Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[CH3:7][N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][C:16](=[O:20])[C:17](=[O:19])[CH:18]=[C:11]2[CH2:10][CH2:9]1>CO>[OH:20][C:16]1[C:17]([OH:19])=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH2:14][CH2:13][C:12]=2[C:15]=1[S:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC2=CC(=O)C(=O)C=C2CC1
Reactant: Sc1cccs1
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(Sc3cccs3)c2CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-thiophenethiol (0.9 g., 0.0076 mole) in 200 ml. of methanol was added portionwise 2 g. (0.0074 mole) of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione, at room temperature under argon. After stirring for 1 hour, the methanol was distilled under vacuum, the residue slurried in 30 ml. of water and filtered. The filtrate was made basic to give the product, 7,8-dihydroxy-3-methyl-6-(2-thienylthio)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 189°-191° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13](O)[CH:12]=2)[CH2:7][N:6]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:4].O=P(Cl)(Cl)[Cl:33]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13]([Cl:33])[CH:12]=2)[CH2:7][N:6]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:4]
Reactant: COC(=O)C1CC(Oc2cc(O)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)C1CC(Oc2cc(Cl)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Crude 4-(2-hydroxy-7-methoxy-quinolin-4-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.18 g, 7.60 mmol) was dissolved in POCl3 (76 mL) and heated to 40° C. overnight. The reaction mixture was concentrated in vacuo and dissolved in CH2Cl2 (40 mL). 4 N HCl in 1,4-dioxane (40 mL) was added and stirred at r.t. for 1 h. The crude material was partitioned between H2O and CH2Cl2 and pH was adjusted to 11 with NaHCO3 and 1 N NaOH. The aqueous layer was extracted with CH2Cl2 (3×150 mL). The combined organic layer was dried with Na3SO4 and concentrated. The crude product was purified by combi-flash to give 2.05 g of 4-(2-Chloro-7-methoxy-quinolin-4-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.
Reaction SMILES: Cl.[CH:2]([O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[NH:32][N:31]=2)=[CH:25][C:21]=1[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[NH:32][N:31]=2)=[CH:25][C:21]=1[C:22]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][CH:2]([CH3:4])[CH3:3])[CH2:7][CH2:8]1)=[O:23]
Reactant: CC(C)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
A solution of 4-isopropoxypiperidine hydrochloride (120 mg, 0.67 mmol) and triethylamine (0.206 mL, 1.48 mmol), in N,N dimethylformamide (2 mL) was added in one portion to a stirred solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (200 mg, 0.67 mmol), triethylamine (0.206 mL, 1.48 mmol) and O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (381 mg, 1.01 mmol) in N,N dimethylformamide (2 mL) at 25° C. The resulting solution was stirred at 25° C. for 4 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (172 mg, 60.6% yield); 1H NMR (399.902 MHz, DMSO) δ 1.06-1.11 (6H, m), 1.21-1.46 (2H, m), 1.61-1.87 (2H, m), 3.04 (1H, t), 3.62 (2H, td), 3.70 (1H, quintet), 3.92-4.01 (1H, m), 4.07 (1H, q), 4.33 (2H, s), 7.19-7.25 (1H, m), 7.32-7.37 (1H, m), 7.38-7.44 (1H, m), 7.81-7.92 (2H, m), 7.96-8.00 (1H, m), 8.26-8.29 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 424.6).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Se:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH2:15].[CH3:16][O:17][C:18]([NH:20][C:21](=NC(OC)=O)SC)=[O:19]>C(O)(=O)C.C(O)C.O>[C:9]1([Se:8][C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:21]([NH:20][C:18]([O:17][CH3:16])=[O:19])[NH:15][C:3]=3[CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc([Se]c2ccccc2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc([Se]c3ccccc3)cc2[nH]1

Procedure:
A mixture of 1,2-diamino-4-phenylselenobenzene (11.3 g. 43 mmole) and 1,3-bis(methoxycarbonyl)-2-methylisothiourea (10.3 g., 50 mmole) in glacial acetic acid (10 ml.), ethanol (100 ml.) and water (100 ml.) was boiled under reflux for two hours and allowed to cool. The reaction mixture was filtered, and the solid product was crystallised from a mixture of equal volumes of acetic acid and methanol to give methyl 5-phenylseleno-2-benzimidazolecarbamate, m.p. 238°-240° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33][CH3:34])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:42](I)[CH3:43]>C(#N)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:30]([CH2:42][CH3:43])[N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33][CH3:34])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnn[nH]2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnnn2CC)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(tetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.9 g) was dissolved in acetonitrile (190 ml). To the solution were added potassium carbonate (1.65 g) and ethyl iodide (0.76 ml), and the mixture was stirred at 50° C. for 16 hours. The solvent was concentrated to 1/3 under reduced pressure, which was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1→1/2) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(1-ethyltetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.05 g) and methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-ethyltetetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.42 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21]O>S(=O)(=O)(O)O>[CH3:21][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (500 mg, 1.89 mmol) in methanol (15 mL) was treated slowly with concentrated sulfuric acid (3 drops). The resulting reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid methyl ester (377 mg, 72%) as a white solid: mp 63-66° C.; EI-HRMS m/e calcd for C16H22O4S (M+) 310.1239, found 310.1230.
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](OCC)=[O:14])[CH3:2].C1(C)C=CC=CC=1.O.[NH2:27][NH2:28]>O>[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]([NH:27][NH2:28])=[O:14])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a 100 mL volume three-necked flask, ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate ((9-a) (10.0 g)) and toluene (35 ml) were added. Hydrazine hydrate (2.13 ml) was added dropwise thereto at 60° C. and the obtained mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature, water was added thereto and the organic layer was removed. The aqueous layer was extracted with toluene. The organic layers were combined and concentrated under reduced pressure to give 9.40 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39).
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=1>>[C:21]([C:18]1[N:19]=[CH:20][C:15]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:16][CH:17]=1)#[N:22]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: N#Cc1ccc(N)cn1
Product: N#Cc1ccc(S(=O)(=O)Cl)cn1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 5-amino-pyridine-2-carbonitrile.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[O:24])=[O:18])=[CH:29][CH:30]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: NCCCn1ccnc1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)NCCCn2ccnc2)ccn1
Yield: 88.2 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), 1-(3-aminopropyl)imidazole (24.65 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(3-imidazole-1-yl-propyl)-isonicotinamide as a colorless solid (44.4 mg, 87.85% yield).
Reaction SMILES: O[C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:4]2[N:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[N:4]2[N:3]=[CH:2][CH:14]=[C:5]2[N:6]=1
Reactant: Oc1cc2ncc3cccnc3n2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccnn2c2ncccc12

Procedure:
75 g. of hydroxypyrazolo[1,5-a]pyrido[3,2-e]pyrimidine are refluxed in 200 ml. of phosphorus oxychloride for 12 hours with stirring. The excess phosphorus oxychloride is removed in vacuo and the remaining oil poured onto ice. The aqueous solution is neutralized with sodium hydroxide and evaporated in vacuo to about 100 ml. The product, 5-chloropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine, crystallizes and is filtered off, yield: 60 g. (73%); m.p. 159.8° (ethyl acetate).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O.C(OC)(C)(C)C>[Pd].C(O)C>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CCO
Solvent: COC(C)(C)C
Product: COC(=O)N1CCc2ccc(N)cc2CC1
Yield: 99.9 %

Procedure:
A mixture of the compound from Step 1 (50 g, 200 mmol) and 10% palladium on carbon (2.5 g) in ethanol (800 mL) is hydrogenated with shaking at 20 psi. Methyl t-butyl ether is added and the mixture filtered through celite and concentrated to give 44 g (100%) of the title compound as a white solid, mp 100-104° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26].O>CC(C)=O>[CH2:25]([O:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOc1cc([N+](=O)[O-])ccc1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-hydroxy-4-nitrobenzoate (500 mg) obtained in Step A of Example 139 in acetone (5.0 mL) were added potassium carbonate (580 mg) and iodoethane (340 μL), and the mixture was stirred overnight with heating under reflux. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (550 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CC(C)CN
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and isobutylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.57 Hz, 6 H) 1.87 (dt, J=13.52, 6.63 Hz, 1 H) 2.44 (s, 3 H) 3.13 (t, J=6.32 Hz, 2 H) 7.67 (d, J=8.08 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1 H) 8.18 (br. s., 1 H) 8.43 (d, J=6.82 Hz, 2 H) 8.70 (t, J=5.31 Hz, 1 H) 8.92 (s, 1 H) 13.18 (br. s., 1 H). MS m/z [M+H]+ 376.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)=[O:11])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH:23]=1.O[Li].O.Cl>CO.O>[CH3:41][C:38]([O:37][C:35]([N:32]1[CH2:31][CH2:30][N:29]([CH2:28][C:24]2[CH:23]=[C:22]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[C:5]([CH2:8][NH:9][C:10]([C:12]4[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=4)[C:18]([OH:20])=[O:19])=[O:11])[CH:4]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:34][CH2:33]1)=[O:36])([CH3:39])[CH3:40]
Reactant: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNC(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Temperature: 80 °C
Yield: 101 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(2′-fluoro-5′-{[({3-[(methyloxy)carbonyl]phenyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperazinecarboxylate (0.26 g, 0.463 mmol) in MeOH/H2O (2/1 mL) was added LiOH.H2O (0.0971 g, 2.32 mmol). The mixture was heated with a microwave at 80° C. for 30 min. Then HCl was added to adjust the pH to ˜5. Then solvents were removed. The residue was extracted with DCM to afford the title compound 0.256 g (100%). LC-MS m/z 548 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[C:9]2/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5].Cl[C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1.C1C[O:37][CH2:36]C1>C(Cl)Cl.O>[CH3:36][O:37][C:26]1[CH:31]=[CH:30][C:29]([C:4]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][CH:10]=[C:9]3/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:5])=[CH:28][CH:27]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccc2nccc(/C=C/c3ccccc3)c2c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc3nccc(/C=C/c4ccccc4)c3c2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-N-methoxy-N-methyl-4-styrylquinoline-6-carboxamide (150 mg, 0.47 mmol) in anhydrous THF (2 mL) was dropwise added dropwise (4-chlorophenyl)magnesium bromide (0.5 M, 1.23 mL, 0.61 mmol) at 0° C. under N2 and the resulting reaction mixture was stirred at 0° C. for 3 hr. The reaction was diluted with CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organics were concentrated and purified by chromatography (15-20% EtOAc/hexanes) to yield (E)-(4-methoxyphenyl)(4-styrylquinolin-6-yl)methanone. (ES, m/z) 366.0 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33][OH:34])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([N:42]=[C:43]=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.Cl.CCOCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][C:10]=1[CH2:33][O:34][C:43](=[O:44])[NH:42][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CO
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 100 mL round bottomed flask under N2 were charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxymethylphenyl]propionic acid tert-butyl ester (3.0 g, 6.11 mmol), cyclohexylisocyanate (4.7 mL, 36.7 mmol), and anhydrous CH2Cl2 (25 mL). A 1.0 M HCl solution in ether (3.06 mL, 3.06 mmol) was added, and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 16 h. The mixture was diluted with CH2Cl2 (100 mL), washed with brine, dried (Na2SO4), and concentrated to a brown oil. This crude oil was purified using the Biotage medium pressure chromatography system (EtOAc:hexanes 5:95) to a colorless oil (3.1 g, 82%). 1H NMR (400 MHz, CDCl3) 1.08-1.24 (m, 1H), 1.26-1.40 (m, 11H), 1.56-1.62 (m, 2H), 1.68-1.72 (m, 2H), 2.41 (t, J=8.3 Hz, 2H), 2.80 (t, J=7.8 Hz, 2H), 3.47 (br s, 1H), 4.56 (br s, 1H), 4.95 (s, 2H), 6.57 (dd, J=8.3, 2.7 Hz, 1H), 6.80 (s, 1H), 6.87 (d, J=8.6 Hz, 1H), 7.33-7.44 (m, 6H), 7.69-7.72 (m, 4H). MS (ES) m/e 616 (M+1).
Reaction SMILES: CS([O:5][CH2:6][C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[I-].[Na+].[SH:32][C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CN(C)C=O>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[S:32][C:6](=[O:5])[C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)COS(C)(=O)=O
Reactant: Sc1nc2ccccc2s1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Sc1nc2ccccc2s1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
A solution of Nα-Boc-Nδ-Cbz-ornithinol methanesulfonate (100 mg), sodium iodide (70 mg), dimethylformamide (2.5 ml), 2-mercaptobenzothiazole (70 mg) and diisopropylethylamine (85 μl) was stirred at 70° C. for 12 h. After cooling to ambient temperature, the reaction mixture was poured into ethyl acetate and worked up. The crude material was chromatographed over silica gel (20 to 50 % ethyl acetate/hexane) to afford titled product (50 mg) as a white solid: 1H NMR (400 MHz, CDCl3) δ1.39 (s, 9H), 1.58-1.69 (m, 4H), 3.22 (m, 2H), 3.54 (m, 2H), 3.99 (m, 1H), 5.12 (s, 2H), 7.23-7.42 (m, 1H), 7.77 (d, J=10.3 Hz, 1H), and 7.86 (d, J=9.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[CH3:33][N:34]=[C:35]=[S:36]>C1COCC1>[CH3:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)[C:2]=1[NH:1][C:35]([NH:34][CH3:33])=[S:36]
Reactant: CN=C=S
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Solvent: C1CCOC1
Product: CNC(=S)Nc1c(C)cc(C)nc1Nc1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (300 mg, 0.66 mmol), methylisothiocyanate (56 μl, 0.86 mmol), and THF (6 ml) was stirred at room temperature for 3 days. The solvent was removed to give N-{[(2-{4-[(4,6-dimethyl -{[(methylamino)carbonothioyl]amino}-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide [MS (ESI) m/z: 527 ([M+H]+), 525 ([M−H]−)]. This was dissolved with MeCN (4 ml) and treated with Mel (54 μl) at 0° C. for 20 hours. After concentration under reduced pressure, the residue was purified by preparative TLC (EtOAc/EtOH=20/1) to afford 170 mg (52%) of the title compounds.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]3[C:5]([CH:6]4[CH2:16][CH:7]4[CH2:8][O:9]3)=[CH:4][CH:3]=2)(=[O:26])=[O:25])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Cl
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 42, 0.1 g), 4-fluoro-2-nitrobenzenesulfonyl chloride (0.115 g) and pyridine (2 mL) in DCM (5 mL) was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether (20%) to give methyl (1aRS,7bSR)-5-(4-fluoro-2-nitrobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.11 g) as a yellow oil.