Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:12]([F:15])([F:14])[F:13])([CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>O>[OH:1][C:2]([C:12]([F:13])([F:14])[F:15])([CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)(C=C(C)C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)=CC(O)(C(=O)O)C(F)(F)F
Temperature: 25 °C

Procedure:
Ethyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is used as starting material. 27.1 g (120 mmole) ethyl 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoate is emulsified in 60 mL water, the pH is adjusted to 8.0 with sodium hydroxide solution, the solution is stirred at room temperature. 6 g of the enzyme (Novozyme 388) is added at room temperature. The mixture is stirred for 10 hours under GC control.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34][CH3:35])=[O:33].[C:36]([Zn]C#N)#[N:37]>CN(C)C=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>[C:36]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34][CH3:35])=[O:33])#[N:37]
Reactant: COC(=O)c1c(Br)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 126C (100 mg), dicyanozinc (222 mg) and Pd(PPh3)4 (21.87 mg, 0.019 mmol) in N,N-dimethylformamide (4 ml) was heated at 180° C. for 400 seconds in a microwave reactor (CEM Discover) and then concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography, eluting with 50%-100% dichloromethane in hexane to provide the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]1([NH:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:19][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2cnccc2n1-c1ccccc1
Yield: 72.6 %

Procedure:
Method A applied to 4-chloro-3-nitropyridine (79 mg, 0.5 mmol), N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as brown solid (76 mg, 73). mp 134-136° C. 1H NMR (DMSO) δ 2.54 (s, 3H), 7.65-7.73 (m, 6H), 8.54 (d, J=5.2Hz, 1H), 9.44 (s, 1H); 13C NMR δ 14.4, 108.2, 126.9, 130.2, 130.3, 133.4, 134.0, 134.8, 139.2, 145.0, 159.2. HRMS (FAB): cal. for C13H12N3 [M+H+]: 210.1031; found: 210.1025.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]=[C:9]([CH:11]([N:23](C(OC(C)(C)C)=O)[CH3:24])[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[ClH:32]>C(OCC)(=O)C>[ClH:32].[CH2:1]([O:3][C:4]([C:6]1[N:10]=[C:9]([CH:11]([NH:23][CH3:24])[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc(C(Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1noc(C(Cc2ccc3ccccc3c2)NC)n1

Procedure:
5-(1-(N-Methyl-tert-butoxycarbonylamino)-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (0.77 g, 1.8 mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (15 ml). After 5 h at 20° C. the reaction mixture was concentrated in vacuo to give 0.72 g of (R) 5-(1-methylamino-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester hydrochloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][N:33]=[CH:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[N:34][N:33]=[CH:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cnnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cnnc3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M56) (280 mg, 0.526 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (121 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.C.[H][H]>[Pd].CO>[NH2:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:11])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(Br)cnc1Br
Yield: 0.1 %

Procedure:
43.00 g (152.52 mol) of 2,5-dibromo-3-nitropyridine are hydrogenated in 1.5 g of Pd (10%) on activated charcoal in 450 ml of methanol until the calculated mount of hydrogen has been consumed, the catalyst is filtered off, and the filtrate is freed from solvent, giving 37.56 g of 3-amino-2,5-dibromopyridine. ##STR12##
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([N+:19]([O-])=O)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[H][H]>[Pt].C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:6]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([NH2:19])[C:4]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOc2ccccc2)c1C
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCOc2ccccc2)c1C
Reaction time: 3 h

Procedure:
Anhydrous toluene (100 ml), 5% platinum on carbon (Pt/C) (1.5 g), and 2,3-dimethyl-5-nitro-6-phenoxy-N-(2-phenoxyethyl)pyridin-4-amine (2.97 g) from Part C were placed in a Parr hydrogenation flask at a hydrogen pressure of 345 kPa for 4 hours with shaking. Additional 5% Pt/C (1.5 g) was added and the reaction was allowed to continue for 3 hours. The reaction mixture was filtered through a fluted filter paper and then through a folded No. 2 Whatman filter. The solvent was removed from the filtrate under reduced pressure and the resulting oil was used in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:16]=2)[CH2:11][CH:10]([NH:24]C(=O)OCC2C=CC=CC=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[NH2:24][CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][N:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:35]
Reactant: O=C(NC1Cc2cc(-c3ccccc3)ncc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC1Cc2cc(-c3ccccc3)ncc2N(Cc2ccccc2)C1=O
Yield: 67.3 %

Procedure:
To a solution of 3G (300 mg, 0.65 mmol) in THF (80 mL) and MeOH (80 niL) at RT was added palladium 5% wt. on activated carbon (150 mg). The reaction mixture was stirred under a hydrogen balloon for lh. The reaction was filtered and the filtrate concentrated to give the title compound as a foam (144 mg, 91%). LC/MS (method A): retention time=2.37 min, (M+H)+=330.
Reaction SMILES: O[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[C:5]([I:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:17].CCN(C(C)C)C(C)C>>[Cl:17][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[C:5]([I:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(O)nc2c(I)cccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Cl)nc2c(I)cccc2c1=O
Temperature: 105 °C
Yield: 77.5 %

Procedure:
At RT, to the off-white solid of 2-hydroxy-8-iodo-3-methylquinazolin-4(3H)-one (700c; 12.79 g, 42.3 mmol) was added POCl3 (46.5 mL, 508 mmol). The resulting white suspension was treated with DIPEA (14.73 mL, 85 mmol) dropwise. The heterogeneous mixture was heated in an oil bath at 105° C. for 26 h. LCMS indicated the reaction was about 60% conversion. It was cooled to RT, and treated with additional POCl3 (12 mL) and DIPEA (14.73 mL, 85 mmol). The resulting dark homogeneous solution was heated at 110° C. in an oil bath for 24 h. LCMS indicated the reaction was about >95% conversion. It was concentrated under reduced pressure. The brown sticky solution was treated with 50 mL of toluene and concentrated under reduced pressure again. The brown residue was cooled with an ice bath, ice was added to the flask, followed by 5 N NaOH solution till pH >9. It was extracted with 3×250 mL of EtOAc. The combined organic solution was washed with 2×25 mL of brine, dried over Na2SO4, filtered and concentrated. The brown residue was purified via silica gel chromatography (25-50% EtOAc in hexanes) to afford 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700; 10.51 g, 32.8 mmol, 77% yield) as an off-white crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.21-8.32 (m, 2H), 7.22 (t, J=7.82 Hz, 1H), 3.77 (s, 3H). m/z (ES, +ve) 328.8 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:12]=2[O:23][CH3:24])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][O:23][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:11]=1[N:10]=[N:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:1][C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)=[O:36])=[CH:4][CH:5]=1)[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)COc1ccc(N=Nc2ccc(CO)cc2)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)COc1ccc(N=Nc2ccc(COC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2)c(OC)c1
Reaction time: 0.17 h

Procedure:
Compound 4 (0.1 g, 0.0302 mmol) was dissolved in DCM (15 mL) and freshly activated 4° A M.S (0.15 g) was added and reaction mixture stirred for 10 minutes. DIPEA (0.215 mL, 1.2 mmol) and DMAP (0.05 g) were added and reaction mixture cooled to 0° C. p-Nitrophenyl chloroformate (0.15 g, 0.0757 mmol) in DCM was added slowly and reaction mixture stirred at 0° C. for 1 hour, followed by an additional 4 hours at room temperature. The remaining procedure was followed as described for compound 5 to obtain compound 6 (E:Z isomers). Yield: 0.11 g (76%). 1H NMR (500 MHz, CDCl3) δ 3.79 (s, 3H, Hn (OMe), for Z), 3.82 (s, 3H, Hn (OMe), for E), 3.99 (s, 3H, aromatic-OMe for Z), 4.00 (s, 3H, aromatic-OMe for E), 4.58 (s, 2H, Hf for Z), 4.71 (s, 2H, Hf for E), 5.21 (s, 2H, Hl for Z), 5.34 (s, 2H, Hi for E), 6.22-6.28 (m, 1H, Hb for Z), 6.44-6.50 (m, 2H, Hb for E), 6.52-6.60 (m, 1H, He for Z), 6.64-6.70 (m, 1H, He for E), 6.84-6.95 (m, 2H, He for Z), 7.30-7.40 (m, 2H, He for E), 7.42-7.50 (m, 1H, Ha for Z), 7.50-7.54 (m, 1H, Ha for E), 7.54-7.58 (m, 2H, Hn for Z), 7.68-7.75 (m, 2H, Hn for E), 7.80-7.90 (m, 4H, Hd for Z and E), 8.08-8.14 (m, 2H, Ho for Z), 8.22-8.30 (m, 2H, Ho for E). 13C NMR (125 MHz, CD3SOCD3) δ 52.3, 52.44 (Cn), 55.4, 56.34 (aromatic-OMe), 65.2, 65.2 (Cf), 67.3, 67.4 (Cl), 70.1, 70.4, 100.2 (Cc), 104.2, 105.3 (Cb), 115.62, 116.9 (Ci), 118.0, 120.04, 121.5, 121.7, 121.75, 122.8, 122.9, 125.3, 126.0, 128.7, 128.9, 129.2, 135.9, 137.3, 145.3, 152.3, 154.4, 155.4, 158.7, 161.7, 168.7 (CO). ESI-MS: [M+H]+ C24H22N3O9 calcd 496.1356, obsd 496.12.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].I[CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCNCC2)C1=O
Reactant: O=C(CCCI)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1N1CN(c2ccccc2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Temperature: 68 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
A mixture of tert-butyl 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)benzoate (370 mg, 0.909 mmol, 1 equiv), 4-iodo-1-phenylbutan-1-one (250 mg, 0.909 mmol, 1 equiv) and potassium carbonate (251 mg, 1.82 mmol, 2 equiv) in N,N-dimethylformamide was stirred at 68° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—1%-10% methanol in dichloromethane) to afford the title compound as a white powder (410 mg, 82%); 1H NMR (400 MHz, DMSO-d6): δ 1.49 (s, 9H); 1.74-1.83 (m, 4H); 2.37 (t, 2H, J=7.2 Hz); 2.61 (t, 2H, J=10 and 11.2 Hz); 2.726-2.73 (m, 4H); 3.05 (t, 2H, J=6.8 and 7.2 Hz); 5.06 (s, 2H); 6.79 (t, 1H, J=7.2 and 7.6 Hz); 6.87 (s, 1H); 6.89 (s, 1H); 7.20 (m, 2H); 7.46-7.69 (m, 6H); 7.76-7.78 (m, 1H); 7.95-7.99 (m, 2H); MS for C34H39N3O4 m/z 554.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH2:11][CH2:12][CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15].[B]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: CCCC1Sc2c(cc(OC)c(Cl)c2Cl)C1O
Agent: [B]
Solvent: CC(=O)O
Product: CCCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
To a mixture of 44 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxy-2-n-propylbenzo[b]thiophene in 275 ml of glacial acetic acid is added 65 ml of boron triluoride etherate and the mixture is warmed on a steam bath until it becomes clear. The solution is stired for 10 mins and then quenched with a mixture of 500 g of ice and 200 ml of a 10% sodium hydroxide solution. The mixture is neutralized with 50% sodium hydroxide solution and then extracted with two 300-ml portions of ethyl ether. The organic layers are combined, washed with 100 ml of a saturated sodium bicarbonate solution, 100 ml of water, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil. Chromatography of the oil on an alumina column using 9:1-hexane:ethyl ether as eluting solvent gives 31 g of 6,7-dichloro-5-methoxy-2-n-propylbenzo[b]thiophene as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][C:16]1[O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[O:20][C:16]=2[CH3:15])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: Cc1cc2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1oc2ccccc2c1C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
is obtained as described in Example 1 from 10.1 g 4-chloro-3-sulfamoylbenzoyl chloride and 5.8 g 2-methylbenzo[b]furan in the presence of 11.4 g aluminum chloride. After evaporation of the extraction agent, the residue is stirred with di-isopropyl ether, and the solids are filtered off. Colorless crystals, m.p. 183° C. (from methanol).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1.[NH3:22]>>[Cl:1][C:2]1[N:11]=[C:10]([NH2:22])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1
Reactant: Fc1ccc(Oc2ccc3nc(Cl)nc(Cl)c3c2)c(F)c1
Reactant: N
Product: Nc1nc(Cl)nc2ccc(Oc3ccc(F)cc3F)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound (1F) (21 g, 0.06 mol) was suspended in ammonia (100 mL of 2.0 M solution in MeOH) and the solution formed after 30 min was stirred at room temperature for 18 h. The precipitate was filtered, the concentrated filtrate triturated with EtOAc, and the organic layers were combined to yield 21.5 g of 2-chloro-6-(2,4-difluorophenoxy)-quinazolin-4-ylamine (1G).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:36]=[C:37]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:30])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:17]=3[CH:31]=2)=[CH:10][CH:11]=[C:12]1[C:37]#[N:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2

Procedure:
tert-Butyl-2-cyano-5-(5-methyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate was prepared from tert-butyl-2-(5-methyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate according to the cyanation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.02 (s, 1H), 7.42-7.38 (m, 2H), 7.32-7.10 (m, 7H), 6.49 (d, J=3.80 Hz, 1H), 4.20 (d, J=14.63 Hz, 1H), 3.99, (d, J=14.41 Hz, 1H), 1.87 (s, 3H), 1.39 (s, 9H); MS (ES) n?z 442 ([M−H]−, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[S:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>>[C:19]1([C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=4)=[S:34])=[CH:7][CH:6]=3)[CH:18]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2cc(-c3ccccc3)c3ccccc3n2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3cc(-c4ccccc4)c4ccccc4n3)cc2)ccc1Cl
Yield: 60.7 %

Procedure:
2-(4-aminophenylthio)-4-phenylquinoline (3.0 mmoles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (3.3 mmoles, 0.79 g) were reacted according to procedure C to yield the title compound 1.03 g, 61%. Mass Spec (FD) 565. Calculated for C29H19ClF3N3 S2 : C, 61.53; H, 3.38; N, 7.42. Found: C, 61.82; H, 3.63; N, 7.43.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:29].FC(F)(F)S(O)(=O)=O>ClCCl>[I:29][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: Oc1ccc2cnccc2c1
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Oc1ccc2cnccc2c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
Under argon atmosphere 1.77 g (12.2 mmol) of compound 7 were added to a solution of 5.0 g (13.5 mmol) bis(pyridin)iodonium tetrafluoroborate in 100 mL of dry dichloromethane. A solution of 2.4 mL (4 g, 26.8 mmol) trifluoromethane sulfonic acid in 20 mL dry dichloromethane was added dropwise at 0° C. and the mixture was stirred for 3 hours at room temperature. The solvents were removed by distillation and the remainder was treated with aqueous NaHCO3 solution. The precipitate was filtered, washed with water and dried to yield 3.2 g (97%) of compound 10 as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=[CH:5]2.[Br-].[Li+].[CH:22]([Mg]Br)([CH3:24])[CH3:23]>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:22]([CH3:24])[CH3:23])[CH:8]=2)[CH:3]=1
Reactant: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Reactant: CC(C)[Mg]Br
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ccc2cc(Br)ccc2c1
Temperature: 80 °C
Yield: 33 %

Procedure:
Under an atmospheric argon gas flow, trifluoromethane sulfonic acid-6-bromo-2-naphthyl ester in an amount of 32 g (90 mmol), dichloro(diphenylphosphinoferrocene)palladium in an amount of 3.6 g (5% by mol), lithium bromide in an amount of 7.8 g (90 mmol) and desiccated tetrahydrofuran in an amount of 100 milliliter were placed into three necked-flask equipped with cooling pipe and having a capacity of 500 milliliter, and then, the resultant solution was cooled down to −20° C. After slowly dripping isopropylmagnesiumbromide in an amount of 90 milliliter (90 mmol, 1 mol/liter (tetrahydrofuran)) into the flask, the resultant solution was stirred under heating at the temperature of 80° C. for 4 hours. After the reaction terminated, adding dilute hydrochloric acid in an amount of 100 milliliter into the reacted solution, an organic layer was separated and washed with the use of sodium bicarbonate solution and sodium chloride solution, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=90/10), and as a result, 9.4 g of aimed compound (white crystal) was obtained (yield: 33%).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:3].[CH3:19][S:20]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=3)[S:29][C:28]=2[CH:43]=1)(=[O:22])=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>>[ClH:1].[CH2:17]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:31]2[C:27]3[CH:26]=[CH:25][C:24]([O:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:43][C:28]=3[S:29][C:30]=2[C:32]2[CH:33]=[CH:34][C:35]([O:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:36][CH:37]=2)=[O:14])=[CH:15][CH:16]=1)[CH3:18]
Reactant: CCN(CC)CCOc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OS(C)(=O)=O)cc3)sc3cc(OS(C)(=O)=O)ccc23)cc1
Reaction time: 1.5 h

Procedure:
A 5.2 g. portion of 4-(2-diethylaminoethoxy)benzoic acid, hydrochloride, was converted to the acid chloride, and used to acylate 5 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene according to the process of Example 5. The amount of aluminum chloride was 15.1 g., and the reaction mixture was stirred for 1.5 hours after its addition. The mixture was worked up as described in Example 5 to obtain a yellow foam, which began to crystallize after standing for several days. It was triturated with denatured ethanol and recrystallized from denatured ethanol to obtain 6.5 g. of purified crystalline product, m.p. 172°-174°.