Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.N1C=CN=C1.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[O:11]([C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)cc(OC)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of 3,5-dimethoxyphenol (6.73 g, 43.7 mmol) in anhydrous dimethylformamide (50 mL) were added imidazole (5.95 g, 87.4 mmol) and t-butylchlorodiphenylsilane (15.0 g, 54.6 mmol), and the mixture was stirred at 50° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane (1:2). The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene as a colorless crystalline powder (melting point: 95.5–96.5° C.) (16.14 g, yield: 94%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[C:7]2=[O:13].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[Cl:12][C:11]1[C:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:31])([F:19])[F:32])=[CH:26][CH:25]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:13])[N:6]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:5]=[CH:4]2
Reactant: C[C@@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)cc3)c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of (S)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propanamide (100.0 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylfonnamide (2 mL, 0.02 mol) was stirred at 60° C. for 3 days. The reaction was only about 40% complete. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the product as light yellow solid. MS m/z=452.1 (M+H). 1H NMR (400 MHz; DMSO-d6) δ10.21 (s, 1H), 8.15 (d, J=8.68 Hz, 1H), 7.74 (d, J=7.76 Hz, 2H), 7.66-7.58 (m, 4H), 7.49 (d, J=7.95 Hz, 1H), 7.25 (s, 1H), 6.43 (d, J=7.50 Hz, 1H), 5.47-5.42 (q, J=7.07 Hz, 1H), 3.90 (s, 2H), 1.53 (d, J=7.39 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[F:19][C:20]([F:27])([F:26])[C:21](=O)[CH2:22][S:23][CH3:24].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:21]([CH2:22][S:23][CH3:24])[C:20]([F:27])([F:26])[F:19])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CSCC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(CSC)C(F)(F)F
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a 100 ml volume three-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (3.04 g) was placed at room temperature, and added dropwise a solution of 1,1,1-trifluoro-3-methylsulfanyl-2-propanone (7-0-2) (2.29 g) in toluene (27 g). After para-toluenesulfonic acid monohydrate (0.028 g) was added, the resulting mixture was stirred under reflux for 45 minutes, and cooled to room temperature. The reaction mixture was poured into water (30 ml), and extracted with ethyl acetate (50 ml) 2 times. The resulting organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (chloroform) to give 2.13 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(1,1,1-trifluoro-3-methylsulfanyl-2-propylidene)-1-methylhydrazine ((4-46)-(1)-39).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[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].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[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: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCN2CCCCC2)ccc1Cl

Procedure:
Prepared according to the method described in Example 69 from 2-chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.1 g), piperidine (1 ml),triethylamine (0.5 ml) and tetrahydrofuran (3 ml). Purification by silica gel chromatography eluting with 5% methanol and 1% triethylamine in dichloromethane gave 2-chloro-5-(2-(piperidin-1-yl)ethylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as a glass. Conversion to the hydrochloride salt upon treatment with excess ethereal hydrochloric acid (2M) gave the title compound as a yellow solid (0.062 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Br)c4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 634.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:28][CH2:27][C@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: OC[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3CO)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into an 8-mL sealed tube, was placed a solution of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (150 mg, 0.50 mmol, 1.00 equiv), (R)-pyrrolidin-2-ylmethanol (150 mg, 1.49 mmol, 3.00 equiv), and potassium carbonate (345 mg, 2.50 mmol, 5.00 equiv) in Tol/DMSO (2.5/0.5 mL). The resulting mixture was stirred overnight at 100° C. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50). This resulted in 120 mg (63%) of (R)-methyl 3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]3[CH2:12][N:11]([C@@H:13]4[CH2:18][C@H:17]([NH2:19])[C@@H:16]([C:20]5[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=5[F:28])[CH2:15][CH2:14]4)[CH2:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.O=C1C[C@H](NC(=O)OCC2C=CC=CC=2)[C@@H](C2C=C(F)C(F)=CC=2F)CC1>CO.[Pd]>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]3[C:8](=[CH:10][N:11]([C@@H:13]4[CH2:18][C@H:17]([NH2:19])[C@@H:16]([C:20]5[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=5[F:28])[CH2:15][CH2:14]4)[CH:12]=3)[N:9]=2)[CH2:2][CH2:3]1
Reactant: N[C@H]1C[C@@H](N2Cc3cnc(C4CC4)nc3C2)CC[C@@H]1c1cc(F)c(F)cc1F
Agent: [Pd]
Agent: O=C1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OCc2ccccc2)C1
Solvent: CO
Product: N[C@H]1C[C@@H](n2cc3cnc(C4CC4)nc3c2)CC[C@@H]1c1cc(F)c(F)cc1F

Procedure:
A solution of [(1S,2R,5S)-5-[2-cyclopropyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-2-(2,4,5-trifluorophenyl)cyclohexyl]amine described in Example 2 (30.0 mg) in methanol (6 mL) was stirred with 10% palladium on carbon (6 mg) for seven days and the resulting product was purified by preparative TLC (silica, 7:93 methanol/dichloromethane) to give the title compound. LC-MS 387.3 (M+1).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[C:9]([C:13]#[N:14])[S:10][C:11]=1[Cl:12].C[O:16][S:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:25][C:21]1[CH:20]=[C:19]([S:17]([C:7]2[CH:8]=[C:9]([C:13]#[N:14])[S:10][C:11]=2[Cl:12])=[O:16])[CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc(Br)c(Cl)s1
Reactant: COS(=O)c1cccc(Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(S(=O)c2cccc(Br)c2)c(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Isopropyl magnesium chloride solution (Aldrich, 2.0 M in THF, 2.92 mL, 5.84 mmol) was added dropwise over 1.5 hours to a −78° C. suspension of 4-bromo-5-chloro-thiophene-2-carbonitrile (Example 24: step b, 1 g, 4.49 mmol) in THF (anhydrous, 20 mL) under argon. The reaction mixture was treated with 3-bromo-benzenesulfinic acid methyl ester solution (Example 24: step d, 1 g, 4.49 mmol, 10 mL of THF) in one portion at −78° C. and then stirred overnight at room temperature. Saturated ammonium chloride solution was added to the mixture and stirred for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (silica gel, 15-25% ethyl acetate/hexanes) to afford the title compound as a light yellow solid (1.33 g, 85% yield). 1H-NMR (CDCl3): δ 7.86-7.88 (m, 1H), 7.69 (dm, 1H, J=7.9 Hz), 7.64 (dm, 1H, J=7.9 Hz), 7.62 (s, 1H), 7.42 (t, 1H, J=7.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)=[N:5][C:6]([S:15][CH3:16])=[N:7]2.[OH-].[K+].Cl>O1CCOCC1>[NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)=[N:5][C:6]([S:15][CH3:16])=[N:7]2
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)[O-])ccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)O)ccc2n1
Temperature: 25 °C

Procedure:
A solution of 5-amino-2-methylthio-4-(3-aminophenyl)-quinazoline-6-carboxylate (example 27f, 658 mg) in 1,4-dioxane was treated with an aqueous solution of KOH (2 M, 4.2 ml) at 70° C. for 18 h. After the reaction mixture was cooled to room temperature, it was acidified to pH 1 with 4 N HCl. The mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the crude title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[CH3:26][S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:38][CH:37]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(S(C)(=O)=O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-[(4-methanesulfonyl-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-di-hydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 4-(methylsulfonyl)benzoic acid. MS calcd. for C27H24ClN3O5S [(M+H)+] 538.1, obsd. 538.2.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.I[C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:18]([NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N:31]2[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]2)[CH:22]=1)=[O:19]>>[CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[C:13][C:15]3[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=3[CH3:40])[C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[C:23]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)[CH:22]=3)=[O:19])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (as prepared above) in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 223-225° C.; 1H NMR (300 MHz, DMSO-d6) δ: 10.72 (1H, s), 8.31 (1H, s), 8.17-8.22 (2H, m), 7.94-7.96 (1H, dd, J=1.5 and 8.1 Hz), 7.75 (1H, s), 7.47-7.61 (4H, m), 6.77-6.80 (1H, d, J=9.0 Hz), 4.42 (1H, m), 2.56 (3H, s), 2.33-2.35 (2H, m), 2.19 (3H, brs), 1.88-1.99 (2H, m), 1.72-1.78 (2H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H26F3N6O: 531.2115. found: 531.2113.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:32]2[CH:33]=[CH:34][C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
To a solution of Boc-D-Tyrosine-Methyl ester (0.150 g, 0.508 mmol), 4-Phenoxyphenyl-boronic acid (0.109 g, 0.508 mmol), and triethylamine (0.355 mL, 2.539 mmol) in anhydrous dichloromethane (DCM) (12.5 mL) at room temperature under an atmosphere of nitrogen was added copper (II) acetate (0.070 g, 0.508 mmol), and the resulting mixture was stirred at room temperature for about 18 h. The reaction mixture was washed with 20 mL of water and 20 mL of DCM and filtered. The DCM layer was then extracted. The aqueous layer was re-extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using ethyl acetate (EtOAc)/hexane (gradient system), to obtain the product (110 mg, 47%): 1H NMR (400 MHz, CDCL3): δ 1.42 (s, 9H), 2.98-3.09 (m, 2H), 3.71 (d, J=5.2 Hz), 4.55-4.58 (m, 1H), 4.98-5.01 (m, 1H), 6.75 (d, 1H, J=8.4 Hz), 6.91-7.02 (m, 6H), 7.07-7.11 (m, 3H), 7.31-7.35 (m, 2H); MS: m/z 364 (MH)+ & no -boc group, m/z 464 (MH)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([NH:32][S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[O:31])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21](O)=[O:22])[CH2:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([NH:32][S:33]([N:36]([CH3:37])[CH3:38])(=[O:34])=[O:35])=[O:31])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]([N:60]=[N+:61]=[N-:62])=[O:22])[CH2:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)CC(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC(C(=O)N=[N+]=[N-])Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of the acid, 13-cyclohexyl-10-((((dimethylamino)sulfonyl)amino)carbonyl)-3-(methyloxy)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6-carboxylic acid, (427.2 mg, 0.79 mmol) in a mixture of PhMe/CH2Cl2 (6 ml/2 ml) at r.t. under N2 was added triethylamine (117 mg, 1.16 mmol), followed by diphenylphosphoryl azide (DPPA) (320 mg, 1.16 mmol). The mixture was stirred at r.t. for 4 hr. The volatiles were then evaporated. The residue was titurated with hydrochloric acid (3× 10 ml, 1N), dried and the crude azide, 13-cyclohexyl-10-((((dimethylamino)sulfonyl)amino)carbonyl)-3-(methyloxy)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6-carbonyl azide, was used without further purification Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=565.21, HPLC Rt=1.988 min.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14](O)([CH3:17])([CH3:16])[CH3:15].CCCCCC>S(=O)(=O)(O)O>[CH2:8]([O:7][C:5]([NH:4][C:3]1[CH:10]=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:2]=1[F:1])=[O:6])[CH3:9]
Reactant: CCOC(=O)Nc1ccccc1F
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CCOC(=O)Nc1ccc(C(C)(C)C)cc1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 111 %

Procedure:
2-Fluoro-N-ethoxycarbonylaniline (1.00 g, 5.46 mmol) prepared as described in Example 1 was dissolved in 77.6% sulfuric acid (5.00 g) to prepare a solution. t-Butyl alcohol (0.440 g, 6.01 mmol) was added dropwise to the solution under a nitrogen atmosphere over a period of 30 min while stirring and heating the solution at 70° C. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. Thereafter, t-butyl alcohol (0.440 g, 6.01 mmol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. t-Butyl alcohol (0.440 g, 6.01 mmol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. The reaction solution was cooled to room temperature. n-Hexane (10 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer. n-Hexane (10 mL) was again added to the sulfuric acid layer to carry out extraction for separation of an organic layer. The organic layers were combined, and the combined organic layer was washed with water and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 1.45 g of N-ethoxycarbonyl-4-t-butyl-2-fluoroaniline as an oily crude product (yield on weight basis 111%). The crude product was further subjected to separation and purification by column chromatography on silica gel to give 1.17 g of a mixture of 4-t-butyl-2-fluoro-N-ethoxycarbonylaniline with 5-t-butyl-2-fluoro-N-ethoxycarbonylaniline (yield 90%, 4-t-Bu: 5-t-Bu=82:18).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28]Cl)=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][I:30])=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCC(C(=O)OCCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCC(C(=O)OCI)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate (4.0 g, 9.4 mmole) in dry acetone (50 ml) was added sodium iodide (6.3 g, 42 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield 4.5 g=93%.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH:9]1[C:17]2[C:12](=[C:13]([C:18]3(O)[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:24][N:21]1[CH2:20][CH:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[CH:11]=[CH:10][NH:9]3)[CH2:23][CH2:22]1
Reactant: CN1CCC(O)(c2cccc3[nH]ccc23)CC1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Product: CN1CC=C(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of 6.4 g of the free base of Example 4 and 200 ml of lN hydrochloric acid was refluxed for 90 minutes and was then cooled to room temperature and was diluted with water. The mixture was made alkaline by addition of potassium carbonate and was then extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The 5.7 g of residue were chromatographed over silica gel and eluted with a 6-3-1 cyclohexane-chloroform-ethyl acetate mixture to obtain 2.5 g of 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 164° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([CH:15]([NH2:18])[CH2:16][CH3:17])[CH3:14]>CS(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCC(N)CC
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (250 mg, 1.21 mmol) and 1-ethyl-propyl amine (105 mg, 1.21 mmol) in DMSO (4 ml) was stirred at room temperature for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentratd to give 280 mg of yellow oil. The oil was purified through silical gel column chromatography using 65% chloroform in hexane as eluent to give 110 mg (35%) of the title compound as a yellow crystal, mp 82-84° C. 1H NMR (CDCl3) δ6.57 (d, 1H), 6.46 (s, 1H), 3.39 (m, 1H), 2.42 (s, 3H), 1.4-1.8 (m, 4H), 0.94 (t, 6H) ppm