Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([OH:11])[C:6]([CH3:12])=[CH:5][C:4]=1[OH:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:14]([O:11][C:7]1[C:6]([CH3:12])=[CH:5][C:4]([OH:13])=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1c(O)cc(C)c(O)c1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1c(O)cc(C)c(OC(=O)c2ccccc2)c1OC
Yield: 71.5 %

Procedure:
Using 5.05 g of 2,3-dimethoxy-5-methyl-1,4-dihydroxybenzene, 3.80 g of benzoyl chloride and 100 ml of pyridine, reaction and workup carried out as in the Reference Example gave 5.57 g of 4-benzoyloxy-2,3-dimethoxy-5-methylphenol, m.p. 109-111° C. Then, this 5.57 g was dissolved in 50 ml of DMF and added dropwise under an argon gas flow to a suspension of 0.84 g of sodium hydride in 50 ml of DMF. After the addition, stirring was continued for 30 minutes, and 2.6 ml of benzyl bromide was added dropwise and stirring continued for 2 hours at room temperature. The reaction mixture was poured into ice water, extracted with ethyl ether, washed with water, the solvent evaporated under reduced pressure, and thus obtained residue dissolved in 100 ml of methyl alcohol, and to this was added dropwise 5.10 g of sodium methylate (28% methyl alcohol solution) under ice-cooling and stirred for 12 hours at room temperature. Evaporation of the solvent under reduced pressure, neutralization with 2N HCl, extraction with ethyl ether and then evaporation of the solvent under reduced pressure gave 3.69 g of yellow oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[CH2:9][O:10][CH:11]([CH3:13])[CH3:12]>O1CCCC1>[CH:11]([O:10][CH2:9][O:4][CH2:3][CH2:2][CH2:1][OH:5])([CH3:13])[CH3:12]
Reactant: CC(C)OCCl
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OCOCCCO
Reaction time: 1 h

Procedure:
A solution of 1,3-propanediol (19.4 g, 255 mmol) in dry tetrahydrofuran (100 ml) under nitrogen at 0°-5° C. was treated with sodium hydride (2.04 g, 85 mmol) and stirred for 1 hour. Chloromethylisopropyl ether (9 g, 83 mmol) in dry tetrahydrofuran (15 ml) was added over 15 min. Stirring was continued for a further 2 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica eluting with dichloromethane:methanol (97:4) to give the title compound as a colourless oil. (5.3 g, 44%). νmax (Film) 3400, 2910, 2860, 2805, 2760, 1460, 1440, 1425, 1410 and 1380 cm-1 ; δH (CDCl3) 1.17 (3H, s, CH3), 1.20 (3H, s,CH3), 1.84 (2H, quintet, J=6 Hz CH2CH2CH2), 2.3 (1H, br s, D2O exchangeable OH), 3.72 (2H, t, J=6 Hz, CH2OCH2OCH(CH3)2) 3.76 (2H, t, J=6 Hz,CH2ON), 3.86 (1H, m, CH(CH3)2), 4.70 (2H, s, OCH2O).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C@:9]([NH:15][S@@](C(C)(C)C)=O)([CH3:14])[CH2:10][CH:11]([OH:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1>>[NH2:15][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=1)([CH3:14])[CH2:10][C@@H:11]([OH:13])[CH3:12]
Reactant: CC(O)C[C@](C)(N[S@](=O)C(C)(C)C)c1cccc(Br)c1
Agent: Cl
Product: C[C@H](O)CC(C)(N)c1cccc(Br)c1

Procedure:
A solution of hydrogen chloride (5 mL; 13 equiv; 20 mmoles) (4 M in dioxane) and (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(3-bromo-phenyl)-3-hydroxy-1-methyl-butyl]-amide (570 mg, 1.6 mmoles, 1.0 equiv) as a single diastereomer is stirred for 5 minutes. The solvent is removed under reduced pressure and the residue is made basic with saturated aqueous sodium bicarbonate. The aqueous phase is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound: MS (m/z): 358, 360 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=O)[C@@:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([OH:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)(=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C@@:15]([OH:21])([C:14]2[NH:13][C:3]3[CH:4]=[CH:5][C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:7][C:2]=3[N:1]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:24][CH:25]=1
Reactant: CCOC(=O)[C@@](O)(Cc1ccc(F)cc1)C(=O)Nc1ccc(NS(C)(=O)=O)cc1N
Solvent: CC(=O)O
Product: CCOC(=O)[C@@](O)(Cc1ccc(F)cc1)c1nc2cc(NS(C)(=O)=O)ccc2[nH]1
Temperature: 75 °C

Procedure:
(R)-ethyl 3-(2-amino-4-(methylsulfonamido)phenylamino)-2-(4-fluorobenzyl)-2-hydroxy-3-oxopropanoate (600 mg, 1.5 mmol) was dissolved in 3 mL of acetic acid and heated at 75° C. for 2 h. The mixture was then concentrated and purified by Combiflash (silica gel column, 8-35% ethyl acetate in hexane) to give the title product.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]2[C:19]([C@H:20]3[CH2:32][CH2:31][O:30][C@H:21]3[CH2:22][O:23]2)=[CH:18][CH:17]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]2[C:19]([C@H:20]3[CH2:32][CH2:31][O:30][C@H:21]3[CH2:22][O:23]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OC[C@@H]1OCC[C@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(N)ccc2c1OC[C@@H]1OCC[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
Trifluoroacetic acid (7 mL) was added to a solution of methyl cis-(3aRS,9bRS)-7-[bis-(tert-butoxycarbonyl)amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 2, 0.66 g) in DCM (15 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was treated with aqueous sodium bicarbonate and extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl cis-(3aRS,9bRS)-7-amino-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.255 g) as a gum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[CH2:19]([O:22][NH2:23])[CH:20]=[CH2:21]>C(OCC)(=O)C>[CH2:19]([O:22][N:23]=[CH:13][C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[NH:10][C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Cl:1])[CH:20]=[CH2:21]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Reactant: C=CCON
Solvent: CCOC(C)=O
Product: C=CCON=Cc1ccccc1Nc1c(Cl)ccc(C)c1Cl
Yield: 94 %

Procedure:
A solution in 3:1 ethanol-pyridine of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde, prepared as in Example 1, steps 1-2, and O-allyl hydroxylamine(1.3 eq) was heated at reflux for 2 days. The reaction mixture was poured into ethyl acetate and the mixture was extracted with 10% aqueous HCl. Chromatography on silica gel (20% CH2Cl2 /hexanes) gave 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde-O-allyl oxime (1.13 g, 94%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@:5]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[Cl:13][C:9]1[CH:8]=[C:7]([C@@:5]([OH:6])([C@@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:4][CH2:3][CH2:2][NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCN)c2cccc(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1

Procedure:
N-((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)methanesulfonamide was prepared by reaction of (R)-tert-butyl 3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate with methanesulfonyl chloride followed by Boc removal using the conditions described in Example 83 Step 2.
Reaction SMILES: [ClH:1].[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=12.[CH3:13][OH:14]>CCOCC>[ClH:1].[CH3:13][O:14][C:11]([C:8]1[CH:9]=[CH:10][N:5]2[CH:4]=[CH:3][N:2]=[C:6]2[CH:7]=1)=[NH:12]
Reactant: CO
Reactant: N#Cc1ccn2ccnc2c1
Agent: Cl
Solvent: CCOCC
Product: COC(=N)c1ccn2ccnc2c1
Yield: 80 %

Procedure:
Hydrogen chloride gas was bubbled through a mixture of imidazo[1,2-a]pyridine-7-carbonitrile (1.0 g, 7.0 mmol), methanol (10 ml) and ether (25 ml) at room temperature for 3 minutes. The resultant mixture was stirred for 3 hours. The solid material was isolated by filtration and was washed with diethyl ether to furnish a 80% pure tan solid (1.7 g). MS:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:6]=1I.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(N(CC)CC)C.O>C1COCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:6]=1[C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15]
Reactant: COC(=O)Nc1cc(C)c(Br)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(C)c(Br)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
(4-Bromo-2-iodo-5-methyl-phenyl)-carbamic acid methyl ester (605 mg, 1.64 mmol) was dissolved in THF (6 ml). (Trimethylsilyl)acetylene (0.70 ml, 4.95 mmol), copper iodide (33.5 mg, 0.175 mmol), Pd(PPh3)2Cl2 (56.5 mg, 0.081 mmol) and triethylamine (0.690 ml, 4.95 mmol) were added and the mixture was stirred at room temperature for four hours. Water was added to the reaction system, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give (4-bromo-5-methyl-2-trimethylsilanylethynyl-phenyl)-carbamic acid methyl ester (548 mg, 98%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.I[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)cc1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Product: Clc1ccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 24 h
Yield: 68.7 %

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (5.0 g, 17.10 mmol) and 9-borabicyclo[3.3.1]nonane (136.8 ml, 68.39 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-4-chloro-benzene (6.12 g, 25.65 mmol), triphenylphosphine (717.5 mg, 2.74 mmol), tetrakis(triphenylphosphine) palladium(0)(395.1 mg, 0.34 mmol), and 3N NaOH (14.0 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H2SO4 then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 4.76 g (69%) of the title compound: mp 87°–90°; mass spectrum (ion spray): m/z=405.4 (M+1); Analysis for C26H29ClN2: calcd: C, 77.11; H, 7.22; N, 6.92; found: C, 76.93; H, 7.06; N, 7.01.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Rh]>[C:1]([O:5][C:6]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Rh]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CC1CCCCC1)C(=O)O
Yield: 71.4 %

Procedure:
A solution of 4.8 g of t-butoxycarbonyl-N-methylphenylalanine in 150 ml of tetrahydrofuran was hydrogenated at 60° for about four days using 60 psi hydrogen gas and 5% rhodium on carbon. The mixture was filtered and the filtrate concentrated to give the title compound (3.5 g) as a colorless oil. The oil was used without further purification. Structure assignment was supported by the nmr spectrum (loss of aromatic protons and appearance of cyclohexyl protons) and by elemental analysis.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C@H:10]1[CH3:27])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[OH:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=2)[C@H:10]1[CH3:27]
Reactant: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.5 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-methyl-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (5.61 g) in THF (50 mL) was added tetrabutylammonium fluoride-THF solution (20.0 mL, 1 mol/L), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound as a colorless oil (yield: 1.42 g, 35%).
Reaction SMILES: FC(F)(F)C(O)=O.C([Si](C)(C)[O:13][CH:14]([CH2:35][N:36]1[C:44](=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]1=[O:46])[CH2:15][N:16]1[C:24]([C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[C:23]2[C:18]([N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22]2=[O:31])=[CH:17]1)(C)(C)C.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[Cl:74][C:75]1[O:79][C:78]([CH:80]=O)=[CH:77][CH:76]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:74][C:75]1[O:79][C:78]([CH:80]2[C:17]3=[C:18]4[N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22](=[O:31])[C:23]4=[C:24]([C:25]4[S:26][CH:27]=[C:28]([CH3:30])[N:29]=4)[N:16]3[CH2:15][CH:14]([CH2:35][N:36]3[C:37](=[O:46])[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:44]3=[O:45])[O:13]2)=[CH:77][CH:76]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(CN2C(=O)c3ccccc3C2=O)O[Si](C)(C)C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN2C(=O)c4ccccc4C2=O)OC3c2ccc(Cl)o2)n1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (0.032 ml, 0.421 mmol) was added to a solution of 6-(2-((tert-butyldimethyl silyl)oxy)-3-(1,3-dioxoisoindolin-2-yl)propyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (50 mg, 0.084 mmol) in toluene (1 ml) and the mixture was stirred for 30 mins. Bismuth triflate (27.6 mg, 0.042 mmol) and 5-chlorofuran-2-carbaldehyde (16.49 mg, 0.126 mmol) were added and the mixture stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml), saturated NaHCO3(aq) (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:18][C:19]1([CH3:43])[CH2:28][CH2:27][C:26]2[N:25]=[CH:24][N:23]=[C:22]([N:29]3[CH2:35][C:34]4[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:33]=4[O:32][CH2:31][CH2:30]3)[C:21]=2[CH2:20]1>>[NH2:1][C:2]1[C:7]([S:8]([CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([C:37]2[CH:38]=[CH:39][C:33]3[O:32][CH2:31][CH2:30][N:29]([C:22]4[C:21]5[CH2:20][C:19]([CH3:18])([CH3:43])[CH2:28][CH2:27][C:26]=5[N:25]=[CH:24][N:23]=4)[CH2:35][C:34]=3[CH:36]=2)=[CH:4][N:3]=1
Reactant: CC(C)(O)CCS(=O)(=O)c1cc(Br)cnc1N
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC(C)(O)CCS(=O)(=O)c1cc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cnc1N

Procedure:
Prepared according to the method of example 5 by using 4-[(2-amino-5-bromopyridin-3-yl)sulfonyl]-2-methylbutan-2-ol (reagent preparation 41) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.52 (s, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 7.50 (s, 1H), 7.43 (d, 1H), 7.06 (d, 1H), 4.70 (s, 2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.35 (m, 2H), 2.79 (t, 2H), 2.48 (s, 2H), 1.82 (m, 2H), 1.68 (t, 2H), 1.15 (s, 6H), 0.90 (s, 6H); MS (EI) for C29H37N5O4S: 552 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.[C:19]([CH2:23][C:24](Cl)=O)([CH3:22])([CH3:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>C(OCC)(=O)C.O>[CH:16]1([CH2:15][N:14]2[C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:9])=[O:10])=[CH:7][C:2]=3[N:1]=[C:24]2[CH2:23][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][CH2:17]1
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of 2-amino-1-(N-cyclopropylmethylamino)-4-(isopropylsulfonyl)benzene (Step E, 113 mg, 0.38 mmol) in ethyl acetate (3 mL) was added tert-butylacetyl chloride (58 μL, 0.42 mmol) at room temperature. After stirring for 1 h, p-toluenesulfonic acid monohydrate (72 mg, 0.38 mmol) was added and the mixture was stirred under reflux for 3 h. Water (5 mL) and aqueous ammonia (0.5 mL) were added and the mixture was extracted with ethyl acetate (15 mL×3) and washed with brine (5 mL). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by pTLC (hexane:ethyl acetate=1:1 then dichloromethane:methanol=10:1 as eluent) to give colorless oil (74 mg), which was recrystalized from ethyl acetate and hexane to afford the title compound (28 mg, 21%) as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:20][CH2:21][CH2:22][CH:4]2[NH:3]1.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1.O.CC(O)=O>C(Cl)CCl>[N:19]1([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]3[N:5]4[CH2:20][CH2:21][CH2:22][CH:4]4[NH:3][S:2](=[O:1])(=[O:23])[C:7]=3[CH:8]=2)[CH:26]=[CH:30][CH:29]=[CH:28]1
Reactant: Nc1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: O=S1(=O)NC2CCCN2c2ccc(Oc3cccc(-n4cccc4)c3)cc21
Reaction time: 1 h

Procedure:
250 mg (0.75 mmol) of {3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl}amine and 137 μl (1.06 mmol) of 2,5-dimethoxytetra-hydrofuran are added to a two-phase mixture of 2.5 ml of water, 1.25 ml of AcOH and 3.75 ml of dichloro-1,2-ethane. Stirring is carried out at 80° C. for 1 hour; the mixture is allowed to return to ambient temperature and is extracted with CH2Cl2. The organic phase is washed with saturated aqueous NaCl solution and dried over MgSO4. The title product is purified by chromatography on a silica column (CH2Cl2/heptane 70/30).
Reaction SMILES: [C:1]1([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=2[N+:23]([O-])=O)[C:17]([NH2:19])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCCC1.[Ni]>[NH2:23][C:22]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][C:14]=1[O:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(OCCc2cccc3ccccc23)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N)c(OCCc2cccc3ccccc23)c1
Yield: 100.4 %

Procedure:
To a solution of 3-(2-naphthalen-1-yl-ethoxy)-4-nitro-benzamide (0.500 g, 1.48 mmol) in 75 mL of tetrahydrofuran at room temperature was added Raney Nickel (0.50 g). The reaction was pressurized to 50 psi of hydrogen for 18 hours. The reaction was then filtered through celite and washed with tetrahydrofuran. The filtrate was then concentrated in vacuo to dryness to yield 4-amino-3-(2-naphthalen-1-yl-ethoxy)-benzamide 455 mg (100%) of a white solid. 1HNMR(300 MHz, DMSO) 8.26 (d, 1H), 7.99 (d, 1H), 7.98 (d,1H), 7.68(m, 5H), 7.33 (m, 2H), 6.93 (bs, 1H), 6.62 (d, 1H), 4.89 (s, 2H), 5.16 (s, 2H), 4.34 (t, 2H), 3.63 (t, 2H). MS(APCI) m/z 307.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:9][CH:10]=3)[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:4]=2[CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44]F)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:18][N:15]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([O:1][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][S:33]([C:30]4[CH:29]=[CH:28][C:27]([CH3:26])=[CH:32][CH:31]=4)(=[O:35])=[O:34])=[CH:14][CH:13]=3)[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]=2[CH:7]=1)[CH:16]=[O:17]
Reactant: CN(C=O)c1ccc2c3ccc(O)cc3n(C(=O)OC(C)(C)C)c2c1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc3c4ccc(N(C)C=O)cc4n(C(=O)OC(C)(C)C)c3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
To tert-butyl 2-hydroxy-7-(N-methylformamido)-9H-carbazole-9-carboxylate (65 mg, 0.19 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (174 mg, 0.38 mmol) in 0.5 mL NMP was added Cs2CO3 (68 mg, 0.21 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (80 mL). It was washed with water (3×50 mL), and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified with silica chromatography (hexane/EtOAc) to afford tert-butyl 2-(N-methylformamido)-7-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)-9H-carbazole-9-carboxylate (AD-CB-004Pb-WZ01191) as a clear oil (75 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.79 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.15 (dd, J=8.4, 2.0 Hz, 1H), 7.00 (dd, J=8.8, 2.4 Hz, 1H), 4.23 (m, 1H), 3.89 (m, 2H), 3.88 (m, 2H), 3.73-3.68 (m, 4H), 3.66-3.63 (m, 2H), 3.41 (s, 3H), 2.42 (s, 3H), 1.76 (s, 9H); MS (ESI) m/z 527 (M+H+).