Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N+:26]([O-])=O)[CH:20]=2)=[CH:4][CH:3]=1.CC(O)=O>C(O)C.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH:20]=2)[NH2:26])=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(-c3ccc(F)cc3)n2n1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(C)c(N)c3)c(-c3ccc(F)cc3)n2n1
Temperature: 80 °C
Yield: 942.3 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.075 g, 0.0198 mmol) in ethanol (6 mL) and water (2 mL) containing AcOH (1.18 mmol) is added iron (0.055 g, 0.991 mmol). The reaction mixture is heated at 80° C. for 2 hours, cooled, concentrated under reduced pressure and sat. aqueous NaHCO3 (50 mL) is added. The mixture is extracted with EtOAc (3×20 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford 0.065 g (95%) of the title compound as a yellow solid: Rf 0.36 (95:5 CH2Cl2:MeOH); LCMS (m/z)=349.4 [M+H]+, tR=2.31 min.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>C(O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:26][CH:22]([CH2:24][CH3:25])[CH3:23])#[N:2]
Reactant: CCC(C)N
Reactant: CCCCCC(=O)Nc1ccc(OCC2CO2)c(C#N)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCC(=O)Nc1ccc(OCC(O)CNC(C)CC)c(C#N)c1
Yield: 19 %

Procedure:
Ten grams (0.035 mol) of 1-(2-cyano-4-n-hexanoylamino-phenoxy)-2,3-epoxypropane were dissolved in 100 ml of ethanol, 7.3 gm (0.1 mol) of sec.butylamine were added, and the mixture was refluxed for one hour. After the solvent was distilled off in vacuo, the residue was purified by column chromatography in the manner described in Example 6. The base thus obtained was dissolved in ethyl acetate, washed with dilute NaOH and water, dried, and evaporated to dryness. The test substance remaining was recrystallized from ethyl acetate with the addition of petroleum ether. Subsequent recrystallization from acetonitrile yielded 2.4 gm of pure white crystalline base. M.p.: 72°-74° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.[F:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[NH:48][CH3:49])[C:41]([O:43][CH3:44])=[O:42]>>[F:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[N:48]([C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][N:7]1[CH2:8][CH2:9][C@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]1)[CH3:49])[C:41]([O:43][CH3:44])=[O:42]
Reactant: CNc1ccc(C(=O)OC)cc1F
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2ccccc2)C1
Agent: COCO[C@H]1CCN([C@@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cc2F)C1
Yield: 52 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 3-fluoro-4-methylaminobenzoate in 52% yield according to the procedures similar to those described in Example 29 (i).
Reaction SMILES: N#N.C(OC([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20]O)[CH2:16][CH2:15]1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.II.[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[N:48]1([CH2:20][C@@H:17]2[CH2:16][CH2:15][C@H:14]([NH2:13])[CH2:19][CH2:18]2)[CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: O=C(N[C@H]1CC[C@@H](CO)CC1)OCc1ccccc1
Reactant: C1CCNC1
Agent: II
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](CN2CCCC2)CC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of cis-4-benzyloxycarbonylaminocyclohexane-methanol (267 mg, 1.01 mmol), triphenylphoshine on polystyrene (3.20 mmol) and imidazole (97 mg, 1.42 mmol) in dry CH2Cl2 (40 mL) was added iodine (416 mg, 1.62 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. The mixture was then filtered, successively washed with 10% aq. Na2SO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude iodide was redissolved in CH3CN (15 mL) and treated with pyrrolidine (0.32 mL, 3.86 mmol) and K2CO3 (533 mg, 3.86 mmol). The reaction mixture was refluxed until completion of the reaction, filtered and concentrated under reduced pressure. The amine was purified by FC (hept-EA, 1:0->1:1) and then the Cbz group was removed by treatment with 10% Pd/C (116 mg) in EtOH (20 mL) under a H2 atmosphere. The title compound was obtained as a white solid. LC-MS-conditions 04: tR=0.99 min; [M+H]+=183.35.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:10]=[C:9]([N:11]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[S:8][C:7]=1[C:20]([O:22]C)=O.[NH3:29]>CO>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][O:5][C:6]1[CH:10]=[C:9]([N:11]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[S:8][C:7]=1[C:20]([NH2:29])=[O:22]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1c(Cl)cccc1Cl
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1c(Cl)cccc1Cl

Procedure:
In a similar manner as described for example 38, 123.1 mg of methyl 3-[(2,6-dichlorobenzyl)oxy]-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 15 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [NH2:1]O.Cl.[C:4]([CH2:12][CH2:13][CH2:14][C:15](=O)[CH3:16])(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C>[CH3:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: CC(=O)CCCC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cccc(-c2ccccc2)n1

Procedure:
To a refluxing mixture of hydroxylamine.HCl (2.1 g) in acetic acid (5 cc) was added a solution of 5-benzoyl-2-pentanone (1.9 g) (step 1) in acetic acid (5 cc) and the suspension refluxed for 3 hours. Acetic acid was then removed in vacuo, the residue treated with H2O (25 cc) and extracted with ethyl acetate (3×25 cc); the organic layer was washed with 25% aqueous NH4OAc, dilute NaHCO3 and brine. After removal of the solvent the residue was purified by chromatography to afford the title compound. p.m.r. (CD3CDCD3) δ 7.1-8.2 (m, 8H), 2.55 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:31]1[CH:32]=[CH:33][CH:34]=[N:35][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:34]4[CH:33]=[CH:32][CH:31]=[CH:36][N:35]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cc(-c3ccccn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 66.2 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol) which was prepared according to the procedure in Step F of Example 26, 5-bromopyridine (0.21 mL, 2.2 mmol) and cesium carbonate (1.08 mg, 3.3 mmol) in water (3 mL) and N,N-dimethylformamide (10 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2.5 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by column chromatography (9:1 hexanes/ethyl acetate to ethyl acetate, then 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to give 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (282 mg, 65%) as a brown oil: ESI MS m/z 387, 389 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1(OC)[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[F:18])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[O:9][N:8]=2)=[C:11]([F:18])[CH:12]=1)#[N:17]
Reactant: COC(=O)C1(OC)CC(c2ccc(C#N)cc2F)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(C(=O)O)on2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(4-cyano-2-fluoro-phenyl)-5-methoxy-4,5-dihydro-isoxazole-5-carboxylic acid methyl ester (172 mg), 1N aqueous NaOH solution (2 mL), and tetrahydrofuran (5 mL) is stirred at room temperature for 3 h. The reaction mixture is acidified with 1 N hydrochloric acid (approximately pH 3) and concentrated in vacuo. The residue is triturated with water and the precipitate is filtered off and dried to give the title compound. LC (method 18): tR=0.38 min; Mass spectrum (ESI−): m/z=231 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[N:12]([CH2:27][CH2:28][CH2:29][CH3:30])[C:11](=[O:31])[C:10]=2[CH:32]=1.[ClH:34]>O1CCOCC1>[ClH:34].[CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]([CH2:27][CH2:28][CH2:29][CH3:30])[C:11](=[O:31])[C:10]=2[CH:32]=1
Reactant: CCCCN1C(=O)c2cc(/C=C/C(=O)OC)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: CCCCN1C(=O)c2cc(/C=C/C(=O)OC)ccc2OC12CCNCC2
Yield: 99 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (182 mg, 0.397 mmol, Intermediate 7) was treated with 4 M HCl in dioxane following the procedure described in Example 1 STEP C, to give (E)-3-{3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride (157 mg, 99%). Reaction with acetaldehyde (24 μl, 0.42 mmol) and NaCN(BH3) (26 mg, 0.42 mmol) following the procedure described in Example 71, Step A, gave (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (123 mg, 80%). The ester was hydrolyzed as described in Example 71, Step B, giving (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid. The resulting acid was treated with NH2OTHP following the procedure described in Example 71, Step C, giving (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Finally, removal of THP protecting group following the procedure described in Example 71, STEP C gave (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide that was purified by preparative LC-MS and obtained as trifluoroacetate salt (18 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCC=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccccc2)CCCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-phenyl-3-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate FA) (1.03 g, 3.42 mmol) in 1,2-dichloroethane (15 ml) was treated with ethyl 7-oxoheptanoate (1.776 g, 10.25 mmol) followed by sodium triacetoxyborohydride (3.62 g, 17.09 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with saturated NaHCO3 (70 ml) and was extracted with DCM (×3). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-60% EtOAc/iso-hexane to give an oil. The product was loaded onto an Isolute™ SCX-2 cartridge, washed with MeOH and eluted with 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo to afford the title compound;
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:26][CH:25]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)OCC(OCC)=O>>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CCOC(=O)COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Agent: CCOC(=O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(O)COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 15 and making non-critical variations using ethyl {4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetate to replace ethyl {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetate, {4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetic acid was obtained (66%) as a colorless solid: mp 223-224° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.00 (s, 1H), 7.31-7.22 (m, 3H), 7.18-7.13 (m, 1H), 7.05-6.98 (m, 2H), 6.92-6.85 (m, 2H), 6.53 (s, 1H), 6.08 (s, 1H), 4.93-4.77 (m, 3H), 4.70-4.61 (m, 3H), 4.21-4.08 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 180.6, 176.6, 170.1, 157.0, 154.7, 144.1, 142.1, 137.8, 131.7, 128.7, 128.5, 123.6, 123.0, 121.2, 114.6, 110.9, 109.4, 98.8, 79.4, 64.4, 64.2, 63.5, 57.2, 42.4; MS (ES+) m/z 459.9 (M+1).
Reaction SMILES: FC1N=CC(C(N2CCN(C3C=C(C)C(C)=CC=3C)CC2)=O)=C(C)C=1.COC1C=CC(CN)=CC=1.Cl[CH2:37][CH2:38][CH2:39][S:40](Cl)(=[O:42])=[O:41].[NH2:44][C:45]1[N:50]=[CH:49][C:48]([C:51]([N:53]2[CH2:58][CH2:57][N:56]([C:59]3[CH:64]=[C:63]([CH3:65])[C:62]([CH3:66])=[CH:61][C:60]=3[CH3:67])[CH2:55][CH2:54]2)=[O:52])=[C:47]([CH3:68])[CH:46]=1>>[O:41]=[S:40]1(=[O:42])[CH2:39][CH2:38][CH2:37][N:44]1[C:45]1[N:50]=[CH:49][C:48]([C:51]([N:53]2[CH2:54][CH2:55][N:56]([C:59]3[CH:64]=[C:63]([CH3:65])[C:62]([CH3:66])=[CH:61][C:60]=3[CH3:67])[CH2:57][CH2:58]2)=[O:52])=[C:47]([CH3:68])[CH:46]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3cnc(N)cc3C)CC2)cc1C
Reactant: O=S(=O)(Cl)CCCCl
Agent: COc1ccc(CN)cc1
Agent: Cc1cc(C)c(N2CCN(C(=O)c3cnc(F)cc3C)CC2)cc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)cc3C)CC2)cc1C

Procedure:
Using (6-fluoro-4-methylpyridin-3-yl)[4-(2,4,5-trimethylphenyl)piperazin-1-yl]methanone (310 mg) described in Preparation Example 180, 4-methoxybenzylamine (2 mL) and 3-chloropropane-1-sulfonyl chloride (0.23 mL) and by the reaction and treatment in the same manner as in Example 229, the title compound (185 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(2,4,5-trimethylphenyl)piperazin-1-yl]methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[C:31]#[N:32])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1>ClCCl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:30])[C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[C:31]#[N:32])=[CH:33][CH:34]=2)=[O:10])=[CH:35][CH:36]=1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)O)c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Reaction time: 1 h

Procedure:
A flask was charged with tert-butyl 2-(4-(4-((4-chlorophenethyl) carbamoyl)phenoxy)-3-cyanophenyl)propanoate (0.098 g) in 1 ml of dichloromethane and 1 ml of TFA, and the reaction was stirred for 1 hour. The reaction was concentrated and dried under vacuum. Isolated 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl) propanoic acid (0.080 g). MS +449.1 [M+1].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:16]([O:19][C:20]1[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][C:21]=1B(O)O)[CH2:17][CH3:18]>>[C:26]([C:25]1[C:20]([O:19][CH2:16][CH2:17][CH3:18])=[C:21]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:3]=2)[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Reactant: CCCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Product: CCCOc1c(-c2cc(C=CC(=O)O)ccc2O)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 4.6 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 2.14 g (7.33 mmol) of 2-propyloxy-3,5-di-tert-butylphenylboronic acid obtained above, 70 mg (4%) of the expected compound were obtained in the form of a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:7]([CH3:32])([CH3:31])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([CH3:32])([CH3:31])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N(CCC(C)C)c2ccc3c(c2)C(C)(C)CCN3C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCN(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCN2C(C)C
Temperature: 40 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
Ethyl 4-[(1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl) (3-methylbutyl)amino]benzoate (Compound 13, 20 mg, 0.05 mmol) was dissolved in ethanol (4.0 mL) and the solution treated with 1.4 M KOH (1.0 mL). The solution was heated to 40° C. and stirred for 24 hours. The solution was cooled and concentrated under reduced pressure. The residue was diluted with water, acidified with 10% HCl, and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (15 mg, 79%) as a solid.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][CH:42]1[C:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][CH2:45][N:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[C:48]([CH3:50])([CH3:49])[CH2:47][CH2:46][CH2:45][N:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC1(C)CCCN(c2ccccc2)C(=O)C1N
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@@H]3C(=O)N(c4ccccc4)CCCC3(C)C)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-4,4-dimethyl-2-oxo-1-phenylazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (10 mg, 0.018 mmol) and Intermediate 34 (4.1 mg, 0.018 mmol) to give a white solid (4.0 mg, 27% yield). Anal. Calcd. for C45H56N4O6S m/z 780.4. found: 781.5 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 7.32 (t, J=7.70 Hz, 2H), 7.28-7.10 (m, 11H), 7.00 (d, J=7.70 Hz, 2H), 5.52 (dd, J=6.05, 2.75 Hz, 1H), 5.07-4.97 (m, 2H), 4.94-4.88 (m, 1H), 4.12-4.00 (m, 1H), 3.60 (s, 3H), 3.58-3.51 (m, 1H), 2.98-2.82 (m, 2H), 2.82-2.63 (m, 5H), 2.59-2.50 (m, 1H), 2.38-2.27 (m, 1H), 2.13-2.02 (m, 1H), 1.97 (br. s., 2H), 1.86-1.75 (m, 3H), 1.75-1.55 (m, 7H), 1.48 (s, 1H), 1.32-1.24 (m, 1H), 0.80 (s, 3H), 0.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: NCCSCCO
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCSCCO)ccc1Cl
Yield: 50.9 %

Procedure:
Prepared according to the method described in Example 2 from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.800 g, Example 1b), 2-(2-aminoethylthio)ethanol (0.584 g) and sodium triacetoxyborohydride (0.715 g) in 1,2-dichloroethane (15 ml). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a white powder (0.536 g).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])(O)=O.[Na+].[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:45]([O:47][CH3:48])=[O:46])=[CH:31][C:32]=3[N:33]3[C:39]=2[C:38]2[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=2[NH:36][C:35](=O)[CH2:34]3)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1.O>[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:45]([O:47][CH3:48])=[O:46])=[CH:31][C:32]=3[N:33]3[C:39]=2[C:38]2[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=2[NH:36][C:35](=[S:2])[CH2:34]3)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Nc1ccccc1-3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=S)Nc1ccccc1-3
Temperature: 100 °C
Reaction time: 1 h
Yield: 165.6 %

Procedure:
P4S10 (352 mg, 0.791 mmol) and NaHCO3 (554 mg, 6.60 mmol) were added to a solution of methyl 13-cyclohexyl-5H-indolo[1,2-d][1,4]benzodiazepine-6(7H)-one-10-carboxylate (511 mg, 1.32 mmol) in dioxane (10 mL). The reaction mixture was heated at 100° C. for 1 h, cooled to rt, and diluted with the dropwise addition of H2O (˜20 mL) while stirring. The resulting yellow precipitate was allowed to settle for 1 h, collected by filtration, flushed with water and dried under N2 to yield methyl 13-cyclohexyl-5H-indolo[1,2-d][1,4]benzodiazepine-6(7H)-thione-10-carboxylate (528 mg, 1.31 mmol, 99%) as yellow solid, which was used without further purification. LCMS: 405 (M+H)+, ret time 2.26 min.