Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:11])=[C:8]([OH:10])[CH:9]=1)[CH3:2].[C:12]([Si:16]([CH3:19])([CH3:18])Cl)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1.O>CC(N(C)C)=O>[C:12]([Si:16]([O:10][C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]=1[F:11])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOc1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of 75.5 g 5-ethoxy-2-fluoro-phenol described in example 1.1 in 250 ml DMA were added 80.2 g t-butyl dimethylchlorsilane and 36.2 g imidazole at 0° C. The reaction mixture was warmed to r.t. After 4 hrs, 400 ml water were added. The mixture was extracted with hexane. The organic layer was washed with water, 10% Na2CO3 solution, water and brine, dried over MgSO4, filtrated and concentrated to give 127.0 g tert-butyl-(5-ethoxy-2-fluoro-phenoxy)-dimethyl-silane as light brown liquid which was used in the next step without further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]2[C:29]([CH3:30])=[N:28][N:27]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:8]=2[N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]=2[F:26])[CH:11]=1)=[O:5].C[Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:9]=[C:8]3[N:27]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)[N:28]=[C:29]([CH3:30])[C:7]3=[C:6]([CH:4]=[O:5])[CH:11]=2)=[C:13]([F:26])[CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2F)nc2c1c(C)nn2C1CCCCO1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.3 %

Procedure:
6-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methoxy-methyl-amide (1.0 g) was dissolved in THF (25 mL). At 0° C. methylmagnesium bromide solution (1 M, 3.9 mL) was added slowly, the mixture was warmed to r.t. while stirring overnight. Saturated ammonium chloride solution was added, the mixture was extracted with dichloromethane, the organic phases were dried over magnesium sulfate and concentrated in a membrane pump vacuum. The residue was purified by fish chromatography (silica, heptane/ethyl acetate gradient) giving 1-[6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone (1.0 g, quantitative yield with impurities).
Reaction SMILES: [CH3:1]I.C(=O)([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[S:18][C:17]([SH:19])=[N:16][C:13]2=[N:14][CH:15]=1.O>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]2[S:18][C:17]([S:19][CH3:1])=[N:16][C:13]2=[N:14][CH:15]=1
Reactant: CI
Reactant: Sc1nc2ncc(Cl)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ncc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 68 h
Yield: 81.5 %

Procedure:
328 g (2.31 mol) of methyl iodide were added dropwise to a stirred suspension of 363 g (2.62 mol) of potassium carbonate and 354 g (1.75 mol) of 6-chloro-2-mercaptothiazolo[4,5-b]pyridine from Example 1.2 in 2.28 l of dimethylformamide at 5° C. The reaction mixture was stirred at ambient temperature for 68 h and then poured into 4.5 l of demineralized water. The precipitate was filtered, rinsed with water (2×500 ml) and then dried in vacuo at 45° C. to give 308.9 g (yield: 81%) of 6-chloro-2-(methylthio)thiazolo[4,5-b]pyridine.
Reaction SMILES: C([NH:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)C1C=CC=CC=1>C(O)=O.[OH-].[Pd+2].[OH-].[C]>[NH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:8])[C:18]=2[N:19]=[CH:20]1
Reactant: CC(C)(C)OC(=O)NCCCn1cnc2c(NCc3ccccc3)nc3ccccc3c21
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Product: NCCCn1cnc2c(N)nc3ccccc3c21
Yield: 41.7 %

Procedure:
30 mg (0.0695 mmol) of 4-benzylamino-1-[3-(tert-butoxycarbonylamino)propyl]-1H-imidazo[4,5-c]quinoline was dissolved in 3 ml of formic acid. 0.1 g of 20% palladium hydroxide-carbon was added thereto and the mixture was refluxed under heating for one day. The reaction mixture was filtered and the filtrate was evaporated to distill off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: methanol:32% acetic acid=6:3:1 (v/v)) to obtain the acetic acid salt of the object. The thus obtained product was subjected to treatment with alkali to obtain the free base. The precipitate thus formed was collected by filtration to obtain 7 mg (0.0290 mmol) of 1-(3-aminopropyl)-1H-imidazo[4,5-c]quinoline-4-amine shown below as faint brown powder. ##STR40## The physicochemical data of this compound was in agreement with compound of Example 5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][N:25]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1nccc2ccccc12
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1nccc2ccccc12

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and isoquinoline-1-carboxylic acid were combined to provide N1-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-1-isoquinolinecarboxamide as a yellow crystalline solid, m.p. 61.0-63.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.94 (t, J=5.9 Hz, 1H), 8.87 (d, J=8.5 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.05-7.96 (m, 3H), 7.84-7.96 (m, 1H), 7.70-7.65 (m, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.37 (dt, J=7.7, 1.0 Hz, 1H), 7.19 (dt, J=7.6, 1.2 Hz, 1H), 6.53 (broad s, 2H), 4.60 (t, J=7.2 Hz, 2H), 3.81 (t, J=6.7 Hz, 2H), 3.41 (m, 2H), 3.28-3.12 (m, 5H), 1.92-1.76 (m, 4H); MS (EI) m/e 468.2261 (468.2274 calcd for C27H28N6O2).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C1COCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:19])=[CH:16][CH:15]=1
Reactant: NCC1CC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
Cyclopropylmethylamine (1.62 g, 22.8 mmol) and triethylamine (3 ml) were dissolved in THF (40 ml) and 4-bromobenzoylchloride (5 g, 22.8 mmol) added over 5 min at 0° C. The reaction was stirred at room temperature for 16 h, reduced to dryness under vacuum and the residue partitioned between DCM (75 ml) and water (75 ml). The aqueous was extracted with DCM (2×50 ml). The combined organic phases were washed with brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica eluting with cyclohexane/ethyl acetate (8:2). The solvent was evaporated from the product fractions under vacuum to give 4-bromo-N-cyclopropylmethylbenzamide (4.3 g, 74%). LCMS: retention time 3.00 min, MH+255.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[NH:14][N:13]=NN=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[C:16](=[O:24])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>N1C=CC=CC=1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:24][C:16]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: c1cc2c(cc1-c1nnn[nH]1)CCO2
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 78.2 %

Procedure:
To a solution of 5-(2,3-dihydro-1-benzofuran-5-yl)-1H-tetrazole (4.40 g, 23.38 mmol) in pyridine (50 mL) was added ethyl 4-chloro-4-oxobutyrate (4.62 g, 28.06 mmol), and the resulting mixture was stirred at room temperature for 30 min and at 100° C. for 3.5 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, 1M hydrochloric acid, 1M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) and recrystallized from hexane/ethyl acetate to give the title compound (5.27 g, yield 78%) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.Cl.[NH2:23][C@H:24]([CH3:28])[C:25]([NH2:27])=[O:26]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:23][C@H:24]([CH3:28])[C:25]([NH2:27])=[O:26])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: C[C@@H](N)C(N)=O
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Agent: Cl
Product: C[C@@H](Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12)C(N)=O

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and (2R)-2-amino-propanamide hydrochloride,
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CC(C)=O.[ClH:24]>>[ClH:24].[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:19])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(N2CCN(C(C)C)CC2)cc1
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)N1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 2 °C

Procedure:
4-(4-Isopropyl-piperazin-1-yl)-benzoic acid methyl ester (0.9 mmol) is dissolved in 4N HCl (2 ml) and heated under reflux for 7 hours. The mixture is cooled in an ice bath to 0-4° C. and acetone is added. The solid material formed is filtered off, washed with cold acetone and dried (vacuum). A pale-brown powder with mp. >270° C., Rf=0.08 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[N:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][OH:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[N:18][CH:17]=[C:16]([O:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(OCc3cccc(Cl)c3)cnc2N)CC1

Procedure:
3′-Amino-6′-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-3s was prepared from 3′-Amino-6′-bromo-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-3r (1.0 g, 2.8 mmol) and 3-chlorobenzyl alcohol (0.36 mL, 3.1 mmol) in a manner analogous to compound I-1b in example 1. The title compound I-3s was obtained as a red viscous oil (394 mg, 34% yield).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1>[CH2:36]([O:35][C:29]1[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH:6]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[CH2:5][C:4]([OH:40])=[O:3])=[CH:15][CH:16]=2)=[CH:23][CH:24]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCOc1ccc(C)cc1-c1ccc(COc2ccc(C(CC(=O)OCC)c3ccc(F)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCOc1ccc(C)cc1-c1ccc(COc2ccc(C(CC(=O)O)c3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 45.3 (56 mg, 0.1 mmol) and 2N NaOH(aq) solution (0.31 mL, 0.62 mmol) in THF (3 mL) was stirred at room temperature overnight. The reactor mixture was concentrated, treated with dilute HCl, and extracted into ethyl acetate. The organic layer washed with water and concentrated to yield product which was purified by flash chromatography to give compound 45 (40 mg). 1H NMR (500 MHz, CDCl3, ppm), δ 0.9 (t, 3H), 1.4 (m, 2H), 1.65 (m, 2H), 2.35 (s, 3H), 3.05 (m, 2H), 3.9 (t, 2H), 4.5 (t, 1H), 5.05 (s, 2H), 6.8-7.5 (m, 15H). MS ESI (neg.) m/e: 511.0 (M−H).
Reaction SMILES: [CH2:1]([P:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O.N>>[N+:15]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][P:8]2(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:3][CH:4]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=P1(Cc2ccccc2)CCCCC1
Agent: N
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(CP2(=O)CCCCC2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To 1-benzylphosphorinane-l-oxide (5.39 g) were added nitric acid (1.94 ml) and sulfuric acid (15 ml) at 0° C., and the mixture was stirred at 50-60° C. for 2 hours. The reaction mixture was added to crushed ice-water, neutralized with ammonia solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3→1:2) to give 1-(4-nitrobenzyl)phosphorinane-1-oxide (2.47 g)as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)\[CH3:5].[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6](/[C:4](/[CH3:5])=[CH:3]/[CH2:2][O:1][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C@H:24]([O:23][CH2:21][CH3:22])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:36][CH:35]=3)=[CH:7][CH:8]=2)=[CH:17][CH:16]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(-c2ccc(/C(C)=C/CO)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)=O)cc3)cc2)cc1)OCC
Yield: 75.4 %

Procedure:
The title compound (275 mg, 75%) was prepared from (E)-1-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-ethanone (200 mg, 0.75 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (188 mg, 0.79 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CS(C)=O>[C:1]1([C@@H:7]([NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([O:20][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: C[C@H](NC1CCc2c(O)cccc2C1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cccc2c1CCC(N[C@@H](C)c1ccccc1)C2
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A solution of (6RS)-5,6,7,8-tetrahydro-6-[((1S)-1-phenylethyl)amino]-1-naphthol (267 mg) in dimethylsulfoxide (3 ml) was added dropwise to a stirred suspension of 60% sodium hydride (44 mg, washed with n-hexane) in dimethylsulfoxide (0.5 ml) at room temperature in a nitrogen atmosphere over 15 minutes, and the mixture was stirred at 50° C. for 10 minutes and cooled to room temperature. Ethyl bromoacetate (167 mg) in dimethylsulfoxide (1 ml) was added thereto and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed twice with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (dichloromethane-ethanol) over silica gel to afford ethyl [(6RS)-5,6,7,8-tetrahydro-6-[((1S)-1-phenylethyl)amino]-1-naphthyloxy]acetate (243 mg) as a brown oil.
Reaction SMILES: [CH2:1]([N:7]1[C:20]2[CH:19]=[CH:18][C:17]([O:21][CH3:22])=[C:16]([CH:23]=[O:24])[C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:25][CH3:26])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Li+].C(N1C2C=CC(OC)=C(CO)C=2SC2C1=CC=C(OC)C=2)CCCCC.C([Li])CCC.[CH3:60][O:61][CH2:62][CH2:63][O:64][CH2:65]Cl>O1CCCC1.C(OCC)C.CCCCCC>[CH2:1]([N:7]1[C:20]2[CH:19]=[CH:18][C:17]([O:21][CH3:22])=[C:16]([CH2:23][O:24][CH2:60][O:61][CH2:62][CH2:63][O:64][CH3:65])[C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:25][CH3:26])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1c2ccc(OC)cc2Sc2c1ccc(OC)c2C=O
Reactant: COCCOCCl
Agent: CCCCCCN1c2ccc(OC)cc2Sc2c1ccc(OC)c2CO
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCN1c2ccc(OC)cc2Sc2c1ccc(OC)c2COCOCCOC

Procedure:
A solution of 2.39 g (6.43 mmol) of 10-hexyl-3,7-dimethoxy-phenothiazine-4-carbaldehyde in 30 ml of tetrahydrofuran was reduced with 7.0 ml of lithium borohydride solution (1M in tetrahydrofuran) analogously to that described in Example 4.1.1.da. The resulting 10-hexyl-3,7-dimethoxyphenothiazine-4-methanol was reacted with 4.0 ml of n-butyllithium solution (1.6M in hexane) and 1.0 g (8.0 mmol) of 2-methoxyethoxymethyl chloride analogously to that described in Example 4.1.1.db. After chromatography on silica gel with diethyl ether/hexane (3:2) 2.33 g (78.5%) of 10-hexyl-3,7-dimethoxy-4-(2-methoxyethoxymethoxymethyl)-phenothiazine were obtained as a light yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4](I)[CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[N:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:23]=2)O1>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([C:19]2[CH:20]=[N:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:23]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Oc1cc(F)c(Cl)cc1I
Product: CC(C)(C)OC(=O)n1cc(-c2cc(Cl)c(F)cc2O)cn1
Yield: 45 %

Procedure:
Prepared using the method of Example 587 using 4-chloro-5-fluoro-2-iodophenol (Preparation 744, 386 mg, 1.42 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (500 mg, 1.70 mmol) gave the title compound as a white solid (200 mg, 38%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10]>>[C:1]([O:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: CCCC(=O)O
Product: CCCC(=O)OC(=O)CCC
Reaction time: 7 h

Procedure:
Molar quantities of butyric acid and butyryl chloride are heated together on a water-bath for 1 hour and then boiled for 7 hours in an oil-bath. Butyric anhydride, b.p. 198°-199° C./765 mm, is obtained on distillation of the resulting mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[CH2:24][CH2:25]2)=[O:11])[CH2:7]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(N1CCN(c2ccccn2)CC1)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
A stirred solution of 2.8 g (0.01 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 25 ml of tetrahydrofuran was treated in turn with 1.6 g (0.01 mole) of 1-(2-pyridyl)piperazine and 1.4 g (0.01 mole) of potassium carbonate. After 30 min, a solid had precipitated which dissolved when approximately 2 g of ice was added. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and a paste-like solid separated which was filtered to yield 3.3 g of crude product. After several attempts to recrystallization from methyl isobutyl ketone, it was recrystallized from acetonitrile to yield 1.25 g (30.7%) of fine white crystals, m.p. 153.5°-154.5° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:12])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([O:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CCCC(O)CCCCl
Product: CC(=O)OC(CCCCl)CCCC(C)C

Procedure:
A mixture of 1-chloro-8-methyl-4-nonanol (22.73 g.; 0.118 mole) and acetic anhydride (24.07 g.; 0.236 mole) is heated on a steam bath for 1-1/2 hours.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21]C(=O)C)=[N:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([O:29]C)=[O:28]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([N:14]([CH2:26][C:27]([OH:29])=[O:28])[S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])=[CH:16][CH:17]=1
Reactant: COC(=O)CBr
Reactant: CC(=O)Nc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc(N)nc2)cc1

Procedure:
prepared by reaction of N-[5-(4-tert-butyl-benzenesulfonylamino)-pyridin-2-yl]-acetamide with methyl bromoacetate
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCSC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of Example 17A (19.9 g, 66 mmol) and triethylamine (9.5 mL, 70 mmol) in THF (200 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (15.08 g, 132 mmol) drop wise over 30 minutes. The mixture was allowed to warm up to room temperature, stirred for 12 hours, and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to a yellow oil. The yellow oil was purified using a Biotage 65+ eluting with 100% ethyl acetate to provide the titled compound. MS (ESI) m/e 380 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 1.44 (m, 9 H) 2.22 (m, 1 H) 2.65 (m, 1 H) 3.05 (m, 1 H) 3.14 (d, 3 H) 3.17 (m, 1 H) 3.74 (m, 3.73 Hz, 1 H) 3.81 (m, 2 H) 4.00 (m, 1 H) 4.53 (m, 1 H) 4.70 (m, 2 H) 5.32 (m, 1 H).