Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[N:7]=[CH:6]2.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][CH:21]=1)[N:7]=[CH:6]2
Reactant: COc1ccc2nc(-c3ccc(C(=O)O)cc3)ncc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ncc3cc(O)ccc3n2)cc1
Yield: 13 %

Procedure:
To a suspension of 4-(6-methoxyquinazolin-2-yl)benzoic acid (220 mg, 0.785 mmol) in anhydrous CH2Cl2 (5 mL) was added AlCl3 (600 mg, 4.55 mmol), the reaction mixture was refluxed overnight. The mixture was quenched with sat.NH4Cl (10 mL), the aqueous layer was extracted with CH2Cl2/MeOH (v/v=10/1, 30 mL×3), the combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which purified by prep-HPLC (0.1% TFA as additive) to give Compound V-1 (27 mg, yield 13%). 1H NMR (MeOD 400 MHz): δ 9.42 (s, 1H), 8.60 (d, J=8.4 Hz, 2H), 8.17 (d, J=8.4 Hz, 2H), 8.00 (d, J=9.2 Hz, 1H), 7.60 (dd, J=9.2, 2.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H). MS (ESI): m/z 266.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][O:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][N:33]=1>>[CH3:30][O:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=2)[N:33]=1
Reactant: COc1n[nH]c2ccccc12
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1nn(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)c2ccccc12

Procedure:
2-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (0.1 g) was reacted with 3-methoxy-1H-indazole via General Procedure I for Buchwald coupling give 16.4 mg 234 following reverse phase purification. MS (Q1) 507.2 (M)+
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:10])=[CH:5][CH:4]=1.[CH3:11][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:13].C(N(CC)CC)C.Cl>CCOCC.C1COCC1>[ClH:1].[CH3:13][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][Cl:10])=[CH:5][CH:4]=2)[CH2:25][CH2:26]1)[CH3:11]
Reactant: ClCc1ccc(CCl)cc1
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1N1CCN(Cc2ccc(CCl)cc2)CC1

Procedure:
A solution of α,α'-dichoro-p-xylene(30.40 g ,0.174 mol), N-[2-(1-methylethoxy)phenyl]piperazine (12.70 g, 0.058 mol), triethylamine (6.08 g, 0.06 mol), and THF (200 mL) was refluxed for 4 h. Ether (100 mL) and 1N HCl (100 mL) were added producing a white suspension which was filtered to give 4-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl chloride hydrochloride.
Reaction SMILES: Cl[C:2]1C=C(Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[CH3:30][N:31]([CH3:42])[C:32]1[N:37]=CC(B(O)O)=C(C)[CH:33]=1>>[CH3:30][N:31]([CH3:42])[C:32]1[N:37]=[CH:2][C:3]([C:9]2[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])=[N:13][C:14]=2[CH2:15][CH3:16])=[C:4]([CH3:5])[CH:33]=1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: Cc1cc(N(C)C)ncc1B(O)O
Product: CCc1nc(-c2cnc(N(C)C)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 6-(dimethylamino)-4-methylpyridin-3-ylboronic acid and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 3448, 2962, 2954, 2933, 1611, 1567, 1520, 1482, 1392, 1376, 1174, 1160, 1046, 741, 737 cm−1; OAMS supporting ions at: ESI+ 418.3; MS (EI) m/z 417 (M+); HRMS (FAB) calcd for C25H31N5O+H1 418.2607, found 418.2611. Anal. Calcd for C25H31N5O: C, 71.91; H, 7.48; N, 16.77. Found: C, 71.59; H, 7.57; N, 16.40.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][C@@H:24]([CH2:41][OH:42])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=2)[CH2:26][O:25][C@@H:24]([CH2:41][OH:42])[CH2:23]1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
Add triethylamine (0.623 mL, 4.473 mmol) and acetic anhydride (0.281 mL, 2.982 mmol) to a solution of (R)-5-[2-(S)-amino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(R)-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (1.20 g, 2.982 mmol) in tetrahydrofuran (30 mL). Stir at room temperature for 45 minutes, concentrate and purify (silica gel chromatography, eluting with 6:94 to 9:91 methanol:dichloromethane) to give the title compound as a white foam (0.906 g, 68.4%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[Sn](CCCC)(CCCC)CCCC>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.COCCOC>[CH3:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]([C:4]2[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:7]([CH3:8])=[C:2]([C:36]3[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=3)[CH:3]=2)=[O:21])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1c(-c2nccn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-methyl)phenyl]1,2-dihydropyridine-3-carboxamide (0.06 g, 0.1 mmol), 1-methyl-2-tributylstannyl-1H-imidazole (0.11 g, 0.5 mmol, prepared according to literature procedures), Pd(PPh3)4 (0.015 g, 0.012 mmol), DME (2 ml) and a magnetic stirrer bar were placed in a vial. The suspension was degassed and the vial was sealed, and subsequently heated (100° C.) with stirring overnight. LC-MS confirmed the conversion of the iodide to the desired product, and the solvents were removed in vacuo. Purification on preparative HPLC afforded the title compound (0.005 g, 10%) as a white solid after freeze-drying the pure fractions.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:3]=12.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][C@H:9]1[O:8][C:4]2=[N:5][CH:6]=[CH:7][C:2]([Br:1])=[C:3]2[O:11][CH2:10]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1COc2c(Br)ccnc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1COc2c(Br)ccnc2O1
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a mixture of intermediate (42) (0.0014 mol) and triethylamine (0.0028 mol) in DCM (5 ml), methanesulfonyl chloride (0.0021 mol) was slowly added at room temperature. The reaction mixture was stirred for 16 hours and was then extracted with water. The separated organic layer was dried, filtered and the solvent was evaporated, yielding 0.42 g of (S)-8-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-methanol methanesulfonate (ester) (intermediate (43).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(C)(=O)=O)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product was isolated as a white solid (34 mg, 31%). LCMS 504.08 (M+H), MP 184-188, HPLC purity, 99%, 1H-NMR (CDCl3, 400 MHz) δ 11.70 (s, 1H), 10.25 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 7.58-7.54 (m, 1H), 7.50-7.42 (m, 2H), 7.34 (s, 1H), 7.12 (d, J=8.6 Hz, 1H), 3.98-3.88 (m, 2H), 3.85-3.78 (m, 2H), 3.65-3.50 (m, 2H), 3.37 (s, 5H), 2.92 (s, 3H), 2.98-2.80 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C@@H:9]([NH:13][C:14]1[NH:22][C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]=2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12].C[C@H](NC1N=C2C(N=C(OC)N2C2CCCCO2)=C(N)N=1)CCC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C@H:9]([NH:13][C:14]1[NH:22][C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]=2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Agent: CCC[C@H](C)Nc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1

Procedure:
Prepared similarly to Intermediate 73 from N2-[(1S)-1-methylbutyl]-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.O>C1COCC1.CCCCCC.C(OCC)(=O)C>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:14][CH2:13][CH2:12][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: BrCc1ccccc1Br
Reactant: OCCN1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccccc1COCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a stirred suspension of potassium tert-butoxide (4.94 g, 44.0 mmol) in anhydrous THF (60 ml) was added dropwise a solution of 1-pyrrolidineethanol (5.07 g, 44.0 mmol) in anhydrous THF (20 ml) at 0° C. After 30 min at same temperature, to this was added dropwise a solution of 2-bromobenzyl bromide (10.0 g, 40.0 mmol) in anhydrous THF (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 3 h. Water and 1:1 mixture of ethyl acetate and hexane were added to the reaction mixture and organic layer was separated. The organic layer was washed with water, brine and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo to afford the titled compound (11.3 g, 99.3%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CS(C)=O.O>[O:18]1[CH2:19][CH2:20][N:15]([C:6]2[N:5]=[C:4]([NH2:8])[CH:3]=[CH:2][CH:7]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc(N2CCOCC2)n1
Temperature: 190 °C
Reaction time: 10 h
Yield: 47.4 %

Procedure:
A mixture containing 4-chloro-2-aminopyridine (164; 26 g, 0.20 mol), K2CO3 (0.40 mol) and morpholine (48; 0.6 mol) in DMSO (150 mL) was stirred at 190° C. for 10 h. Upon cooling to room temperature, the reaction mixture was diluted with water (300 mL) and the resulting mixture was extracted with ethyl acetate (4×150 mL). The combined organic layers were washed with water (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=10:1) to afford 6-morpholinopyridin-2-amine 165 (17 g, 47%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)=[CH:3]1.[CH3:22][N:23]([CH3:29])[C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:22][N:23]([CH3:29])[C@H:24]1[CH2:28][CH2:27][N:26]([C:16](=[O:17])[C:15]2[CH:20]=[CH:21][C:12]([CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:13][CH:14]=2)[CH2:25]1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccccc23)cc1
Reactant: CN(C)[C@H]1CCNC1
Product: CN(C)[C@H]1CCN(C(=O)c2ccc(Cc3cn(C)c4ccccc34)cc2)C1

Procedure:
Using essentially the same procedure described in Example 228 and employing methyl 4-((1-methyl-1H-indol-3-yl)methyl)benzoate and (S)—N,N-dimethylpyrrolidin-3-amine as starting materials, the title compound is obtained as a white solid, mp 101-105° C., identified by H1 NMR and mass spectral analyses. MS (ES) m/z 362.2; MS (ES) m/z 723.4.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:18]=[C:17]([CH2:19][CH:20]([NH2:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:16][N:15]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:29]=1[C:30](Cl)=[O:31]>>[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:18]=[C:17]([CH2:19][CH:20]([NH:26][C:30](=[O:31])[C:29]2[C:28]([Cl:27])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:37])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:16][N:15]=1)=[O:8])([CH3:4])([CH3:5])[CH3:3]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(N)Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1
Agent: Cl
Product: CCOC(=O)C(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared from 2-[5-(2-amino-2-ethoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester hydrocloride and 2,6-dichlorobenzoylchloride in the manner described in example 3B. MS (CI) m/z 525.9 (M+1), 425.9 (M−99).
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.C([O-])([O-])=O.[K+].[K+].[Br:20][CH2:21][CH2:22]Br>C(#N)C>[Br:20][CH2:21][CH2:22][N:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: COC(=O)c1cc(C(=O)OC)[nH]n1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)OC)n(CCBr)n1
Reaction time: 12 h

Procedure:
A solution of this ester (5.0 g, 27.2 mmol) in 150 ml of anhydrous acetonitrile was treated with K2CO3 (5.2 g, 40.0 mmol) and 1,2-dibromoethane (25.0 ml, 291 mmol). The resulting mixture was heated to reflux under argon. After 25 min the reaction suspension was cooled, filtered and the filtrate evaporated to dryness at reduced pressure and placed on a high vacuum line for 12 h. The resulting white solid was recrystalized from hexane to give 3-2 as a white solid.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)#[N:5].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[N+:16]=[N-:17]>CO>[NH2:14][C:13]1[N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:16]=[N:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]#[N:5])=[CH:7][CH:8]=1
Reactant: N#CCc1ccc(C#N)cc1
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(-c2nnn(-c3ccc(Cl)cc3Cl)c2N)cc1
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a stirred and ice-cooled solution of sodium methoxide (0.388 g, 7.1802 mmol) in methanol (30 ml), 4-cyanophenylacetonitrile (0.817 g, 5.7442 mmol) and 1-azido-2,4-dichloro-benzene (0.900 g, 4.7868 mmol) are added portion wise under a nitrogen atmosphere. The reaction mixture is allowed to attain room temperature spontaneously overnight, concentrated in vacuo, added water and extracted with ethylacetate (3×100 ml). The combined organic layers are dried over MgSO4, filtered and evaporated to give a dark brown gummy residue (1.425 g, 90% mass balance). This crude material is purified by column chromatography over silica gel (230-400 mesh) eluting with 20% ethylacetate in petroleum ether, to afford the title compound as a yellow solid (0.450 g, 29% yield). LC-ESI-HRMS of [M+H]+ shows 330.0319 Da. Calc. 330.031326 Da, dev. 1.7 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc3[nH]ccc3c2)c2cc(N)ccc2n1Cc1ccccc1
Solvent: CC#N
Product: O=C(O)c1c(-c2ccc3[nH]ccc3c2)c2cc(NS(=O)(=O)c3ccccc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-1H,1′H-3,5′-biindole-2-carboxylate and phenylsulfonyl chloride followed the procedure of Example 1 Step 3 as a gray solid: 1H NMR (DMSO-d6) δ 5.75 (s, 2H, 6.46 (t, J=2.0 Hz, 1H, 6.99 (dd, J=8.3, 2.0 Hz, 1H, 7.00-7.10 (m, 4H, 7.18-7.32 (m, 3H, 7.36-7.46 (m, 3H, 7.45-7.55 (m, 3H), 7.60-7.68 (m, 3H, 9.88 (s, 1H, 11.14 (s, 1H, 12.80 (br s, 1H; MS (ESI) m/z 522 (MH+); MS (ESI) m/z 520 [M-H]−; HRMS calcd for C30H24N3O4S: 522.1485; found (ESI+): 522.1473; Anal. calcd for C30H23N3O4S.0.5H2O.0.5 ACN: C, 67.56; H, 4.66; N, 8.90. Found: C, 67.54; H, 4.57; N, 8.76.
Reaction SMILES: [ClH:1].C(OC(CNCC[C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:14])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[NH2:29][C@H:28]([CH2:36][OH:37])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH2:35])[N:29]=[C:28]2[C:36]([N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:14]
Reactant: CC(C)(C)OC(=O)CNCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3COC(=O)[C@H](N)CO)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.26 ml of 4N HCl in dioxane are added to 850 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl 3-(tert-butoxycarbonylmethylamino)propionate in 20 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 1 h, evaporated to dryness in vacuo and recrystallised from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([N:27]2[CH2:28][CH2:29][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:17])[CH2:25][CH2:26]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(C(=O)c2c(C)noc2-c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (0.100 g, 0.35 mmol), 1-(2-methylphenyl)piperazine (0.092 g, 0.52 mmol), and 1-hydroxybenzotriazole (0.096 g, 0.71 mmol) in 5:1 CH2Cl2:DMF was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.136 g, 0.71 mmol), and the reaction was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and washed twice with H2O, once with brine, and then dried over Na2SO4, filtered, and concentrated to give the title compound, which was used directly in the following step.
Reaction SMILES: CN(C)CCCN=C=NCC.C(NC(C)C)(C)C.Cl.[C:20]1([C:26]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])([OH:35])[CH:28]([OH:44])[CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53]([CH2:60][C:61](O)=[O:62])=[CH:52]1.Cl.[Cl-].[Na+]>ClCCl.O.ON1C2C=CC=CC=2N=N1>[C:45]1([C:26]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH:33]3[C:61](=[O:62])[CH2:60][C:53]3[C:54]4[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=4)[NH:51][CH:52]=3)[C:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])([OH:35])[CH:28]([OH:44])[CH2:27]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CC(C)NC(C)C
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2C(C(=O)Cc3c[nH]c4ccccc34)NCC21
Temperature: 0 °C
Reaction time: 15 h
Yield: 74.5 %

Procedure:
0.46 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.34 cm3 of diisopropylamine are added to a solution of 0.9 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindole-4,5-diol hydrochloride, 0.4 g of 3-indolylacetic acid and 20 mg of 1-hydroxybenzotriazole hydrate in 90 cm3 of dichloromethane, cooled to 0° C. The mixture is stirred at room temperature for 15 hours, acidified with 0.1N HCl and then taken up in an aqueous saturated solution of sodium chloride. The organic phase is decanted, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The foam obtained is recrystallized from 10 cm3 of boiling acetonitrile. 0.85 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(3-indolyl)acetylperhydroisoindole-4,5-diol is obtained in the form of a white solid which melts at 266° C.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4](Cl)=[C:3]([CH:8]=O)[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:23][NH2:24].C(=O)(O)[O-].[Na+]>>[NH:23]1[C:4]2=[N:5][CH:6]=[CH:1][CH:2]=[C:3]2[CH:8]=[N:24]1
Reactant: NN
Reactant: O=Cc1cccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: c1cnc2[nH]ncc2c1
Temperature: 120 °C
Yield: 61.5 %

Procedure:
2-Chloro-3-pyridinecarboxyaldehyde (1.0 g, 7.0 mmol) and p-toluenesulfonic acid monohydrate (700 mg) were dissolved in hydrazine monohydrate (1.4 mL, 28.0 mmol). The resulting mixture was heated at 120° C. for 10 minutes in a sealed tube under irradiation with a macrowave of 100 watts. After cooled to room temperature, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution and extracted with DCM (50 mL) three times. The organic layer was dried over anhydrous sodium sulfate. The concentrated residue was purified by silica gel (Fuji Silysia, BW300, 30 g, n-hexane:ethyl acetate=1:1) to give 1H-pyrazolo[3,4-b]pyridine (513 mg, yield: 62%).