Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:15][C:16]2[CH:28]=[CH:27][C:19]([CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl>CO.C(Cl)Cl.[Ni](Cl)Cl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:15][C:16]2[CH:28]=[CH:27][C:19]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C=Cc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nickel chloride (20 mg) was suspended in 1 ml of methanol and 9 ml of methylene chloride, followed by gradual addition of 120 mg of sodium borohydride at 0° C. At the same temperature, ethyl 4-[2-(4-chlorobenzenesulfonamido)-2(3-pyridyl)ethyl]cinnamate dissolved in 0.5 ml of methanol and 4.5 ml of methylene chloride was added and stirred at room temperature for eight hours. To the reaction mixture was added dropwise 2N hydrogen chloride at 0° C., until the mixture became acidic. The organic phase was separated and extracted with methanol-methylene chloride (5:95 v/v). The organic phases were combined and washed in saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column which was eluted with methanol-methylene chloride (5:95 v/v) for purification, followed by recrystallization in methylene chloride-hexane, to produce 70 mg of ethyl 3-(4-[2-(4-chlorobenzenesulfonamido)-2(3-pyridyl)ethyl]phenyl}propionate. The spectrometric data thereof supports the structure of [24] as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[N:7]([CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]1)=[O:21])[CH2:6][CH2:5]2.[CH2:32]([O:36]C=C)[CH2:33]CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:32]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[N:7]([CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]1)=[O:21])[CH2:6][CH2:5]2)(=[O:36])[CH3:33]
Reactant: C=COCCCC
Reactant: O=C(CN1CCc2cc(Br)ccc2C1c1ccccc1Cl)N1CCN(C2CCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2c1ccccc1Cl
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To a solution of 2-[6-bromo-1-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-1-(4-cyclobutyl-piperazin-1-yl)-ethanone (310 mg, 0.62 mmol) in dry DMF (5.0 ml) is added n-butylvinyl ether (310 mg, 3.98 mmol, 5.0 eq.), TEA (75 mg, 0.74 mmol, 1.2 eq.), 1,3-bis(diphenylphosphino)propane (7 mg, 0.0017 mmol, 0.0276 eq.), and palladium acetate (3.5 mg, 0.015 mmol, 0.025 eq.) under nitrogen. The resulting mixture is stirred at 80° C. for 7 hr. Water (20 ml) is added to quench the reaction, and the mixture is extracted with EtOAc (10 ml×3). The combined organic phase is washed with water, and treated with concentrated HCl (1.0 ml). The mixture is stirred at rt for 2 hr, and then basified with saturated sodium carbonate solution. The organic phase is collected, and the aqueous phase is extracted with EtOAc (10 ml×2). The combined organic phase is dried over sodium sulfate, and concentrated. The residue is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.74 (1H, s), 7.59 (1H, dd), 7.41 (1H, dd), 7.10˜7.25 (3H, m), 6.72 (1H, d), 5.22 (1H, s), 3.81 (1H, m), 3.04˜3.52 (7H, m), 2.78˜2.98 (2H, m), 2.67 (1H, m), 2.55 (3H, s), 2.41 (1H, m), 2.27 (1H, m), 1.96˜2.14 (4H), 1.60˜1.92 (4H); MS (+VE) m/z 466.00 (M+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[S:11][C:10]([C:16]#[N:17])=[N:9][C:8]=1[CH:7]=[CH:6]2>Cl.N1C=CC=CC=1.Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[S:11][C:10]([C:16]#[N:17])=[N:9][C:8]=1[CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccc3nc(C#N)sc32)c1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1nc2ccc3cc(O)ccc3c2s1

Procedure:
7-Methoxynaphtho[2,1-d]thiazole-2-carbonitrile (88 mg, 0.366 mmol) was suspended in 3 g of pyridine hydrochloride salt and sealed in a 5-mL microwave vial containing a stir bar. The mixture was irradiated at 220° C. for 25 minutes (min), then taken up in 1 N HCl and extracted three times with a mixture of DCM and EtOAc. The concentrated residue was purified by silica gel chromatography. 1H NMR (CD2Cl2) d 8.10 (d, 1H); 8.03 (d, 1H); 7.88 (d, 1H); 7.39 (d, 1H); 7.31 (dd, 1H);
Reaction SMILES: [CH:1]1([O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[N:21]=[CH:22][S:23][C:24]=1C=C>C1(C)C=CC=CC=1>[CH:1]1([O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:24]2[S:23][CH:22]=[N:21][C:20]=2[CH3:19])[C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCCCCC(OC1CCCCC1)C(=O)OC
Reactant: C=Cc1scnc1C
Solvent: Cc1ccccc1
Product: COC(=O)C(CCCC/C=C/c1scnc1C)OC1CCCCC1
Temperature: 100 °C

Procedure:
A mixture of methyl 2-hydroxyoct-7-enoate (6.88 g, 0.040 mmol), dichloromethane (40 mL), 3,4-dihydro-2H-pyran (7.4 mL, 0.082 mol), and 6 drops of trifluoroacetic acid was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo to yield methyl 2-(cyclohexyloxy)oct-7-enoate, which was used in the next step without further purification. A solution of methyl 2-(cyclohexyloxy)oct-7-enoate (500.0 mg, 1.95 mmol) dissolved in toluene (33 mL) containing 4-methyl-5-vinylthiazole (1.11 mL, 19.5 mmol) and Grubb's 2nd generation catalyst (166 mg, 0.195 mmol) was flushed with argon and heated in a sealed tube at 100° C. for 20 h. After cooling to room temperature, the solvent was removed in vacuo and the resulting residue was purified via flash silica gel chromatography (Analogix IF-280, SF25-115 g column, gradient 90:10-80:20 Heptane:EtOAc) to yield (E)-methyl 2-(cyclohexyloxy)-8-(4-methylthiazol-5-yl)oct-7-enoate. MS (ES+) 354 (M+1).
Reaction SMILES: C([NH:5][C:6](=[O:27])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])=[CH:11][C:10]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[N:9][CH:8]=1)(C)(C)C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:7]([C:6]([NH2:5])=[O:27])=[CH:8][N:9]=[C:10]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)[CH:11]=2)=[C:14]([CH3:20])[CH:15]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1C(=O)NC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1C(N)=O
Temperature: 95 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
9.7 g (25 mmol) N-tert-Butyl-4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide suspended in 48.5 ml toluene was heated to 95° C. and 24.0 g methanesulfonic acid was added dropwise giving an emulsion, which was stirred at 100° C. for two hours. After cooling to room temperature, the phases were separated and the organic phase was washed with deionized water. The combined aqueous phases were cooled to 0° C. and 28% aqueous sodium hydroxide was slowly added to increase the pH to ca. 12.5. The suspension obtained was extracted with dichloromethane. The combined organic extracts were dried and concentrated in a rotary evaporator. 100 ml Propyl acetate was added and the solution was concentrated in a rotary evaporator. A second portion of 100 ml propyl acetate was added and the solution was concentrated to ca. 23 g, forming a suspension to which 8.3 ml n-hexane was added. The suspension was stirred at 0° C. for one hour. The precipitate was filtered off, washed with n-hexane/propyl acetate 9:1 and dried in a vacuum oven to yield 8.0 g (97 %) 4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide as a light yellow powder of m.p.=198–202° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]([S:13]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:25]=2[NH:24][CH:23]=[CH:22]3)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].Cl.CN(C)[CH:31]=[O:32]>O>[Cl:6][C:7]1[CH:8]=[C:9]([S:13]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:25]=2[NH:24][CH:23]=[C:22]3[CH:31]=[O:32])(=[O:14])=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(Nc1cccc2cc[nH]c12)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(NS(=O)(=O)c3cccc(Cl)c3)cccc12

Procedure:
1.3 ml (13.9 mmol) of phosphorous oxychloride was added dropwise to 14.5 ml of dimethylformamide at 10° C. or less under stirring in nitrogen atmosphere. After stirring at about 5° C. for 30 minutes, 2.50 g (8.15 mmol) of 3-chloro-N-(1H-indole-7-yl)benzenesulfonamide synthesized in the same manner as in Example 1 was added thereto in three portions. After stirring at about 5° C. for further 30 minutes, 200 ml of cooled water was added thereto. The reaction mixture was adjusted to pH about 14 by adding a 1N aqueous sodium hydroxide and then to pH about 2 by adding 1N hydrochloric acid, and then extracted by adding ethyl acetate thereto. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, to give 1.45 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12]([Cl:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OCc2ccccc2)cc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(OCc2ccccc2)cc(C(=O)Cl)c1
Reaction time: 0.5 h

Procedure:
3-(Benzyloxy)-5-methoxybenzoic acid (162) (2.57 g, 0.01 mmol) and thionyl chloride (4.80 g, 0.04 mmol) were suspended in 200 mL of dry toluene. The reaction mixture was stirred for 30 min and then dimethyl formamide (3 drops) was added. The mixture was stirred for 24 h and then evaporated to dryness. The residue was directly used for the next step without further purification.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([NH+:8]1[C:12]2=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:20]=[C:11]2[N:10]2[CH2:21][CH2:22][CH:23]([CH3:31])[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:9]12)[CH3:7]>CS(C)=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([NH+:8]1[C:12]2=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:20]=[C:11]2[N:10]2[CH2:21][CH:22]=[C:23]([CH3:31])[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:9]12)[CH3:7]
Reactant: CC[NH+]1C2=C(c3ccccc3)C(C)CCN2c2nc3ccccc3nc21
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CC[NH+]1C2=C(c3ccccc3)C(C)=CCN2c2nc3ccccc3nc21
Yield: 80 %

Procedure:
5-Ethyl-1,2-dihydro-3-methyl-4-phenyl-5H-pyrido[1',2':1,2]-imidazo[4,5-b]quinoxalinium perchlorate (3.1 g.) in 40 ml. of dimethyl sulfoxide is heated on a hot plate for 10 minutes. The dimethyl sulfoxide solution is poured into an excess of diethyl either and a green oil separates. The oil is crystallized from a chloroform-ether solution. Recrystallization from chloroform-ether affords 80% yield of product having a melting point of 262°-264° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C)C=O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:19][CH:18]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(F)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 40.4 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-fluoro-benzyl bromide (60 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(4-fluoro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (61 mg, 41%) as a white solid. APCI-MS (M+H) 315.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].F[P-](F)(F)(F)(F)F.[Cl:15]/[C:16](=[CH:21]\N(C)C)/[CH:17]=[N+](C)C.C(N(CC)CC)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[N:4][C:3]([C:2]([F:7])([F:6])[F:1])=[N:5][CH:21]=1
Reactant: CN(C)/C=C(\Cl)C=[N+](C)C
Reactant: N=C(N)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 38 mmol trifluoroacetamidine in 70 ml acetonitrile was added 37.92 mmol ((Z)-2-Chloro-3-dimethylamino-allylidene)-dimethyl-ammonium hexafluoro phosphate (CAS: 291756-76-8) followed by 45.5 mmol triethylamine. The yellow solution was stirred at room temperature for 5 hours, then poured onto water and extracted 3 times with ether. The combined extracts were dried over sodium sulfate, filtered and distilled at 760 mm Hg to provide the title compound. MS (m/e): 182.2 (M+, 100%)
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[N:23]([C@@H:26]1[CH2:31][C@H:30]([OH:32])[C@@H:29]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[O:28][CH2:27]1)=[N+:24]=[N-:25].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[N:23]([C@H:26]1[CH2:27][O:28][C@H:29]([CH2:33][O:34][Si:35]([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36])[C:30](=[O:32])[CH2:31]1)=[N+:24]=[N-:25]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@H](N=[N+]=[N-])C[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@H](N=[N+]=[N-])CC1=O
Reaction time: 1.25 h
Yield: 76.2 %

Procedure:
A Dess-Martin reagent (876 mg, 2.00 mmol) was added to a dichloromethane (10 ml) solution of 1,5-anhydro-2-azido-6-O-[tert-butyl(dimethyl)silyl]-2,3-dideoxy-D-ribo-hexitol (450 mg, 1.25 mmol) under ice cooling and the resulting mixture was stirred for 75 minutes. Aqueous sodium thiosulfate solution was added under ice cooling, then the resulting mixture was subjected to extraction with ether and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=50:1→20:1 (v/v)] to give 272 mg (76%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:22]1([N:28]=[C:29]=S)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:29]([NH:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: S=C=Nc1ccccc1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(Nc4ccccc4)o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add phenyl isothiocyanate (97 uL, 0.512 mmol) and stir for 3.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling to room temp dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and suspend the resulting residue in 1 N NaOH (5 mL). Collect the solid and wash with water. Take the solid up in boiling toluene/EtOAc. Allow to cool. Collect the solid, wash with Et2O, and dry in a vac-oven to afford the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.03 (t, J=7.39 Hz, 1H) 7.39 (t, J=7.96 Hz, 2H) 7.63-7.69 (m, 3H) 7.71 (d, J=1.26 Hz, 1H) 7.73 (t, J=1.89 Hz, 1H) 7.77 (tautomer A, d, J=8.59 Hz, 1H) 7.83 (tautomer B. dd, J=8.46, 1.52 Hz, 1H) 7.91 (dd, J=8.46, 1.52 Hz, 1H) 8.05 (tautomer B. d, J=1.01 Hz, 1H) 8.17 (tautomer A, s, 1H) 10.68 (s, 1H) 13.30 (d, J=4.17 Hz, 1H); MS (m/z)=422.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH2:34][CH2:35][CH:36]([OH:42])[CH2:37][NH:38][CH:39]1[CH2:41][CH2:40]1>>[CH:39]1([NH:38][CH2:37][CH:36]([OH:42])[CH2:35][NH:34][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:41][CH2:40]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NCC(O)CNC1CC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC(O)CNC1CC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 1-amino-3-cyclopropylamino-propan-2-ol to give the titled compound as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[Cl:24][C:16]1[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([Cl:13])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:28]([C:11](=[O:12])[NH:10][CH2:8][CH3:9])[N:27]=1
Reactant: COC(=O)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.5 %

Procedure:
Triethylamine (0.20 g, 2.0 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of methyl 3-(2,6-dichloro-4-trifluoromethylphenyloxy)pyrazole-5-carboxylate (0.53 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (chloroform), to give a white solid of methyl 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-1 (N-ethylcarbamoyl)pyrazole-5-carboxylate (0.15 g, yield: 23.5%). mp: 88-90° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (t, J=7.3 Hz, 3H), 3.37 (dq, J=6.0 and 7.3 Hz, 2H), 3.95 (s, 3H), 6.21 (s, 1H), 6.40-6.60 (m, 1H), 7.68 (d, J=0.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[OH:8].N.OO.Cl.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[OH:22]>O>[NH2:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:21][C:19]2[CH:18]=[CH:17][C:16]([OH:22])=[C:15]([Cl:14])[CH:20]=2)[C:4](=[O:9])[CH:3]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Nc1cc(O)ccc1O
Agent: Cl
Agent: N
Agent: OO
Solvent: O
Product: NC1=CC(=O)C(Nc2ccc(O)c(Cl)c2)=CC1=O
Reaction time: 5 h

Procedure:
0.02 mole (2.78 g) of 3-amino-4-hydroxy phenol is dissolved in 200 cc of water to which have been added 20 cc of ammonia (22° Be). To this solution there are initially added 100 cc of H2O2 (20 volumes) and the immediately thereafter, with good agitation, 0.02 mole (3.60 g) of 2-chloro-4-amino phenol hydrochloride in 200 cc of water. The reaction mixture is left to stand for 5 hours at ambient temperature at which time it is filtered to recover the 2-amino-5-(3'-chloro-4'-hydroxyanilino)-1,4-benzoquinone which is then washed with water, recrystallized in a mixture of dimethylformamide and water and dried for 5 hours under a vacuum with a boiling water bath. The product is chromatographically pure.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[C:17]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]2)=[O:26])=[CH:16][C:15]=1[Cl:38].[O-2].[Ca+2]>ClCCl.CO>[NH2:13][C:14]1[C:19]2[CH2:20][C:21]([CH3:23])([CH3:24])[O:22][C:18]=2[C:17]([C:25]([NH:27][CH:28]2[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][NH:37][C:2]3[N:11]=[C:10]([OH:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)[CH2:32][CH2:33]2)=[O:26])=[CH:16][C:15]=1[Cl:38]
Reactant: Oc1nc(Cl)nc2ccccc12
Reactant: CC1(C)Cc2c(N)c(Cl)cc(C(=O)NC3CCN(CCCN)CC3)c2O1
Agent: [Ca+2]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)Cc2c(N)c(Cl)cc(C(=O)NC3CCN(CCCNc4nc(O)c5ccccc5n4)CC3)c2O1
Temperature: 140 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
A mixture of 4.15 g of 2-chloro-4-hydroxyquinazoline, 4.57 g of 4-amino-N-[1-(3-aminopropyl)-4-piperidinyl]-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamide (described in EP-0,445,862) and 0.80 g of calcium oxide was stirred for 1 hour at 140° C. The reaction mixture was dissolved in a mixture of dichloromethane and methanol. The whole was washed with water, dried, filtered and evaporated. The residue was purified twice by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 90:10; CH2Cl2 /CH3OH(NH3) 88:12). The eluent of the desired fraction was evaporated and the residue was boiled in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 g (50.8%) of 4-amino-5-chloro-2,3-dihydro-N-[1-[3-[(4-hydroxy-2-quinazolinyl)amino]propyl]-4-piperidinyl]-2,2-dimethyl-7-benzofurancarboxamide; mp. 159.6° C. (comp. 12).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:15]=1)(=[O:8])[O:5]CC)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][O:12][CH2:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[N:15][C:16]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=1)[CH3:27]
Reactant: CCOP(=O)(CCCOCc1ccc(-c2ccc(CC)cc2)c(-c2ccccc2)n1)OCC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(COCCCP(=O)(O)O)nc2-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of crude {3-[5-(4-ethyl-phenyl)-6-phenyl-pyridin-2-ylmethoxy]-propyl}-phosphonic acid diethyl ester (18 mg, 0.039 mmol) in CHCl3 (2 ml) at room temperature was added TMSI (77 mg, 0.39 mmol) dropwise. After the mixture was stirred for 1 hour, the solvent was removed in vacuo to recover a yellow oily residue. The residue was taken-up in THF/H2O (4:1) and stirred at room temperature overnight. The mixture was extracted with ethyl acetate. The combined organic layers were washed with NaHSO3, and water, and brine, and dried over Na2SO4. The filtered solvents were concentrated in vacuo and the residue was purified by MPLC on silica gel (0-100% MeOH in ethyl acetate) to give the title compound as a white solid.