Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1.C(N(CC)CC)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(CN)CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(CNc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1)CNS(=O)(=O)c1cccnc1
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a solution of Example 74 (55.0 mg, 0.167 mmol) in DMF (1 mL) was added triethylamine (0.070 mL, 0.50 mmol) and pyridine-3-sulfonyl chloride (35.5 mg, 0.200 mmol). After 4 hours, the reaction was quenched with 20% brine and extracted with EtOAc (2×). The organic layers were combined, concentrated, and purified by reverse-phase HPLC as described in Example 56 to give the title compound (28.5 mg) as trifluoroacetic acid salts. 1H NMR (500 MHz, DMSO-d6) ppm 0.89 (s, 6H), 2.68 (d, J=7.02 Hz, 2H), 3.13 (s, 2H), 6.80 (s, brd, 1H), 6.89 (d, J=1.22 Hz, 1H), 6.94 (s, 1H), 7.22 (dd, J=8.09, 4.73 Hz, 1H), 7.60 (dd, J=7.63, 4.58 Hz, 1H), 7.77 (t, J=6.87 Hz, 1H), 8.12-8.18 (m, 2H), 8.28-8.35 (m, 2H), 8.77 (d, J=6.41 Hz, 1H), 8.94 (d, J=2.14 Hz, 1H), 12.19 (s, 1H). MS (APCI+) m/z 471.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:18]([C:17]3[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=3[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(Cl)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 7-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [82771-60-6]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[C-]#N.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([NH:8][C:9](=[O:10])[N:17]([CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:7])[CH3:6]
Reactant: CNc1ccccc1
Reactant: CC(C)(N=C=O)c1cccc(Br)c1
Agent: [C-]#N
Product: CN(C(=O)NC(C)(C)c1cccc(Br)c1)c1ccccc1
Temperature: 60 °C
Yield: 86.4 %

Procedure:
2.4 g of m-bromo-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, was added to 1.1 g of N-methylaniline and the mixture was heated at 60° C. for 2 hours. After allowing the reaction mixture to cool, the precipitated white crystals were separated by filtration and washed with n-hexane to obtain 3.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:20])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[CH:23](O)[CH2:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH:23]4[CH:24]5[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]5)[CH2:22]4)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN2CCC1CC2
Reactant: Cn1c(-c2cccc(Cl)c2)nc2ccc(O)cc2c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(Cl)c2)nc2ccc(OC3CN4CCC3CC4)cc2c1=O
Reaction time: 20 h
Yield: 12.9 %

Procedure:
To a solution of 2-(3-chlorophenyl)-6-hydroxy-3-methylquinazolin-4(3H)-one (Intermediate 33A) (100 mg, 0.35 mmol), 3-quinuclidinol (44 mg, 0.35 mmol) and triphenylphosphine (137 mg, 0.35 mmol) in tetrahydrofuran (2 mL) was added dropwise diisopropyl azodicarboxylate (0.103 mL, 0.52 mmol). The reaction was stirred for 20 h. The mixture was purified by scx cartridge (1 g) followed by acidic prep hplc then scx (500 mg) to afford 2-(3-chlorophenyl)-3-methyl-6-(quinuclidin-3-yloxy)quinazolin-4(3H)-one (18 mg, 0.045 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[O:12]1[CH2:14][C@@H:13]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2>C(O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:14][CH:13]([OH:12])[CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:7]1)=[O:5])[CH3:2]
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(CC(O)COc2cccc3ncccc23)C1
Temperature: 25 °C

Procedure:
Piperidine-3-carboxylic acid ethyl ester (43) (1.0 g; 6.36 mmol) and (R)-5-oxiranylmethoxy-quinoline (2) (1.28 g; 6.36 mmol) are combined in 10 mL of absolute ethanol. The mixture is heated at reflux for 16 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is chromatographed on silica gel (1:1 acetone:hexanes) affording the desired product (44) as an oil. ESMS:MH+ 359
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(=O)c1cccc(C)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3'-methylacetophenone (0.87 g, 6.46 mmol), trimethylsilyl triflate (1.44g, 6.46 mmol), triethylamine (0.653 g, 6.46 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.0 g, 3.23 mmol). m.p. 161°-162° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 2.39 (s, 3H), 3.42 (m, 1H), 6.86 (s, 1H), 6.92 (d, 1H), 7.07 (t, 1H), 7.13 (t, 1H), 7.28 (d, 1H), 7.39 (d, 1H), 7.4 (t, 1H), 7.64 (d, 1H), 7.67 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]([OH:17])=O)[C:6]2=[O:18].C(N(CC)CC)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH2:43][N:44]1[CH2:48][CH2:47][NH:46][C:45]1=[O:49]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]([NH:43][N:44]1[CH2:48][CH2:47][NH:46][C:45]1=[O:49])=[O:17])[C:6]2=[O:18]
Reactant: COc1cc2[nH]cc(C(=O)O)c(=O)c2cc1OC
Reactant: NN1CCNC1=O
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2[nH]cc(C(=O)NN3CCNC3=O)c(=O)c2cc1OC
Temperature: 0 °C
Reaction time: 6 h
Yield: 43.6 %

Procedure:
To a suspension of 1,4-dihydro-6,7-dimethoxy-4-oxo-3-quinolinecarboxylic acid (39.9 g, 0.160 mol) in 3.2 l of N,N-dimethylformamide, triethylamine (32.4 g, 0.320 mol) was added. At 0° C. and under nitrogen protection, diphenyl chlorophosphate (43.0 g, 0.160 mol) was added dropwise and the mixture was stirred for 6 hours at 0° C. A solution of N-amino-imidazolidine-2-one (16.2 g, 0.160 mol) in N,N-dimethylformamide was added and stirring was continued at 0° C. overnight. The triethyl ammonium salt (26 g) was filtered off and the filtrate evaporated in vacuo. The residual oil was triturated with 1 l of ethyl acetate and 1 l of water. The resulting solid was filtered off, washed with water and ethyl acetate and dried in vacuo. The crude product was stirred with 270 ml of 0.2N sodium hydroxide solution of 2 days, filtered off, washed with water and dried in vacuo to give 23.2 g of the title compound, melting point>300° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[C:12]([CH:15]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16](OCC)=[O:17])(=O)[CH3:13]>CC1C=CC=CC=1C.CC1C=CC(S(O)(=O)=O)=CC=1.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:15]1[C:12]([CH3:13])=[N:1][C:2]2[N:6]([N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=2)[C:16]=1[OH:17])[CH3:26]
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Reactant: CCOC(=O)c1cc(N)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1O
Yield: 75.3 %

Procedure:
A suspension of ethyl 5-amino-1H-pyrazole-3-carboxylate (35.5 g, 229 mmol, prepared according to WO 2008015271), diethyl 2-acetylsuccinate (51.2 mL, 275 mmol) and TsOH.H2O (0.218 g, 1.144 mmol) in o-xylene (500 mL) was refluxed using a Dean-Stork condensor for 5 h. (Note: The suspension turned into a clear homogeneous solution and then in about 15 min a yellow solid started precipitated out of solution). Then, the reaction mixture was cooled, diluted with hexanes (250 mL), filtered, washed with hexanes and dried to afford ethyl 6-(2-ethoxy-2-oxoethyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (53 g, 75% yield) as light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.61 (br. s., 1H), 6.49 (s, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.34 (s, 3H), 1.33 (t, J=7.2 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H). LCMS (M+H)=308.04.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]2OC(C)(C)C(C)(C)O2)[CH:3]=1.[F:18][C:19]([F:38])([F:37])[C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=C[N:29]=[C:28](Br)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:18][C:19]([F:37])([F:38])[C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[C:26]1[CH:27]=[CH:28][N:29]=[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[NH2:8])[CH:31]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(Br)c1
Reactant: CC1(C)OC(c2cc(Cl)ccc2N)OC1(C)C
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: COCCOC
Solvent: O
Product: Nc1ccc(Cl)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-chloro-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzenamine (300 mg, 1.17 mmol, 1.00 equiv) in ethylene glycol dimethyl ether (15 mL), N-(3-(trifluoromethyl)benzyl)-2-bromoisonicotinamide (432 mg, 1.20 mmol, 1.00 equiv), a solution of sodium carbonate (636 mg, 6.00 mmol, 5.00 equiv) in water (3.0 mL), and Pd(PPh3)4 (138 mg, 0.12 mmol, 0.10 equiv). The resulting solution was stirred for 2 h at 85° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined, and washed with brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1-5:1). The product was obtained as 260 mg (55%) of a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH4+:12].[OH-]>[Cl-].[Na+].O>[NH2:12][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(N)(=O)=O)cn1
Temperature: 110 °C

Procedure:
6-Chloropyridine-3-sulfonic acid amide (200 mg, 1 mmol) was placed in a sealed tube with 2 mL 28% aq. NH4OH and heated to 110° C. for 4 h. The mixture was diluted with brine and the title compound was collected as a solid (120 mg, 67%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH3:11][NH2:12]>C1COCC1>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:12][CH3:11])[N:3]=[CH:4][N:5]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncnc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,6-dichloro-pyrimidine-5-carbaldehyde Compound 2a (0.5 g), methylamine (88 mg) and THF (50 mL) were added to a flask. The mixture was stirred at rt overnight, then concentrated and the residue was purified by flash chromatography (silica gel, hexane:EtOAc/5:5) to afford 4-chloro-6-methylamino-pyrimidine-5-carbaldehyde Compound 2b (0.40 g, 82%). 1H NMR (300 MHz, CDCl3) δ 10.38 (s, 1H), 9.15 (s, 1H), 8.45 (s, 1H), 3.15 (d, 3 H). MS (ESI) m/z: 172 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]1[C@@H:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][C:40]([C:42]4[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=4)=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48]1([N:58]=[C:59]=[O:60])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:59](=[O:60])[NH:58][C:48]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]=[CH:50][CH:49]=2)[CH2:13][C@H:12]1[C@@H:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][C:40]([C:42]4[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=4)=[CH:41][C:36]=3[N:35]=[CH:34]2)[CH:30]=[CH:29][N:28]=1)[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: O=C=Nc1cccc2ccccc12
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from (S,S)-2-[1-(1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)piperazine-2-yl)-ethylamino]-4-[5-(pyridine-4-yl)benzimidazol-1-yl]pyrimidine (72 m,) and naphthyl isocyanate (23 mg) according to the procedure described in EXAMPLE 14, Step F. Mass spectrum (ESI) 704.2 (M+1).
Reaction SMILES: CNC(C1C2C=C(C3C(Cl)=CN=C(NCCCN4CCNC[C@H]4C)N=3)SC=2C=CC=1)=O.[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([CH3:51])=[CH:49][N:48]=[C:47](Cl)[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35].C(OC([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68][NH2:69])[CH2:62][C@@H:61]1[CH3:70])=O)(C)(C)C>>[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([CH3:51])=[CH:49][N:48]=[C:47]([NH:69][CH2:68][CH2:67][CH2:66][N:63]4[CH2:64][CH2:65][NH:60][C@@H:61]([CH3:70])[CH2:62]4)[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3C)cc12
Reactant: C[C@H]1CN(CCCN)CCN1C(=O)OC(C)(C)C
Agent: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN[C@@H](C)C4)ncc3C)cc12

Procedure:
Using the method of (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and (S)-4-(3-aminopropyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 439 [M+H].
Reaction SMILES: [I:1]Cl.[CH2:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[CH2:5][O:4]1.C(=O)(O)[O-].[Na+]>ClCCl.CO>[I:1][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][O:4][CH2:3]2)=[CH:7][C:8]=1[NH2:12]
Reactant: ClI
Reactant: Nc1ccc2c(c1)COC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc2c(cc1I)COC2
Reaction time: 1 h

Procedure:
Dropwise, add a 1.0 M solution of iodine monochloride (64 mmol) to a solution of 1,3-dihydro-isobenzofuran-5-ylamine (64 mmol) in dichloromethane (200 mL), methanol (50 mL) and sodium bicarbonate (96 mmol). After stirring for 1 h, quench the reaction with aqueous sodium metabisulfite (100 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×100 mL). Combine the organics and dry over sodium sulfate. Filter the reaction and remove solvent under vacuum. Chromatograph (0-20% ethyl acetate/hexane) the crude mixture over silica gel to give the title compound as a tan solid. 1H NMR (CDCl3, 400 MHz): δ 4.10 (bs, 2H), 4.97 (s, 4H), 6.63 (s, 1H), 7.49 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[CH:17](OC)(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:17][N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nccc(-n2cnc3ccc(Br)cc32)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (750 mg, 2.68 mmol) in mixture of methanol (7 mL) and THF (30 mL) was added trimethyl orthoformate (8.81 ml, 80.32 mmol) and TsOH (0.04 ml, 0.27 mmol). The reaction mixture was stirred at 70° C. for 1 h. Then another portion of trimethyl orthoformate (4.4 ml, 40.16 mmol) was added. Stirring at 70° C. was continued for another 6 hr. The reaction mixture was allowed to cool down to RT then a saturated aqueous solution of NaHCO3 was added. The product was extracted into DCM (×3) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give the title compound; 1H NMR (500 MHz, DMSO) δ 7.08-7.24 (3H, m), 7.50 (1H, dd, J=8.51, 1.89 Hz), 7.71 (1H, d, J=8.51 Hz), 8.37 (1H, d, J=5.52 Hz), 8.83 (1H, d, J=1.73 Hz), 9.08 (1 H, s); LC-MS (Method B): m/z=+289.9, 291.8 (M+H)+. This compound, with LC-MS purity=70%, was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](Cl)=O.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][C:20]([NH2:25])=[C:21]([NH2:24])[CH:22]=2)[NH:17][C:16](=[O:26])[CH2:15]1>>[CH3:13][C:14]1([CH3:27])[C:23]2[CH:22]=[C:21]3[NH:24][C:10]([C:2]4[NH:1][C:9]5[C:4]([CH:3]=4)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[N:25][C:20]3=[CH:19][C:18]=2[NH:17][C:16](=[O:26])[CH2:15]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Product: CC1(C)CC(=O)Nc2cc3nc(-c4cc5ccccc5[nH]4)[nH]c3cc21
Yield: 45 %

Procedure:
In a manner analogous to that described in Example 2, from indole-2-carboxylic acid chloride and 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one (see Example 13 a)), after column chromatography, there was obtained a yield of 45% of theory of the title compound; m.p. 264°-267° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[H][H]>[C].[Pd].C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)CCO2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)CCO2
Yield: 99.4 %

Procedure:
5% Palladium-carbon (1 g, containing 50% water) was added to an ethanol (150 ml) solution of ethyl (E)-3-(2.3-dihydrobenzofuran-5-yl)-2-propenoate (14.7 g, 66.7 mmols), and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 14.6 g (yield: 99%) of the target compound. This was oily.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[CH3:12]I>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:12])[S:8][C:7]=2[CH:11]=1
Reactant: CI
Reactant: COc1ccc2ccsc2c1
Product: COc1ccc2cc(C)sc2c1
Yield: 64.5 %

Procedure:
The same operations as in Preparation example 1 were carried out using 180 mg of 6-methoxybenzo[b]thiophene, and 450 mg of methyl iodide in place of cyclohexanone, and then purification was carried out by TLC (developing solvent, chloroform:n-hexane=1:19) to obtain 126 mg of 6-methoxy-2-methylbenzo[b]thiophene.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][S:5]([N:8]([C@@H:10]([CH2:14][CH:15]=[CH2:16])[C:11]([OH:13])=O)[CH3:9])(=[O:7])=[O:6].[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[C@@H:25]([NH:34][CH2:35][C@@H:36]([OH:48])[C@@H:37]([NH2:47])[CH2:38][C:39]2[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41]([Cl:46])[CH:40]=2)[CH2:24]1)[CH:20]=[CH2:21]>>[CH2:19]([O:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[C@@H:25]([NH:34][CH2:35][C@@H:36]([OH:48])[C@@H:37]([NH:47][C:11](=[O:13])[C@@H:10]([N:8]([CH3:9])[S:5]([CH2:4][CH2:3][C:2]([F:1])([F:18])[F:17])(=[O:6])=[O:7])[CH2:14][CH:15]=[CH2:16])[CH2:38][C:39]2[CH:40]=[C:41]([Cl:46])[CH:42]=[C:43]([Cl:45])[CH:44]=2)[CH2:24]1)[CH:20]=[CH2:21]
Reactant: C=CC[C@@H](C(=O)O)N(C)S(=O)(=O)CCC(F)(F)F
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(Cl)cc(Cl)c2)c2cc(OC)ccc21
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(Cl)cc(Cl)c2)NC(=O)[C@H](CC=C)N(C)S(=O)(=O)CCC(F)(F)F)c2cc(OC)ccc21
Yield: 24 %

Procedure:
Step DM (1): (S)-2-(3,3,3-Trifluoro-N-methyl-propylsulfonamido)pent-4-enoic acid (33 mg, 0.11 mmol, from Preparation J) was coupled with (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-dichloro-phenyl)butan-2-ol (50 mg, from Preparation BG) by a procedure analogous to Step DL (1) to afford 19.1 mg of (S)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-yl)-2-(3,3,3-trifluoro-N-methylpropylsulfonamido)pent-4-enamide as a clear oil. LC-MS Rt 2.10 min (method A), (M+H)+=722.1, 724.0; HRMS (M+H)+=722.2031; 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J=8.2, 1H) 7.18 (s, 1H) 7.08 (s, 2H) 6.95 (d of d, J=8.5, 2.1, 1H) 6.78 (d, J=8.8, 1H) 5.91 (m, 1H) 5.66 (m, 1H) 5.31 (d, J=17.4, 1H) 5.24-5/12 (m, 3H) 4.82 (d, J=4.6, 1H) 4.72 (br d, J=6.7, 1H) 4.21 (d of d, J=5.2, 5.2, 1H) 4.10 (m, 3H) 4.01 (m, 3H) 3.80 (s, 3H) 3.26 (d, J=12.2, 1H) 3.10 (m, 5H) 2.90-2.80 (m, 2H) 2.72-2.50 (m, 5H0, 2.56 (s, 3H) 2.44-2.31 (m, 2H) 1.32 (t, J=7.3, 2H) 1.24 (s, 1H).