Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]([F:79])([F:78])[C:34]1[CH:35]=[C:36]([C:44]([CH3:77])([CH3:76])[C:45]([N:47]([C:49]2[CH:50]=[N:51][C:52]([NH:63][CH:64]([CH2:74][OH:75])[CH2:65][O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])=[CH:53][C:54]=2[C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:56]=2[CH3:62])[CH3:48])=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.[C:80](O)(=[S:82])[CH3:81]>C1COCC1>[F:79][C:33]([F:32])([F:78])[C:34]1[CH:35]=[C:36]([C:44]([CH3:77])([CH3:76])[C:45]([N:47]([CH3:48])[C:49]2[C:54]([C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:56]=3[CH3:62])=[CH:53][C:52]([NH:63][CH:64]([CH2:65][O:66][Si:67]([C:70]([CH3:72])([CH3:73])[CH3:71])([CH3:68])[CH3:69])[CH2:74][O:75][C:80](=[S:82])[CH3:81])=[N:51][CH:50]=2)=[O:46])[CH:37]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:39]=1
Reactant: Cc1cc(F)ccc1-c1cc(NC(CO)CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OCC(CO[Si](C)(C)C(C)(C)C)Nc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
To a solution of 0.19 mg (0.71 mmol) triphenylphosphine in 10 ml dry THF were added 0.12 g (0.71 mmol) diethyl azodicarboxylate at 0° C. under argon. After 30 min a solution of 0.50 g (0.71 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxymethyl-ethylamino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide in 5 ml dry THF and 0.06 g (0.9 mmol) thioacetic acid were added. The reaction mixture was allowed to warm to room temperature over night. Dilution with a saturated aqueous solution of sodium hydrogencarbonate was followed by extraction with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.28 g (52%) of the title compound as a white solid. MS m/e (%): 760 (M+H+, 100)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]#[N:20])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:22].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]([NH2:20])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(-c3ccc(F)cc3)cc(C#N)nc2c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2c(-c3ccc(F)cc3)cc(C(N)=O)nc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-(4-Fluorophenyl)-7-methylquinoline-2-carbonitrile (1-6, 25 mg, 0.095 mmol, 1.0 equiv.) was dissolved in acetone (2.3 mL)/water (1.5 mL) and sodium percarbonate (79.0 mg, 0.477 mmol, 5.0 equiv) was added. The resulting mixture was stirred at 50° C. for 1 hour. The mixture was cooled and concentrated. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier). Fractions containing product were pooled and treated with Na2CO3. The resulting mixture was extracted with CHCl3. The combined organic layers were dried (MgSO4), filtered, and concentrated to afford 4-(4-fluorophenyl)-7-methylquinoline-2-carboxamide (1-7). LRMS m/z (M+H)+ 280.9 found, 281.3 required.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][OH:20])[OH:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][O:20][C:33](=[O:34])[C@H:29]([CH:30]([CH3:31])[CH3:32])[NH:28][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[OH:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 49 %

Procedure:
1-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (17.95 g. 61.6 mmol), Boc-L-valine (6.69 g, 30.8 mmol), DMAP (0.38 g, 3.1 mmol), and DCC (7.10 g, 34.4 mmol) in 240 mL CH2Cl2 and 60 mL DMF were stirred at rt under N2 for 18 h. The reaction mixture was filtered, concentrated under vacuum, and redissolved in 200 mL EtOAc. The organic solution was washed with 50 mL saturated NH4Cl. The aqueous phase was reextracted with 50 mL EtOAc. The organic phases were combined, washed successively with 50 mL saturated NaHCO3 and 50 mL brine, dried over NA2SO4 and concentrated under vacuum. Flash column chromatography of the crude material on silica gel (eluent 2/1 petroleum ether-EtOAc, and then EtOAc) gave 7.41 g (49%) of the title compound (alternative nomenclature: 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl:36][C:37]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:38]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH2:46]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:37]=2[Cl:36])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (489 mg, 2.13 mmol) in dry DCM (10 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.116 g, 5.82 mmol) and triethylamine (0.3 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 2-(2,4-dichlorophenoxy)phenylamine (AMR01026, 491 mg, 1.93 mmol) in dry DCM (5 mL) was added. After stirring at room temperature for 72 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 4-[2-(2,4-Dichlorophenoxy)phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (754 mg, 84%) as a white solid (mp 120-121° C. from hexane), which was used in the next step without further purification. Rf: 0.31 (Hexane/EtOAc 7:3) LC/MS (APCI) tr=1.39 min, m/z 464.96 (21), 462.94 (M−−H, 32), 253.90 (66), 251.89 (100). 1H NMR (270 MHz, CDCl3) δ 1.44 (9H, s, 3CH3), 1.70 (2H, m, CH2), 1.86 (2H, br d, CH2), 2.40 (1H, tt, J=11.3, 3.7 Hz, CH), 2.77 (2H, br t, CH2), 4.14 (2H, m, CH2), 6.71 (1H, dd, J=8.2, 1.7 Hz, ArH), 6.94 (1H, d, J=8.9 Hz, ArH), 7.01 (1H, td, J=8.2, 1.5, ArH), 7.12 (1H, td, J=8.2, 1.5 Hz, ArH), 7.21 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.48 (1H, d, J=2.5 Hz, ArH), 7.76 (1H, br s, NH) and 8.40 (1H, dd, J=7.9, 1.5 Hz, ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)O)c1C(=O)O
Reaction time: 13 h
Yield: 84 %

Procedure:
A mixture of 10% Pd/C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) was charged to a 2.5 L Parr hydrogenator, under a nitrogen atmosphere. Hydrogen was charged to the reaction vessel for up to 55 psi. The mixture was shaken for 13 hours, maintaining hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite bed and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was reslurried in ether and isolated by vacuum filtration. The solid was dried in vacuo to a constant weight, affording 54 g (84% yield) of 3-aminophthalic acid as a yellow product. 1H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (brs, 2H). 13C-NMR (DMSO-d6) δ: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[CH:24][CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(CCBr)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(O)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.36 g-see Preparation 3), 4-hydroxyphenethyl bromide (0.26 g), sodium bicarbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (40 ml) and aqueous sodium bicarbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give a foam which was further purified by column chromatography on alumina eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.09 g.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[N:19][C:20]#[N:21])SC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:22][NH2:23]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:23][CH3:22])=[N:19][C:20]#[N:21])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC(=NC#N)NCCCCCc1csc(NC(=N)N)n1
Reactant: CN
Solvent: CCO
Product: CNC(=NC#N)NCCCCCc1csc(NC(=N)N)n1
Reaction time: 8 h

Procedure:
To a solution of 2-guanidino-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazole in ethanol was added ethanolic methylamine (33% w/v, 15 ml.). The mixture was allowed to stand overnight and then evaporated to dryness. The residue was crystallized from acetonitrile to give 2-guanidino-4-[5-(2-cyano-3-methylguanidino)pentyl]thiazole, m.p. 109°-113° C.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: CNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Br)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To 800 mg of N,N-dimethylformamide were added 260 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 130 mg of 3-methylaminoazetidine dihydrochloride, and 300 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 247 mg of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].O>C1CCN2C(=NCCC2)CC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Reactant: NCC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C(O)CNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 150 °C

Procedure:
A mixture of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (10.0 g, 0.03 mol) and glycine (4.8 g, 0.06 ml) in DBU (100 ml) is heated at 150° C. under an atmosphere of argon for 40 hours. The still hot reaction mixture is poured into water. After washing the aqueous phase with ethyl acetate the pH is adjusted to 5 by adding citric acid. The resulting precipiate is filtered and recrystallized from dimethylformamide/ethanol to give the product in form of yellow crystals, m.p. 136–138° C. (with decomposition).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].O.[CH:13]([Cl:16])(Cl)Cl>CN(C)C=O>[Cl:16][C:13]1[CH:5]=[CH:6][C:1]([C:7]2[CH2:8][O:9][C:8](=[O:10])[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:2][CH:3]=1
Reactant: O=C([O-])Cc1ccccc1
Reactant: ClC(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCC(c2ccc(Cl)cc2)=C1c1ccccc1
Reaction time: 4 h

Procedure:
2-bromine-1-(4-chlorophenyl)-ethanone (2, 102.6 g, 0.44 mol) and potassium phenylacetate (1, 104.5 g, 0.6 mol) are heated to 80° C. in dimethyl formamide (600 mL) while being stirred for 4 hours and are then cooled. After the addition of water (1 L), chloroform is used for extraction (3 times 300 mL), and the chloroform extract is washed with water and then dried (Na2SO4) and concentrated to dryness. For crystallization, diisopropyl ether is added (500 mL) and the crystals, which are formed in the cold [and have] a melting point of 111-113° C., are collected (yield 92 g, 78% with reference to 2).
Reaction SMILES: [CH2:1]([Si:9]([CH3:14])([CH3:13])N(C)C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:15][C:16]([F:27])([F:26])[C:17]([O:19]C(=O)C(F)(F)F)=[O:18]>>[F:15][C:16]([F:27])([F:26])[C:17]([O:19][Si:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH3:14])[CH3:13])=[O:18]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCCC[Si](C)(C)N(C)C
Product: CCCCCCCC[Si](C)(C)OC(=O)C(F)(F)F

Procedure:
Additionally, for example when mixing octyldimethyl(dimethylamino)silane as the silicon compound B and trifluoroacetic anhydride as the acid B, the trifluoroacetic anhydride is rapidly reacted to form octyldimethylsilyl trifluoroacetate as the acid A.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)[S:25][C:18]=12.[O:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47]O)[CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:13][C:14]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=3)[O:32][CH2:47][CH2:46][N:43]3[CH2:44][CH2:45][O:40][CH2:41][CH2:42]3)[S:25][C:18]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(O)c4)sc23)c(F)c1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Yield: 66.5 %

Procedure:
Diethylazodicarboxylate (0.6 mL, 3.84 mmol) was added to the solution of 160 (1.05 g, 2.75 mmol), 2-morpholinoethanol (0.5 mL, 3.84 mmol) and triphenylphosphine (1.01 g, 3.84 mmol) in tetrahydrofuran (27 mL). The reaction mixture was stirred until its completion, quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluent MeOH-DCM (2:98) to afford title compound 161 (906 mg, 66% yield) as a light-yellow solid. LRMS (M+1) 496.3 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([F:28])[CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 503.4 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)=[O:11].Br[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:32][CH:31]([CH3:33])[CH2:30][N:12]([C:10]([C:2]1[N:3]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)=[O:11])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3[nH]2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.38 g) and (2-bromoethyl)benzene (810 μl) in N,N-dimethylacetamide (30 ml) was added cesium carbonate (2.93 g), and the mixture was stirred at 65° C. for 15 hr. (2-Bromoethyl)benzene (810 μl) was added to the reaction mixture, and the mixture was further stirred at 65° C. for 5 hr. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object product (1.40 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([O:13][CH3:14])[C:11]#[CH:12]>C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([C:12]#[C:11][CH2:10][O:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: C#CCOC
Reactant: Nc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Product: COCC#Cc1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Fluoro-4-iodoaniline (2.00 g, 8.44 mmol), CuI (32 mg, 0.17 mmol), and (Ph3P)2PdCl2 (119 mg, 0.17 mmol) were weighed into a flask which was sealed and flushed with N2. A solution of methyl propargyl ether (0.65 g, 9.28 mmol) in TEA (8 mL) was added, then the entire mixture stirred 15 hours at room temperature. The reaction mixture was diluted with diethyl ether (100 mL), filtered through Celite®, then all solvents removed under reduced pressure. The resulting dark brown oil was purified by filtration through a plug of flash silica (10% EtOAc/hexanes as eluant) to afford 2-fluoro-4-(3-methoxy-1-propynyl)aniline as a pale orange oil which rapidly solidified to give a dark orange solid (1.38 g, 91%); 1H NMR [400 MHz, (CD3)2SO] δ 7.07 (dd, J=12.2, 1.8 Hz, 1 H), 6.98 (dd, J=8.2, 1.7 Hz, 1 H), 6.71 (dd, J=9.3, 8.4 Hz, 1 H), 5.56 (s, 2 H), 4.26 (s, 2 H), 3.29 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].O>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1cccnc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-3-pyridinol (5 g) in THF (100 ml) at 0° was added sodium hydride (1 g, 80% suspension in oil). The mixture was stirred under nitrogen for 30 min and methyl bromoacetate (3.26 ml) was added dropwise. The mixture was then heated under reflux for 2 h, poured into water (300 ml) and extracted with ethyl acetate (2×250 ml). The combined organic extracts were dried and concentrated to give a solid which was triturated with ether to give the title compound as a white solid (4.5 g), m.p. 63°-64° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C=CC(Br)=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[N:24]C(N2CCNCC2)=[N:26][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:24]=[CH:23][C:22]([Br:21])=[CH:27][N:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Reactant: Brc1cnc(N2CCNCC2)nc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Yield: 93 %

Procedure:
Prepared according to the method for the preparation of 4-(4-bromophenyl)-piperazine-1-carboxylic acid tert-butyl ester, from 5-bromo-2-piperazin-1-ylpyrimidine (5.00 g), to yield the title compound as a white solid (6.55 g, 93%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:17]=[C:16]([CH3:18])[N:15]([CH3:19])[N:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][N:15]1[C:16]([CH3:18])=[CH:17][C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[N:14]1
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)C2)nn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CCNC2)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.1 %

Procedure:
To a stirred solution of 3-(1,5-dimethyl-1H-pyrazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.19 mmol) in dry CH2Cl2 (1 mL) was added TFA (2 mL, 20% in CH2Cl2) at 0° C. The reaction mixture was stirred at room temperature for 3 h. TLC showed the disappearance of starting material. The reaction mixture was concentrated in vacuum to afford crude 1,5-dimethyl-3-pyrrolidin-3-yl-1H-pyrazole (33 mg, 91%), which was used for the next step without purified.