Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.C([O-])([O-])=O.[Cs+].[Cs+].[O:41]1[C:43]2([CH2:48][CH2:47][S:46][CH2:45][CH2:44]2)[CH2:42]1.Cl>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([O:33][CH2:42][C:43]3([OH:41])[CH2:48][CH2:47][S:46][CH2:45][CH2:44]3)=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: C1CC2(CCS1)CO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (100 mg) in N,N-dimethylformamide (2 mL) is added Cs2CO3 (106 mg) and 1-oxa-6-thiaspiro[2.5]octane (37 mg). The mixture is stirred for 12 hour at 100° C. The mixture is diluted with water, acidified with 1 M aqueous HCl solution and extracted twice with ethyl acetate. The combined organic phases are washed with water and brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 80:20:0→0:80:20) to give the title compound. Yield: 31 mg; LC (method 7): tR=1.16 min; Mass spectrum (ESI+): m/z=579 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:26])([C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:26])([F:1])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
2.76 ml of 7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecan-1-ol is dissolved in 20 ml of absolute pyridine, mixed at 0° C. with 2.48 g of p-toluenesulfonyl chloride and stirred for 3 hours under cold conditions. Then, the reaction mixture is stirred into water, extracted with dichloromethane, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Column-chromatographic purification on silica gel with a hexane-ethyl acetate gradient yields 4.33 g of 7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl tosylate as a clear oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:26]=[CH:25][C:17]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1.[F-].[Cs+].O>CS(C)=O>[C:19]1([N:18]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[C:17]2[CH:25]=[CH:26][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N(c2ccccc2)c2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
One hundred and twenty (120) ml of DMSO as a solvent was added to 10.0 g of N,N′-diphenylbenzidine (29.7 mmol), 8.38 g of p-fluoronitrobenzene (59.4 mmol), and 4.5 g of cesium fluoride (29.7 mmol), and the mixture was stirred in a nitrogen atmosphere at 100° C. for 24 hours. Following reaction, the mixture was poured with stirring into 2500 ml of cold water to obtain crude crystals of N,N′-diphenyl-N-(4-nitrophenyl)-1,1′-biphenyl-4,4′-diamine (NTPD). Subsequently, the mixture was dried for 12 hours in a vacuum at 60° C.
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:39][C:40]1[O:44][C:43]([C:45]([F:48])([F:47])[F:46])=[C:42]([S:49](Cl)(=[O:51])=[O:50])[CH:41]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([S:49]([C:42]2[CH:41]=[C:40]([CH3:39])[O:44][C:43]=2[C:45]([F:48])([F:46])[F:47])(=[O:51])=[O:50])[CH2:6][CH2:5]1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C(F)(F)F)o1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cc(S(=O)(=O)N2CCN(CC(C)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a solution of 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (16.0 mg, 0.036 mmol) in DCM (0.3 mL) was added triethylamine (7.6 μL, 0.054 mmol) followed by 5-methyl-2-(trifluoromethyl)furan-3-sulfonyl chloride (11 mg, 0.043 mmol). The reaction was stirred at room temperature for 1 h and trifluoroacetic acid (0.5 mL) was added to reaction vial. After stirring for 1 hour, the solvent was removed in vacuo. The residue was dissolved in methanol (1 mL) and treated with ethylenediamine (0.1 mL). The reaction solution was stirred for 1 hour and diluted with methanol and purified with preparative LCMS (C18 column eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to give the desired product as white solid (7.8 mg, 41%). 1H NMR (300 MHz, DMSO-D6): δ 12.17 (s, 1H); 8.73 (s, 2H); 8.34 (s, 1H); 7.64 (d, 1H); 7.59 (d, 1H); 7.03 (d, 1H); 4.76 (m, 1H); 3.02 (m, 5H); 2.78-2.50 (m, 5H); 1.53 (d, 3H); LCMS calculated for C22H25F3N7O3S(M+H)+: m/z=524.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].CC(C)([O-])C.[K+].C(O[CH2:16][C:17]1[O:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:21]=1)(=O)C>CN(C)C=O.CO>[CH3:28][N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][C:19]1[O:18][C:17]([CH2:16][S:5][CH2:4][CH2:3][NH2:2])=[CH:21][CH:20]=1
Reactant: NCCS
Reactant: CC(=O)OCc1ccc(CCCCN(C)C)o1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCCCc1ccc(CSCCN)o1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Cysteamine hydrochloride (4.5 g) was added to a cooled solution of potassium-t-butoxide (8.98 g) in dry dimethylformamide (125 ml). The mixture was stirred for 20 min and [5-[4-(dimethylamino)butyl]-2-furanyl]methyl ethanoate (9.6 g) was added. The reaction was heated at 90° for 4 hr, poured onto an ice-water mixture and extracted with chloroform. Distillation of the organic extract gave a yellow oil which after column chromatography on silica, using methanol/0.880 ammonia (9:1) as eluent, and a further distillation afforded a colourless oil b.p. 140°/0.05 mm Hg. Found: C, 60.81; H, 9.86; N, 10.44, Calc. for C13H24N2OS: C, 60.91; H, 9.44; N, 10.93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH3:19])=[C:16]([C:20]#[N:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:23])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH3:19])=[C:16]([CH2:20][NH2:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C#N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CN
Temperature: 25 °C
Yield: 102.6 %

Procedure:
Borane dimethyl sulfide complex (0.73 ml) is added to a solution of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophene-3-carbonitrile (2.8 g) in THF (21 ml) at reflux. After 30 minutes at reflux, the reaction is cooled down to room temperature. HCl (6.2 ml, 1.25M in MeOH) is added and the reaction mixture is refluxed for 30 minutes. The mixture is then concentrated in vacuo to yield C-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-yl}-methylamine as a brown foam (2.9 g). The crude product is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.O.NN>CCO.[Ni]>[ClH:1].[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:11][S:12][C:13]2[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH3:20])[N:14]=2)[CH:4]=1
Reactant: Cc1cc(O)nc(SCc2cc([N+](=O)[O-])ccc2Cl)n1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(O)nc(SCc2cc(N)ccc2Cl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a mixture of 2-{[(2-chloro-5-nitrophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (500 mg, 1.6 mmol) in absolute EtOH (15 mL) was added hydrazine hydrate (1 mL, 32 mmol) and Raney nickel. The reaction mixture was stirred at room temperature overnight. The solid material was filtered on Celite. The pad was recovered and suspended in a mixture of MeOH/EtOAc/CH2Cl2 (100 mL). The mixture was filtered. The filtrate was recovered, evaporated, and dried in vacuo, affording the 2-{[(5-amino-2-chlorophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (45 mg, 10% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:30][CH2:29]2)=[C:24]([CH:31]=O)[CH:23]=1>COCCOC.C(OCC)C>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:30][CH2:29]2)=[C:24]([CH:31]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:23]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2Cl)ccc1C1CC1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3Cl)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102450.9 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (15.70 g, 0.11 mol) in anhydrous 1,2-dimethoxyethane (285 ml) is added sodium methoxide (6.50 g, 0.12 mol) in one portion, and the mixture is stirred at this temperature for 30 minutes. A solution of 2′,4′-dichloro-4-cyclopropylbiphenyl-3-carbaldehyde (13.70 g, 0.047 mmol) is then added dropwise over 20 minutes, maintaining temperature below 10° C. The reaction mixture is stirred at this temperature for 2 hours, then allowed to warm to room temperature before diluting with diethyl ether and distilled water. The two phases are separated, and the aqueous phase is extracted again with diethyl ether (×2). Organic fractions are combined, washed with brine, then dried over magnesium sulphate. The suspension is filtered and filtrate concentrated in vacuo. The aqueous phase is further acidified with 2M hydrochloric acid then extracted again with diethyl ether (×2), dried over magnesium sulfate and concentrated in vacuo. All organics are combined, then diluted with toluene and azeotroped (×4) to afford 4-[1-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (20.0 g) which is of sufficient purity to use directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:11])[C:7]=1[C:8](=[O:10])[CH3:9].[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:18][CH2:9][C:8]([C:7]1[C:6]([CH3:11])=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1c(C)cc(-c2ccccc2)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.2 %

Procedure:
To a solution of 1-(3,5-dimethyl-(1,1′-biphenyl)-4-yl)ethanone (1.89 g, 8.43 mmol) in acetonitrile (16.9 mL) was added tetrabutylammoniumtribromide (TBABr3, 4.07 g, 8.43 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(3,5-dimethyl-(1,1′-biphenyl)-4-yl)ethanone (3.2 g), which was used directly for the next step without further purification.
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[O:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1.C[O:15][C:16](=[O:67])[C@@H:17]([NH:34][C:35]([C@@H:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][NH:38]1)=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=2[CH3:33])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:66][C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][C:62]=1[Cl:65])[CH2:58][O:57][C:54]1[CH:55]=[CH:56][C:51]([C@H:49]2[CH2:48][O:47][C:43]3=[CH:44][C:45]4[CH2:46][C@@H:37]([C:35]([NH:34][C@@H:17]([CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][C:26]6[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=6[CH3:33])=[CH:21][CH:20]=5)[C:16]([OH:67])=[O:15])=[O:36])[N:38]([C:11]([C:9]5[N:10]=[C:6]([CH3:5])[O:7][CH:8]=5)=[O:13])[CH2:39][C:40]=4[CH:41]=[C:42]3[O:50]2)=[CH:52][CH:53]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(C(=O)O)co1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)co1
Reaction time: 0.67 h

Procedure:
EDC (5 eq.) and 2-methyl-oxazole-4-carboxylic acid (10 equiv) were dissolved in DCM and stirred 40 min. To this solution was added (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester and stirred for 12 h. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (12 mg). LCMS (m/z): 866.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-:13])=[C:9]([CH3:14])[C:8]=1[CH3:15].Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>O1CCCC1>[CH3:14][C:9]1[C:8]([CH3:15])=[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=[CH:11][N+:10]=1[O-:13]
Reactant: ClCc1ccccn1
Reactant: Cc1c(OCCO)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(OCCOCc2ccccn2)cc[n+]([O-])c1C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
0.39 g of 60% sodium hydride was added to a suspension of 1.20 g (6.5 mmol) of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide in 40 ml of tetrahydrofuran under cooling with ice in a nitrogen atmosphere to obtain a mixture. This mixture was stirred for 0.5 hour, followed by the addition of 0.83 g (6.5 mmol) of 2-chloromethylpyridine. The obtained mixture was heated under reflux for 8 hours, cooled and filtered. The filtrate was concentrated and purified by silica gel column chromatography (solvent: ethyl acetate/n-hexane=4:1~CHCl3 /MeOH=19:1) to obtain 0.61 g of 2,3-dimethyl-4-(2-pyridylmethoxyethoxy)pyridine N-oxide.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:9]3[N:10]=[C:11]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:12]=[CH:13][C:14]=3[C:6]=2[CH:5]=[CH:4][N:3]=1.[ClH:40].O1CCOCC1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[C:7]2[N:8]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:9]3[N:10]=[C:11]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)=[CH:20][N:21]=4)[N:12]=[CH:13][C:14]=3[C:6]=2[CH:5]=[CH:4][N:3]=1.[ClH:40]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5ccnc(Cl)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1nccc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 197 (0.173 g, 0.315 mmol) was dissolved in 10 mL of DCM and to this was added 4N HCl in dioxane (1.97 mL, 7.88 mmol). The solution was stirred at room temperature overnight and then concentrated under vacuum to give a yellow solid. The solid obtained was sonicated in Et2O and a yellowish solid was collected on filter paper to give compound 190 as an HCl salt (0.164 g, 100%). 1H NMR (500 MHz, DMSO-d6) δ 10.56 (1 H, br. s.), 9.42 (1 H, s), 8.87 (2 H, br. s.), 8.28 (1 H, d, J=4.9 Hz), 8.19 (1 H, d, J=5.1 Hz), 8.09 (1 H, d, J=2.9 Hz), 7.97 (1 H, d, J=9.0 Hz), 7.75 (1 H, dd, J=9.3, 2.0 Hz), 5.96-6.07 (2 H, m, J=9.2, 8.9, 8.8, 8.8 Hz), 3.37-3.43 (4 H, m), 3.26-3.33 (4 H, m), 2.54-2.65 (2 H, m), 2.01-2.12 (4 H, m), 1.66-1.77 (2 H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 449.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[CH:35]=[C:34]([Cl:40])[C:33]([Cl:41])=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:33]1[C:34]([Cl:40])=[CH:35][C:36]2[C:37]3[CH2:38][CH2:39][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:27][CH2:28][C:29]=3[N:30]([CH2:42][C:43]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:44])[C:31]=2[CH:32]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)Cn2c3c(c4cc(Cl)c(Cl)cc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 18 h
Yield: 32.6 %

Procedure:
DMAP (60 mg, 0.49 mmol), p-anisidine (66 mg, 0.54 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc and washed with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (gradient, 99:1 to 95:5) to give 81 mg of impure product. Then, crystallization from EtOAc/heptane gave 73 mg (29%) of a white solid: mp 151-151.5° C.; IR (diffuse reflectance) 3288, 1695, 1661, 1550, 1513, 1473, 1422, 1367, 1318, 1269, 1250, 1172, 1161, 1118, 831 cm−1; MS (CI) m/z 518 (M+H+), 222, 221, 220, 167, 166, 124, 59, 58, 52, 51; Anal. Calcd for C26H29Cl2N3O4: C, 60.24; H, 5.64; N, 8.10; found: C, 60.23; H, 5.73; N, 8.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1.[F:18][C:19]([F:56])([F:55])[C:20]1[CH:21]=[C:22]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:27]([Sn](CCCC)(CCCC)CCCC)[N:26]=[N:25]1>O1CCOCC1.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>[F:56][C:19]([F:18])([F:55])[C:20]1[CH:21]=[C:22]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:27]([C:14]([C:13]2[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10][O:11][C:12]=2[CH3:17])=[O:15])[N:26]=[N:25]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reaction time: 18 h
Yield: 50 %

Procedure:
Heat a mixture of 3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride (187 mg, 0.681 mmol) and 1-(3,5-bis-trifluoromethyl-benzyl)-4-(tri-n-butylstannanyl)-5-phenyl-1H-[1,2,3]triazole (300 mg, 0.454 mmol) in the presence of PdCl2(PPh3)2 (32 mg) in degassed 1,4-dioxane (3.0 mL) at 80° C. After 18 h., concentrate in vacuo and purify the residue by chromatography on silica gel to provide the title compound (50% yield) as a light yellow foam. MS (ES) 609.0 (M++1); TLC Rf=0.1 (6% acetone in hexanes).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:6].[Br:19][CH2:20][C:21](Br)=[O:22].C(OCC)C>C(OCC)(=O)C>[CH3:1][N:2]([C:21](=[O:22])[CH2:20][Br:19])[C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5](=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13]
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=C(Br)CBr
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 56 g of 2-methylamino-2', 5-dichlorobenzophenone in 400 cc of ethyl acetate there are added an equal volume of ice and then 23 cc of bromoacetylbromide. After stirring overnight at room temperature, 300 cc of ethyl ether are added. The solvent layer is decanted, washed with 2 N caustic soda, and then washed with water until neutral. It is then dried over sodium sulfate, filtered, and evaporated to dryness. The residue is treated with petroleum ether and then recrystallized from ethyl acetate. In this way there are obtained 65 g of crystals; yield: 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27]([O:32]C)=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.B(F)(F)F.CCOCC.B.O1CCCC1.C(OCC)C>O1CCCC1.Cl.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([CH2:17][N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27]([OH:32])=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: COc1ncccc1CC1CCN(C(=O)[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: B
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ncccc1CC1CCN(C[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 66.3 %

Procedure:
A solution of 1-((9S,10S)-2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)-4-(2-methoxy-3-pyridylmethyl)piperidine (1.80 g. 3.92 mmol) in tetrahydrofuran (50 mL) was treated with boron trifluoride etherate (612 mg, 4.31 mmol) and borane-tetrahydrofuran (14.9 mL of a 1.0M solution, 14.9 mmol). The resulting solution was heated to reflux for 3 h. The mixture was then concentrated on a rotary evaporator to give a colorless residue. The residue was dissolved in concentrated hydrochloric acid (50 mL, 12N) and heated to reflux for 3 h. The solution was concentrated to dryness on a rotary evaporator to give a glassy residue. This residue was dissolved in methanol (100 mL) and concentrated to dryness on a rotary evaporator (3×) to give a white foam. This foam was dissolved in methanol (5 mL) and added to rapidly stirred diethyl ether (200 mL) to give a white precipitate which was collected and washed with diethyl ether to give the hydrochloride salt of the title compound (1.3 g, 2.60 mmol, 66%) as an off-white powder, mp 211°-215° C.