Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:15]4[CH2:22][C:21]5[CH2:20][NH:19][CH2:18][C:17]=5[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28](I)[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:15]4[CH2:22][C:21]5[CH2:20][N:19]([CH2:28][CH3:29])[CH2:18][C:17]=5[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CC2=C(C1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
To a solution of 1-cyclopropyl 6,8-difluoro-7-[3,7-diazabicyclo [3.3.0]-oct-1(5)-en-3-yl]-1,4-dihydro-4-oxoquinoline-3-carboxyl-ic acid (0.37 g) in dimethyl formamide (30 ml), which was prepared in Example 11, ethyliodide (0.17 g) and potassium carbonate (powder, 1 g) were added and stirred at room temperature for 24 hours. To the reaction mixture, water (100 ml) was added and the precipitate was filtered. The filter cake was purified by silica gel column chromatography (CHCl3 :methanol:acetic acid=6:3:1) to give the title compound (0.21 g, yield 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:15][C:14]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:12]([Cl:11])[CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
2-Chloro-4-hydroxybenzaldehyde (324 mg, 2.07 mmol), 3,4-dichlorobenzyl alcohol (513 mg, 2.90 mmol), and triphenylphosphine (760 mg, 2.90 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.32 mL, 2.90 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was washed with hexane/dichloromethane (6/1 (v/v)), whereby the objective title compound was obtained as a white solid (244 mg, yield: 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31]O)=[NH:30])=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:21][N:31]=[C:29]([C:28]5[CH:33]=[CH:34][C:25]([NH2:24])=[N:26][CH:27]=5)[N:30]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.13) (169 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (68 mg, 30%). MS (EI) 453.0 [(M)+]; mp 243° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccccc1Cl
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccccc1Oc1ccccc1Cl

Procedure:
A solution of 2-chloro-(2-nitrophenoxy)benzene (5.00 g) in tetrahydrofuran (100 mL) was shaken in a Parr Hydrogenator over Raney nickel at 5 psi hydrogen at room temperature for 4 hours. The catalyst was filtered from the reaction, and the solution was evaporated under vacuum to a yellowish oil which crystallized on standing. The solid was crushed, suspended in hexane and filtered to yield the title compound as a light orange solid. Mp: 44°-45° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([N:28]2[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:32][CH2:33]2)[S:26][CH:27]=1
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 35.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (226 mg, 0.835 mmol), 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (104 mg, 35.6%) as a solid.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:23])[C@@H:6]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:7]C(OC(C)(C)C)=O)[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:23])[C@@H:6]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:7])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOC(=O)[C@H](N)CCc1ccccc1
Temperature: 25 °C

Procedure:
The allyl ester from Step A of this Example (1.96 g; 6.136 mmol) was dissolved in dry methylene chloride (10 ml) and anisole (5 ml) was added. The mixture was stirred at room temperature and trifluoroacetic acid was added drop by drop to the ester over 5 minutes. The reaction mixture was stirred at room temperature for a further 2 h then the volatiles removed on a rotary evaporator under reduced pressure to give a thick oil. The oil was dissolved in methylene chloride (50 ml) and shaken with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was discarded and the methylene chloride layer dried over anhydrous magnesium sulfate powder, filtered and the volatiles removed under reduced pressure. The oil that remained after evaporation was chromatographed on silica gel using a solvent gradient beginning with ethyl acetate and hexanes (1:1) to neat ethyl acetate and then with a eluant of ethanol and ethyl acetate in the ratio 1:4 v/v. The product (1.1 g; 81.7%) was isolated after the chromatography. FAB-MS:- calculated for C13H17NO2 219.1; found 219.8 (M).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:25][CH2:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[CH3:22][N:21]([CH3:23])[C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]2[CH:7]=[CH:8][C:9]3[NH:10][C:33]([C:32]4[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][OH:25])=[CH:36][CH:35]=4)=[N:1][C:4]=3[CH:5]=2)=[O:24])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(OCCO)cc4)nc3c2)cc1

Procedure:
Compound 218 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-dimethylaminobenzamide and 4-(2-hydroxyethyloxy)benzaldehyde. [M+H]+ calcd for C24H24N4O3: 417.19; found: 417.00.
Reaction SMILES: [OH-].[K+].CO[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][N:8]=1)=[O:6].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][CH2:26][NH2:27])[CH:21]=[CH:22][C:23]=1[Cl:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][CH2:26][NH:27][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][N:8]=2)=[O:6])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: COC(=O)c1ccc(C(C)(C)C)cn1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(C(=O)NCCc2ccc(Cl)c(Cl)c2)nc1
Reaction time: 2 h
Yield: 58.1 %

Procedure:
Potassium hydroxide (2 M aq. solution, 0.98 mL, 1.96 mmol) was added at RT to a solution of 5-tert-butyl-pyridine-2-carboxylic acid methyl ester (synthesized according to J. Org. Chem. 1998, 63, 7840-7850; 189 mg, 0.98 mmol) in THF (2.6 mL), then after stirring for 2 h, the reaction mixture was evaporated. The residue was taken up in DMF (12 mL), then after addition of 2-(3,4-dichloro-phenyl)-ethylamine (204 mg, 1.07 mmol), 4-methylmorpholine (297 mg, 2.93 mmol), and HBTU (556 mg, 1.47 mmol), the reaction mixture was stirred at RT for 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and concentrated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 5-tert-butyl-pyridine-2-carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-amide (200 mg, 58%). White solid, MS (ISP): 351.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 7-(benzyloxy)-6-methoxyquinolin-4-ol (24.60 g, 87.45 mmol) in toluene (75 mL) was added phosphorus oxychloride (90 mL) slowly. The reaction was heated to reflux for 2 hours, and then cooled to room temperature, diluted with EtOAc (200 mL). The resulted solution was poured into a mixture of ice and 3 N NaOH in portions. The pH of the mixture was adjusted with 3 N NaOH to 7˜8. The organic phase was separated, washed with water (200 mL) followed by brine (100 mL) and concentration in vacuo. The title compound was obtained as a white solid (22.1 g, 84.5%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:30])=[C:8]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:21][S:20][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:5])[C:7]([OH:30])=[C:8]3[C:22]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:21][S:20][C:9]=23)=[CH:17][CH:16]=1)#[N:19]
Reactant: CCOC(=O)c1nc(-c2ccc(C#N)cc2)c2snc(-c3ccc(F)cc3)c2c1O
Reactant: NCC(=O)O
Product: N#Cc1ccc(-c2nc(C(=O)NCC(=O)O)c(O)c3c(-c4ccc(F)cc4)nsc23)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-(4-cyano-phenyl)-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 447.1 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCOCC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(C(=O)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (2-morpholin-4-yl-2-oxo-1-phenylethyl)carbamic acid tert-butyl ester (3.0 mmol) in CH2Cl2 (6.0 mL) is added TFA (2.0 mL) at 0° C. After stirring at room temperature for 24 h, the reaction mixture is basified to pH 8 with sat. aq NaHCO3. The mixture is extracted with CH2Cl2, and then the combined organic extracts are dried over Na2SO4 and concentrated in vacuo to give the title compound; 1H NMR (CDCl3) δ 2.02 (s, 2H), 3.09-3.14 (m, 1H), 3.20-3.25 (m, 1H), 3.34-3.40 (m, 1H), 3.46-3.60 (m, 3H), 3.65-3.71 (m, 1H), 3.74-3.80 (m, 1H), 7.27-7.34 (m, 5H).
Reaction SMILES: S[C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9]C(NCCN3CCOCC3)=O)[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].N1N=CN2C=1C=CC=N2.C(=O)([O-])O>O.CS(C)=O>[S:8]1[C:4]2[CH:3]=[CH:2][CH:22]=[CH:21][C:5]=2[N:6]=[C:7]1[NH2:9]
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc2ccccc2s1
Temperature: 190 °C
Reaction time: 0.5 h

Procedure:
280 mg of 1-(6-sulphanyl-benzothiazol-2-yl)-3-(2-morpholin-4-yl-ethyl)urea, 2 cm3 of dimethyl sulphoxide and 240 mg of potassium carbonate are introduced, at 20° C., in a microwave tube equipped with a magnetic stirrer. The suspension thus obtained is stirred for 5 minutes before the addition of 200 mg of 3-chloro-6-(1-methyl-1H)-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazine. The reaction mixture is then heated in a microwave oven for 10 minutes at 190° C., and then poured into 100 cm3 of water. The resulting mixture is stirred for 30 minutes under cold conditions. The solid is filtered off, washed with 3×100 cm3 of water and then spin-filter-dried. The brown powder thus obtained is purified by chromatography on silica gel (eluent: 95/5/0.5 dichloromethane/methanol/aqueous ammonia). A small amount of methanol and of hydrochloric acid in solution in dioxane is added to the fractions containing the expected product (to improve solubility). The fractions are combined and concentrated under reduced pressure. The oil thus obtained is taken up with 20 cm3 of a saturated aqueous solution of hydrogen carbonate (pH 8-9). The precipitate formed is filtered off and then washed with 3×20 cm3 of water and dried under vacuum. 120 mg of 6-{[6-(1-methyl-1H)-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-amine are thus obtained in the form of a light brown solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:35][OH:36])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].[CH:37]([Si:40](Cl)([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[OH:1][C@H:2]([CH2:35][O:36][Si:40]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:37]([CH3:39])[CH3:38])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
N-[(2S)-2,3-Dihydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (265 mg, 0.514 mmol) synthesized in Example (35a) was dissolved in dichloromethane (10 mL), and triisopropylsilyl chloride (0.12 mL, 0.691 mmol), triethylamine (0.21 mL, 1.51 mmol) and 4-dimethylaminopyridine (6.0 mg, 0.049 mmol) were added, followed by stirring at room temperature for 24 hours under nitrogen atmosphere. Water (10 mL) was added, and the solution was separated with dichloromethane (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-50%) to afford the desired product (177 mg, yield 51%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu][C:24]#[N:25]>O1CCOCC1.[C-]#N.C([N+](CC)(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:24]#[N:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C#N)nc3N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
To a solution of 0.20 g (0.54 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 5 ml dioxane were added 195.0 mg (2.17 mmol) copper(I)cyanide, 22.5 mg (22 μmol) tris(dibenzylideneacetone)dipalladium(0), 48.2 mg (87 μmol) 1,1′-bis(diphenylphosphino)ferrocene and 0.13 g (0.81 mmol) tetraethylammonium cyanide and the suspension was heated to reflux and stirred for 1.5 h. The mixture was cooled to room temperature, filtered and the filtrate was washed successively with aqueous saturated sodium bicarbonate solution, aqueous 10% citric acid solution, brine, dried over magnesium sulfate, filtered and evaporated. The residue was immediately purified by flash column chromatography on silica gel (0.032–0.063 mm) to afford the desired compound as a colorless foam (98.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C1C(=O)N([Br:23])C(=O)C1.O>CN(C=O)C>[Br:23][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c3ccccc3c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3ccc(Br)cc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Methoxy-9H-carbazole (Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71, 9403-9410) (0.029 g, 0.147 mmol) was dissolved in dry DMF (0.28 mL) and NBS (0.026 g, 0.147 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 h under absence of light. The solution was poured into water (2 mL), filtered and washed with water. The title compound was isolated as a grey solid (0.033 g, 82%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>ClCCl>[CH3:27][S:24]([O:12][CH2:11][CH:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(CO)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(COS(C)(=O)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 10.2 g (46 mmol) of 2-(3,4-methylenedioxyphenyl) hexyl alcohol, were added 50 ml of dichloromethane and 7.7 ml (55 mmol) of triethylamine, and further added dropwise under cooling with ice 4.3 ml (55 mmol) of mesyl chloride. After stirring for one hour at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and dried over anhydrous magnesium sulfate. By evaporating off the solvent, 2-(3,4-methylenedioxyphenyl)hexyl methanesulfonate was obtained in an almost quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]([O:16]C)(OC)[C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1.Cl>C1COCC1>[OH:18][C:3]1([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=2)[C:4](=[O:16])[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)=[C:2]1[CH3:1]
Reactant: COc1cccc([Mg]Br)c1
Reactant: COc1cccc(C2=C(C)C(=O)C2(OC)OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(C2=C(C)C(O)(c3cccc(OC)c3)C2=O)c1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
A THF solution (12 mL) of 2-methyl-4,4-bis(methyloxy)-3-[3-(methyloxy)phenyl]-2-cyclobuten-1-one (245) (0.500 g, 2.02 mmol, 1 equiv) was cooled to ca. −78° C. 3-Methoxyphenylmagnesium bromide (3.02 mL, 1.0 M, 1.5 equiv) was added. After 5 min, aqueous HCl (3 N, 20 mL) was added. Extraction with EtOAc (3×20 mL) was followed by washing with 50% aqueous NaHCO3, drying (Na2SO4), filtration, and concentration to a bright yellow oil. Radial chromatography (SiO2, 4 mm plate, 80:20; hexanes/EtOAc) afforded the title compound (246) as a bright yellow oil (0.515 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 7.39-7.29 (m, 4H), 7.10-6.88 (m, 4H), 3.88 (s, 3H), 3.85 (s, 3H), 2.47 (s, 3H); TLC (60:40; hexanes/EtOAc): Rf=0.23.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:13][C:14]([Cl:20])([Cl:19])[C:15](=[NH:18])OC.[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:21]([OH:24])(=[O:23])[CH3:22].[NH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:15](=[NH:18])[C:14]([Cl:20])([Cl:19])[Cl:13]
Reactant: Nc1cnc2ccccc2c1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: N=C(Nc1cnc2ccccc2c1N)C(Cl)(Cl)Cl
Yield: 80 %

Procedure:
In the same manner as in Ref. Ex. 17, 1.59 g of 3,4 -diaminoquinoline (V-1) in 20 ml of acetic acid was treated with 1.9 g of methyl trichloroacetimidate to give 3.13 g (yield: 80%) of the titled compound (VIII-2).
Reaction SMILES: C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35]O)([CH3:30])([CH3:29])[CH3:28].[C:38]1(=[O:44])[NH:42][C:41](=[O:43])[CH:40]=[CH:39]1>O1CCCC1>[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35][N:42]1[C:38](=[O:44])[CH:39]=[CH:40][C:41]1=[O:43])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=CC(=O)N1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN1C(=O)C=CC1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A toluene solution of Mitsunobu reagent (diethyl azodicarboxylate) (1.106 g/ml, 8.2 mmol, 1.29 ml) was gradually added to a tetrahydrofuran solution (25 ml) of triphenylphosphine (2.15 g, 8.2 mmol) at −78° C. To the thus obtained solution, a tetrahydrofuran solution (5 ml) of (2-hydroxyethyl)carbamic acid tert-butyl ester (1.32 g, 8.2 mmol) and maleimide (794 mg, 8.2 mmol) was added, followed by stirring at −78° C. for 5 minutes and further stirring at room temperature for 36 hours. The thus obtained reaction solution was concentrated, ether was added thereto, and the formed precipitate was removed by filtration. The thus obtained filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 2-(maleimido)ethylcarbamic acid tert-butyl ester (531 mg, 2.53 mmol, yield 31%).