H), 1.49 (s, 9H), 1.33 (s, 9H), 1.23 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:7].[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:33]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][CH2:9][N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:6](=[O:7])[C:5]1[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc(C(=O)N(CCC2CCCN2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(=O)N(CCC2CCCN2Cc2ccccc2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Trimethoxy-N-(2-methyl-3-phenyl-allyl)-N-(2-pyrrolidin-2-yl-ethyl)-benzamide 0.11 g (2.5 mmol) and freshly distilled benzaldehyde 0.026 g (2.5 mmol) was taken in 10 ml of dry methanol. Acetic acid 0.022 ml (3.7 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 30 min and sodium cyanoborohydride 0.023 g (3.7 mmol) was added at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 14 hr. The reaction mixture was concentrated, and the residue was diluted with water and extracted with chloroform (3×20 ml). Organic layer was washed with 10% NaHCO3 solution, water and brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography over silica gel to yield the pure desired compound. This was converted to its hydrochloride salt using dry HCl in ether to obtain 90 mg of product. Yield: 63%.