Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[C:25]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][N:10]=1>>[CH3:22][CH:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:1][CH2:2][CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[N:14]=2)=[C:16]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([CH:33]3[CH2:34][CH2:35]3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:17]=1)[CH3:21]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using 2-aminoethyl-methyl-sulfone (396 mg, 3.22 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}cyclopropanesulfonamide (140 mg, 0.322 mmol) the title compound was obtained as a white solid (41 mg, 23% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.84 (s, 1H), 8.17 (d, J=4.0 Hz, 1H), 7.48 (br. s., 1H), 7.37 (s, 2H), 7.33 (s, 1H), 7.27 (d, J=7.5 Hz, 1H), 6.34 (d, J=3.5 Hz, 1H), 3.67 (d, J=5.5 Hz, 2H), 3.35-3.44 (m, 2H), 3.25-3.30 (m, 1H), 3.02 (s, 3H), 2.54-2.64 (m, 1H), 1.37 (d, J=6.8 Hz, 6H), 0.92 (d, J=6.2 Hz, 4H). MS (ESI): 522.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:9]=[C:13]=[O:14])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N)=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)N=C=O)cc1

Procedure:
To 4-methoxybenzamide (2.6 mmol) in dichloromethane (10 mL) was added oxalyl chloride 98% (6.61 mmol) dropwise. The mixture was heated to reflux for 20 h. Reaction completion monitored by TLC. The solvent was removed in vacuo (40° C., 760 mmHg) to obtain title compound D11, which was immediately used without purification.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH2:34]([N:38]([CH2:65][CH2:66][CH2:67][CH3:68])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[C:41]([O:47][Si:48]([C:61]([CH3:64])([CH3:63])[CH3:62])([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:40]=1)[CH2:35][CH2:36][CH3:37].O>O1CCCC1.C(OCC)(=O)C>[CH2:34]([N:38]([CH2:65][CH2:66][CH2:67][CH3:68])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[CH:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[C:41]([O:47][Si:48]([C:61]([CH3:62])([CH3:64])[CH3:63])([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:40]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 3 h
Yield: 62.9 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 3.17 g of phenyllithium (19% solution in dibutylether) (7.16 mmol), and 2.57 g (6.5 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under ice cooling. Next, 3.17 g (6.5 mmol) of 4-dibutylamino-2-tert-butyldiphenylsiloxybenzaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred for 3 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.32 g of a yellowish brown oily matter (yield: 62.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.C(N(CC)CC)C.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([NH:36][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:17]=3[Cl:24])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])(=[O:13])=[O:12])[CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)Cl
Reactant: NC1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)NC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a solution of 5-(2,6-Dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfonyl chloride (1.3 grams, 3.2 mmol) in methylene chloride (30 mL) at 0° C. was added triethylamine (0.58 mL, 4.1 mmol) followed by cyclobutylamine (0.27 mL, 3.2 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with 1N hydrochloric acid (25 mL) and extracted with methylene chloride (3 times 15 mL). The combined organic extracts were washed with 1N HCl (20 mL), saturated aqueous NaHCO3 (2 times 20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (30% ethyl acetate in hexane) to afford the title compound (531 mg). 1H NMR (400 MHz, CDCl3) δ8.28 (s, 2H), 7.28 (d, 1H), 7.07-7.04 (dd, 1H), 6.98 (d, 1H), 5.26 (d, 1H), 3.96 (s, 3H), 3.71-3.69 (m, 1H), 1.99-1.92 (m, 2H), 1.74-1.68 (m, 2H), 1.57-1.48 (m, 2H). MS (APCI−) Calc: 446.1, Found: 445.2 (M−1).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:42][CH2:43][O:44]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:34]=[CH:35][C:30]([C:28]2[O:29][C:25]([CH3:24])=[C:26]([CH2:42][CH2:43][O:44][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)([CH3:14])[C:4]([OH:23])=[O:3])=[CH:12][CH:11]=3)[N:27]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-(4-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 51, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 1, Part I) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-fluoro-phenoxy)-2-methyl-propionic acid 1H NMR (400 MHz, CDCl3) δ 8.04 (d, 2H, J=6.65 Hz), 7.68 (d, 2H, J=6.65 Hz), 7.64 (d, 2H, J=7.04 Hz), 7.48–7.38 (m, 3H, 7.19 (d, 2H, J=8.99 Hz), 6.94–6.82 (m, 6H), 4.22 (t, 2H, J=6.65 Hz), 3.23 (d, 1H, J=14.08 Hz), 3.12 (d, 1H, J=14.08 Hz), 3.05 (t, 2H, J=6.65 Hz) 2.42 (s, 3H), 1.37 (s, 3H); HRMS (ES+) m/z exact mass calcd for C34H31NO5F 552.2186, found 552.2202
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH2:19][OH:20])=[CH:13]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>ClCCl.[O-2].[Mn+4].[O-2]>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH:19]=[O:20])=[CH:13]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.9 %

Procedure:
Manganese (IV) oxide (3.2 g, 36 mmol) was added to [5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-methanol (0.7 g) in dichloromethane (150 mL). The mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and the filtrate was concentrated. The residue was recrystallized from ethyl acetate and hexane to give 0.18 g of 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH:23]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccnc(-c2cccc3c2oc2ccccc23)c1
Yield: 90.6 %

Procedure:
4-dibenzofuranboronic acid (5.0 g, 23.6 mmol), 2-chloro-4-methylpyridine (2.6 g, 20 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (0.36 g, 0.8 mmol), and potassium phosphate (11.4 g, 50 mmol) were mixed in 100 mL of toluene and 10 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, Pd2(dba)3 was added (0.18 g, 0.2 mmol) and the mixture was heated to reflux under nitrogen for 8 h. The mixture was cooled and the organic layer was separated. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with dichloromethane. 4.7 g of desired product was obtained after purification.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].S(Cl)(Cl)=O.[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21])[CH2:11][CH3:12]>>[C:20]([C:15]1[CH:16]=[C:17]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:18]=[CH:19][C:14]=1[O:13][CH2:10][CH2:11][CH3:12])(=[O:22])[CH3:21]
Reactant: CCCOc1ccccc1C(C)=O
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1C(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a mixture of chlorosulphonic acid (27 mL) and thionyl chloride (3.6 mL) at 0° C. was added portionwise 1-(2-propoxyphenyl)ethanone (5.0 g, 28.1 mmol). The resulting mixture was stirred at 0° C. for 20 min. and at room temperature overnight, poured cautiously into ice-water and extracted with methylene chloride. The organic solution was washed sequentially with water, aqueous sodium bicarbonate and brine, dried (MgSO4), and the solvent removed under reduced pressure to yield the title compound (6.3 g, 81%) as an off-white solid.
Reaction SMILES: ClC1C=C([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])C=CC=1C(O)=O.[Cl:22][C:23]1[CH:31]=[C:30](S(Cl)(=O)=O)[CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[Cl:22][C:23]1[CH:31]=[CH:30][C:29]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:12])=[O:13])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(C(=O)O)c(Cl)c2)C1
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)C1

Procedure:
In the same way, 2-chloro-4-(cis-3,5-dimethylpiperidinosulfonyl)-benzoic acid, m.p. 233°-234° C., is prepared from 2-chloro-4-chlorosulfonylbenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([F:20])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[N:24]=1.Cl.[OH-].[Na+]>O.C(O)C>[NH2:29][C:25]1[N:26]=[C:27]([NH:1][C:2]2[CH:19]=[C:18]([F:20])[C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:21])[CH:3]=2)[CH:28]=[CH:23][N:24]=1
Reactant: Nc1nccc(Cl)n1
Reactant: N#Cc1c[nH]c2nccc(Oc3c(F)cc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1c[nH]c2nccc(Oc3c(F)cc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
250 mg (0.65 mmol) of 4-(4-amino-2,6-difluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 92 mg (0.71 mmol) of 4-chloropyrimidine-2-amine are suspended in 10 ml of water and 5 ml of ethanol. 0.32 ml (1.29 mmol) of 4N hydrochloric acid is added, and the mixture is heated at reflux for 2 h. The mixture is made alkaline using concentrated aqueous sodium hydroxide solution, diluted with water and extracted with ethyl acetate. The organic phase is separated off and concentrated. The crude product is purified by preparative HPLC. This gives the title compound as crystals.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:35](=[O:45])[C@H:36]([CH2:40][S:41](Cl)(=[O:43])=[O:42])[CH:37]([CH3:39])[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:35](=[O:45])[C@H:36]([CH2:40][S:41]([N:19]1[CH2:20][CH2:21][N:16]([C:13]2[N:14]=[CH:15][C:10]([C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)=[CH:11][N:12]=2)[CH2:17][CH2:18]1)(=[O:43])=[O:42])[CH:37]([CH3:39])[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
5-(4-Fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride (0.57 g) was added to a solution of 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)-oxazolidin-2-one (0.77 g) in dichloromethane (20 ml) followed by triethylamine (0.84 ml), and the mixture stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, and the residue dissolved in ethyl acetate (40 ml) and washed with 10% citric acid (2×20 ml), water (20 ml), saturated sodium bicarbonate solution (20 ml), water (20 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated. The resultant residue was then purified by silica gel column chromatography with 3.5% diethyl ether/dichloromethane as eluent to provide the title compound as a white solid (0.70 g, 69%).
Reaction SMILES: C(N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)C(C)C.Br[C:20]1[S:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.Br[C:39]1[CH:45]=[CH:44][C:42](N)=[CH:41][CH:40]=1>>[N:37]1[CH:36]=[CH:35][N:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25]([C:23]3[S:24][C:20]([C:39]4[CH:45]=[CH:44][CH:42]=[CH:41][CH:40]=4)=[CH:21][CH:22]=3)=[O:26])=[CH:30][C:31]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)s1
Reactant: Nc1ccc(Br)cc1
Agent: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(-c2ccccc2)s1

Procedure:
The title compound was prepared as described in Example 51A, substituting 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.14 (t, J=6.0 Hz, 1H), 8.50 (dd, J=7.1, 0.7 Hz, 1H), 7.91-7.88 (m, 1H), 7.84 (d, J=3.9 Hz, 1H), 7.72 (dt, J=8.3, 2.4 Hz, 2H), 7.57 (d, J=3.9 Hz, 1H), 7.53 (d, J=1.2 Hz, 1H), 7.49-7.33 (m, 4H), 6.86 (dd, J=7.0, 1.7 Hz, 1H), 4.50 (d, J=5.8 Hz, 2H); MS (ESI(+)) m/e 334 (M+H).
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:14]>>[F:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:14]
Reactant: Cc1c(F)c(F)cc(C#N)c1F
Reactant: O=S(=O)(O)O
Product: Cc1c(F)c(F)cc(C(N)=O)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2,4,5-trifluoro-3-methylbenzonitrile (0.50 g) in concentrated sulfuric acid (0.3 ml) was stirred on an oil bath (90° to 100° C.) for 1 hour. After cooling, to the reacting mixture was added ice-water (5 ml), the resulting precipitate was collected by filtration, washed with water sufficiently and dried to give the title compound (0.52 g), mp 105°-108° C. This crystals were recrystallized from hexane to give colorless crystals, mp 112°-113° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:20]([OH:22])=[O:21]>CC(O)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:16][C:17]2[C:25](=[CH:24][CH:23]=[C:19]([C:20]([OH:22])=[O:21])[CH:18]=2)[N:26]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=C(C(=O)c1ccco1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nc(-c3ccco3)c(-c3ccccc3)nc2c1
Yield: 27.2 %

Procedure:
A solution of 1-(furan-2-yl)-2-phenylethane-1,2-dione (100 mg, 0.50 mmol, 1.00 equiv) and 3,4-diaminobenzoic acid (76 mg, 0.50 mmol, 1.00 equiv) in AcOH (3 mL) was stirred under reflux for 3 hrs in a 50-mL round-bottom flask. The resulting mixture was concentrated under vacuum, quenched with water. Solids were collected by filtration affording 43 mg (27%) of 2-(furan-2-yl)-3-phenylquinoxaline-6-carboxylic acid as a grey solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]=2)[N:5]=1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([CH:9]([C:8]2[C:4]([CH2:3][O:2][CH3:1])=[N:5][N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[N:12]=3)[CH:7]=2)[OH:10])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COCc1nn(-c2cccc(C(F)(F)F)n2)cc1C=O
Solvent: C1CCOC1
Product: COCc1nn(-c2cccc(C(F)(F)F)n2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution (100 mL) of 3-(methoxymethyl)-1-[6-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbaldehyde (5.3 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (25.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (4.6 g, 67%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16](O)=[O:17].C1(C(O)=O)C2C(=CC3C(C=2)=CC=CC=3)C=CC=1.C1(CO)C2C(=CC3C(C=2)=CC=CC=3)C=CC=1>C1COCC1>[Br:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:16][OH:17]
Reactant: O=C(O)c1cccc2c(Br)c3ccccc3cc12
Agent: O=C(O)c1cccc2cc3ccccc3cc12
Agent: OCc1cccc2cc3ccccc3cc12
Solvent: C1CCOC1
Product: OCc1cccc2c(Br)c3ccccc3cc12

Procedure:
10-Bromo-1-anthracenecarboxylic acid made from 1-anthracenecarboxylic acid (15B) by the procedure of E. Barnett, J. W. Cook, and H. H. Grainger, Ber. 57 B, 1775 (1924), was reduced with BH3 in THF by the procedure outlined in 15C to give (10-bromo-1-anthracenyl)methanol mp 125°-127°, (EtOAc/hexane), (C, H, Br).
Reaction SMILES: [C:1]1([S:7]([CH2:10][NH:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:29])=[C:18](C(OC(C)(C)C)=O)[C:19]=3[Cl:21])[NH:14][C:13]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([S:7]([CH2:10][NH:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:29])=[CH:18][C:19]=3[Cl:21])[NH:14][C:13]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)c(C(=O)OC(C)(C)C)c(Cl)c2c1NCS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
Dissolve 3-[(phenylsulfonyl)methylamino]-2-carbethoxy-4,6-dichloro-tert-butyloxycarbonyl-indole (400 mg, 0.758 mmol) in methylene chloride (15 mL). Add, by dropwise addition, trifluoroacetic acid (15 mL) and stir at room temperature for 3 hours. Evaporate the solvent in vacuo and treat the resulting residue with saturated sodium hydrogen carbonate. Extact into methylene chloride and dry (MgSO4). Recrystallize (ethyl acetate/hexane) to give the title compound (70 mg, 22%); mp 244°-45° C.
Reaction SMILES: [OH-].[Li+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][C:13]([O:15]C)=[O:14].CO>O.C1COCC1>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)Cc1cc2ccccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc2ccccc2[nH]1
Yield: 72.7 %

Procedure:
A solution of lithium hydroxide (346 mg, 8.25 mmol) in water (2 ml) was added to methyl indole-2-acetate (520 mg, 2.75 mmol) (prepared using the method of Capuano et al, Chem. Ber., 1986, 119, 2069) in THF (2 ml) and methanol (6 ml) and the mixture stirred for 1 h. The mixture was concentrated in vacuo, diluted with water (20 ml) and extracted with diethyl ether (2×10 ml). The aqueous layer was carefully acidified to pH 2 with 1M HCl and extracted into dichloromethane (3×20 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give indole-2-acetic acid (350 mg, 72%) as a pink solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Br[CH2:12][C:13]1[CH:32]=[CH:31][C:16]2/[C:17](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:18]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=3[O:20][CH2:21][C:15]=2[CH:14]=1>>[C:28](/[C:27](=[C:17]1/[C:18]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=2[O:20][CH2:21][C:15]2[CH:14]=[C:13]([CH2:12][CH:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7])[CH:32]=[CH:31][C:16]/1=2)/[CH3:30])#[N:29]
Reactant: COCC(=O)CC(=O)OC
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: COCC(=O)C(Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N)C(=O)OC
Yield: 82.7 %

Procedure:
[step 1] Using methyl 4-methoxy-3-oxobutanoate (816 mg, 5.58 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (1.0 g, 2.79 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 13G, step 1, (E)-methyl 2-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-4-methoxy-3-oxobutanoate (977 mg, 83%) was obtained.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].COCCOC[C:13]1[C:26]2[NH:27][N:28]=[C:24]3[C:25]=2[C:16]([C:17](=[O:29])[C:18]2[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:15]([OH:30])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][O:30][C:15]1[CH:14]=[CH:13][C:26]2[NH:27][N:28]=[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17](=[O:29])[C:16]=1[C:25]=23
Reactant: CC(C)CCBr
Reactant: COCCOCc1cc(O)c2c3c(n[nH]c13)-c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3
Temperature: 80 °C

Procedure:
Isopentyl bromide is added to a mixture of 3-(2-methoxyethoxymethyl)5-hydroxyanthra[1,9cd]pyrazol-6(2H)-one and potassium carbonate in dimethylformamide at room temperature. After stirring the mixture for sixteen hours, water is added, and the mixture was extracted with ethyl acetate (×2). The combined organic layer is washed with aqueous sodium bicarbonate, water, 1N hydrochloric acid, and brine, dried and evaporated. The reside is taken in 6N hydrochloric acid and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), and the combined organic layer is washed with brine, dried, and evaporated. The residue is purified by column chromatography to afford the title compound as yellow solid.