Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:43]1COCC1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:32][CH:28]1[N:29]([CH3:43])[CH2:30][CH2:31][N:26]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:16]3[CH:17]=[C:18]4[C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[NH:1][CH:2]=[CH:3]6)=[CH:11][NH:12][C:13]4=[N:14][CH:15]=3)=[CH:20][CH:21]=2)[CH2:27]1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCNC(C)C5)cc4)cnc32)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC1CN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CCN1C
Reaction time: 1 h

Procedure:
3-(1H-indol-5-yl)-5-(4-((3-methylpiperazin-1-yl)methyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (40 mg) was suspended in 3 mL of methanol and THF (1 mL) and treated with paraformaldehyde (−50 mg) and stirred for one hour. To this was added 50 mg of sodium triacetoxyborohydride. The reaction stirred 1 hr at room temperature. The mixture was concentrated in vacuo, taken up in EtOAc and washed with water and brine and dried over MgSO4. The residue was suspended in methanol and treated with 5 N NaOH and heated at 50 C for one hour. The mixture was diluted with dichloromethane and washed with water and brine, dried over MgSO4 and purified by MPLC silica gel chromatography (0-20% MeOH in DCM) to yield an analytical sample 10 mg (436 M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[C:13](Br)[C:14]=1[NH2:15])=[O:4].[C:17]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[C:13]([CH3:17])[C:14]=1[NH2:15])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(N)c(Br)cc2ncccc12
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1c(N)c(C)cc2ncccc12
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
To 1.59 g (5.66 mmol) of 6-amino-7-bromo-quinoline-5-carboxylic acid methyl ester in 30 mL of dioxane under an atmosphere of argon is added 2.35 g (17.0 mmol) of K2CO3, 323 mg (0.28 mmol) of tetrakis(triphenylphsophine)palladium and 710 mg (5.66 mmol) of trimethylboroxine. The reaction mixture is stirred in a microwave oven at 180° C. for 10 minutes. After filtration over Celite and concentration in vacuo, the residue is purified by flash chromatography (SiO2, ethyl acetate) y to afford 550 mg of product (45%) as a yellowish solid; LC/MS:217/218 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][CH3:27])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.C(OC1C=CC2C3N(CC(C)C)C(CCC)=NC=3C(N)=NC=2C=1)C1C=CC=CC=1>>[CH2:26]([C:20]1[N:21]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)[CH3:27]
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Agent: CCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Yield: 35.8 %

Procedure:
The general method described in Part J of Example 1 was followed using 7-benzyloxy-2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (3.43 g, 9.54 mmol) in lieu of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine. The crude product was recrystallized from acetonitrile, isolated by filtration, and dried for two days in an oven at 60° C. to provide 0.92 g of 2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol as an off-white solid, mp >250° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([OH:18])=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([Cl:22])=[O:18])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)O)n2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reaction time: 2 h

Procedure:
2′-(Acetylamino)-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxylic acid, Compound (4), (100 mg; 0.35 mmol; 1 eq.) is suspended in DCM (6 ml). Oxalyl chloride (92 μl; 1.06 mmol; 3 eq.) is added followed by anhydrous dimethylformamide (5.5 μl; 0.07 mmol; 0.20 eq.). After 2 hours, a sample is quenched with MeOH, showing that the reaction is complete. The solvents are evaporated affording 2′-acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride which is used in the next step without further purification. HPLC (method A), Rt: 1.90 min (purity: 92.0%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]2[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=2[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30][S:31]([CH2:34][CH2:35][NH2:36])(=[O:33])=[O:32]>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:17][C:18]2[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=2[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][NH:36][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2ccc(C=O)cc2)ncc1F
Reactant: CS(=O)(=O)CCN
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2ccc(CNCCS(C)(=O)=O)cc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
2-({5-Fluoro-2-[(4-formylphenyl)amino]-4-pyrimidinyl}amino)-N-(1-methylethyl)benzamide (80 mg, 0.2 mmol, 1.0 eq), [2-(methylsulfonyl)ethyl]amine (100 mg, 0.6 mmol, 3.0 eq), and CH2Cl2 (2.0 mL) were added to a vessel, which was sealed and stirred at room temperature for 16 h. Solvent was removed by evaporation to leave a residue. NaBCNH4 (37 mg, 0.6 mmol, 3.0 eq) in CH2Cl2 (2.0 mL) was added was added to the residue and the reaction mixture was stirred at room temperature until the reaction was substantially complete, as determined by HPLC. The final product was purified by preparative HPLC using water (0.1% formic acid); acetonitrile (0.1% formic acid) as mobile phase. The desired compound was isolated as an off-white solid. (20 mg, 20% yield) MS: M(C24H29FN6O3S)=500.60, (M+H)+=501.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[N:9]1[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:21]=3[N:27]=2)[C:10]1=[O:28])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([C@@H:8]([N:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:21]=4[N:27]=3)[C:10]2=[O:28])[CH2:7][C:6]([OH:37])=[O:5])=[CH:34][CH:33]=1
Reactant: COc1ccc([C@H](CC(=O)OC(C)(C)C)n2ccn(CCCc3ccc4c(n3)NCCCC4)c2=O)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc([C@H](CC(=O)O)n2ccn(CCCc3ccc4c(n3)NCCCC4)c2=O)cn1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a solution of 3-7 (0.85 g, 1.67 mmol) in dichloromethane (10 mL) was added anhydrous TFA (5 mL). After 4 hours, the mixture was concentrated, diluted with toluene, and re-concentrated. The residue was chromatographed on silica gel (15:10:1:1 to 15:10:1:1 EtOAc/EtOH(NH4OH/H2O) to give 600 mg of 3-8 as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C@:4]2([C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([NH2:20])=[CH:10][CH:11]=3)[N:3]=[C:2]1[NH2:21].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO.CCOC(C)=O>[NH2:21][C:2]1[O:1][CH2:6][CH2:5][C@:4]2([C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([NH:20][C:29](=[O:30])[C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=2)=[CH:10][CH:11]=3)[N:3]=1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncccc12
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1ncccc12
Reaction time: 2 h
Yield: 29.6 %

Procedure:
The (S)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.008 g, 0.028 mmol) was dissolved in MeOH (1 mL). The 5-chloropicolinic acid (4.91 mg, 0.031 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (8.63 mg, 0.031 mmol) were added. After 2 h, additional MeOH (0.5 mL) was added, followed by additional 5-chloropicolinic acid (2.5 mg, 0.015 mmol) and additional 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (4.3 mg, 0.015 mmol). After 14 h, the reaction was taken up in EtOAc (75 mL). The organic phase was washed with half-saturated NaHCO3 (2×10 mL), then with saturated brine (10 mL), dried over MgSO4 and concentrated. The residue was purified by preparative TLC, using 12.5% MeOH-dcm to afford (S)—N-(2′-amino-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide (3.5 mg, 0.0083 mmol). MS (m/z) 422 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 9.88 (s, 1H), 8.57 (s, 1H), 8.27 (m, 2H), 7.89 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=7.4 Hz), 7.76 (m, 2H), 7.32 (d, 1H, J=8.4 Hz), 7.20 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 1.98 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C[O-].[Na+].Cl.CCO.CN1C2C(N=C(N)NC=2NCC1CNC1C=[CH:32][C:31]([C:34]([NH:36][CH:37](C(O)=O)[CH2:38][CH2:39]C(O)=O)=O)=CC=1)=O>>[C:31]12([C:32]3[O:5][N:4]=[C:1]([CH3:2])[N:3]=3)[CH2:39][CH:38]1[CH2:37][NH:36][CH2:34]2
Reactant: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Reactant: CC(N)=NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(C23CNCC2C3)n1
Yield: 82 %

Procedure:
The N-benzyl-2,5-dihydropyrrole ester was prepared, as described (Chem. Pharm. Bull. 1985, 33(7), 2762) by treating ethyl propiolate and N-(methoxymethyl)-N-(trimethylsilylmethyl)-N-benzylamine in DCM with 0.1M TFA in DCM, followed by aqueous work up and silica gel chromatography, in 44% yield. The cyclopropyl group was furnished by treatment with trimethylsulfoxonium Iodide and NaH in DMSO at room temperature, followed by aqueous work up and silica gel chromatography, in 43% yield as described in the literature (Korean J. of Med. Chem. 1994, 4(2), 119). The N-benzyl group was removed with palladium on carbon and ammonium formate in methanol. The Boc protecting group was directly installed with DMAP, TEA and Boc2O in DCM, followed by silica gel chromatography, in 60% yield for both steps. The oxadiazole ring was prepared as described above, by reaction with acetamide oxime and sodium methoxide in methyl THF. Aqueous work up and silica gel chromatography provided the intermediate in 54% yield. Standard deblocking with HCl-EtOH provided the desired product, as the HCl salt, in 82% yield.
Reaction SMILES: O[C:2]1([C:23]2[C:32]([OH:33])=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[N:4]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]1=[O:22].ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[OH:33][C:32]1[C:23]([CH:2]2[C:10]3[CH:9]=[C:8]4[O:11][CH2:12][CH2:13][O:14][C:7]4=[CH:6][C:5]=3[N:4]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]2=[O:22])=[CH:24][C:25]2[O:30][CH2:29][CH2:28][O:27][C:26]=2[CH:31]=1
Reactant: COCCOCCN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2cc3c(cc21)OCCO3
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: COCCOCCN1C(=O)C(c2cc3c(cc2O)OCCO3)c2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one was obtained (54%) as a pale yellow solid: MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH:13]([CH2:15][NH:16][CH3:17])[CH2:14][C:3]1=2.C([O-])([O-])=O.[K+].[K+].[CH3:24][N:25]=[C:26]=[O:27]>O1CCCC1>[CH3:24][NH:25][C:26](=[O:27])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[CH2:14][CH:13]([CH2:15][NH:16][CH3:17])[CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: CNCC1Cc2c(n(C)c3ccc(O)cc23)C1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNCC1Cc2c(n(C)c3ccc(OC(=O)NC)cc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-4-methyl-2-[(methylamino)methyl]cyclopent[b]indol-7-ol (1.7 g, 0.007 mole) in 30 ml of tetrahydrofuran, was added milled K2CO3 (1.2 g, 0.01 mole), followed by methyl isocyanate (0.4 ml, 0.07 mole). After stirring at ambient temperature for two hours, the mixture was filtered, and the filtrate concentrated to a yellow oil (~2 g), which was dissolved in ethyl acetate then washed with water and then dried over anhydrous MgSO4. After filtering, the solvent was evaporated to afford a tan solid, ~1.0 g, which was eluted on a silica gel column with 5% methanol/dichloromethane via HPLC. The desired fraction was concentrated to a tan foam (0.8 g, m.p. ~50° C.), which was recrystallized from ethyl ether to give the product as a tan solid, 0.6 g, m.p. 216° C. (dec).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:26][N:27]([CH3:43])[C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:42])=[CH:33][C:34](=[O:41])[N:35]2[CH2:38][CH:39]=O)=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:39][CH2:38][N:35]4[C:36]5[C:31](=[CH:30][CH:29]=[C:28]([N:27]([CH3:43])[CH3:26])[CH:37]=5)[C:32]([CH3:42])=[CH:33][C:34]4=[O:41])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(CC=O)c2cc(N(C)C)ccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(N(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To 2 mL of a chloroform solution containing 0.21 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.15 g of (7-dimethylamino-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 10 μL of acetic acid and 0.20 g of sodium triacetoxyborohydride were added, and stirred at room temperature overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate: 8 mol/L ammonia/methanol=50:1], to give 0.14 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-dimethylamino-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]([NH:9][CH:3]([CH2:4][CH2:5]2)[CH2:2]1)=[O:8].[ClH:10].[CH3:11][OH:12]>>[ClH:10].[NH2:9][C@@H:3]1[CH2:4][CH2:5][C@H:6]([C:7]([O:12][CH3:11])=[O:8])[CH2:1][CH2:2]1
Reactant: CO
Reactant: O=C1NC2CCC1CC2
Agent: Cl
Product: COC(=O)[C@H]1CC[C@@H](N)CC1
Reaction time: 8 h

Procedure:
Dissolve 3-isoquinuclidone (1.5 g) in methanol (50 mL) and saturated with HCl. Let stand overnight then warm to reflux for 16 hours. Evaporate the solvent in vacuo to give cis-4-amino-cyclohexanecarboxylic acid, methyl ester hydrochloride as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A reaction vessel was charged with 15 g of 4-hydroxy-4'-bromobiphenyl, 14 g of octyl bromide, 16 g of potassium carbonate and 100 ml of MEK, and the mixture was refluxed with stirring for 8 hours (the disappearance of the starting materials was confirmed by GLC). The reaction liquid was filtered to remove solids. The filtrate was concentrated and the residue was recrystallized from acetone to obtain 18 g (90%) of 4-octyloxy-4'-bromobiphenyl.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>>[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([S:59]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])(=[O:61])=[O:60])=[CH:55][CH:54]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 38 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-chlorobenzenesulfonyl chloride as described in example 2, affording the title compound in 38% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.[NH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[SH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2.[OH-].[Na+]>COCC(O)=O.O.ClCCl>[CH3:1][O:2][CH2:3][C:4]1[S:18][C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Nc1cnc2ccccc2c1S
Reactant: COCC(=O)Cl
Agent: COCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COCc1nc2cnc3ccccc3c2s1
Temperature: 140 °C

Procedure:
Methoxyacetyl chloride (1.8 mL) was added to a mixture of 3-aminoquinoline-4-thiol (2.8 g) in methoxyacetic acid (15 mL). The reaction was heated at about 140° C. for 1 hour and then allowed to cool to ambient temperature. The reaction mixture was diluted with a small amount of water, made basic with 10% sodium hydroxide and then extracted with dichloromethane (300 mL). The extract was washed with sodium bicarbonate, washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide crude product as a dark oil. The oil was dissolved in dichloromethane and then placed on a layer of silica gel. The silica gel was eluted with 1:1 hexane:ethyl acetate. The eluant was concentrated under vacuum to provide 2.3 g of 2-(methoxymethyl)thiazolo[4,5-c]quinoline as an orange solid.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31].[CH:32]1([C:35]#[C:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:32]1([C:35]2[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]4[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=4[F:30])[N:15]3[N:14]=2)[CH2:34][CH2:33]1
Reactant: Cc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Reactant: COC(=O)C#CC1CC1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C2CC2)nn2c(OCc3c(F)cccc3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
1.0 g (2.22 mmol) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 7.2 ml of DMF, and 496 mg (4.00 mmol) of methyl 3-cyclopropylprop-2-ynoate were added. 552 mg (4.00 mmol) of potassium carbonate were added and the mixture was stirred at RT for 3 h. Subsequently, the mixture was poured onto 50 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 384 mg of the title compound were obtained (46% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([Cl:13])[CH:9]=[CH:8]2.[Br:14]Br.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>CO>[Br:14][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11]2
Reactant: COc1cccc2ccc(Cl)nc12
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Br)c2ccc(Cl)nc12
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of 8-methoxy-2-(chloro)quinoline CAS [74668-74-9] (1.0 g, 4.4 mmol) in MeOH (6.25 mL) was treated with a 1.5 N solution of bromine in MeOH (3.53 mL, 5.3 mmol) over 15 min period. The reaction mixture was stirred 2 h, treated with a 1 N aqueous Na2S2O3 solution (20 mL) followed by EtOAc (100 mL). The organic portion was washed with brine followed by a saturated aqueous solution of NaHCO3 followed by brine. The organic phase was dried over Na2SO4, filtered, evaporated, and purified by silica gel chromatography eluting with CH2Cl2 to afford titled compound as a colorless solid (49%). 1H NMR (CDCl3) 8.44 (dd, J=8.8, 1.2, 1H), 7.73 (dd, J=8.4, 1.2, 1H), 7.51 (dd, J=8.8, 1.2, 1 H), 6.97 (d, J=8.4, 1H), 4.06 (s, 3H). LC/MS 3.45 min, [M+1]+ 271/273.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([CH2:8][CH3:9])[CH2:6][OH:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([CH2:8][CH3:9])[CH2:6][O:7][S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CC[C@H](CO)Cc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](COS(C)(=O)=O)Cc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
A flask was charged with 7.2 g (36 mmol) of (S)-2-(2,4-difluoro-benzyl)-butan-1-ol and 30 mL of dichloromethane, and the solution was cooled to 0° C. To this solution was added 7.53 mL (54 mmol) of triethylamine, and the mixture was stirred cold for 5 minutes. Then 3.1 mL (39.6 mmol) of methane sulfonyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The dichloromethane was removed under reduced pressure, and the residue was partitioned between 1 N HCl aq. and diethyl ether. The ether layer was collected and washed with sat. aq. sodium bicarbonate, water, and brine. The ether layer was dried over sodium sulfate, filtered, and the ether was removed under reduced pressure. This procedure gave 9.54 g (95% yield) of (2S)-methanesulfonic acid 2-(2,4-difluoro-benzyl)-butyl ester as an orange oil. This material was used without further purification.