Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8]1.[NH2:23][C:24]1[C:25]([C:31]([OH:33])=O)=[N:26][C:27](Br)=[CH:28][CH:29]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[NH2:23][C:24]1[C:25]([C:31]([NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:22])[C:6]=2[N:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([CH2:13][NH2:14])[CH2:8]2)=[O:33])=[N:26][C:27]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[F:34])=[CH:28][CH:29]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cn1ncc(N)c1N1CCC[C@H](CNC(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)ccc2N)c1N1CCC[C@H](CN)C1
Yield: 18 %

Procedure:
Following the procedures for Example 141, (R)-tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate, 3-amino-6-bromopicolinic acid were coupled and the intermediate amide was reacted with 2-fluorophenylboronic acid under palladium catalyzed Suzuki conditions to give 129 as a white solid (33 mg, 18%) over three steps. 1H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 8.03 (dt, J=9.6, 4.8, 1H), 7.81-7.60 (m, 2H), 7.49-7.20 (m, 4H), 7.07 (s, 2H), 3.67 (s, 3H), 3.30-3.20 (m, 2H), 3.15-2.96 (m, 3H), 2.73 (dd, J=25.7, 14.9, 1H), 1.92-1.44 (m, 4H), 1.03 (dd, J=21.1, 10.1, 1H). ESIMS m/z=424.1 (M+1)
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)(=O)C>>[CH2:4]1[CH2:3][CH2:2][C:1]2([CH2:7][C:8](=[O:10])[O:14][C:12](=[O:13])[CH2:11]2)[CH2:6][CH2:5]1
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2(CCCCC2)CC(=O)O1
Temperature: 25 °C

Procedure:
To a 100-mL round-bottomed flask was added 1,1-cyclohexanediacetic acid (2.03 g, 9.99 mmol) and acetic anhydride (11.6 mL). The reaction mixture was held at reflux for 2 hours, and then cooled to room temperature. Volatiles were removed via vacuum distillation (0.1 Torr, 20°-60° C.). The resulting crude product was dried under vacuum (0.1 Torr) at 80° C. for 14 hours to yield the title compound as a white solid which was used without further purification (1.75 g, 96%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](CC3C=CC(OC)=CC=3)[N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.IC1C=CN=C2NN=C(C(C)C)C=12.COC1C=CC(CCl)=CC=1.Cl.[CH3:47][N:48]1[CH:52]=[C:51]([C:53]2[N:54]=[CH:55][NH:56][CH:57]=2)[CH:50]=[N:49]1>>[CH:11]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[N:56]2[CH:57]=[C:53]([C:51]3[CH:50]=[N:49][N:48]([CH3:47])[CH:52]=3)[N:54]=[CH:55]2)[NH:8][N:9]=1)([CH3:12])[CH3:13]
Reactant: COc1ccc(Cn2nc(C(C)C)c3c(I)ccnc32)cc1
Reactant: Cn1cc(-c2c[nH]cn2)cn1
Agent: CC(C)c1n[nH]c2nccc(I)c12
Agent: COc1ccc(CCl)cc1
Agent: Cl
Product: CC(C)c1n[nH]c2nccc(-n3cnc(-c4cnn(C)c4)c3)c12
Yield: 63 %

Procedure:
According to Example 97(1), 4-iodo-3-isopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine was prepared using compound (100a) (15.5 g) instead of compound (40d) and using 4-methoxybenzyl chloride instead of {2-(chloromethoxy)ethyl}silane and was used in the subsequent reaction without being purified. According to Example 97(2), 3-isopropyl-1-(4-methoxybenzyl)-4-{4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl}-1H-pyrazolo[3,4-b]pyridine was prepared using 4-iodo-3-isopropyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole and was used in the subsequent reaction without being purified. This 3-isopropyl-1-(4-methoxybenzyl)-4-{4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl}-1H-pyrazolo[3,4-b]pyridine was dissolved in trifluoroacetic acid (60 mL) and anisole (19 mL), followed by reflux for 5 hr. The reaction solution was concentrated and then diluted with acetonitrile, and saturated sodium bicarbonate water was added thereto. The precipitate was collected by filtration and was dried under reduced pressure to obtain compound (100b) (12.3 g, the third stage yield: 63%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[Cl:42][C:43]1[CH:47]=[CH:46][NH:45][N:44]=1>>[C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:45]3[CH:46]=[CH:47][C:43]([Cl:42])=[N:44]3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:22])[F:23])=[N:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Reactant: Clc1cc[nH]n1
Product: Cc1c(Cc2ccc(-n3ccc(Cl)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 18a using {8-chloro-2-difluoromethoxy-4-methyl-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid tert-butyl ester and 3-chloro-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][CH2:23][C:24]1[C:25]([CH3:32])=[C:26]([CH:30]=O)[NH:27][C:28]=1[CH3:29]>>[CH3:33][N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][C:24]1[C:25]([CH3:32])=[C:26]([CH:30]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:27][C:28]=1[CH3:29]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(CCCN(C)C)c1C
Yield: 77.5 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (239 mg, 1.0 mmol)was condensed with 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 333 mg (83%) of 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-(2-methoxyphenyl)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:39][CH3:40])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](O)=[O:27])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:39][CH3:40])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](=[O:27])[NH:65][S:62]([CH:59]4[CH2:61][CH2:60]4)(=[O:64])=[O:63])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Reactant: NS(=O)(=O)C1CC1
Agent: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-methoxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (50 mg, 0.079 mmol) and CDI (755 mg, 4.66 mmol) in tetrahydrofuran (5 mL) was heated at reflux for 1 h. It was then cooled to rt, and then cyclopropanesulfonamide (11.51 mg, 0.095 mmol) was added, followed by DBU (0.042 mL, 0.277 mmol). This reaction mixture was stirred at rt for 18 h, and then concentrated in vacuo to give the crude product as a light colored oil. Purification by preparative HPLC gave 15 mg (26%) of tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-14a-(cyclopropylsulfonylcarbamoyl)-2-methoxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>>[Br-:1].[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:8][CH:9]=1
Reactant: BrCCCCCc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccncc1
Product: Cc1cc[n+](CCCCCc2ccc(-c3ccccc3)cc2)cc1
Product: [Br-]
Temperature: 65 °C
Yield: 86 %

Procedure:
A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (348 mg, 1.15 mmol) and 4-picoline (1 mL) was heated at 60-70° C. for 12 hrs. The resulted mixture was washed with diethyl ether and then dissolved in water (15 mL). The aqueous solution was extracted with diethyl ether (30 mL×3). Water was removed by lyophilization to afford 391 mg of the title compound. Yield: 86%. 1H NMR (300 MHz, CDCl3) δ 1.42 (m, 2H), 1.69 (m, 2H), 2.04 (m, 2H), 2.57 (s, 3H), 2.62 (t, J=7.2 Hz, 2H), 4.85 (t, J=7.2 Hz, 2H), 7.15-7.62 (m, 9H), 7.82 (d, J=6.0 Hz, 2H), 9.25 (d, J=6.0 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 22.3, 25.5, 30.7, 31.6, 35.2, 61.0, 126.8, 126.9, 127.1, 128.7, 128.8, 128.9, 138.5, 140.7, 141.1, 144.0, 158.7 ppm.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6]
Reactant: OCCOCCO
Reactant: C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: OCCOCCOC1CCCCO1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To 800 mL of CH2Cl2 were added diethylene glycol (57 mL, 0.6 mol) and p-toluenesulfonic acid monohydrate (5.7 g, 30 mmol) successively. Then tetrahydropyran (27.4 mL, 0.3 mol) was added dropwise at 0° C. The reaction mixture was stirred overnight and quenched with H2O, extracted with CH2Cl2, washed with H2O and brine successively, concentrated through rotary evaporation, and subjected to silica gel chromatography using CH2Cl2/MeOH as the eluent to afford compound 28 (32.5 g, 0.17 mol, 57% yield) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 4.59 (t, J=4.0 Hz, 1H), 3.85-3.80 (m, 2H), 3.68-3.64 (m, 4H), 3.59-3.55 (m, 3H), 3.48-3.44 (m, 1H), 2.98 (br, 1H), 1.81-1.76 (m, 1H), 1.71-1.65 (m, 1H), 1.59-1.46 (m, 4H).
Reaction SMILES: COC(=O)[C:4]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([OH:20])=[C:6](C(OC)=O)[C:5]=1[OH:21].Cl.C1C=CC=CC=1>O.[OH-].[Na+].CCOCC>[C:14]1([C:13]2[CH:12]=[C:11]([OH:20])[CH:6]=[C:5]([CH:4]=2)[OH:21])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1c(O)cc(-c2ccccc2)c(C(=O)OC)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: Oc1cc(O)cc(-c2ccccc2)c1
Reaction time: 14 h
Yield: 54.8 %

Procedure:
6.00 g (0.0199 mole) of 2,4-dihydroxy-6-phenyl-isophthalic acid dimethyl ester is dissolved under nitrogen in 40 ml of water and 40 ml of 2 N sodium hydroxide solution. The light-red solution is refluxed for one hour; it is then cooled with an ice bath and carefully acidified with 8.0 ml of concentrated hydrochloric acid (carbon dioxide evolution). The mixture is then refluxed and boiled for 14 hours in a nitrogen atmosphere. The emulsion obtained after cooling is extracted twice with 100 ml of ether each time. The combined ether layers are dried with magnesium sulphate and concentrated in vacuo to obtain 3.98 g of crude product in the form of yellow crystals. This crude product is dissolved in 20 ml of ether; 50 ml of benzene is added and the ether then distilled off. 5-Phenylresorcinol crystallises out on standing. After cooling, there is added 50 ml of hexane, and the crystals are filtered off under suction; this yields 2.44 g of cream-coloured crystals, M.P. 154°- 158°. Repeated crystallisation from 40 ml of benzene with the addition of 40 ml of hexane yields 2.03 g of 5-phenyl-resorcinol as colourless crystals, M.P. 157°-158°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC=C)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCN(c3cccc4cccnc34)CC2)cc1
Agent: C=COC(=O)Cl
Solvent: ClCCl
Product: c1cnc2c(N3CCNCC3)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 8-(4-benzyl-piperazin-1-yl)quinoline (2.63 g, 8.7 mmol) in methylene chloride (30 ml) was added vinyl chloroformate (1.1 ml, 13 mmol) at room temperature slowly. The reaction mixture was refluxed for 2 hours, and then concentrated under vacuum. The residue was dissolved in 12 N hydrochloric acid (20 ml) and stirred at room temperature for 1 hour. The mixture was concentrated, the residue was taken up with 40 ml ethanol and heated up to 50° C. for 2 hours. The solvent was removed under vacuum, the residue was dissolved in 1 N sodium hydroxide-ethyl acetate and extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under vacuum. Chromatography (10-30% methanol -methylene chloride plus ammonium hydroxide) afforded 1.86 g (90%) yellow oil; MS EI m/e 213 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([Li])[CH2:17][CH2:18]C.C(Br)C=C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:18][CH:17]=[CH2:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCCc1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of (tert-butoxy)-N-(6-methyl(2-pyridyl))carboxamide in tetrahydrofuran (0.1 M) was added n-butyl lithium (2.1 eq) at −78° C. and the solution was warmed to 25° C. and stirred for 1 hr. The solution was then cooled back down to −78° C. followed by addition of allyl bromide (1.5 eq) and continued strirring for 1 hr. The reaction was quenched with saturated ammonium chloride, diluted with ethyl acetate and separated. The organic layer was washed with brine and dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5% EtOAc/Hexane). EI-MS m/z 249(M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:21]=[O:22].C(O)(=O)C>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[C:9]=1[CH:21]=[O:22])[C:5]#[N:6]
Reactant: CN(C)C=O
Reactant: N#Cc1cc(F)cc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(C=O)c(F)c1
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 3,5-difluorobenzonitrile (1 gm, 7.1 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.769 gm, 7.1 mmol) was added at −78° C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.62 g, 8.5 mmol) was added dropwise to the reaction mixture and stirring was continued for about 45 minutes. Acetic acid (1.5 mL) and water (40 mL) were added to the cold solution of reaction mixture. The aqueous phase was extracted with diethyl ether (4×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using hexane and ethyl acetate as gradient system to afford pure 3,5-difluoro-4-formylbenzonitrile (0.5 gm, 31.25%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][CH:35]=1)[O:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[F:36][C:19]([F:18])([F:37])[C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][CH:35]=1)[O:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:27]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
A solution of 1.5 grams (0.011 mole) 3-nitroaniline and 1.0 gram (0.011 mole) triethylamine in 100 milliliters toluene was placed in a flask. There was slowly added, with stirring, a solution of 3.2 grams (0.011 mole) 2-(3-trifluoromethylphenoxy) nicotinoyl chloride in 25 milliliters toluene. The rate of addition was controlled so as to maintain the temperature below 35° C. After the addition was complete the mixture was stirred at 45° C. for one hour, cooled, poured into 100 milliliters toluene, and washed with two 150-milliliter portions of water. The organic phase was separated, dried with magnesium sulfate, filtered and the solvent removed to produce 3.3 grams (73.3% of theoretical yield) of the desired product, m.p. 90°-95° C. The structure was confirmed by mass spectrometry.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([Cl:14])(=[O:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl>[Br:22][C:4]1[C:5]2[C:10](=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc2ccc(S(=O)(=O)Cl)cc21
Solvent: ClCCl
Product: Cn1cc(Br)c2ccc(S(=O)(=O)Cl)cc21
Reaction time: 2.5 h
Yield: 98.2 %

Procedure:
A solution of 1-methyl-1H-indole-6-sulfonyl chloride (8.764 g, 38.2 mmol) in DCM (190 ml) was treated with n-bromosuccinimide (7.47 g, 42.0 mmol). The resulting mixture was stirred in the dark for 2.5 h, then filtered through a silica gel pad. The filter pad was washed with DCM (2×), and the filtrates were combined. The combined solution was concentrated to give 3-bromo-1-methyl-1H-indole-6-sulfonyl chloride (11.562 g, 37.5 mmol, 98% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ=8.08 (dd, J=0.4, 1.7 Hz, 1 H), 7.87-7.80 (m, 1 H), 7.79-7.70 (m, 1 H), 7.42 (s, 1 H), 3.93 (s, 3 H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OC
Temperature: 140 °C
Yield: 63.5 %

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.13 g), furan-3-yl boronic acid (0.036 g), palladium chloride dppf adduct with DCM (0.026 g) and cesium carbonate (0.3 g) in THF (3.5 ml) and water (0.5 ml) was sealed in a microwave vial and degassed. The mixture was then heated in the microwave at 140° C. for 10 minutes. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic phase was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give ethyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-methoxy-benzoate (0.08 g) as a colourless gum.
Reaction SMILES: N.CC(C)(C)CC[NH2:6].[O:9]=[C:10]1[C:18]2([C:22]3=[CH:23][C:24]4[O:28][CH2:27][O:26][C:25]=4[CH:29]=[C:21]3[O:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[CH2:30][C:31]1[O:35][C:34]([C:36]([F:39])([F:38])[F:37])=[C:33]([C:40](O)=[O:41])[CH:32]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC(O)=O>CO>[O:9]=[C:10]1[C:18]2([C:22]3=[CH:23][C:24]4[O:28][CH2:27][O:26][C:25]=4[CH:29]=[C:21]3[O:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[CH2:30][C:31]1[O:35][C:34]([C:36]([F:38])([F:39])[F:37])=[C:33]([C:40]([NH2:6])=[O:41])[CH:32]=1
Reactant: CC(C)(C)CCN
Reactant: O=C(O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Agent: N
Agent: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Solvent: CO
Product: NC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 12.49 and making non-critical variations using 7 N ammonia solution in methanol to replace 3,3-dimethylbutylamine, and 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylic acid to replace (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid, 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide was obtained (86%) as a colorless solid: mp 172-174° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 7.32-7.27 (m, 1H), 7.20-7.17 (m, 1H), 7.11-7.06 (m, 1H), 6.97-6.94 (m, 1H), 6.70 (s, 1H), 6.49 (s, 1H), 6.09-6.02 (m, 3H), 5.83 (ABq, 2H), 5.85-5.84 (m, 2H), 5.03-4.85 (m, 3H), 4.67-4.64 (m, 1H); MS (ES+) m/z 473.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=O)[C:7](=[O:13])[NH:8]2.IC1C=CC=C2C=1C(=O)C(=O)N2.CC(=C)C.[CH:32]1[C:37]([NH:38][NH2:39])=[CH:36][CH:35]=[C:34]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:33]=1.Cl>>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:39][NH:38][C:37]1[CH:36]=[CH:35][C:34]([S:40]([NH2:43])(=[O:41])=[O:42])=[CH:33][CH:32]=1)[C:7](=[O:13])[NH:8]2
Reactant: CC(C)=Cc1cccc2c1C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: C=C(C)C
Agent: Cl
Agent: O=C1Nc2cccc(I)c2C1=O
Product: CC(C)=Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 51 %

Procedure:
By methods described in Procedure L, 4-(2-methyl-propenyl)-1H-indole-2,3-dione was prepared from 4-iodo-1H-indole-2,3-dione and isobutylene in 34% yield: 1H NMR (DMSO-d6): δ1.82 (s, 3H), 1.90 (s, 3H), 6.79 (d, J=7.9 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 10.97 (s, 1H); APCI−MS m/z 200 (M−1)−. Condensation of 4-(2-methyl-propenyl)-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound as a yellow solid (51% yield): 1H NMR (DMSO-d6): δ1.84 (s, 3H), 2.04 (s, 3H), 6.78 (s, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.24 (s, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 11.11 (s, 1H), 12.91 (s, 1H); APCI−MS m/z 369 (M−1)−. Anal. Calcd for C18H18N4O3S: C, 58.36, H, 4.90; N, 15.12; S, 8.66. Found C, 58.41, H, 4.87; N, 15.18; S, 8.56.