Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH2:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:26][CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])([CH3:24])[CH3:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: C=CC(=O)OC
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C(C)(C)N)cc3)n2)cc1Cl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCNC(C)(C)c1ccc(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl) phenyl)propan-2-amine, acetic acid (132 mg, 0.306 mmol) was added to a 5 mL microwave vial equipped with a stirring bar. Methyl acrylate (52.6 mg, 0.611 mmol), and MeOH (3.0 mL) were added, the vial capped, and the reaction heated to 120° C. for 90 min under microwave irradiation (Biotage Optimizer, 300 W). After 90 min another aliquot of methyl acrylate (52.6 mg, 0.611 mmol) was added and the reaction submitted for another 60 min at 120° C. Reaction was cooled and the solvent removed under reduced pressure. Crude material was purified by RP-HPLC (A=50 mM ammonium acetate, B=acetonitrile; 30-70% B over 30.0 min (21.0 mL/min flow rate); 21.2×250 mm Thermo Hyperprep C18 column, 8 μm particles) to give methyl 3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)propan-2-ylamino)propanoate (83.5 mg; 59.7%). LCMS (Table 1, Method f) Rt=2.78 min, m/z=458.29 (M+H)+,
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[S:7])=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[S:7])=[CH:21][CH:22]=1
Reactant: Cc1ccc(C(=S)c2cc(CC(=O)O)cc3c2OCC3)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(C(=S)c2cc(CC(=O)O)cc3ccoc23)cc1

Procedure:
7-(4-Methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid (1.0 g) was heated at reflux in carbon tetrachloride (100 ml) containing n-bromosuccinimide (0.54 g) and a catalytic quantity of benzoyl peroxide. After approximately 2 hours the reaction mixture was cooled and extracted with dilute aqueous sodium carbonate. The aqueous extract was acidified with hydrochloric acid, extracted with ethyl acetate, dried and evaporated to yield a residue which was crystallized from acetone/hexane to give (7-(4-methylthiobenzoyl)benzofuran-5-ylacetic acid, m.p. --151°-153° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[OH:20])(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C>[N:24]1[CH:25]=[CH:26][C:21]([C:19]([C:11]2[NH:10][C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[O:20])=[CH:22][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)c2ccncc2)cc2ccncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccncc1)c1cc2ccncc2[nH]1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
[1-(Phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl](pyridin-4-yl)methanol (Reference Example 22, 217 mg, 0.59 mmol) was dissolved in ethanol (10 mL). A 10% solution of sodium hydroxide (6 mL) was added and the reaction mixture was refluxed for 4.5 hours and then stirred at ambient temperature for the weekend. The solvent was removed under vacuum. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated to give (pyridin-4-yl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (air-oxidation product) (86 mg, 65%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.26 (1H, s), 7.75-7.77 (1H, m), 7.90-7.92 (2H, m), 8.18 (1H, d, J=5.6 Hz), 8.81-8.83 (2H, m), 8.90 (1H, s); ESI MS m/z=224 [C13H9N3O+H]+; HPLC (Method A) >99% (AUC), tR=7.6 min.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)[CH:10]([OH:15])[C:11]([F:12])([F:14])[F:13]
Reactant: [H][H]
Reactant: OC(C(c1cccc(C(F)(F)F)c1)N(Cc1ccccc1)Cc1ccccc1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC(c1cccc(C(F)(F)F)c1)C(O)C(F)(F)F

Procedure:
In a continuous-flow hydrogenation apparatus (H-Cube from Thales Nano, Budapest, Model HC-2-SS), a solution of 168 mg (0.37 mmol) of the compound from Example 98A in 50 ml of methanol was hydrogenated (conditions: Pd(OH)2/C cartridge, flow rate of 1 ml/min, RT, standard hydrogen pressure). The reaction mixture was concentrated on a rotary evaporator and the residue was briefly dried in an HV. This was the title compound (93 mg, 92% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH2:11][OH:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH:11]=[O:12]
Reactant: N#CCc1ccc(Cl)c(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#CCc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [4-chloro-3-(hydroxymethyl)phenyl]acetonitrile from the previous step (1 eq.) in CH2Cl2 (0.14 M) was added Dess-Martin periodinane (1.1 eq.) portionwise. The resulting suspension was stirred at RT for 3 h. The reaction was quenched with MeOH and H2O. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:11][N:10]=[C:9]2[CH3:18])=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:9]([CH3:18])=[N:10][N:11]=[C:12]2[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])=[CH:5][CH:4]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1nnc([C@H]2CCCN2)n1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc([C@H]2CCCN2C(=O)Nc2ccc(Cl)cc2)n1Cc1ccc(Cl)cc1
Yield: 87.3 %

Procedure:
(R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole hydrochloride (58 mg, 0.2 mmol) was dissolved in dichloromethane (2 ml). 4-chlorophenyl isocyanate (0.031 ml, 0.2 mmol) and N,N-diisopropylethylamine-(0.050 ml) were added while stirring. The reaction mixture was stirred for 12 h then evaporated to dryness. Purification by silica gel column chromatography (methanol/dichloromethane gradient, 0-15% methanol) afforded the desired product as a white amorphous solid (75.1 mg, 87%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:36][CH2:37][CH2:38][CH2:39][N:40]1[C:44]2=[N:45][CH:46]=[CH:47][CH:48]=[C:43]2[C:42]([C:49]2[C:50](=[O:68])[NH:51][C:52](=[O:67])[C:53]=2[C:54]2[C:59]3[S:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[C:58]=3[CH:57]=[CH:56][CH:55]=2)=[CH:41]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH:57]1[C:58]2[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=3[S:60][C:59]=2[C:54]([C:53]2[C:52](=[O:67])[NH:51][C:50](=[O:68])[C:49]=2[C:42]2[C:43]3[C:44](=[N:45][CH:46]=[CH:47][CH:48]=3)[N:40]([CH2:39][CH2:38][CH2:37][OH:36])[CH:41]=2)=[CH:55][CH:56]=1
Reactant: CC(C)(C)[Si](OCCCn1cc(C2=C(c3cccc4c3sc3ccccc34)C(=O)NC2=O)c2cccnc21)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cccc3c2sc2ccccc23)=C1c1cn(CCCO)c2ncccc12
Yield: 67 %

Procedure:
TBAF (0.85 mL, 0.085 mmol; 1 M solution in THF) was added dropwise to a solution of 3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-dibenzothiophen-4-yl-pyrrole-2,5-dione Compound 19a (0.039 g, 0.06 mmol) in THF (1 mL) under nitrogen. After 18 hours the mixture was concentrated and purified by column chromatography (SiO2) to give Compound 28 (0.017 g, 67%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.35 (dd, J=7.7, 1.5 Hz 1H), 8.25 (s, 1H), 8.21 (dd, J=6.8.3, 1.5 Hz, 1H), 8.01 (dd, J=4.7, 1.5 Hz, 1H), 7.68 (m, 3H), 7.39 (m, 2H), 6.68 (dd, J=8.1, 1.5 Hz, 1H), 6.55 (dd, J=8.1, 4.7 Hz, 1H), 4.42 (t, J=6.8 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 2.03 (m, 2H); MS (ES) m/z: 454 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1.[Si](OCC1[C@@H](CO)C1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)(C(C)(C)C)(C)[CH3:25].C(I)C>>[CH2:1]([O:2][CH2:3][CH:4]1[C@@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1)[CH3:25]
Reactant: CC1(C)CCC(C)(C)c2cc(C3(C)C(CO[Si](C)(C)C(C)(C)C)[C@H]3CO)ccc21
Reactant: COCC1[C@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: CCI
Product: CCOCC1[C@@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 81 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 6a using Intermediate 5 as the starting material and ethyl iodide as the alkylating reagent provided the title compound (65 mg, 81% yield) as a colorless oil:
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:10]([CH3:16])=[N:9][CH:8]=1)=O.C(=O)(O)O.[C:22]1([NH:28][C:29]([NH2:31])=[NH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[O-].[Na+].O>CC(N(C)C)=O>[NH:28]([C:29]1[N:31]=[C:5]([C:7]2[N:11]([CH:12]3[CH2:13][CH2:14][CH2:15]3)[C:10]([CH3:16])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C1CCC1
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C1CCC1
Temperature: 160 °C
Yield: 33.6 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-cyclobutyl-2-methylimidazole (Method 37; 466 mg, 2 mmol), phenylguanidine hydrogen carbonate (434 g, 2.2 mmol) and sodium methoxide (238 mg, 4.4 mmol) were suspended in anhydrous DMA (5 ml) and the mixture heated at 160° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and poured into water (50 ml). The solution was extracted EtOAc (2×50 ml). The combined extracts were washed with water (2×50 ml) and then brine (2×50 ml), dried and the volatiles removed by evaporation. The residue was triturated with ether, collected by filtration and air dried to give the title compound (205 mg, 35%) as a brown solid. NMR: 1.63 (m, 2H), 2.35 (m, 4H), 2.53 (s, 3H), 5.5 (m, 1H), 6.96 (d, 2H), 7.28 (m, 4H), 7.70 (d, 2H), 8.39 (d, 1H), 9/45 (s, 1H); m/z 306.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]2[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][C:7]=12)([O-:3])=[O:2].Cl>CO>[N+:1](/[CH:4]=[CH:5]/[C:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:7]=12)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(/C=C/[N+](=O)[O-])c3ccccc3n2CC1
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])/C=C/c1c2n(c3ccccc13)CCNCC2
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A solution of tert-butyl 11-[(E)-2-nitroethenyl]-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate (396 mg, 1.1 mmol) in methanol (10 mL) is cooled to 0° C. and treated with a saturated solution of hydrochloric acid in methanol (5 mL). After 3 hrs, the volatiles are removed under reduced pressure, diluted with 5M sodium hydroxide (15 mL), and extracted twice with dichloromethane (20 mL). The combined organics are washed once with brine (15 mL), dried over MgSO4, filtered, and concentrated to give a yellow solid. This material is recrystallized from dichloromethane/ethyl acetate to afford 209 mg of 11-[(E)-2-nitroethenyl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole as a light yellow solid, mp 225-226° C. IR (drift) 1603, 1488, 1469, 1318, 1301, 1281, 1257, 1251, 1206, 1187, 1062, 976, 946, 763, 745 cm−1; OAMS supporting ions at: ESI+ 258.1.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][N:7]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[C:33]([CH:34]=[O:35])=[C:32]([N:36]4[CH2:48][CH2:47][C:46]5[N:45]6[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]6)=[CH:39][C:38]=5[C:37]4=[O:49])[N:31]=[CH:30][CH:29]=3)[CH:21]=2)=[N:17][CH:18]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:10][O:11][CH2:12]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:29]=[CH:30][N:31]=[C:32]([N:36]4[CH2:48][CH2:47][C:46]5[N:45]6[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]6)=[CH:39][C:38]=5[C:37]4=[O:49])[C:33]=3[CH2:34][OH:35])[CH:21]=2)=[N:17][CH:18]=1)[CH3:2]
Reactant: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 161g (120 mg, 0.18 mmol) in methanol (20 mL) was added NaBH4 (21 mg, 0.54 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. Then the mixture was poured into water (20 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×40 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue solid was purified by prep-HPLC to afford 161 (97 mg, 81%) as white solid. MS-ESI: [M+H]+ 665. 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 7.93 (s, 1H), 7.84-7.82 (m, 2H), 7.35 (d, J=4.5 Hz, 1H), 7.28 (s, 1H), 6.82 (d, J=9.0 Hz, 1H), 6.32 (s, 1H), 5.01-4.99 (m, 1H), 4.73-4.64 (m, 5H), 4.45-4.40 (m, 1H), 4.30 (t, J=12.0 Hz, 1H), 3.94-3.91 (m, 1H), 3.85-3.83 (m, 2H), 3.72 (s, 3H), 3.55-3.53 (m, 1H), 3.34-3.32 (m, 1H), 3.14-3.12 (m, 2H), 3.04-2.92 (m, 2H), 2.84-2.82 (m, 2H), 2.59-2.57 (m, 1H), 2.46-2.44 (m, 2H), 2.38-2.36 (m, 1H), 2.06-2.01 (m, 2H), 1.90-1.86 (m, 2H), 1.68-1.66 (m, 1H), 1.43-1.39 (m, 1H), 0.82 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH:20][CH3:21])=[O:19])=[O:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH3:35]>O>[F:22][CH:2]([F:1])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:34][CH3:35])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH:20][CH3:21])=[O:19])=[O:4]
Reactant: CCI
Reactant: CNC(=O)c1[nH]c2ccc(O)cc2c1CCNC(=O)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2[nH]c(C(=O)NC)c(CCNC(=O)C(F)F)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{2-[(difluoroacetyl)amino]ethyl}-5-hydroxy-N-methyl-1H-indole-2-carboxamide (102 mg) and N,N-dimethyl formamide (3.00 mL) were added potassium carbonate (55.2 mg) and ethyl iodide (0.0318 mL), followed by stirring at room temperature for 2 hours, then warming to 60° C., and stirring overnight. To this mixture was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and subsequently dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 94:6) to obtain a colorless solid. The obtained solid was washed with hexane:ethyl acetate=2:1 to obtain 3-{2-[(difluoroacetyl)amino]ethyl}-5-ethoxy-N-methyl-1H-indole-2-carboxamide (9.00 mg) as a colorless solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]1([S:7]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[CH3:24])=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1CCSc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C(=O)c2ccccc2)c(C)n1CCS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
In 15 ml of methylene chloride was dissolved 589 mg (1.76 mmoles) of 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)ethyl phenyl sulfide, and 350 mg (1.72 mmoles) of m-chloroperbenzoic acid (85% purity) was added. The mixture was stirred at room temperature for 16 hours. The organic layer was washed with a 1.0 N aqueous solution of sodium hydroxide, and then water, dried, and concentrated, and chromatographed on a column of silic gel using benzene/ethyl acetate as an eluent to afford compound (410)(562 mg, 1.60 mmoles, 91%).
Reaction SMILES: CCOC(C)=O.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([C:20]2[N:21]=[C:22]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=5)=[CH:32][C:27]=4[O:26][CH2:25][CH2:24][N:23]3[CH:40]=2)=[N:18][C:17]([NH:41]C(=O)O)=[N:16]1>CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([C:20]2[N:21]=[C:22]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=5)=[CH:32][C:27]=4[O:26][CH2:25][CH2:24][N:23]3[CH:40]=2)=[N:18][C:17]([NH2:41])=[N:16]1
Reactant: O=C(O)Nc1nc(-c2cn3c(n2)-c2ccc(-c4ccc(Cl)cc4)cc2OCC3)n(-c2ccccc2Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1nc(-c2cn3c(n2)-c2ccc(-c4ccc(Cl)cc4)cc2OCC3)n(-c2ccccc2Cl)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 34.1 %

Procedure:
A solution of EtOAc/HCl (20 mL) was added to 1-(2-chlorophenyl)-5-(9-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-ylcarbamic acid (270 mg, 0.6 mmol) in EtOAc (10 mL) in portions. The resulting mixture was stirred at 50° C. for 5 h. The reaction mixture was filtered and the solid was collected to give 570 (100 mg, 34%). 1H NMR (DMSO, 400 MHz) δ 7.73-7.69 (m, 5H), 7.63-7.61 (m, 2H), 7.55-7.52 (m, 1H), 7.48 (dd, J=2.0, 6.8 Hz, 2H), 7.28-7.25 (m, 2H), 4.80-4.30 (b, 2H), 4.45 (s, 4H). LCMS (ESI) m/z 489.1 (M+H+)
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:26])([CH2:15][N:16]1[CH:25]=[C:19]2[N:20]=[CH:21][C:22]([Br:24])=[CH:23][C:18]2=[N:17]1)[C:13]#[N:14]>C1COCC1>[Br:24][C:22]1[CH:21]=[N:20][C:19]2=[CH:25][N:16]([CH2:15][C:12]([NH:11][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=3)([C:13]#[N:14])[CH3:26])[N:17]=[C:18]2[CH:23]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(I)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-iodobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 182) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (8.3 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=510, RT=0.59 min.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([CH3:36])([CH3:35])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[N:25][N:26]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:34])[CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.COC(C(C)(C)CC1C=C(C)C(C2NC3C=C(C(O)=O)C=CC=3N=2)=C(C)C=1)=O.CC1C=CC=CC=1C(NN)=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:12][C:10]1[CH:11]=[C:6]([CH2:5][C:4]([CH3:36])([CH3:35])[C:3]([OH:37])=[O:2])[CH:7]=[C:8]([CH3:34])[C:9]=1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[N:25][N:26]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccccc5C)o4)cc3[nH]2)c(C)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Agent: Cc1ccccc1C(=O)NN
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nnc(-c2ccc3nc(-c4c(C)cc(CC(C)(C)C(=O)O)cc4C)[nH]c3c2)o1

Procedure:
3-{3,5-Dimethyl-4-[6-(5-o-tolyl-[1,3,4]oxadiazol-2-yl)-1H-benzoimidazol-2-yl]-phenyl}-2,2-dimethyl-propionic acid methyl ester. Add EDC (380 mg, 1.98 mmol) and HOBt (268 mg, 1.98 mmol) to a stirring solution of 2-[4-(2-methoxycarbonyl-2-methyl-propyl)-2,6-dimethyl-phenyl]-3H-benzoimidazole-5-carboxylic acid (626 mg, 1.65 mmol) and 2-methyl-benzoic acid hydrazide (248 mg, 1.65 mmol) in DMF (6 mL) under N2. Upon disappearance of the carboxylic acid by LC/MS, dilute the reaction with EtOAc (60 mL) and extract with water (20 mL) followed by brine (10 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Dissolve the residue in DMF (6 mL) and add Burgess reagent (1.18 g, 4.95 mmol). Heat the mixture my microwave irradiation to 150° C. for 15 min. Dilute the reaction with EtOAc (100 mL) and extract with water (25 mL). Extract the organic phase with saturated NaHCO3 (2×25 mL) followed by brine (20 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Purify the residue by silica gel chromatography (10-45% ACN/DCM) to afford the title compound as a yellow oil: (M+H)+495.3.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([CH2:10][C:11](OCC)=O)=[O:9])=[CH:6][CH:5]=1.[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:21][C:20]=1CCl>C1COCC1>[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:21][C:20]=1[CH2:11][CH2:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:17][CH:16]=1)=[O:9]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 64.7 %

Procedure:
Sodium hydride (1.3 g, 55 mmol) was suspended in THF (75 mL) and cooled to 0° C. The title compound of Example 1 (14.9 g, 55 mmol) was dissolved in THF (75 mL) and added dropwise to the suspension over 30 minutes. The resulting solution was stirred an additional 30 minutes after which time solid 5-methyl-2-phenyl-4-oxazolyl methyl chloride (10.0 g, 48 mmol) was added in portions over five minutes. The reaction mixture was refluxed for 48 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in acetic acid (120 mL) and concentrated HCI (30 mL), and refluxed for five hours. The reaction mixture was cooled to room temperature and poured onto ice-water (300 mL). The aqueous solution was extracted twice with ethyl acetate (500 mL) and the organic extracts were combined and washed with brine (250 mL), dried (MgSO4) and concentrated in vacuo. Purification on silica gel, eluting with hexane/ethyl acetate (4/1), resulted in a crude solid which was further purified by recrystallization from hexane to afford the title compound (11.5 g, 65%) as white crystals. mp 80-81° C. 1HNMR (60 MHz, CDCl3): δ2.2 (s, 3H), 2.8 (m, 2H), 3.2 (m, 2H), 7.2-8.0 (m, 9H).