Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])=[CH:5][CH:6]=1.[F:18][C:19]([F:24])([F:23])C([O-])=O.[Na+].Cl.C(Cl)Cl>CN(C)C(=O)C.[Cu]I>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]([C:19]([F:24])([F:23])[F:18])=[CH:6][CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccc(Br)s1
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc([N+](=O)[O-])ccc1-c1ccc(C(F)(F)F)s1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A stirred solution of 8.0 g (0.026 mole) of 2-bromo-5-(2-methoxy-4-nitrophenyl)thiophene, 13.9 g (0.1 mole) of sodium trifluoroacetate and 9.7 g (0.05 mole) of copper(I)iodide in 160 ml of dry N,N-dimethylacetamide was heated at 175° C. for four hours. The reaction mixture was cooled to room temperature then poured into 400 ml of 2N hydrochloric acid and ice (approximately 1:1). Methylene chloride was added and the resultant mixture filtered. The filtrate separated into two phases. The organic phase was separated then washed with three portions of 2N hydrochloric acid and one portion of water. The washed organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to leave a residue. The residue was subjected to column chromatography on silica gel, eluting with toluene, to yield 1.8 g of a mixture of 2-(2-methoxy-4-nitrophenyl)-5-trifluoromethylthiophene and 2-(2-methoxy-4-nitrophenyl)thiophene.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18].[C:23]([C@@H:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:27]=1)#[N:24].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH:15][C@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([O:19][C@H:25]([C:23]#[N:24])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:27]=1)=[O:18]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h

Procedure:
Into 4.5 ml of methylene chloride containing 22.5 mg of 4-dimethylaminopyridine are added 439 mg (1.48 mmol) of (R)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid and 329 mg (1.46 mmol) of (S)-α-cyano-3-phenoxybenzyl alcohol. The solution is cooled in an ice bath and 380 mg (1.82 mmol) of dicyclohexylcarbodiimide is added. The mixture is stirred at 0° for 1 hour and is then worked up by partition between ether/hexane. The aqueous phase is extracted with ether, and the ether extract is washed with water (2×) and brine, dried over magnesium sulfate, filtered and evaporated. The product is purified by radial thin layer chromatography (2 mm silica gel rotor eluting with 12% ether/hexane). Higher diastereomeric purity is obtained by further radial tlc, yielding the final product (S)-α-cyano-3-phenoxybenzyl (R)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, specific rotation=+46.3° (in CHCl3), diastereomer purity=~98%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 6.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 22.2) and (3S,4S)-pyrrolidine-3,4-diol to afford an off-white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=477.9 [M+H]+, m/z=475.8 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.55 (d, J=11.13 Hz, 2H) 3.91-4.09 (m, 4H) 5.18 (d, J=2.81 Hz, 2H) 7.34 (d, J=9.05 Hz, 2H) 7.80-7.93 (m, 2H) 8.34 (d, J=1.96 Hz, 1H) 8.67 (d, J=1.96 Hz, 1H) 10.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4]Br.[CH3:13][C:14]1([CH3:20])[CH2:18][O:17][NH:16][C:15]1=[O:19].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O1CCOCCOCCOCCOCCOCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4][N:16]1[C:15](=[O:19])[C:14]([CH3:20])([CH3:13])[CH2:18][O:17]1
Reactant: CC1(C)CONC1=O
Reactant: O=[N+]([O-])c1cccc(Cl)c1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CON(Cc2c(Cl)cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of 2-chloro-6-nitrobenzyl bromide (17.5 g, 0.07 mole), 4,4-dimethyl-3-isoxazolidinone (11.5 g, 0.1 mole), potassium carbonate (13.8 g, 0.1 mole), and 1,4,7,10,13,16-hexaoxacyclooctadecane (0.5 g, 0.002 mole) in acetonitrile (500 ml) was stirred at ambient temperature overnight. The reaction mixture was poured into ethyl acetate (500 ml) and the mixture washed with water (3×200 ml). The dried (magnesium sulfate) ethyl acetate layer was concentrated under reduced pressure to yield a liquid. The liquid product was subjected to chromatography on silica gel, eluting with 1:9 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield a white solid. The solid was recrystallized from ethyl acetate to yield 10.5 g of 2-[(2-chloro-6-nitrophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone, m.p. 86°-88° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[C@H:10]([C:15]([OH:17])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C@H]1C[CH2:23][NH:22][CH2:21][C@H]1C(O)=O.C(N(CC)CC)C.Cl.CNC.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH3:21][N:22]([CH3:23])[C:15]([C@H:10]1[C@@H:11]([CH3:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:17]
Reactant: C[C@H]1CCNC[C@H]1C(=O)O
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Agent: CNC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N(C)C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of cis-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (prepared by N-Boc protection of cis-4-methylpiperidine-3-carboxylic acid, synthesized by the method described in Bulletin de la Societe Chimique de France 1986, 4, 663-8.) (0.4 g, 1.64 mmol) in tetrahydrofuran were added triethylamine (0.2 mL, 1.64 mmol), dimethylamine hydrochloride (132 mg, 1.64 mmol), and 1,1′-carbonyldiimidazole (CDI, 265 mg, 1.64 mmol). After 2 h, the mixture was quenched with water and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford cis-tert-butyl 3-(dimethylcarbamoyl)-4-methylpiperidine-1-carboxylate (0.3 g, 68%) as a yellow solid. The material was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:42])[CH2:23][CH2:24][C:25](=[O:41])[N:26]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32])=O)(C)(C)C>C(Cl)Cl>[CH2:34]([O:33][N:26]([C:25](=[O:41])[CH2:24][CH2:23][C:22](=[O:42])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
6,17-Bis(benzyloxy)-7,10-dioxo-6,11,17-triazaheptadecane-nitrile (9) was synthesized by slowly adding trifluoroacetic acid (TFA, 40 mL) to (8) (6.00 g, 10.1 mmol) in CH2Cl2 (100 mL). The solution was stirred at 0° C. for 15 minutes and at room temperature for 30 minutes. Solvents were removed by rotary evaporation, aqueous NaHCO3 was added and the product was extracted into CHCl3. Column chromatography on silica gel, eluting with 5% CH3OH/CHCl3, afforded 4.3 g (87%) of (9): NMR δ 1.2-1.8 (m, 10 H), 2.2-3.3 (m, 10 H), 3.62 (t, 2 H, J=7), 4.63 (s, 2 H), 4.82 (s, 2 H), 5.5 (br s, 1 H), 5.87 (br s, 1 H), 7.15-7.35 (m, 10 H). Anal. calcd. for C28H38N4O4 : C, 67.99; H, 7.74; N, 11.33. Found: C, 67.82; R, 7.79; N, 11.29 [Bergeron at al, Tetrahedron (1989), supra].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:17]([O:14][C:13]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:8]([C:9]([O:11][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[O:10])[CH:7]=1)=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCBr
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc([N+](=O)[O-])c1
Yield: 74 %

Procedure:
A mixture of 1.0 g (4.7 mmol) of 5-nitroisophthalic acid, 3.1 ml (10.3 mmol) of 1-bromotetradecane and 2.0 g (15 mmol) of potassium carbonate in 40 ml of anhydrous DMF was stirred and heated at 100° for 20 hours. Water was added to the cooled reaction mixture and the resultant solid was filtered and recrystallized from methylene chloride-methanol to give 2.1 g (74% yield, mp 60°-61°) of 5-nitro-1,3-benzenedicarboxylic acid ditetradecyl ester.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[O:4][C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH:11]1([CH2:10][N:7]2[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[O:4][C@H:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:2]([NH:1][C:38](=[O:39])[C@H:36]([CH3:37])[NH:35][C:33](=[O:34])[CH2:32][C:27]3[CH:28]=[C:29]([F:31])[CH:30]=[C:25]([F:24])[CH:26]=3)[C:8]2=[O:9])[CH2:13][CH2:12]1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a stirred solution of (2R,3S)-3-amino-5-(cyclopropylmethyl)-2-phenyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (72b) (150 mg, 0.486 mmol) in dichloromethane (4 mL) was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (130 mg, 0.534 mmol), HOBt (75 mg, 0.555 mmol), NMM (60 mg, 0.594 mmol) and EDAC-HCl (103 mg, 0.537 mmol). After stirring at ambient temperature under nitrogen overnight the solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic solution was separated, washed with 1N aqueous HCl then dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 5:1 (v/v) dichloromethane:ethyl acetate to afford the title compound (230 mg, 88%) as a white solid. TLC Rf=0.22 (5:1 dichloromethane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.20 (m, 1H), 0.36-0.64 (m, 3 h), 1.14 (m, 1H), 1.21 (d, 3H, J=7.0 Hz), 3.47 (s, 2H), 3.52 (m, 1H), 4.10-4.29 (m, 2H), 5.05 (t, 1H, J=7.0 Hz), 5.68 (d, 1H, J=7.4 Hz), 5.90 (d, 1H), 6.24 (d, 1H), 6.68-6.85 (m, 3H), 7.28 (s, 4H), 7.36, s, 5H). MS APCI, m/z=534 (M+1). LC/MS: 2.78 min.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[O:28]=[C:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][S:2]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:17][CH:18]=2)[CH2:23][CH2:24]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
The title compound was prepared from 4-(chlorosulfonyl)benzoic acid and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 2.36 (t, J=6.0 Hz, 4H), 3.49 (t, J=6.0 Hz, 4H), 6.87 (d, J=9.3 Hz, 2H), 6.91 (d, J=9.3 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 8.04 (d, J=8.1 Hz, 2H), 9.97 (s, 1H), 13.10 (brs, 1H); MS (ES) m/z: 374.9 (MH+); HRMS Calcd. for C18H19N2O5S(MH+): 375.1009. Found: 375.1009.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])[CH3:2].C([Li])CCC.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)=[C:24]([F:35])[C:23]=1[F:36])[CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:31]2([OH:34])[CH2:32][CH2:33][CH:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[C:23]([F:36])[C:24]=3[F:35])[CH2:29][CH2:30]2)=[C:6]([F:10])[C:5]=1[F:11])[CH3:2]
Reactant: CCOc1cccc(F)c1F
Reactant: CCCCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(C2CCC(O)(c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: 30 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
1-Ethoxy-2,3-difluorobenzene (27) (7.0 g) and THF (200 ml) were added to a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. n-Butyl lithium (1.57 M in n-hexane; 31.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 1-(4-butoxy-2,3-difluorophenyl)-cyclohexane-4-one (28) (12.5 g) dissolved in THF (50 ml) was slowly added dropwise in the temperature range of 50° C. to 60° C., and stirring was continued for another 60 minutes. The obtained reaction mixture was cooled to 30° C., and then poured into a vessel containing an aqueous solution of ammonium chloride (3%; 400 ml) and toluene (200 ml) cooled to 0° C., and mixed. Then the mixture was allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 19.0 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-(4-butoxy-2,3-difluorophenyl)cyclohexan-1-ol (29). The obtained compound (29) was yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH3:3].[Cl:18]N1C(=O)CCC1=O>N1C=CC=CC=1>[Cl:18][C:12]1[S:11][C:9]2[N:10]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[O:14])[C:8]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCOc1nc2sccc2c(=O)n1CCC
Solvent: c1ccncc1
Product: CCCOc1nc2sc(Cl)cc2c(=O)n1CCC
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
In a sulfonation flask, 10.1 g (0.04 mol) of 2-propoxy-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are added with stirring to 50 ml of absolute pyridine. The internal temperature is then raised to 70-75° C. and 9.0 g (0.07 mol) of N-chlorosuccinimid (NCS) are added over about 10 minutes in smallish portions. After stirring for 2 hours at 70-75° C., the pyridine is removed in a water-jet vacuum and the residue taken up in ethyl acetate. After washing twice with cold dilute aqueous hydrochloric acid, drying over sodium sulfate and removing the solvent in a water-jet vacuum, the crude product is obtained. The purification of the crude product is accomplished by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:5), giving 7.8 g 6-chloro-2-propoxy-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one in the form of a white powder having a melting point of 62-65° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:9][C:8]=2[CH:23]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:32])C=1.O.C(=O)([O-])O.[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]3([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[O:32][CH:9]3[C:8]=2[CH:23]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C=C1CNC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C2OC21CNC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-2H-1-benzopyran (0.5 g, 1.52 mmol) in dichloromethane (10 ml) at 0° C. was treated with m-chloroperbenzoic acid (70%, 0.45 g, 1.52 mmol). After stirring for sixteen hours at room temperature, water and sodium hydrogen carbonate were added and the organic phase separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (95/5), to give 0.43 g of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran 1NMR (CDCl3): δ1.4 (s, 3H), 1.6 (s, 3H), 3.7 (dd,1H), 3.85 (s, 1H), 4.15 (dd, 1H), 6.70 (br.s, 1H), 6.95 (d, 1H), 8.2 (d, 1H), 8.30 (s, 1H).
Reaction SMILES: [C:1]1([C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]2[CH:12]=[N:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH2:23][NH2:24])[CH:20]=[CH:21][CH:22]=3)=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:37][C:38]1[C:47]([F:48])=[CH:46][CH:45]=[C:44]2[C:39]=1[C:40](=[O:54])[NH:41][C:42]([C:49](OCC)=[O:50])=[N:43]2>C(O)C>[F:37][C:38]1[C:47]([F:48])=[CH:46][CH:45]=[C:44]2[C:39]=1[C:40](=[O:54])[NH:41][C:42]([C:49]([NH:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][CH2:14][O:13][C:10]3[N:11]=[CH:12][N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:9]=3)[CH:18]=1)=[O:50])=[N:43]2
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2ccc(F)c(F)c2c(=O)[nH]1
Solvent: CCO
Product: O=C(NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1)c1nc2ccc(F)c(F)c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
A suspension of 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy]ethyl)oxy}phenyl}methanamine obtained in Reference Example 32 (300 mg, 1.18 mmol) and ethyl 5,6-difluoro-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 57 (562 mg, 1.18 mmol) in ethanol (10 mL) was stirred at 80° C. for 12 hr. The insoluble material was filtered off hot, and the filtrate was allowed to cool to room temperature. The precipitated solid was collected by filtration using glass filter, and the obtained solid was washed with diethyl ether to give 5,6-difluoro-4-oxo-N-({3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methyl)-3,4-dihydroquinazoline-2-carboxamide as a pale-yellow powder (330 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH3:29])=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][S:30]([C:23]2[CH:24]=[C:25]([CH3:29])[C:26]([Cl:28])=[CH:27][C:22]=2[Cl:21])(=[O:32])=[O:31])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cc(F)c(Oc3cnc4ccccc4c3)c(Cl)c2)c(Cl)cc1Cl
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)phenylamine (186.2) (0.420 g) in pyridine(2.2 ml), was added 2,4-dichloro-5-methylbenzenesulfonylchloride 0.360 g. The mixture was stirred at room for 1 hr. The reaction mixture was purified directly by column chromatography (silicagel, AcOEt:Hexane=1:3). The product was triturated by hexane to give title compound (0.522 g). (73%) as a solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]([NH:11][CH2:12][CH2:13][NH2:14])([CH3:10])[CH3:9].Cl[CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])=[O:19]>C(N(CC)CC)C>[CH:8]([NH:11][CH2:12][CH2:13][NH:14][CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])=[O:19])([CH3:10])[CH3:9]
Reactant: CC(C)NCCN
Reactant: Cc1cccc(C)c1NC(=O)CCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CCNCCNC(C)C
Yield: 63.2 %

Procedure:
Three hundred milliliters of a toluene solution of a mixture of N-isopropyl-1,2-ethylenediamine (20.0 g), 3-chloro-2',6'-dimethylpropionanilide (13.9 g) and triethylamine (10 ml) is treated as in Example 1 to provide a pale yellow powder. Recrystallization from n-hexane provides a colorless needle in an amount of 11.5 g (yield: 63.2%). m.p. 69.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Si](C=[N+]=[N-])(C)(C)[CH3:22]>C1COCC1.CO>[CH3:22][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([F:20])=[C:4]([F:19])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (17.4 g, 48.1 mmol) in THF-MeOH (100 mL-30 mL) was added TMSCHN2 (31.0 mL, 62.0 mmol, 2M solution in hexanes) at room temperature. The resulting mixture was stirred for 2 hours, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude product (18.0 g, 99%) that was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:16].O.O.[C:19](O)(=[O:23])[C:20](O)=[O:21]>Cl>[OH:21][C:20]1[C:19]([OH:23])=[N:16][C:3]2[CH:4]=[CH:5][C:6]3[C:7]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[N:1]=1
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=S(=O)(O)c1cccc2c1ccc1nc(O)c(O)nc12
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 0,5 g (2,1 mmol) 1,2-diaminonaphthalene-5-sulphonic acid and 0,75 g (5,8 mmol) oxalic acid dihydrate in 25 ml 4N hydrochloric acid was refluxed for 4 h. After cooling to 25° C., the precipitate was filtered off and washed with 5 ml 4N hydrochloric acid and 5 ml ice-cooled water. The crude product was dissolved in 15 ml 4N sodium hydroxide, and then reprecipitated with 4N hydrochlorid acid to give 0,35 g (57%) of 2,3-dihydroxy-benzo(f)quinoxaline-7-sulphonic acid.