Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH:13]([N:26]1[CH2:29][CH:28]([CH2:30]OS(C)(=O)=O)[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH:13]([N:26]1[CH2:29][CH:28]([CH2:30][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([F:3])[CH:12]=3)[CH:8]=[CH:9]2)[CH2:27]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc2ccn(CC3CN(C(c4ccccc4)c4ccccc4)C3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a suspension of sodium hydride (60% mineral oil dispersion, 0.19 g, 4.6 mmol) in anhydrous DMF (20 mL) was added 6-fluoroindole (0.65. g, 2.6 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then a solution of methanesulfonic acid 1-benzhydryl-azetidine-3-ylmethyl ester (0.78 g, 2.3 mmol) in DMF was introduced at 0° C. The resulting mixture heated at 60° C. for 16 hours. The reaction was quenched with water and extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (10-30% ethyl acetate-hexane). The product-containing fractions were concentrated under vacuum to give 0.60 g (52%) of the title compound as a light brown oil. MS ES m/e 371 (M+H)+; 1H NMR (500 MHz, DMSO-D6): 2.76-2.79 δ (m, 3H), 3.05-3.07 δ (m, 2H), 4.29-4.31 δ (m, 3H), 6.37 δ (m, 1H), 6.78-6.83 δ (m, 1H), 7.09-7.13 δ (m, 2H), 7.18-7.22 δ (m, 4H), 7.31-7.35 δ (m, 6H), 7.46 δ (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH:5]=O.[N+:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])([O-:20])=[O:19]>C(OC(=O)C)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]([N+:18]([O-:20])=[O:19])=[CH:5][C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])=[CH:3][N:2]([CH3:17])[CH3:1]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CC(=CN(C)C)c1ccc(Cl)cc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of 73.1 g (0.29 mol) of the compound of Example 13, 34.0 g (0.29 mol) of methyl nitroacetate and 600 ml of acetic anhydride was stirred and heated at 90°-95° for 45 minutes. The reaction mixture was allowed to cool to room temperature and the crystalline product was collected by filtration. The filtrate was concentrated in vacuo and the residue was slurried with ether (200 ml.) and filtered. The combined materials were washed with ether and dried to give 91.0 g (89%) of red orange crystals, m.p. 193°-197°. Recrystallization from benzenedimethylformamide (6:1,1725 ml) afforded 78.8 g (77%) of product, m.p. 198°-200°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:13][CH2:14][CH2:15][CH2:16][N:7]1[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:9]=[N:8]1
Reactant: ClCCCBr
Reactant: Clc1ccc2nn[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: ClCCCn1nnc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
6-chloro-1H-benzotriazole (15.4 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 3-chlorobromopropane (31.4 g, 0.10 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Post treatment was performed based on common method two for synthesis. The solution was separated and purified by HPLC to produce 7.3 g of 1-(3-chloropropyl)-6-chloro-1H-benzotriazole, with a yield of 31.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[C@H:16]([CH3:27])[CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:14]3[CH2:19][CH2:18][NH:17][C@H:16]([CH3:27])[CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(C2(c3ccc(Cl)cc3)CCCCC2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CN(C2(c3ccc(Cl)cc3)CCCCC2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of (R)-tert-butyl 4-(1-(4-chlorophenyl)cyclohexyl)-2-methylpiperazine-1-carboxylate (0.80 g, 2.03 mmol) in 1,4-dioxane (5 mL) at 0° C. was added dropwise a saturated solution dioxane-HCl (4 mL). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was washed with ethyl acetate. The pH of the residue was adjusted to 7 using aqueous 10% sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 0.5 g of (R)-1-(1-(4-chlorophenyl)cyclohexyl)-3-methylpiperazine.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Methyl (7R)-7-[(tert-butoxycarbonyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.14 M) in DCM was treated with TFA (10 eq) and stirred at RT for 1 h. The reaction was diluted with DCM and cautiously basified with aq. NaHCO3, before separating the phases and extracting the aqueous with DCM. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the product as an off-white foam (100%) that was used without further purification. (ES+) m/z 405 (M+H)+; [α]D, +42.3, c=1, MeOH
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18].ClCC(OCC)=O.O>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[N:15]1[CH2:16][C:17]([CH3:20])([CH3:18])[O:19][CH2:1][C:2]1=[O:4]
Reactant: Cc1cccc(NCC(C)(C)O)c1Br
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(=O)CCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(N2CC(C)(C)OCC2=O)c1Br

Procedure:
To a solution of potassium tert-butoxide (472 mg, 4.21 mmol) in THF (4 mL) was added a solution of 1-(2-bromo-3-methylphenylamino)-2-methylpropan-2-ol (724 mg, 2.80 mmol) in THF (10 mL), followed by ethyl 2-chloroacetate (0.45 mL, 4.21 mmol). After 1 h at RT an additional 1 eq of potassium t-butoxide (472 mg, 4.21 mmol) and ethyl 2-chloroacetate (0.450 mL, 4.21 mmol) were added. After 6 h water was added, followed by EtOAc. The organic phase was separated, dried over MgSO4 and the solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography (30-80% EtOAc/hexanes). 4-(2-Bromo-3-methylphenyl)-6,6-dimethylmorpholin-3-one was isolated as a light-yellow solid.
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: COc1ccc(OCCCCCCI)c(Cl)c1
Reactant: CCOP(=O)(CC(C)=O)OCC
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 19.3 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)6, R is C2H5, R' is CH3CO] was prepared from 0.47 g of lithium hydride, 11.6 g of diethyl acetonylphosphonate and 22 g of 6-(2-chloro-4-methoxyphenoxy)hexyl iodide according to the procedure of Example 2(b). The product was chromatographed on Florisil and further purified by preparative TLC on silica gel to give 5.0 g of diethyl [1-acetyl-7-(2-chloro-4-methoxyphenoxy)heptyl]phosphonate as a yellow oil; MIC vs. herpes simplex type 2=6 mcg/ml. The IR and NMR spectra were consistent with the assigned structure.
Reaction SMILES: C([O:3][C:4](=[O:17])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.[OH-].[Na+].O1CCCC1>CO>[CH2:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([OH:17])=[O:3])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@@H]1CCCN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
N-Benzyl-L-proline ethyl ester (1.00 g, 4.3 mmol) was combined with aqueous 2N sodium hydroxide (5.0 mL, 10.0 mmol), tetrahydrofuran (2.0 mL) and MeOH (2.0 mL) and the mixture stirred at rt. until hydrolysis was complete. The mixture was then treated in a manner similar to preparation 104. Concentration of the filtrate netted 0.79 g (90%) of crude acid as a light yellowish solid. MS(ES): (M+1)+ 206.3, 207.3.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:7]([OH:15])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:1]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:7]([O:15][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCCc1cc2ccccc2c(O)c1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCCc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccc(F)cc1
Yield: 78 %

Procedure:
3-Butyl-2-(4-fluorophenyl)-1-naphthalenol (166) (0.25 g, 0.83 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMSO at 100° C. to give 0.26 g (78%) of the title compound (167) as a colorless viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J=7.3 Hz, 3H), 1.20-1.30 (m, 2H), 1.40-1.50 (m, 2H), 2.56 (t, J=7.9 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 7.06-7.14 (m, 2H), 7.40 (t, J=7.6 Hz, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.71 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 9.81 (s, 1H). LCMS (ESI): m/z 399 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11].Br[CH2:19][CH2:20]Br>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([C:13]2([C:14]([O:16][CH3:17])=[O:15])[CH2:20][CH2:19]2)[CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11]
Reactant: BrCCBr
Reactant: COC(=O)Cc1cc(F)c(OC)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cc(F)c(OC)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
Sodium hydride (0.326 g, 8.14 mmol) was added in one portion to methyl 2-(3,5-difluoro-4-methoxyphenyl)acetate (1.76 g, 8.14 mmol) in DMF (46.3 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. Following this 1,2-dibromoethane (0.772 mL, 8.96 mmol) was added to the reaction mixture and the solution was stirred for 5 minutes. Additional sodium hydride (0.326 g, 8.14 mmol) was then added and the reaction allowed to stir for 2 hours. The reaction mixture was quenched with saturated NH4Cl (50 mL). The reaction mixture was diluted with EtOAc (75 mL), and washed sequentially with water (4×50 mL) and saturated brine (50 mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution at 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(3,5-difluoro-4-methoxyphenyl)cyclopropanecarboxylate (1.540 g, 78%) as a colourless gum.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].C(OCC)(=O)C.[OH-].[NH4+:24]>>[NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:8][C:3]=1[C:4]([NH2:24])=[O:5]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(S(N)(=O)=O)c(F)cc1N
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(S(N)(=O)=O)c(F)cc1N
Reaction time: 65 h
Yield: 60 %

Procedure:
A mixture of 4.8 g (0.0193 molecule) of methyl 2-amino-4-fluoro-5-sulphamylbenzoate (7) in 75 ml of concentrated ammonium hydroxide was taken to 50°, to obtain complete solution. The solution was cooled and returned to ambient temperature, diluted with a fresh solution of 75 ml of concentrated ammonium hydroxide and allowed to rest for 65 hours. It was extracted with ethyl acetate (1×250 ml; 4×500 ml) and the extracts were combined, dried over anhydrous magnesium sulphate and concentrated in vacuo, to give a solid. The latter was ground with 25 ml of ethyl acetate, to give 2.7 g (60.0%) of pure product (8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=1)[N:8]=[C:7]([CH3:18])[CH:6]=[CH:5]2.[Se](=O)=[O:20]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=1)[N:8]=[C:7]([CH:18]=[O:20])[CH:6]=[CH:5]2
Reactant: O=[Se]=O
Reactant: COCCCOc1cc(F)cc2ccc(C)nc12
Solvent: O
Solvent: C1COCCO1
Product: COCCCOc1cc(F)cc2ccc(C=O)nc12
Yield: 87.3 %

Procedure:
To a solution of 6-fluoro-8-(3-methoxypropoxy)-2-methylquinoline (0.22 g, 0.87 mmol) in dioxane (20 mL) and water (0.2 mL) was added selenium dioxide (0.12 g, 1.0 mmol) and the resultant mixture was heated at reflux for 5 hours. The cooled reaction mixture was filtered through a plug of Celite®, washing the solids with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to provide the title compound (0.20 g, 89%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10]C)=O.[NH2:12][NH2:13]>C(O)C>[NH2:12][NH:13][C:8](=[O:10])[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1
Reactant: COC(=O)CC1CCCCN1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CC1CCCCN1

Procedure:
To a solution of methyl 2-piperidylacetate (1.082 mL, 5.84 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.283 mL, 5.84 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as a gummy white solid in a quantitative yield and was used without further purification: ES-MS (m/z) 158 [M+H]+.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:37])=[CH:7][CH:6]=1)([OH:4])=O.[C:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:41])[NH:39][NH2:40]>>[C:43]([O:42][C:38]([NH:39][NH:40][C:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([C:25]3[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:37])=[CH:9][CH:10]=1)=[O:4])=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: [Na]
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1

Procedure:
The compound obtained in Example 21 and tert-butyl carbazate are treated in the same manner as in Example 22 to give 2-[4-(tert-butoxycarbonylhydrazinocarbonyl)phenyl]-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone as listed in Table 4.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][C:13]([O:16][C:17](/[N:19]=[N:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])([CH3:15])[CH3:14]>C1COCC1>[CH3:11][O:10][C:3]1[C:2]([N:19]([C:17]([O:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:18])[NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1
Reactant: COc1nc(SC)ncc1Br
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COc1nc(SC)ncc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 5-bromo-4-methoxy-2-(methylthio)pyrimidine (25.3 g, 108 mmol) in THF (250 mL) was added under argon isopropylmagnesium chloride LiCl in THF (108 mL, 140 mmol) at 0° C. The mixture was allowed to warm up to rt and stirred for 1 h. di-tert-butylazodicarboxylate (24.8 g, 108 mmol) was added and the mixture was stirred 1 h at rt, quenched by addition of a saturated aqueous solution of ammonium chloride (250 mL) then extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel column chromatography (hexane/EtOAc, 100:0→75:25) to afford 37.2 g of the title compound as a white solid. tR: 1.17 min (LC-MS 4); ESI-MS: 387.3 [M+H]+ (LC-MS 4), Rf=0.79 (hexane/EtOAc, 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Cl:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
2-Chloro-4-hydroxy-benzaldehyde obtained in Step A was dissolved in CH3CN (20 mL). After Cs2CO3(8.7 g, 0.027 mol) was added thereto, benzyl bromide (1.5 mL, 0.013 mol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was filtered by using celite, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (1.89 g, 59%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.Cl.O1CCOCC1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:9]1[C:8]([Cl:7])=[CH:16][C:12]([C:13]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:15])=[CH:11][N:10]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: C1CCNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(c1cnc(Cl)c(Cl)c1)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid (5.76 g; 30.0 mmol) and 4M hydrogen chloride in dioxan (7.5 mL; 30.0 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2×15 mL) then added to a solution of pyrrolidine (3.0 mL; 36.0 mmol) and triethylamine (10.0 mL; 72 mmol) in DCM (150 mL). The mixture was stirred at RT for 6 hours, the DCM evaporated in vacuo, the residue partitioned between water (75 mL) and ethyl acetate (100 mL), the organic layer washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound which was further purified by crystallisation from ethyl acetate and isohexane (6.88 g). 1H NMR δ (CDCl3): 1.9 (m, 4H), 3.4 (m, 2H), 3.6 (s, 3H), 7.9 (s, 1H) and 8.4 (s, 1H); m/z 245 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C@H:11]([CH2:16][OH:17])[C@H:12]([CH2:14][CH3:15])[CH3:13].C(N(CC)CC)C.CCOC(C)=O.CCCCCC>C(Cl)Cl>[OH:17][CH2:16][C@@H:11]([NH:10][S:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])[C@@H:12]([CH3:13])[CH2:14][CH3:15]
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccco1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccco1
Temperature: 25 °C
Yield: 8 %

Procedure:
2-Furansulfonyl chloride (1.01 g, 8.69 mmol) was added dropwise (5 min) as a solution in CH2Cl2 (5 mL) to a 0° C. solution of L-isoleucinol (0.909 g, 7.83 mmol) in CH2Cl2 (20 mL) and triethylamine (2.42 mL, 17.38 mmol). The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was complete. It was diluted with CH2Cl2 (100 mL) and the organic layer was washed with 1N HCl (2×50 mL) and saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain a crude black oil (0.65 g). The crude product was purified by column chromatography, silica gel 230-400 mesh, eluent: starting with 1:3 EtOAc-hexane and ending with 1:2 EtOAc-hexane to furnish N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-2-furansulfonamide as an amorphous white solid (0.155 g, 72.12%). Mass Spectrum (−ESI): 246 (M−H)−. Anal. Calc'd for C10H17ClNO4S: C, 48.57; H, 6.93; N, 5.66. Found: C, 48.72; H, 6.78; N, 5.39.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:27][C:25]1[CH:24]=[C:23]([S:28]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:30])[CH:22]=[C:21]([Cl:20])[CH:26]=1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3,5-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21]S(C2C=CC(C)=CC=2)(=O)=O)[C:14]([C:32]2[CH:36]=[CH:35][O:34][C:33]=2[CH2:37][OH:38])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:42]([O:41][C:39]([N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:32]2[CH:36]=[CH:35][O:34][C:33]=2[CH2:37][OH:38])=[CH:13][CH:12]=1)=[O:40])([CH3:44])([CH3:45])[CH3:43]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2CO)c1OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2CO)c1O
Temperature: 45 °C
Yield: 92.4 %

Procedure:
1M aqueous sodium hydroxide (50 mL) was added to a solution of methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-(2-hydroxymethylfuran-3-yl)-2-(4-methylbenzene-sulfonyloxy)-benzoate (Intermediate 18, 3.82 g) in methanol (100 mL) and the mixture was stirred and heated at 45° C. for 1.5 hours. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate and acidified with acetic acid. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-50% to give methyl 6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxy-3-(2-hydroxymethylfuran-3-yl)-benzoate (2.65 g) as a white foam.