Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[NH:8]2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>C(Cl)Cl>[Si:23]([O:13][CH2:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([N+:16]([O-:18])=[O:17])=[C:2]([F:1])[CH:10]=2)([CH3:15])[CH3:14])([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(CO)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a stirred solution of 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (10.0 g) in CH2Cl2 was added TBSCl (8.9 g), imidazole (8.1 g, 0.12 mol) at room temperature. The mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to give 2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole (5.3 g, 38%). 1H NMR (300 MHz, CDCl3) 9.51 (s, 1 H), 8.31 (d, J=7.5 Hz, 1 H), 7.02 (d, J=11.7 Hz, 1 H), 6.32 (s, 1 H), 3.63 (s, 2 H), 1.35 (s, 6 H), 0.99 (s, 9 H), 0.11 (s, 6 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:15])=[O:5])[CH3:2].CS(O)(=O)=O.[N-:21]=[N+]=[N-].[Na+].[OH-].[NH4+]>C(Cl)(Cl)Cl>[O:15]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:21]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1CCCCCCCC1=O
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCCCCCCC(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Ethoxycarbonyl-cyclononanone (13.72 g, 64.7 mmol) is dissolved in chloroform (200 mL) and cooled to 0° C. Methanesulfonic acid (62.4 g, 650 mmol) is added, followed by sodium azide (12.68 g, 195 mmol). The reaction is stirred at room temperature for 30 minutes, and then heated to reflux for 4 hours. The reaction mixture is poured onto ice, made basic with concentrated ammonium hydroxide (pH=9), and extracted several times with methylene chloride. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (40% ethyl acetate/hexane) to give ethyl 2-oxo-1-azacyclodecane-10-carboxylate, m.p. 101°-103° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1)([CH3:4])[CH3:3].[Cl:16][CH2:17][C:18]([NH:20][CH2:21]O)=[O:19]>S(=O)(=O)(O)O>[Cl:16][CH2:17][C:18]([NH:20][CH2:21][C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[C:7]([S:12]([CH3:15])(=[O:14])=[O:13])[C:8]=1[OH:11])=[O:19]
Reactant: O=C(CCl)NCO
Reactant: CC(C)(C)c1ccc(O)c(S(C)(=O)=O)c1
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(CNC(=O)CCl)c(O)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
13.5 g (0.06 mol) of 4-(1,1-dimethylethyl)-2-methylsulfonylphenol are dissolved in 100 ml of concentrated sulfuric acid. 6.63 g (0.054 mol) of 2-chloro-N-hydroxymethylacetamide are added and the mixture is stirred at room temperature for 10 minutes. It is then poured onto ice-water and the crude product is filtered off with suction and recrystallized from toluene.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Cl:19])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(CCc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(CCc2ccccc2)c1
Yield: 99 %

Procedure:
The resulting alcohol (140 mg) was dissolved in 1 ml of chloroform, and 0.3 ml of thionyl chloride was added. The mixture was reacted at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure to give 150 mg (yield 99%) of 3-phenethylbenzyl chloride as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[CH:21](OCC)(OCC)OCC>C(O)C>[Br:20][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][CH:18]=1)[N:1]=[CH:21][N:6]([CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:4]2=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: CC(CNC(=O)c1cc(Br)ccc1N)Cn1ccnc1
Solvent: CCO
Product: CC(Cn1ccnc1)Cn1cnc2ccc(Br)cc2c1=O

Procedure:
A mixture of 3.37 g of 2-amino-5-bromo-N-[3-(1H-imidazol-1-yl)-2-methylpropyl]benzamide, 5 ml of triethyl orthoformate and 10 ml of ethanol was heated at reflux temperature for 20 hours. The reaction mixture was concentrated, triturated with ether and then boiled with ethyl acetate. The insoluble product was filtered off, mp 159°-162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:25])=[N:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[C:15]=3[CH3:16])=[CH:9][N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.[O:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][C:43]=2[NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[C:15]([CH3:16])=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:45]4[CH:46]=[CH:47][C:42]([N:39]5[CH2:38][CH2:37][O:36][CH2:41][CH2:40]5)=[C:43]([NH:57][S:58]([CH3:61])(=[O:59])=[O:60])[CH:44]=4)[CH:3]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[CH:9]=2)[C:12]([CH3:25])=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)c(NS(C)(=O)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCOCC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 45.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example-14) (250 mg, 0.451 mmol) was coupled with N-(2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (intermediate 51) (259 mg, 0.677 mmol) in sodium carbonate (143.4 mg, 1.353 mmol), Toluene/ethanol/water (3/8/1 ml). This afforded 150 mg (45.59% yield) of the titled compound. MS: m/z=728.9 (M+1).
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C@@H:10]2[C:24](=[O:25])[N:23]3[CH2:26][C@H:27]([O:29][C:30]4[N:31]=[C:32]5[C:37](=[C:38]6[C:43]=4[CH:42]=[CH:41][CH:40]=[CH:39]6)[CH:36]=[C:35]([F:44])[CH:34]=[CH:33]5)[CH2:28][C@H:22]3[C:21](=[O:45])[NH:20][C@:19]3([C:47]([O:49]CC)=[O:48])[CH2:46][C@H:18]3[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(N[C@@H]1C(=O)N2C[C@H](OC3N=C4C(=C5C=3C=CC=C5)C=CC=C4)C[C@H]2C(=O)N[C@]2(C(OCC)=O)C[C@H]2C=CCCCCC1)=O)(C)(C)C>>[CH:1]1([O:6][C:7]([NH:9][C@@H:10]2[C:24](=[O:25])[N:23]3[CH2:26][C@H:27]([O:29][C:30]4[N:31]=[C:32]5[C:37](=[C:38]6[C:43]=4[CH:42]=[CH:41][CH:40]=[CH:39]6)[CH:36]=[C:35]([F:44])[CH:34]=[CH:33]5)[CH2:28][C@H:22]3[C:21](=[O:45])[NH:20][C@:19]3([C:47]([OH:49])=[O:48])[CH2:46][C@H:18]3[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC1CCCC1)C(=O)N1C[C@H](Oc3nc4ccc(F)cc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC1CCCC1)C(=O)N1C[C@H](Oc3nc4ccc(F)cc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Product: O=C(N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccc(F)cc4c4ccccc34)CN2C1=O)OC1CCCC1

Procedure:
Example 37e was prepared according to the procedure used for the preparation of Example 67c, substituting the product of Example 37d for the product of Example 24b.
Reaction SMILES: [CH2:1]1[CH:11]2[C:5](=[N:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10]2=[O:12])[CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.CCCCCC>[CH2:17]([N:9]1[C:10](=[O:12])[CH:11]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]2=[N:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccccc2N=C2CCCCC12
Reactant: BrCc1ccccc1
Solvent: CCCCCC
Solvent: CCO
Product: O=C1C2CCCCC2=Nc2ccccc2N1Cc1ccccc1
Yield: 66 %

Procedure:
Using 1,2,3,4,10,11a-hexahydro-11H-dibenzo [b,e][1,4]diazepin-11-one and benzyl bromide, the titled compound was synthesized in substantially the same procedure as in Working Example 4. Yield 66%. m.p. 123°-125° C. (ethanol-hexane).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[C:10]([O:14][C:15](=[O:28])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C)C=O>[C:10]([O:14][C:15](=[O:28])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)=[C:21]([O:26][CH3:27])[CH:20]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1O
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CCNC(=O)OC(C)(C)C)ccc1OCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
34.6 g (0.23 mol) of 1-chloromethyl-3-fluoro-benzene in 50 ml of dry dimethylformamide were added to a suspension of 55.9 g (0.209 mol) of [2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester, 43 g of K2CO3 and 3.4 g of potassium iodide in 400 ml of dry dimethylformamide. The reaction was stirred at room temperature overnight. Solvent was removed, water was added to the residue and the product was extracted with ethyl acetate. The crude oil obtained was triturated with diethyl ether. The solid was filtered and 58.2 g (74% yield) of the title product were obtained.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1>C1COCC1.[Li+].[OH-].O>[Br:25][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:10]=[CH:9][CH:8]=3)[N:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1cccc(Nc2ncnc(Nc3cccc(Br)c3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cccc(Nc2ncnc(Nc3cccc(Br)c3)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{3-[4-(3-Bromo-phenylamino)-[1,3,5]triazin-2-ylamino]-phenyl)-acetic acid methyl ester (142 mg, 0.3425 mmol) was dissolved in THF (34.5 ml) and 1N LiOH/water (6.85 ml). The reaction was stirred vigorously at RT for 2 h. The organic solvent was evaporated off. The aqueous solution was acidified to pH 3 with 1N HCl, whereupon a white precipitate formed. The precipitate was filtered and dried under vacuum, giving {3-[4-(3-bromo-phenylamino)-[1,3, 5]triazin-2-ylamino]-phenyl}-acetic acid. MS m/z 401=[M+H]+. Calc'd for C17H14BrN5O2: 399.03.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C(=O)OC.NN.[OH-].[K+]>C(O)CO.O>[CH3:1][NH:2][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: COC(=O)N(C)CCc1ccc2[nH]cc(S(=O)(=O)c3ccccc3)c2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CNCCc1ccc2[nH]cc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 110 °C

Procedure:
To a stirred solution of methyl methyl{2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl}carbamate (171 mg, 0.46 mmol) in ethylene glycol (5 ml) was added H2NNH2 (147 mg, 4.6 mmol), KOH (1.9 g 13.8 mmol), and heated to 110° C. for 12 hours. The mixture was cooled to room temperature, diluted with water (5 mL) and extracted with EtOAc. The combined organic layers were washed with water (7 mL), brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a residue which is triturated with CH2Cl2 to afford an off white solid, (131 mg, 93%). Mp: 151-154° C., MS (ES−) 313 (M−H).
Reaction SMILES: S(=O)(=O)(O)O.O.[F:7][C:8]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:10]([C:11]([O:13]C)=[O:12])[C:9]=1[C:21]([O:23]C)=[O:22]>C(O)(=O)C>[F:7][C:8]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:10]([C:11]([OH:13])=[O:12])[C:9]=1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Yield: 73.3 %

Procedure:
Sulfuric acid (99%, 45 ml) was added cautiously to water (45 ml) and the resulting solution mixed with glacial acetic acid (450 ml). To this solution was added dimethyl 3,4,5,6-tetrafluorophthalate (90.0 g) and the resulting mixture heated at reflux for six hours. The solution was concentrated under reduced pressure to remove acetic acid and water. Fresh acetic acid (450 ml) and water (75 ml) were added to the residue and refluxing continued overnight (16 hours). The solution was concentrated again under reduced pressure to a semisolid. Hydrochloric acid (37%, 150 ml) was added and the mixture warmed until all the solids dissolved. The solution was concentrated under reduced pressure to 125 ml. Cooling gave crystals which were collected and washed with 37% hydrochloric acid. Recrystallization from 130 ml 24% hydrochloric acid followed by drying under vacuum at room temperature gave tetrafluorophthalic acid (59 g, 73%); mp 159°-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1ccc(OCCBr)cc1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(NC(C)=O)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and N-{4-[(2-bromoethyl)oxy]phenyl}acetamide: 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1 H), 7.90 (s, 1 H), 7.80 (d, J=8.5 Hz, 1 H), 7.54 (d, J=8.5 Hz, 1 H), 7.39 (d, J=9.0 Hz, 2 H), 6.71 (d, J=9.0 Hz, 2 H), 4.63 (t, J=4.9 Hz, 2 H), 4.18 (t, J=4.9 Hz, 2 H), 2.82 (t, J=4.9 Hz, 2 H), 1.94 (s, 3 H), 1.73-1.49 (m, 2 H), 0.94 (t, J=4.9 Hz, 3 H); MS (ES) m/z 396 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:31]=[C:30]([NH2:32])[N:29]([CH3:33])[N:28]=2)[CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[C:31]([C:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=3)=[C:30]([NH2:32])[N:29]([CH3:33])[N:28]=2)[CH:22]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2cccc(-c3cc(N)n(C)n3)c2)C(=O)OCc2ccccc2)cc1
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: COc1ccc(CN(Cc2cccc(-c3nn(C)c(N)c3C3=CCCCC3)c2)C(=O)OCc2ccccc2)cc1
Yield: 70.8 %

Procedure:
A solution of EXAMPLE 56D (4.5 g, 10 mmol) in acetic acid (100 mL) was treated with cyclohexanone (2 mL, 20 mmol) at ambient temperature for 4 days. The mixture was concentrated and the residue partitioned between dilute sodium hydroxide and ethyl acetate. The organic layer was washed with water and concentrated and the residue purified by flash chromatography on silica gel using ethyl acetate to give 3.8 g (71%) of the title compound. MS (DCI): m/z 537 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1.[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1>CN(C=O)C.O>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:5]([CH:3]3[CH2:4][N:1]([C:21]4[C:16]([Cl:15])=[N:17][CH:18]=[CH:19][N:20]=4)[CH2:2]3)=[N:6][C:7]=2[CH:13]=1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: Clc1nccnc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2[nH]c(C3CN(c4nccnc4Cl)C3)nc2c1
Temperature: 100 °C

Procedure:
A mixture of 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared by Preparation 2) (1.0 g, 4.83 mmol) and 2,3-dichloro-pyrazine (0.71 g, 10.4 mmol) was dissolved in DMF (20 mL) and heated for 2 h at 100° C. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo to afford the product as a yellow solid.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([C:4]2[N:3]([O:2][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2nccn2O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: Cl
Product: CN(C(=O)On1ccnc1-c1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-(4-nitrophenyl)imidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (90%, yellow crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:34]([O:36]C)=[O:35])=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:19]([C:29](=[O:32])[NH:30][CH3:31])[C:18]=3[CH:33]=2)=[CH:12][CH:13]=1.[CH3:38]O.[OH-].[Na+].Cl>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:34]([OH:36])=[O:35])=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)=[C:19]([C:29](=[O:32])[NH:30][CH3:31])[C:18]=3[CH:33]=2)=[C:12]([CH3:38])[CH:13]=1
Reactant: CO
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(-c4ccccc4Cl)c(C(=O)OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(-c4ccccc4Cl)cc3C)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
To a 25 mL round-bottomed flask was added methyl 2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate (43.8 mg, 0.079 mmol), methanol (1 mL), THF (1 mL) and 8 equivalents of a 1M solution of sodium hydroxide (0.63 mL, 0.63 mmol). The mixture was stirred at room temperature for 48 hours. The crude product was diluted with 20 mL of ethyl acetate, made acidic with 0.5M HCl, extracted, washed with brine, dried over sodium sulfate, filtered and evaporated to dryness giving 47.2 mgs (96% yield) of 2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylic acid as yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. LCMS m/z 500.2 (M+H), Rt=3.426 min., 90% purity.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1[NH:29][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][CH:37]([CH3:40])[O:36][CH2:35]2)=[N:31][N:32]=1>>[CH3:27][C:28]1[N:29]=[C:30]2[N:33]([CH:34]3[CH2:39][CH2:38][CH:37]([CH3:40])[O:36][CH2:35]3)[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:31]2[N:32]=1
Reactant: Cc1nnc(NC2CCC(C)OC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(C)OC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 29.3 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.89 g) and 5-methyl-N-(6-methyltetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.18 g, 30%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:17]=1[N+:24]([O-:26])=[O:25].CCOC(C)=O.O>CN(C=O)C>[CH2:7]([O:14][C:20]1[CH:21]=[C:16]([F:15])[C:17]([N+:24]([O-:26])=[O:25])=[C:18]([F:23])[CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
Potassium carbonate (544 mg, 3.94 mmol) and benzyl alcohol (0.3 ml, 2.8 mmol) were added to a solution of 2,4,6-trifluoronitrobenzene (500 mg, 2.8 mmol) in DMF (5 ml). This mixture was stirred at RT overnight. Work up (EtOAc/H2O) afforded the title compound (521 mg) as a yellow liquid which was used in the next step without fuRTher purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[CH2:47]([O:49][C:50]([CH2:52][N:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]1[C:62](Cl)=[O:63])=[O:51])[CH3:48].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:62]([C:54]1[N:53]([CH2:52][C:50]([O:49][CH2:47][CH3:48])=[O:51])[C:61]2[C:56]([CH:55]=1)=[CH:57][CH:58]=[CH:59][CH:60]=2)=[O:63])=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: CCOC(=O)Cn1c(C(=O)Cl)cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)NCc2nnc(C)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.4 g) was dissolved in dimethylformamide (70 ml). 1-Ethoxycarbonylmethylindole-2-carbonyl chloride (3.03 g) and triethylamine (7.0 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from ethanol to give 4.33 g of ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate.