Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1.C(OCC)(=O)C>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:11]2([OH:10])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(C#N)cc2)CC1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of 4-iodobenzonitrile (510 mg, 2.22 mmol, 1.1 equiv) in THF (3 mL) was added to a 10 mL round-bottom flask and the system purged with nitrogen. The mixture was cooled to −40° C. then isopropylmagnesium chloride (1.16 mL of a 2.0 M soln in THF, 2.32 mmol, 1.15 equiv) was added dropwise over 20 minutes. The resulting mixture was stirred at −40° C. for 2 hours then tert-butyl 4-oxoazepane-1-carboxylate (431 mg, 2.02 mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise over 15 minutes. The resulting mixture was stirred at −40° C. for 1 hour then diluted into ethyl acetate (15 mL) and washed with 0.2 M HCl (10 mL), 0.1 M HCl (5 mL), saturated sodium bicarbonate (5 mL) then brine (5 mL). The organics were dried (Na2SO4), filtered and evaporated. To remove remaining ketone and aldol by-product, the residue was dissolved in acetonitrile (3 mL) then hydrazine (0.2 mL) was added and heated at 60° C. for 4 hours. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL), followed by 0.5 M phosphoric acid (3×20 mL), saturated sodium bicarbonate (10 mL) and brine (10 mL). The organics were dried (Na2SO4), filtered and evaporated. The residue was purified by silica column chromatography (hexanes/ethyl acetate) to obtain the title compound as a pink oil which solidified upon standing (303 mg, 47%). m/z (ES+) 317 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23](OC(C)(C)C)=[O:24])=[N:21][CH:22]=3)[CH2:13][CH2:12]2)[CH2:6][CH2:5]1)[CH3:3].[CH3:30][NH2:31]>>[CH3:30][NH:31][C:23]([C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:2]([CH3:3])[CH3:1])[CH2:5][CH2:6]3)[CH2:16][CH2:15]2)=[CH:22][N:21]=1)=[O:24]
Reactant: CC(C)N1CCC(CC2CCN(c3ccc(C(=O)OC(C)(C)C)nc3)CC2)CC1
Reactant: CN
Product: CNC(=O)c1ccc(N2CCC(CC3CCN(C(C)C)CC3)CC2)cn1

Procedure:
N-Methyl-5-(4-{[1-(1-methylethyl)-4-piperidinyl]methyl}-1-piperidinyl)-2-pyridinecarboxamide was prepared using an analogous process to that described in Examples 10 and 11 from 1,1-dimethylethyl 5-(4-{[1-(1-methylethyl)-4-piperidinyl]methyl}-1-piperidinyl)-2-pyridinecarboxylate (may be prepared as described in Example 4) and methylamine. The compound displayed 1H-NMR and mass spectral data that were consistent with structure. MS electrospray (+ion) 359 (MH+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[N:35]1([CH2:40][CH2:41]O)[CH:39]=[N:38][CH:37]=[N:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:41][CH2:40][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: OCCn1cncn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1cncn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
The starting material was prepared as follows Diethyl azodicarboxylate (1.1 ml, 7 mmol) was added dropwise to a solution of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one-(1.7 g, 5.55 mmol), 2-(1,2,4-triazol-1-yl)ethanol (791 mg, 7 mmol), (Ann. Pharm. Fr. 1977,35,503-508) and triphenylphosphine (1.8 g, 7 mmol) cooled at 5° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The mixture was poured directly on to a column of silica and eluted with methylene chloride/methanol (95/5) to give 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.64 g, 74%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:21][C:22](=[O:27])[C:23](=[O:26])[CH2:24][CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:26][CH:23]([CH2:24][CH3:25])[C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:28])=[O:27]
Reactant: CCC(=O)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(O)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxobutanamide obtained in Example 17 (237 mg, 0.62 mmol) in methanol (5 mL) was added sodium borohydride (24 mg, 0.62 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 170 mg (yield: 72%) of the title compound. Melting point: 146-147° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C([C@@H]1[C@H](N)C2[CH:30]=[CH:31][S:32]C=2CC1)CC>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[CH:30]=[CH:31][S:32][C:19]=3[CH2:18][CH2:17][C@@H:16]2[CH2:15][CH2:14][CH3:13])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCC[C@H]1CCc2sccc2[C@H]1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting cis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.65, 7.05, 6.92, 5.68, 4.31, 2.97-2.80, 2.68, 2.53, 2.05, 1.97, 1.71, 1.51-1.25, 0.86; HRMS (FAB) calcd for C19H27N3S+H 330.2004, found 330.2001. Anal. Calcd for C19H27N3S: C, 69.26; H, 8.26; N, 12.75; S, 9.73. Found: C, 69.21; H, 8.28; N, 12.35.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][N:16]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:31])#[N:9]>>[C:8]([C:10]1[CH:11]=[C:12]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][N:16]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:31])#[N:9]
Reactant: COC(=O)c1ccc(C)c(-n2cnc3c(C#N)cc(I)cc3c2=O)c1
Reactant: CN1CCNCC1
Product: COC(=O)c1ccc(C)c(-n2cnc3c(C#N)cc(N4CCN(C)CC4)cc3c2=O)c1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material N-methyl piperazine was reacted with methyl 3-(8-cyano-6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate to give methyl 3-[8-cyano-6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.24 (s, 3H), 2.49 (m, 4H, masked by DMSO), 3.36 (m, 4H), 3.88 (s, 3H), 7.63 (d, 1H), 7.70 (d, 1H), 8.03 (m, 2H), 8.13 (d, 1H), 8.28 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:29])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[ClH:39]>O>[ClH:39].[ClH:39].[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:29])[CH2:10][CH2:9]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 76 parts of 1-{-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 280 parts of ethanol are added 120 parts of a hydrochloric acid solution and 250 parts of water. The whole is stirred for 30 minutes at room temperature. Upon cooling in an ice-bath, the product is precipitated. It is filtered off, washed with 2-propanone and with 2,2'-oxybispropane, and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride, hydrate; mp. 237.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.CN(C=O)C.[CH3:18][C:19]([NH2:22])([CH3:21])[CH3:20]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:19]([CH3:21])([CH3:20])[CH3:18])[N:8]=[CH:7]2
Reactant: Clc1ncc2cccc(Br)c2n1
Reactant: CC(C)(C)N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1ncc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.5 %

Procedure:
8-Bromo-2-chloroquinazoline (D-L Chiral Chemicals, LLC, Princeton, N.J.) (200 mg, 0.82 mmol) was treated with DMF (2.0 mL) and 2-methylpropan-2-amine (Aldrich Chemical Company, 0.44 mL, 4.11 mmol) and stirred at RT overnight (17 h). The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine (2×), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO Combiflash RF (12 g Thomson SingleStep column, using a gradient of 0-50% EtOAc in hexanes) affording 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (94 mg, 0.34 mmol, 41% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (1H, s), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=7.9, 1.3 Hz), 7.05 (1H, t, J=7.7 Hz), 5.43 (1H, br. s.), 1.54 (9H, s). m/z (ESI, +ve ion) 280.0/282.0 (M+H)+. A 5-mL glass microwave reaction vessel was charged with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (120 mg, 0.46 mmol), K2PO4 (182 mg, 0.86 mmol), Pd2dba3 (Strem Chemicals, 13.07 mg, 0.014 mmol), Xphos (Strem Chemicals, 13.61 mg, 0.03 mmol) and 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (80 mg, 0.29 mmol) in dioxane (2.5 mL) and water (0.80 mL). The reaction was stirred and heated in a heating block at 110° C. for 1 h. The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine and concentrated. The crude residue was purified on the ISCO Combiflash RF (25 g Thomson SingleStep column, using a gradient of 0-20% MeOH) affording 2-(2-(tert-butylamino)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (53.9 mg, 0.16 mmol, 56% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (1H, br. s.), 9.17 (1H, s), 8.10 (1H, d, J=6.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.35 (1H, s), 7.25 (1H, t, J=7.6 Hz), 7.05 (1H, br. s.), 6.98 (1H, br. s.), 3.40-3.47 (3H, m), 2.92 (2H, br. s.), 1.52 (9H, s). m/z (ESI, +ve ion) 336.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=2)[C:22]=1[CH3:39].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:32]4[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2cncc(F)c2)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cncc(F)c2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 150 °C

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (43 mg, 0.16 mmol; described herein), 4-chloro-7-fluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline (47 mg, 0.16 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (4 μL, 0.1 equiv, 16 μmol), and NMP (190 μL, 1.9 mmol). The reaction was heated in a microwave at 150° C. for 4 h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-2-(5-fluoro-3-pyridinyl)-3-methyl-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.69 (1H, m), 8.60 (1H, d, J=2.7 Hz), 7.84 (1H, m), 7.76 (2H, m), 7.64 (1H, d, J=2.7 Hz), 7.33 (1H, m), 6.81 (1H, s), 6.21 (1H, d, J=2.7 Hz), 3.89-3.97 (4H, m), 3.72-3.79 (4H, m), 3.24 (4H, m), 2.89-2.98 (4H, m), 2.33 (3H, s). Mass Spectrum (ESI) m/e=519.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:14]([CH3:15])[N:13](O)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[Sn]Cl.C[OH:21]>>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:14]([CH2:15][OH:21])[N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN1C(c2cccc([N+](=O)[O-])c2)=NNN1O
Reactant: CO
Agent: Cl[Sn]Cl
Product: Nc1cccc(-c2nnnn2CO)c1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a solution of (3-nitrophenyl)(hydroxy)acetonitrile (3.5 g, 19.6 mmol) in 100 mL toluene was added sodium azide (8 g, 123 mmol) and Bu3SnCl (26 ml, 98 mmol). The mixture solution was heated at reflux for 10 hours. The solvent was removed in vacuo, the residue was dissolved in water, acidified with 1N HCl, and extracted with 3×100 mL ethyl acetate. The crude product was purified by flash chromatography on silica gel to afford 5-(3-nitrophenyl)(hydroxy)methyltetrazole (2.0 g, 9 mmol, 46%) as yellow solid. To a solution of 5-(3-nitrophenyl)(hydroxy)-methyltetrazole (1.3 g, 5.9 mmol) in 50 mL methanol was added SnCl2 (8 g, 35.4 mmol). The resulting reaction mixture was heated at 60° C. for 20 minutes. The reaction mixture was dried in vacuo, then purified directly over an ion-exchange column to afford 5-(3-aminophenyl)(hydroxy)methyltetrazole (1.0 g, 5.2 mmol, 88%), which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[C:21](=[N:23]S(Cl)(=O)=O)=[O:22].[OH-].[K+]>O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:21]([NH2:23])=[O:22])=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1c[nH]c2cccc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.4 g. 4-Benzyloxyindole (see Helv. Chim. Acta, 54. 2411/1971) are dissolved in 20 ml. anhydrous acetonitrile, cooled to 0° C. and mixed with 1.8 ml. N-carbonylsulphamoyl chloride in 20 ml. acetonitrile. After a reaction period of about 1 hour, a solution of 3.4 g. potassium hydroxide in 34 ml. water is added thereto and the reaction mixture then stirred for 1 hour at ambient temperature. After evaporating the solvent, the residue is taken up in 200 ml. 2 N hydrochloric acid and extracted with methylene chloride. From the methylene chloride extract there are obtained 4.8 g. (45% of theory) 4-benzyloxy-3-aminocarbonylindole, which is recrystallized from ethyl acetate; m.p. 176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([C:16]#[C:17][CH:18]3[CH2:20][CH2:19]3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:21]=1.[C:22]12([CH3:34])[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]2[C:31](Cl)=[O:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:31]([CH:23]3[CH2:24][CH:25]4[C:28]([CH3:30])([CH3:29])[C@@:22]3([CH3:34])[CH2:27][CH2:26]4)=[O:32])[C:9](=[O:11])[O:8][C:7]([C:16]#[C:17][CH:18]3[CH2:20][CH2:19]3)([C:12]([F:13])([F:14])[F:15])[C:6]=2[CH:21]=1
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Reactant: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(C(=O)N1C(=O)OC(C#CC3CC3)(C(F)(F)F)c3cc(Cl)ccc31)C2
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 39.6 %

Procedure:
To a solution containing (+) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (12.97 g, 0.041 mol), 4-dimethylaminopyridine (1.02 g, 0.0083 mol), and (-) camphanic acid chloride (14.22 g, 0.06556 mol) in 350 mL of dry dichloromethane, stirred under argon in an ice bath, was added triethylamine (22.84 mL, 0.164 mol). The cooling bath was removed and the reaction was allowed to proceed at room temperature. After 75 min. the reaction was judged complete by thin layer chromatography (SiO2, 4% EtOAc in CHCl3), and the solution was diluted with 500 mL of CHCl3 then washed with 10% citric acid (2X), water (1X), and brine (1X). Drying (MgSO4), filtration, and removal of the solvent in vacuo left a colorless foam. This material was triturated with 200 mL of boiling hexane. On cooling to room temperature the desired diastereomeric camphanate imide precipitated. The solid was collected on a frit, washed with a little cold hexanes and dried in vacuo to give 7.79 g of 6-chloro-1-(1S)-camphanoyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as white crystals. mp: 164°-165° C. HPLC purity: 99.2% @254 nm. 1H-NMR (CDCl3): δ0.77 (s, 3H), 0.86-0.96 (m, 4H), 1.08 (s, 3H), 1.19 (s, 3H), 1.44 (m, 1H), 1.76 (m, 1H), 1.95 (m,1H), 2.51 (m, 2H), 7.42 (dd, J=2.4,9.0 Hz, 1H), 7.63 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:21][CH:22]3[O:24]C3)[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][S:12]2(=[O:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:25](O)C.C(Cl)(Cl)Cl.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CC(C)=O>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[CH3:25][CH:15]1[CH2:14][CH2:13][S:12](=[O:19])(=[O:20])[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:21][CH2:22][OH:24])[S:16]1(=[O:17])=[O:18]
Reactant: COc1ccc(C2(CC3CO3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Reactant: CCO
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2(CCO)S(=O)(=O)CCC(C)S2(=O)=O)cc1OC

Procedure:
3.76 g of 2-(3,4-dimethoxyphenyl)-2-(2,3-epoxypropyl)-m-dithiane-1,1,3,3-tetraoxide are heated at reflux for 18 hours under argon with 50 ml of ethanol, 30 ml of chloroform and 1.95 g of N-methyl-homovetratrylamine. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform/ethanol (98:2). The oil obtained is dissolved in acetone and treated with an equivalent amount of anhydrous oxalic acid. The precipitate is filtered off and recrystallized from methanol/acetone. The racemic α- (3,4-dimethoxyphenethyl)-methylamino!-methyl-2-(3,4-dimethoxyphenyl)-m-dithiane-2-ethanol-1,1,3,3-tetraoxide oxalate (1:1) obtained crystallizes with 1 mol of acetone and melts at 162°-164° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:35])[CH2:19][S:20][C:21]2[N:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:23][N:22]=2)[CH2:12]1.ClC(Cl)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOCC>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:35])[CH2:19][S:20][C:21]2[N:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[CH:25][N:26]=2)[CH2:12]1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COc1ccc(-c2cnc(SCC(=O)NCC3CCNC3)nc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: COc1ccc(-c2cnc(SCC(=O)NCC3CCN(Cc4cccc(Cl)c4Cl)C3)nc2)cc1
Reaction time: 8 h

Procedure:
2,3-Dichlorobenzaldehyde (115 mg, 0.66 mmol, 1.5 equiv.) was added to N-(pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylthio]acetamide in dichloroethane (3.4 mL, 0.44 mmol). Excess Na(OAc)3BH (0.2 g, 0.9 mmol, ~3 equiv.) was added and the resulting suspension was stirred vigorously overnight. The reaction mixture was diluted with ether and quenched with 1 M hydrochloric acid to afford a cloudy mixture. The organic layer was carefully removed and the aqueous phase made basic with 5 M aqueous sodium hydroxide to pH 11. After thorough extraction with ethyl acetate, the combined organic phases was washed with brine, then dried over sodium sulfate and concentrated. Chromatography on silica (0-10% methanol in ethyl acetate) afforded N-(1-(2,3-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylsulfanyl]acetamide that was converted to the hydrochloride salt using 4 M hydrochloric acid solution in dioxane and ether (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10](C3C=CC=CN=3)=[N:11][C:7]=2[CH:6]=1.[CH3:37][N:38]1[CH:42]=[CH:41][C:40](C(O)=O)=[N:39]1>>[F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:40]3[CH:41]=[CH:42][N:38]([CH3:37])[N:39]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2c(F)cccc2F)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccn(C)n4)nc3cc2Oc2c(F)cccc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 203 or in accordance with the method or by combining it with an ordinary method but using 4-(2,6-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 235 and 1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:17]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Yield: 100.3 %

Procedure:
2-Chloro-5-nitropyridine (500.0 mg), methyl 4-hydroxybenzenecarboxylate (958.6 mg) and potassium carbonate (1.31 g) were suspended in acetonitrile (5 mL), and heated under reflux for 16 hours. Water (50 mL) was added to the reaction liquid, extracted with ethyl acetate (50 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (50 mL), water (50 mL) and saturated saline water (50 mL) in that order. The organic layer was dried with magnesium sulfate, and evaporated under reduced pressure to obtain the entitled compound (867.7 mg) as a brown solid.