Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:31]2[CH:30]=[CH:29][O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[O:28]1[CH:29]=[CH:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:15]3[CH2:14][CH2:13][CH:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[CH:8]=4)[CH2:17][CH2:16]3)=[CH:24][CH:25]=[CH:26][C:27]1=2
Reactant: Fc1ccc2cc(C3CCNCC3)ccc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2ccoc2c1
Solvent: CO
Product: O[C@H](COc1cccc2occc12)CN1CCC(c2ccc3cc(F)ccc3c2)CC1
Yield: 36.5 %

Procedure:
A solution 4-(6-fluoronaphth-2-yl)piperidine (0.075 g, 0.327 mmol) and (S)-(+)-4-(oxiranylmethoxy)benzo[b]furan (0.062 g, 0.327 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient elution) to give the final title compound as a white amorphous solid (0.050 g, 37%). FDMS m/e=420 (M++1). [α]D=11.31 (c 0.531, methanol). C26H26FNO3.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:18][CH2:19][CH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(O)CCC>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: OCCCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Reaction time: 3 h

Procedure:
A mixture of 24.3 g. (0.1 mole) of 4-(p-fluorobenzoyl)-piperidine hydrochloride, 12.5 g. (0.125 mole) of 3-chloropropanol and 42.0 g. (0.5 mole) of sodium bicarbonate in 500 ml. of n-butanol was stirred at reflux for 15 hours. An additional 3.0 g. (0.025 mole) of 3-chloropropanol was added after thin layer chromatography showed incomplete reaction and the reaction was continued for 3 hours. The cooled reaction mixture was filtered, the filtrate concentrated at reduced pressure and the residual oil crystallized by trituration in isopropyl ether. The tan solid weighed 23 g. (87%) and melted at 107°-109° C. Recrystallization from benzene-isooctane gave 17.7 g. of material melting at 111°-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>N1C=CC=CC=1>[CH2:31]([O:30][C:28]([N:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[N:11]=[C:10]1[S:20][C:21]([F:26])([F:25])[CH:22]([F:23])[F:24])=[O:29])[CH3:32]
Reactant: Fc1ccc(-c2nc(SC(F)(F)C(F)F)[nH]c2-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)n1c(SC(F)(F)C(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 0 °C
Yield: 67.5 %

Procedure:
To an ice-cooled mixture of 4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylthio)imidazole (1.5 g) in pyridine (20 ml) was added ethyl chloroformate (1.3 g). The progress of the reaction was monitored by thin layer chromatography. Additional ethyl chloroformate (7.0 g, added in three portions) and warming to room temperature were required to force the reaction to completion. The reaction mixture was poured into water, and the crystalline solid was collected and washed with water. There was obtained 1.2 g of colorless product, mp 137°-139°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Sc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: COc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 89.7 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone (1.06 g, 2.9 mmol, 1.0 equiv) and thiourea (221.5 mg, 2.9 mmol, 1.0 equiv) in EtOH (20.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)thiazol-2-amine (890.9 mg, 2.6 mmol) as yellow solids in 90% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.40 (d, J=8.7 Hz, 2 H), 7.00 (d, J=8.7 Hz, 2 H), 6.86-6.87 (m, 4 H), 6.33 (s, 1 H), 3.78 (s, 3 H), 2.03 (s, 6 H); ESI-MS m/z 343.9 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([S:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[S:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]1([C:41]2[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:35]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:40]=[CH:39][C:38]([O:1][CH2:2][CH2:3][C:4]2[N:5]=[C:6]([S:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[S:7][CH:8]=2)=[CH:37][CH:36]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(Sc1nc(CCO)cs1)C(=O)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccccc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3 %

Procedure:
To a suspension of 2-{[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin (0.3 g) synthesized in Example 713-1 in tetrahydrofuran (3.0 mL) were added triphenylphosphine (0.12 g) and 4-phenylphenol (0.17 g), and the mixture was left standing for 15 min. Thereto was added diisopropyl azodicarboxylate (40% toluene solution, 0.26 ml), and the mixture was stirred at room temperature for 30 min. The resin was collected by filtration from the reaction mixture, and washed three times with tetrahydrofuran. This operation was repeated three times, and the obtained resin was washed three times each with dimethylformamide, tetrahydrofuran and methanol, and vacuum dried. To the resin was added trifluoroacetic acid, and the mixture was left standing at room temperature for 4 hr. The resin was filtered off and the filtrate was concentrated by blowing nitrogen gas thereto, and purified by HPLC to give the title compound (0.012 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>C(O)CC(C)C.CO>[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH3:20])[CH:8]=3)[N:3]=2)=[CH:29][CH:28]=1)(=[O:24])=[O:25]
Reactant: COc1ccc2nc(Cl)nc(Nc3ccccc3)c2c1
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Solvent: CO
Solvent: CC(C)CCO
Product: CNS(=O)(=O)Cc1ccc(Nc2nc(Nc3ccccc3)c3cc(OC)ccc3n2)cc1

Procedure:
A solution of 2-chloro-6-methoxy-4-phenylamino-quinazoline (1.15 g) and N-methyl-(4-aminophenyl)-methanesulfonamide (prepared as described in Tetrahedron Letters 1992, 33, 8011) (0.89 g) in 5 mL of isopentylalcohol is stirred under nitrogen at 180° C. for 20 min in a sealed vessel. The warm reaction mixture is diluted with methanol and the hydrochloride salt, which is crystallizing on cooling, is filtered off. The crude product is redissolved in ethylacetate and aqueous sodium carbonate solution and extracted with ethylacetate. The organic extracts are dried and evaporated and the solid residue is titurated with diethylether to give N-methyl-[4-(6-methoxy-4-phenylamino-quinazolin-2-ylamino)-phenyl]-methanesulfonamide as light yellow crystals melting at 212-215° C.; (Rf (A2) 0.16. Recrystallisation from methanolic hydrogen chloride and diethylether yields N-methyl-[4-(6-methoxy-4-phenylamino-quinazolin-2-ylamino)-phenyl]-methanesulfonamide hydrochloride as light yellow crystals melting at 264-268° C.; Rf (A2) 0.16, FAB-MS: (M+H)+ =450. Analytical data: C23H23N5O3S+HCl.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]#[CH:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>C(Cl)Cl>[C:1]([NH:8][C@H:9]([C:12]#[CH:13])[CH2:10][O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C#C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C#C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
To a solution of (R)-N-Boc-2-amino-but-3-yn-1-ol (150 mg, 0.81 mmol) (Example 104B) and imidazole (110 mg, 1.62 mmol) (Aldrich) in CH2Cl2 (10 mL) was added at 0° C. tert-butyldimethylsilyl chloride (146 mg, 0.97 mmol) (Fluka). After 5 min the reaction mixture was poured into H2O and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated to a residue which after silica gel column chromatography with a 0-30% Et2O in hexanes gradient afforded the product. (Yield 210 mg, 83%).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][NH2:13]>O>[CH3:12][NH:13][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CN
Solvent: O
Product: CNc1ccc([N+](=O)[O-])cc1N

Procedure:
12.5 g (0.079 mol) of 2-fluoro-5-nitroaniline and 100 ml methylamine (40% in water) are stirred for 48 hours at ambient temperature. The precipitated product is diluted with water, suction filtered, washed and dried.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](/[CH:25]=[C:26](/[C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])\[CH3:27])[CH:23]=2)[NH:18][CH:17]=1)[C:8]([O:10][CH3:11])=[O:9].[CH2:34](Br)[CH:35]=[CH2:36].Cl>CN(C)C=O.O>[CH2:36]([N:18]1[C:19]2[C:24](=[CH:23][C:22](/[CH:25]=[C:26](/[C:28](=[O:33])[NH:29][CH2:30][CH2:31][CH3:32])\[CH3:27])=[CH:21][CH:20]=2)[C:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=2[O:4][CH3:3])=[CH:17]1)[CH:35]=[CH2:34]
Reactant: C=CCBr
Reactant: CCCNC(=O)/C(C)=C/c1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C(\C)C(=O)NCCC)ccc21
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
Sodium hydride (0.048 g of a 60% dispersion in oil) was added to a stirred solution of methyl E-3-methoxy-4-[5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl]benzoate (0.5 g) in N,N-dimethylformamide (5 ml), under an atmosphere of nitrogen. After 0.5 hr, allyl bromide (0.14 g) was added and stirring continued for 3 hr. The solution was acidified with 1M hydrochloric acid (10 ml), diluted with water (20 ml), extracted with ethyl acetate (twice), and the organic phase was washed with water (4 times), brine, and dried (MgSO4). The solvent was evaporated to give an oil which was purified by flash chromatography, eluting with 2:1:1 hexane:methylene chloride:ethyl acetate, to give methyl E-4[1-allyl-5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl)-3-methoxybenzoate (0.36 g, 66%) as a white foam; partial NMR (250 MHz, DMSO-d6) 0.87(t, 3H, CH2CH2CH3), 1.47(m, 2 H, CH2CH2CH3), 1.99(s, 3H, CCH3), 3.11(m, 2H, CH2CH2CH3), 3.83(s, 3H, OCH3), 3.90(s, 3H, OCH3), 4.06(s, 2H, ArCH2Ar'), 4.77(br d, J=5.3 Hz, 2H, NCH2CH:C), 5.00-5.16(m, 2H, olefinic H), 6.0(m, 1H, olefinic H), 7.94(br t, 1H, NHCO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:9]1.C1C(=O)N([Br:32])C(=O)C1>>[Br:32][CH2:19][C:12]1[NH:11][C:10]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccccc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1Cl
Yield: 60 %

Procedure:
Ethyl 4-(2-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (10 g, 27.6 mmol) was reacted with NBS (5.41 g, 30.4 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (7.3 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH:42]1(N)CC[CH2:43]1.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:36]1([NH:35][CH2:34][CH2:33][N:31]2[CH:32]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]3)[CH:29]=[N:30]2)[CH2:37][CH2:43][CH2:42]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Reactant: NC1CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNC5CCC5)c4)cc23)CC1
Yield: 38 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting cyclobutanamine (31 mg, 0.43 mmol) for the 2-aminoethanol to afford 10 mg of the title compound (38%).
Reaction SMILES: [CH3:1][N:2]([CH3:57])[C:3]1[S:4][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C@H:17]([CH2:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][C:33]=3[O:34][CH3:35])[C:30]([NH:36]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:29][CH:28]=[CH:27]4)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]2=[O:56])(=[O:10])=[O:9])=[CH:6][N:7]=1.[Cl:58]CCl>O1CCOCC1.Cl>[ClH:58].[CH2:21]([O:20][C:18](=[O:19])[C@H:17]([N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][S:8]([C:5]2[S:4][C:3]([N:2]([CH3:1])[CH3:57])=[N:7][CH:6]=2)(=[O:9])=[O:10])[C:13]1=[O:56])[CH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[C:30]([NH2:36])=[N:29][CH:28]=[CH:27]2)[CH3:22]
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H](Cc1cc2ccnc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1OC)N1CC[C@H](NS(=O)(=O)c2cnc(N(C)C)s2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC)N1CC[C@H](NS(=O)(=O)c2cnc(N(C)C)s2)C1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The ethyl (2R)-2-[(3S)-3-(2-(dimethylamino)thiazol-5-ylsulphonylamino)-2-oxopyrrolidin-1-yl]-3-(7-methoxy-1-(tritylamino)isoquinolin-6-yl)propanoate obtained above (0.35 g, 0.44 mmol) is dissolved in 5 ml of dichloromethane. The medium is cooled to 0° C. and 0.5 ml of a 4N solution of hydrochloric acid in dioxane is added. The medium is stirred at 20° C. for 18 h. It is concentrated to dryness and the residue is triturated from ether and filtered off. It is purified on a column of silica (40 g, gradient CH2Cl2/MeOH/NH4OH; 100:0 to 90:10:0.5). The product thus obtained is dissolved in 5 ml of dichloromethane and salified with 0.5 ml of a 4N solution of hydrochloric acid in dioxane. The medium is concentrated and the residue is triturated from ether and dried over P2O5. 230 mg of a solid are obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[I:15]Cl>C(O)(=O)C>[I:15][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[OH:1]
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: ClI
Solvent: CC(=O)O
Product: O=C(O)c1cc2ccccc2c(I)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
3-Hydroxynaphthalene-2-carboxylic acid (0.5 g, 2.7 mmol) was suspended in acetic acid (5 mL) and with stirring iodine monochloride (135 μL, 2.7 mml) was added. The suspension was stirred at room temperature for 1 hour, filtered and washed with water. Drying afforded 0.72 g (85%) of 4-iodo-3-hydroxynaphthalene-2-carboxylic acid as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][C:31]=1[F:38])[CH:27]=[CH2:28]>CN(C=O)C.CCOC(C)=O>[CH2:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:11]([C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:32][C:31]=1[F:38])[CH:27]=[CH2:28]
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reactant: C=CCOc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.5 %

Procedure:
To a solution of (2R)-2-(4-chlorobenzenesulfonylamino)-4-methyl-pentanoic acid amide (1.00 g, 3.29 mmol), and Cs2CO3 (1.29 g, 3.95 mmol) in DMF (25 mL) was added 1-allyloxy-4-bromomethyl-2-fluorobenzene (ref.: Graham, S. L. et al., EP Patent Application No. EP 487270 (1992): 0.88 g, 3.67 mmol). The resulting solution was stirred at rt for 18 h. The reaction was then diluted with 9:1 EtOAc:hexanes (350 mL) and washed with H2O (4×200 mL), brine, and dried over Na2SO4, to afford the titled compound (393 mg) as a white solid in 26% yield. MS (ESI), (M+H)+469.1; 1H NMR (CDCl3) δ 7.66 (d, 2H, J=8.1), 7.45 (d, 2H, J=8.1), 7.11 (d, 1H, J=12.0), 6.98 (m, 1H), 6.84 (t, 1H, J=8.0), 6.22 (br s, 1H), 6.04 (m, 2H), 5.42 (m, 1H), 5.16 (br s, 1H), 4.59 (m, 2H), 4.40 (m, 3H), 1.83 (m, 1H), 1.32 (m, 1H), 1.14 (m, 1H), 0.76 (d, 3H, J=7.0), 0.68 (d, 3H, J=7.0).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:12]=[CH:11]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1Br
Solvent: C1CCOC1
Product: Brc1nccc2cc[nH]c12

Procedure:
The route shown in Scheme 1 below exemplifies synthesis of certain 7-aryl(heteroaryl) and 7-anilino-6-azaindole-1-sulfonamide compounds of the present invention. 2-Bromo-3-nitropyridine (1) reacts with vinylmagnesium bromide in THF, at −40-50° C. to afford 7-Bromo-6-azaindole (2), which reacts with 4-methoxyphenylsulfonyl chloride to provide 7-bromo-1-(4-methoxyphenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (3). The sulfonamide (3), is then either treated with a substituted or unsubstituted phenylboronic acid, Pd(PPh3)4, and K2CO3 in toluene/EtOH to afford final compound (4) or treated with a substituted or unsubstituted aniline in pyridine to yield final compound (5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([C:19]#[CH:20])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Cc1cc(Br)ccn1
Reactant: C#Cc1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Product: CCN1c2ncc(/C=C/c3ccnc(C)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 83.8 %

Procedure:
By a procedure analogous to that described in Example 51b, 48 mg (0.15 mmol) of 2-chloro-5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one coupled with 4-bromo-2-picoline (31 mg, 0.15 mmol) to provide 51 mg (83%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1.OS(O)(=O)=O>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)=[CH:13][CH:12]=2)[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccncc1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C2=NNC(=O)CC2)cc1)c1ccncc1

Procedure:
A solution containing 0.36 g (0.003 mol) of 4-acetylpyridine and 0.57 g (0.003 mol) of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one in a mixture of 40 ml of toluene and 40 ml of DMT was refluxed over night with a Dean-Stark separator in the presence of catalytic amount of conc. H2SO4. The solvents were evaporated in vacuo and the residue treated with NaHCO3 -solution. The product was filtered and crystallized from ethanol. Yield 0.53 g (60%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[NH2:29][CH:30]1[CH2:36][CH:35]2[N:37]([C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]([C:48]#[N:49])=[CH:40][CH:39]=3)[CH:32]([CH2:33][CH2:34]2)[CH2:31]1>CN(C=O)C>[C:48]([C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]([N:37]2[CH:35]3[CH2:34][CH2:33][CH:32]2[CH2:31][CH:30]([NH:29][C:8](=[O:10])[CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:36]3)=[CH:39][CH:40]=1)#[N:49]
Reactant: CCOCCOCC(=O)O
Reactant: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCCOCC(=O)NC1CC2CCC(C1)N2c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
165RL54 (19 mg, 0.13 mmol), O-benzotriazol-1-yl-N,N,N,N-tetramethyluronium tetrafluorophosphate (HBTU, 49 mg, 0.13 mmol), 1-hydroxybenzotriazole (18 mg, 0.13 mmol) and triethylamine (37 PL, 0.26 mmol) were dissolved in DMF (4 mL). 165RL21 (36 mg, 0.13 mmol)) was added and the mixture was shaken at rt for 30 min. The solvent was removed in vacuo and the product was purified by flash chromatography on silica gel using ethyl acetate/methanol (9:1) as eluent, giving the desired compound (38.1 mg, 72%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[CH3:9][CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])[N:4]=1)[CH3:10]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 60-63° C.; 1H NMR (300 MHz, CDCl3) δ7.28-7.21 (m, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.06-6.98 (m, 2H), 6.92 (s, 1H), 6.50 (s, 1H), 6.26 (s, 1H), 5.15 (d, J=16.2 Hz, 1H), 4.95 (d, J=16.2 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H), 3.37-3.22 (m, 1H), 1.39 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 178.5, 177.2, 155.2, 150.2, 144.6, 142.1, 138.3, 132.2, 128.8, 123.7, 123.4, 121.1, 114.1, 111.6, 109.7, 99.4, 80.1, 64.5, 63.9, 58.1, 40.6, 33.3, 23.1; MS (ES+) m/z 434.9 (M+1).