Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].[OH-].Cl>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)C1(c2ccc3[nH]ccc3c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2ccc3[nH]ccc3c2)CC1
Temperature: 45 °C
Yield: 87 %

Procedure:
To a solution of methyl 1-(1H-indol-5-yl)cyclopropanecarboxylate (1.74 g, 8 mmol) in CH3OH (50 m L) and water (20 mL) was added LiOH (1.7 g, 0.04 mol). The mixture was heated at 45° C. for 3 hr. Water was added and the mixture was acidified with concentrated HCl to pH ˜3 before being extracted with EtOAc (20 mL×3). The organic layers were dried over anhydrous Na2SO4 and evaporated to give 1-(1H-indol-5-yl)cyclopropanecarboxylic acid (1.4 g, 87%). 1H NMR (300 MHz, DMSO-d6) 7.43 (s, 1H), 7.30-7.26 (m, 2H), 7.04 (dd, J=1.5, 8.4 Hz, 1H), 6.35 (s, 1H), 1.45-1.41 (m, 2H), 1.14-1.10 (m, 2H).
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.C1(C2C=CC(C([N:19]3[C:25]4[CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=[CH:29][C:24]=4[CH2:23][N:22]4[C:34](C(N5CCN(C)CC5)=O)=[CH:35][CH:36]=[C:21]4[CH2:20]3)=O)=CC=2)CCCCC1.CO>Cl>[CH3:33][O:32][C:30]([C:27]1[CH:28]=[CH:29][C:24]2[CH2:23][N:22]3[CH:34]=[CH:35][CH:36]=[C:21]3[CH2:20][NH:19][C:25]=2[CH:26]=1)=[O:31]
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(C3CCCCC3)cc1)Cc1ccc(C(=O)N3CCN(C)CC3)n1C2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(c1)NCc1cccn1C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 500.2 %

Procedure:
To a stirred solution of tin(II) chloride dihydrate (23 g, 3.5 equiv.) in 2 N hydrochloric acid (106 mL) was added the [4-(2-formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acid methyl ester of Step A (8 g). Methanol (200 mL) was then added and the reaction mixture was stirred at 40° C. for 2 hours. The reaction was then cooled to room temperature, quenched by the addition of saturated aqueous sodium carbonate (20 mL) and filtered through Celite. The filter pad was washed with methanol and hot ethyl acetate. The filtrate and washings were combined, concentrated in vacuo to a volume of 300 mL and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of 200 mL. Acetic acid (1 g) and 10% palladium on charcoal (1.5 g) were added and the mixture was hydrogenated overnight at atmospheric pressure. The reaction was then filtered through Celite and the solvent removed in vacuo to give a dark brown crystalline solid (16.4 g). This was dissolved in dichloromethane and filtered through a silica gel pad eluting with dichloromethane to provide the title compound which was recrystallized from 1,2-dichloroethane to yield a yellow crystalline solid (5.7 g), m.p. 198–200° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([CH3:12])=[CH:4][CH:3]=1.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.C[N:23](C=O)C>>[Cl:1][C:2]1[C:7]([C:8]([NH2:23])=[O:9])=[C:6]([F:11])[C:5]([CH3:12])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(Cl)c(C(N)=O)c1F

Procedure:
To 6-chloro-2-fluoro-3-methylbenzoic acid (10 g, 53 mmol) is added CH2Cl2 (60 mL), DMF (0.5 mL) and oxalyl chloride (9.25 mL, 106 mmol). The reaction mixture is allowed to stir until it reaches homogeneity and is then concentrated in vacuo. The residue is poured onto a 50:50 mixture of ice and 36% ammonium hydroxide to yield 6-chloro-2-fluoro-3-methylbenzamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>ClCCl>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])(=[O:32])=[O:31]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNS(=O)(=O)c1ccc(Cl)cc1Cl
Reaction time: 4 h
Yield: 4.1 %

Procedure:
To a solution of 33 mg of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 25 mg of 2,4-dichlorobenzenesulfonyl chloride in 0.8 ml of dichloromethane was added 40 μl of pyridine under ice-cooling, and stirring was continued at room temperature for 4 hours. After removing the solvent, to the residue were added 1.0 ml of ethanol and 0.3 ml of 2N aqueous sodium hydroxide, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water, and neutralized with 2N hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. Then, the residue was purified by HPLC using a reverse-phase column by using an elution solvent of water-acetonitrile-trifluoroacetic acid system, to give 2.0 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH:11]1[CH:6]2[CH2:7][C:8]([CH3:19])([CH3:18])[CH2:9][CH2:10]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28].N#N.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH:12]([C:25]1[CH:24]=[CH:23][C:22]([O:27][CH3:28])=[CH:21][CH:26]=1)[CH:11]1[CH:6]2[CH2:7][C:8]([CH3:19])([CH3:18])[CH2:9][CH2:10]1
Reactant: COc1ccccc1Br
Reactant: COc1ccc2c(c1)C1CC(C)(C)CCC1CC2=O
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C2C(=O)c3ccc(OC)cc3C3CC(C)(C)CCC32)cc1
Yield: 89.6 %

Procedure:
Using a 2 neck v shaped flask, combine 6-Methoxy-3,3-dimethyl-2,3,4,4a,10,10a-hexahydro-1H-phenanthren-9-one (1.3 g, 4.9 mmol), and 4 bromoanisole (0.16 ml, 4.9 mmol) in dioxane (40 ml) exchange with N2 add sodium t-butoxide, Add Pd[P(C4H9)3]2 exchange with N2. Heat at 80° stirring over night. Keeping reaction under N2 quench with acetic acid (6 ml). Dilute with ethyl acetate (50 ml), wash with saturated aqueous sodium bicarbonate 3× (50 ml), with brine (40 ml), dry, and concentrate. Chromatograph residue on an biotage eluting with 0-10% ethyl acetate in hexanes to give the title compound (1.6 g, 90%): 1H NMR (CDCl3) δ 8.02-7.99 (d, 1H), 7.07-7.05 (d, 2H), 6.9-6.88 (d, 2H), 6.85-6.82 (dd, 1H), 6.69-6.68 (d, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.17-3.12 (m, 1H), 2.68-2.62 (m, 1H), 1.68-1.60 (m, 1H), 1.52-1.44 (m, 3H), 1.41-1.37 (m, 1H), 1.30-1.24 (m, 1H), 1.18-1.13 (m, 1H), 1.1 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:25](=[O:27])[CH3:26])[CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C(Cl)(Cl)Cl>[CH2:18]([O:17][C:15]1[CH:14]=[C:13]([C:25](=[O:27])[CH2:26][Br:1])[CH:12]=[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 22.2 %

Procedure:
A solution of 2.4 mL (46 mmol) of Br2 in 45 mL of CHCl3 was added dropwise over 1 h to a chilled, stirring solution of 9.66 g (29 mmol) of 3′,5′-dibenzyloxyacetophenone (45) in 40 mL of CHCl3. The resulting solution was allowed to warm to room temperature over 1 hour with good stirring, then poured into 100 mL of cold H2O and transferred to a separatory funnel where the CHCl3 fraction was isolated, washed with brine solution, dried (Na2SO4), filtered, and concentrated to 10.8 g. This material was applied to 500 g of silica gel, eluting with CHCl3 to obtain 2.65 g (22%) of compound 46 as a white solid. 1H NMR (CDCl3) δ 4.39 (s, 2H), 5.08 (s, 4H), 6.85 (t, 1H, J=2.1 Hz), 7.20 (d, 2H, J=2.4 Hz), 7.31-7.44 (m, 10H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][SH:10].[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:20])=[O:21])[CH:15]=[CH:16][C:17]=1[S:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH3:3]
Reactant: COCCOCCS
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCSc1ccc(S(N)(=O)=O)cc1Cl
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL microwave tube was added sodium hydride (0.6 g) in terahydrofuran (10 mL) to give a suspension. 2-(2-Methoxyethoxy)ethanethiol (1 g) was added slowly. After stirring for 30 minutes, 3-chloro-4-fluorobenzenesulfonamide (1.54 g) dissolved in 10 mL tetrahydrofuran was added slowly. The mixture was heated at 110° C. for 30 minutes in a Biotage Initiator microwave reactor. Water was added, the product was extracted with ether (20 mL×3), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica eluting with 0-25% ethyl acetate in hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19]>>[CH3:12][C:10]1([CH3:11])[C:13]([CH3:15])([CH3:14])[O:16][B:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])[O:9]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: [K+]
Product: CC1(C)OB(c2ccccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)OC1(C)C

Procedure:
The title compound was prepared by coupling 2-aminobenzeneboronic acid pinacol ester and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (prepared in Example 11, step (d)) according to the procedure in Example 32, step (c). Mass spectrum (ESI, m/z): Calcd. for C23H33BN4O4Si, 469.2 (M+H), found 468.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH2:17]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35])[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH2:17]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:35])[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Oc1ccc(Cl)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. methylene chloride is added 10.4 g. 2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated and the residue is crystallized from diisopropyl ether.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:22]([O-])=O)=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[Cl:21])[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[NH2:22])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2Cl)c1N
Temperature: 70 °C
Yield: 72.5 %

Procedure:
A suspension of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-chloro-4-iodo-phenyl)-amine (Intermediate 10, 0.823 g, 1.8 mmol) in ethanol (12 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (0.920 g, 5.3 mmol) in water (2.4 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and the organic phase was dried over anhydrous Na2SO4 and concentrated to yield 6-allyloxy-N2-(2-chloro-4-iodo-phenyl)-3,4-difluoro-benzene-1,2-diamine as an off-white solid (570 mg). 1H-NMR (400 MHz, CDCl3): δ 3.86 (2H, bs), 4.54 (2H, d, J=5.2), 5.34 (1H, d, J=10.8), 5.42 (1H, d, J=17.2), 5.66 (1H, bs), 6.02-6.09 (1H, m), 6.20 (1H, d, J=8.4), 6.62-6.66 (1H, m), 7.33 (1H, dd, J=2, 8.4), 7.63 (1H, d, J=2).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([N:21]1[C:32]2[C:24](=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28]C(C(O)=O)=[CH:26]3)[CH2:23][CH2:22]1)(=[O:20])[NH2:19].C(N(CC)CC)C>CN(C=O)C>[C:18]([N:21]1[C:32]2[C:24](=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:26]3)[CH2:23][CH2:22]1)(=[O:20])[NH2:19]
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Reactant: NC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 1 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol, H. B. Gamper, M. W. Reed, T. Cox, J. S. Virosco, A. D. Adams, A. A. Gall, J. K. Scholler and R. B. Meyer,Jr. Nucleic Acids Res., 1993, Vol. 21, No.1, 145-150) was added dropwise to a solution of 3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid (1.4 g, 6.1 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J.Orq.Chem., 1987, Vol.52, 1521-1530) and triethylamine (1.4 ml, 10 mmol) in 15 ml of anhydrous DMF. After 1 hr, the reaction mixture was concentrated under vacuum (0.2 mm). The residue was triturated with 2 ml of dry dichloromethane. Ethyl ether (50 ml) was added and the mixture was left at 0° C. overnight. The precipitate was collected by filtration on sintered glass funnel, washed first with 50% ether/CH2Cl2 (10 ml), then with ether (50 ml) and dried in vacuo. The product was obtained as a yellow solid (1.8 g, 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.32 (s, 1H, NH), 8.13 (d, 1H, J=9 Hz, C4-H), 8.01 (m, 1H, C6F4H), 7.41 (s, 1H, C8-H), 7.26 (d, 1H, J=9 Hz, C5-H), 6.17 (s, 2H, CONH2), 3.99 (t, 2H, J=9 Hz, NCH2CH2), 3.30 (t, 2H, J=9 Hz, NCH2CH2). Anal. Calcd. for C18H11N3O3F4×2H2O: C, 50.3; H, 3.52; N, 9.7. Found; C, 50.81; H, 3.60; N, 9.95.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:45])[C:7](=[CH2:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:34])[CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24]CC2C=CC=CC=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:33])[CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
175 mg of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in the presence of 12 mg of [Ru2Cl4 (S-Binap)2 ]·(NEt3) in 30 ml of methanol for 20 hours at room temperature and under 30 bar. The reaction mixture is filtered, concentrated by evaporation and purified by means of FC (hexane/ethyl acetate=1:1). The title compound so obtained (Rf in hexane/ethyl acetate=1:1)=0.15 is deprotected by hydrogenation with 90 mg of 10% Pd/C in 10 ml of methanol at room temperature and under normal pressure to form N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([N:19]([CH2:24][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:26][CH2:27][OH:28])[CH2:20][CH2:21][O:22][CH3:23])=[O:18])[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([N:19]([CH2:24][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:26][CH2:27][O:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:21][O:22][CH3:23])=[O:18])[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: COCCN(CC(CCO)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
0.526 g of methanesulfonyl chloride are added to a mixture of 1.8 g of the product obtained in step 4 and 0.46 g of triethylamine in 40 ml of dichloromethane. The reaction mixture is stirred at ambient temperature for 1 h and is then concentrated under vacuum. The residue is taken up with ethyl acetate, washed with water, dried over Na2SO4 and concentrated under vacuum to give 2 g of the expected product
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>CC(O)C>[N:1](=[CH:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:4]([CH3:3])[CH:5]=1)[NH2:2]
Reactant: Cc1cc(Nc2ncnc3ccc(C=O)cc23)ccc1Oc1ccccc1
Reactant: NN
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3ccc(C=NN)cc23)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(6-Hydrazonomethylquinazolin-4-yl)-(3-methyl-4-phenoxyphenyl)amine is prepared by adding hydrazine (50 mg, 1.00 mmol) to a solution of 4-(3-methyl-4-phenoxyphenylamino)-quinazoline-6-carbaldehyde (250 mg, 0.70 mmol) in a 1:1 mixture of DCM:IPA (6 mL). After stirring at room temperature for 4 hours, excess hydrazine and solvent are removed under reduced pressure to give the desired hydrazone as a brown solid which is carried forward without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH3:10])=[CH:3][C:2]=1[N:1]1[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: COc1ccc(C)c(N)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COc1ccc(C)c(-n2cccc2)c1
Temperature: 25 °C

Procedure:
A solution of 88.4 g (0.64 mole) of 3-amino-4-methylanisole in 1.4 liters of glacial acetic acid is heated to 106° and, at this temperature, 114 g (0.86 mole) of 2,5-dimethoxytetrahydrofuran are added in the course of 30 minutes. The mixture is then immediately cooled to room temperature and concentrated in a vacuum rotary evaporator. Distillation of the residue in a high vacuum yields 4-methyl-3-(pyrrol-1-yl)-anisole, b.p. 93°-95°/0.04 torr. Rf (toluene/ethyl acetate=10:1):0.57.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][S:9][CH:10]=1)CCC.Cl[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]>>[N+:25]([C:24]1[CH:23]=[CH:22][S:21][C:20]=1[C:6]1[N:7]=[CH:8][S:9][CH:10]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Product: O=[N+]([O-])c1ccsc1-c1cscn1

Procedure:
4-(3-Nitrothiophen-2-yl)thiazole was prepared from 4-(tributylstannyl)thiazole (0.51 g, 1.31 mmol) and 2-chloro-3-nitrothiophene (0.21 g, 1.31 mmol) according to protocol E. Retention time (min)=2.012, method [1], MS (ESI) 212.9 (M+H).
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ccc2nc3ccccc3c(N)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C=Cc1ccc2nc3ccccc3c(N)c2c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a 10 mL rbf equipped with a nitrogen bubbler were charged 3-bromo-9-aminoacridine 5 (120 mg, 0.44 mmol), tert-butyl acrylate (75 μL, 0.48 mmol) and anhydrous DMF (1 mL). Tri-(O-tolyl)phosphine (25 mg, 0.08 mmol) and palladium (II) acetate (6 mg, 0.03 mmol) were added. The reaction mixture was stirred at room temperature and degassed by applying nitrogen flow and vacuum successively (3 times). The mixture was finally placed under nitrogen atmosphere and triethylamine (185 μL, 1.32 mmol) was added. The red-orange solution was heated to 110° C. for 3 hours and then cooled to room temperature. The brown-orange solution was filtered through Celite and washed with ethyl acetate. This organic layer was then washed with water and concentrated in vacuo to give the crude product as an orange oil. Purification by Flashmaster II using a gradient elution (DCM→DCM:MeOH 60:40) afforded pure 3-(9-amino-acridin-2-yl)-acrylic acid tert-butyl ester 6 as an orange solid (75 mg, 53%). 1H NMR and LCMS analyses conformed to structure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=2)[N:8]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[N:8]=1
Reactant: CCOC(=O)CCc1cc(-c2ccc(C)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(CCCO)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.8 %

Procedure:
To a solution of ester 17c (0.11 g, 0.27 mmol) in 5 mL of THF was added LiAlH4 (32 mg, 0.85 mmol). The reaction mixture was stirred for 6 hours at room temperature. EtOAC (10 mL) and water (5 mL) were added successively. The solvent was removed in vacuo and the resulting solid was filtered. The crude product was purified by column chromatography (EtOAc/Hexanes in adequate proportions) to give the titled compound (80 mg, 81%) as a white solid. mp 123.4-125.6° C. 1H NMR (300 MHz, DMSO-d6): δ 7.79 (d, J=9 Hz, 2H), 7.47-7.42 (m, 2H), 7.39 (d, J=9 Hz, 2H), 7.20 (d, J=8 Hz, 2H), 7.13 (d, J=8 Hz, 2H), 6.49 (s, 1H), 4.52 (t, J=5 Hz, 1H), 3.53-3.45 (m, 2H), 2.73-2.59 (m, 2H), 2.31 (s, 3H), 1.87-1.75 (m, 2H).
Reaction SMILES: [OH-].[K+].C(N(CC)C(=O)[S:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C>CO.C1COCC1>[SH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CCN(CC)C(=O)Sc1cc(OC)c(OC)cc1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(S)c(C(=O)c2ccccc2)cc1OC
Temperature: 25 °C
Yield: 87.8 %

Procedure:
Potassium hydroxide pellets (58.6 g) was slowly added to a solution of the product (85.0 g) from step (j) dissolved in 1 L of methanol/THF (1:1). After refluxing for 3 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was triturated with 1N HCl then extracted with EtOAc. The organic layer was separated, washed with 2×250 ml of 1N HCl then washed with 3×400 ml of 1N NaOH. The aqueous basic layers were combined and acidified with conc. HCl to afford the title product (54.8 g) as a gold solid. 1H NMR was consistent with the proposed structure.