Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.F[C:25]1[CH:26]=[CH:27][C:28]2[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]3[C@@H:31]([CH3:35])[CH2:32][O:33][C:34]=1[C:29]=23>CS(C)=O>[NH2:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:25]3[CH:26]=[CH:27][C:28]4[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]5[C@@H:31]([CH3:35])[CH2:32][O:33][C:34]=3[C:29]=45)[CH2:13]2)[CH2:10][CH2:11]1
Reactant: C[C@H]1COc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COc2c(N3CC[C@@H](C4(N)CC4)C3)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 36.5 %

Procedure:
After adding 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (252 mg, 1.12 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (3 ml), 10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (244 mg, 928 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 18 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduce pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (50 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (6 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 4 ml of water to the reaction solution and washing this acidic aqueous solution with chloroform (10 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by recrystallization from ethanol and then dried under a reduced pressure. 125 mg (36.5%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH2:24][N:25]2[C:29](=O)[C:28]3=[CH:31]C=CC=[C:27]3[C:26]2=O)=[N:22][N:21]=[C:20]1[CH2:36][N:37]1CCCCC1.O.NN>C(O)C>[F:18][C:15]([F:17])([F:16])[C:13]1[CH:12]=[CH:11][C:10]2[N:19]3[C:23]([CH2:24][N:25]4[CH2:29][CH2:31][CH2:28][CH2:27][CH2:26]4)=[N:22][N:21]=[C:20]3[CH2:36][N:37]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: O=C(c1ccccc1Cl)c1cc(C(F)(F)F)ccc1-n1c(CN2CCCCC2)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CN3CCCCC3)n1-2

Procedure:
In the manner given in Example 27, 2'-chloro-5-trifluoromethyl-2-[3-(piperidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-trifluoromethyl-1-(piperidinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:11]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[CH2:12][CH3:13]>CN(C)C=O>[CH3:1][O:2][CH2:3][O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:11][CH2:12][CH3:13])[CH:15]=1
Reactant: CCCc1cccc(O)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cccc(OCOC)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Methoxymethyl chloride (8.4 mL) and potassium carbonate (30 g) were added to an N,N-dimethylformamide (150 mL) solution of 3-propylphenol (10 g) at room temperature, followed by stirring at 50° C. for one day. The reaction solution was poured into ice water. The insoluble matter was filtered off, and extracted with a hexane-ethyl acetate (1:1) mixed solvent. The organic layer was successively washed with water and brine. The resultant was dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane only to hexane:ethyl acetate=10:1), to thereby obtain the title compound (8.0 g) having the following physical properties.
Reaction SMILES: O[C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>P(Cl)(Cl)(Cl)=O>[Cl:12][C:2]1[C:3]([C:8]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: NC(=O)c1ncccc1O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncccc1Cl
Yield: 14.9 %

Procedure:
To a solution of 3-hydroxypicolinamide (2.00 g, 14.5 mmol) in phosphorus oxychloride (10 mL) at room temperature was added phosphorus pentachloride (6.00 g, 28.8 mmol). The mixture was heated at reflux for 90 min, and the solvent was removed by distillation. The residue was poured into water, the aqueous solution was neutralized by addition of sodium bicarbonate, and was extracted with ethyl acetate. The organic phase was filtered through silica gel, the filtrate was concentrated, and the residue was subjected to flash chromatography on silica gel, affording 300 mg of 3-chloro-2-cyanopyridine. 1H NMR (CDCl3) δ7.50 (dd, 1, J=4.8, 8.4), 7.89 (dd, 1, J=1.6, 8.4), 8.63 (dd, 1, J=1.6, 4.8).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]=[CH2:22]>CC(C)=O>[CH2:22]([O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(F)ccc1C(=O)OC
Temperature: 25 °C

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (0.27 mol), K2CO3 (0.41 mol), and KI (27 mmol) were charged in a 1-l reactor under N2. Acetone (500 ml) was added, followed by 3-bromo-propene (0.33 mol). The mixture was refluxed for 6 h under N2. The mixture was cooled to room temperature and filtered to remove the solid. The solvent was removed under vacuum, and the residue dissolved in water (200 ml) and CH2Cl2 (300 ml). The organic and aqueous layers were separated and the aqueous phase extracted with CH2Cl2. The organic layers were combined and dried with Na2SO4. The solvent was removed under vacuum to give Intermediate I-40 as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:20](=[O:21])[C:19]([Br:18])([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 85.5 %

Procedure:
4-Nitrophenol (8 gm, 56 mmol) in 100 ml anhydrous tetrahydrofuran was placed under a nitrogen atmosphere and cooled in an icebath. To this was added triethylamine (6.2 g, 61 mmol) followed by the dropwise addition of bromoisobutyryl bromide (14.1 g, 61 mmol) in 20 ml anhydrous tetrahydrofuran over 5 min. After stirring for 16 h, the solids were filtered off and the solution concentrated, and then recrystallized from 100 ml methanol to give 13.8 g yellow solid, >99% pure by HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(C(=O)N2CCNCC2)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.1 %

Procedure:
To a solution of 1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (may be prepared as described in Description 14) (100 mg, 0.487 mmol) in DMF (10 ml) was added 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (152 mg, 0.585 mmol). Finally DIPEA (0.255 ml, 1.462 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Solvent was removed by evaporation, the residue was dissolved in ethyl acetate and the solution extracted with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to dryness and the residue was purified by MDAP to yield the title compound (42 mg) as a white powder.
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](O)=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([I:1])=[CH:3][N:4]=1
Reactant: COc1ccc2c(O)ncc(I)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)ncc(I)c2c1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
A solution of 4-iodo-6-methoxyisoquinolin-1-ol (2 g, 6.64 mmol) in POCl3 (10 mL) was refluxed for 4 h. After concentration, the residue was taken into a mixture of 100 mL of DCM and 50 mL of water, cooled to 0° C., neutralized with 3 N NaOH, dried over MgSO4, concentrated and purified via silica gel chromatography (5-20% EtOAc:Hex) to give the pure product 1-chloro-4-iodo-6-methoxyisoquinoline (1.3 g, 4.07 mmol, 61.2% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.22 (d, J=9.3 Hz, 1H), 7.54 (dd, J=9.3, 2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 4.03 (s, 3H). MS: MS m/z 320(M++1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH2:10]([SH:12])[CH3:11]>O>[CH2:10]([S:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:11]
Reactant: CCS
Reactant: OCc1ccccc1O
Solvent: O
Product: CCSCc1ccccc1O
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 99.2 g (0.8 mol) of 2-hydroxymethyl-phenol and 124 g (2 mol) of ethylmercaptan was heated for 5 hours to 170° C. in a VA autoclave, whilst stirring. After cooling to room temperature, the unconverted ethylmercaptan and the water of reaction were distilled off under normal pressure, and subsequently the 2-ethylthiomethyl-phenol was distilled off under 1.5 mm Hg. 128 g of 2-ethylthiomethyl-phenol (ca. 95% of theory) were obtained.
Reaction SMILES: [Na].[S:2](Cl)(Cl)=O.[Cl:6][CH2:7][CH2:8][CH:9]1[CH2:15][N:14]([CH3:16])[C:13](=O)[C:12]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=[N:21][C:11]=2[O:10]1>C1(C)C=CC=CC=1>[Cl:6][CH2:7][CH2:8][CH:9]1[CH2:15][N:14]([CH3:16])[C:13](=[S:2])[C:12]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=[N:21][C:11]=2[O:10]1
Reactant: O=S(Cl)Cl
Reactant: CN1CC(CCCl)Oc2ncc(-c3ccccc3)cc2C1=O
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ncc(-c3ccccc3)cc2C1=S
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
The entire portion of the above sodium salt was added ~400 ml of thionyl chloride slowly (reaction was slightly exothermic) and stirred at room temperature for 10 minutes. The thionyl chloride was removed by rotary evaporation at 70° C. and the residue azeotroped once with toluene. The residue was suspended in 600 ml of methylene chloride and to the suspension was added diisopropylethylamine cautiously until the solution was basic. The reaction solution was washed with 3×200 ml of 1N hydrochloric acid and 3×200 ml of 1N sodium hydroxide, dried over sodium sulfate, filtered, concentrated by rotary evaporation, taken up in toluene, charcoaled twice and concentrated by rotary evaporation. The residue (60 g) was taken up in ethyl acetate and passed through a short bed of silica gel using 25% hexane-75% ethyl acetate as the eluant. Similar fractions were combined to give ~25 g of crude (but 95% (min)) purity oil which is 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-phenylpyrido[3,2-f] -1,4-oxazepin-5(4H)-one. To 12.5 g (0.04 mole) of the above amide was added 125 ml of toluene and 16 g (0.04 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithio-2,4-diphosphotane-2,4-disulfide. The reaction mixture was heated to reflux for 4 hr. After standing overnight, the toluene was decanted off, washed with 3×100 ml of 1N sodium hydroxide, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was further purified by column chromatography using silica gel as the stationary phase and eluting with ethyl acetate: hexane 1:1, (v/v). Like fractions were combined and concentrated giving 8.5 g (64%) of desired product, m.p. 156°-58° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:21]([S:30][CH2:31][C:32]3[C:37]([F:38])=[CH:36][C:35]([S:39]([NH:42][CH2:43][CH2:44][CH2:45][N+:46]([CH3:49])([CH3:48])[CH3:47])(=[O:41])=[O:40])=[CH:34][C:33]=3[F:50])=[N:20][CH:19]=2)([CH3:17])[CH3:16])=[CH:11][C:10]=1[O:51]C.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:21]([S:30][CH2:31][C:32]3[C:33]([F:50])=[CH:34][C:35]([S:39]([NH:42][CH2:43][CH2:44][CH2:45][N+:46]([CH3:47])([CH3:48])[CH3:49])(=[O:41])=[O:40])=[CH:36][C:37]=3[F:38])=[N:20][CH:19]=2)([CH3:16])[CH3:17])=[CH:11][C:10]=1[OH:51]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCC[N+](C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: BrB(Br)Br
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(C)(c1ccc(Cl)c(O)c1)c1cnc(SCc2c(F)cc(S(=O)(=O)NCCC[N+](C)(C)C)cc2F)n1-c1ccc(F)cc1

Procedure:
The title compound was prepared by treating 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)-N,N,N-trimethylpropan-1-aminium 2,2,2-trifluoroacetate with boron tribromide in DCM, followed by standard workup and then purified by preparative HPLC. MS (EI) m/z 667.4 (M+).
Reaction SMILES: [Si]([O:8][C@@H:9]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]1[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:54]=[CH:53][C:19]([C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C@H:33]([CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:34][S:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:28]([N+:50]([O-:52])=[O:51])[CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:67][C:64]1[CH:65]=[CH:66][C:61]([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[C@H:9]([OH:8])[CH:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][C@H:33]([CH2:42][CH2:43][N:44]5[CH2:45][CH2:46][O:47][CH2:48][CH2:49]5)[CH2:34][S:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[C:28]([N+:50]([O-:52])=[O:51])[CH:27]=4)(=[O:25])=[O:24])=[O:21])=[CH:53][CH:54]=3)[CH2:14][CH2:15]2)=[CH:62][CH:63]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 79.4 %

Procedure:
4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-nitrophenylsulfonyl)benzamide (INTERMEDIATE 75, 329.0 mg, 0.33 mmol) was charged in a 100 ml flask under nitrogen and treated with TBAF (10.0 ml, 1.0 M in THF, 10 mmol). The resulting solution was stirred at room temperature for 35 minutes whereupon the volatiles were removed under reduced pressure. The concentrate was diluted with DCM (100 ml) and washed with 1N aq. NaHSO4 (100 ml), and saturated aq. NaHCO3 (30 ml), then dried (Na2SO4), filtered, and evaporated under vacuum. The concentrate was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→5% MeOH/DCM) followed by further purification by column chromatography (ISCO, 12 g silica gel column, eluting with 0→90% DCM/[10% of 2M NH3 in MeOH/90% DCM]) to provide the title product (228 mg, yield: 78%)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH2:7][NH:8]CC1C=CC=CC=1)([OH:6])[CH2:4][OH:5]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:7][C:3]([OH:6])([C:2]([F:17])([F:16])[F:1])[CH2:4][OH:5]
Reactant: OCC(O)(CNCc1ccccc1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NCC(O)(CO)C(F)(F)F
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A solution of 3,3,3-trifluoro-2-{[(phenylmethyl)amino]methyl}-1,2-propanediol (8.33 g, 33.4 mmol) in ethanol (550 ml) containing palladium hydroxide on carbon (20%, 800 mg) was stirred under an atmosphere of hydrogen for 24 hours. The catalyst was filtered off via a pad of celite and the filtrate was concentrated under reduced pressure, toluene was added and the solution evaporated again under reduced pressure to give the title compound (5.06 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CO)cn1

Procedure:
Methyl 6-methylnicotinate (0.05 mole) is stirred in dry tetrahydrofuran (50 ml.) at 10° C. while solid lithium aluminum hydride (0.0125 mole) is added over one hour. Water (10 ml.) is added with stirring, and the mixture is concentrated to dryness. The residue is extracted several times with hot isopropanol and the combined extracts are filtered and concentrated to dryness to give 2-methyl-5-hydroxymethylpyridine.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1>>[CH3:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)=[O:18])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: Ic1ncn2ccsc12
Product: Cc1ccc(C(=O)c2ncn3ccsc23)cn1
Yield: 82.8 %

Procedure:
7-(6-Methylpyridin-3-yl)carbonylimidazo[5,1-b]-thiazole (885 mg) was prepared in the same manner as in step a) of Synthesis Example 3, except that 1.10 g of 7-iodoimidazo[5,1-b]thiazole and 532 mg of 2-methylpyridine-5-aldehyde were used as the starting compounds.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([CH3:24])([CH3:23])[C:14]([N:16]3[CH:20]4[CH2:21][CH2:22][CH:17]3[CH2:18][CH2:19]4)=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1.S([O-])([O-])(=O)=O.[Mg+2].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]=O)[CH:40]=1.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[CH:17]12[N:16]([C:14](=[O:15])[C:13]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=3)=[C:4]4[CH2:3][CH2:2][NH:1][CH2:46][CH2:45][C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)([CH3:24])[CH3:23])[CH:20]([CH2:19][CH2:18]1)[CH2:21][CH2:22]2
Reactant: O=CCc1cccnc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNCCc2cccnc2)c1
Reaction time: 0.1 h
Yield: 51.8 %

Procedure:
To a solution of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-aza-bicyclo[2.2.1]hept-7-yl)-2-methylpropan-1-one (183 mg in 10 mL dry chloroform) at 0° C. was added 305 mg magnesium sulfate followed by a solution of 100 mg pyridin-3-yl-acetaldehyde in 1.0 mL chloroform and the mixture stirred at low temperature. After 6 minutes, a solution of 52 mg sodium cyanoborohydride in 0.80 mL methanol was added and the pH djusted to pH6 by the addition of 10% acetic acid in methanol. After 30 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic portion was washed successively with saturated ammonium chloride, sodium bicarbonate and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 93:7; then 88:12) gave the title compound (118 mg).
Reaction SMILES: [C:1]([N:4]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:28])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:39])=O>C(Cl)Cl>[C:1]([N:4]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([Cl:39])=[O:27])=[CH:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:28])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)O)cc2)c2ccccc21
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)Cl)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
To a suspension of 3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoic acid (50 mg, 0.10 mmol, 1 equ.) in methylene chloride (0.5 mL) was added a 2M solution of oxalyl chloride in methylene chloride (82 uL, 0.16 mmol, 1.6 equ.). Reaction mixture was stirred at room temperature for 30 m., and then concentrated to give 3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoyl chloride. To a solution of the preformed acid chloride in methylene chloride (0.5 mL) was added methyl-alfG-amino-isobutyrate hydrochloride (31 mg, 0.20 mmol, 2 equ.) and diisopropylethylamine (52 uL, 0.30 mmol, 3 equ.). Reaction mixture was stirred at room temperature for 20 h. and concentrated. The residue was dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexane: 4/1 to 10/0 gradient) to afford methyl 2-{[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoyl]amino}-2-methylpropanoate (105 mg, 46%).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([N+:19]([O-])=O)[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:23]S(O)(=O)=O.O=S(=O)=O.B(O)(O)O.[S]>>[OH:23][C:14]1[C:15]2[C:16](=[O:18])[C:17]3[C:8](=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])[C:9](=[O:22])[C:10]=2[C:11]([NH2:19])=[CH:12][CH:13]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: OB(O)O
Agent: [S]
Product: Nc1ccc(O)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Reaction time: 6 h

Procedure:
50 parts of 1,5-dinitroanthraquinone are heated in 500 parts of 30% strength oleum for 3 hours at 50° C. 25 parts of boric acid are then added with cooling in the course of 20 minutes, the resulting reaction mixture is then cooled down to 15° to 20° C. and 7 parts of sulphur are added to it. After 6 hours' further stirring at 15° to 20° C. the reaction mixture is worked up as indicated. 25.8 parts of 1-hydroxy-4-amino-8-nitroanthraquinone are obtained.