Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2].[N:32]1([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45]O)=[CH:41][CH:40]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:45][C:42]3[CH:41]=[CH:40][C:39]([CH2:38][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:44][CH:43]=3)[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Reactant: OCc1ccc(CN2CCOCC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCc3ccc(CN4CCOCC4)cc3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. (4-Morpholin-4-ylmethyl-phenyl)-methanol (100 mg; 0.48 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) was added followed by 1,1′-(Azodicarbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 5 h, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method A). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt: 2.47 min.
Reaction SMILES: B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](=[O:46])[C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([C@@H:38]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=2)[OH:46])[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC([C@H](O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a solution of (−)-DIP-chloride™ (6.42 g, 20.0 mmol) in THF (10 mL) at 0° C. was added 4-(4-bromobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.68 g, 10.0 mmol). The mixture was stirred at room temperature for 29 hours. Aqueous work-up and purification gave (S)-4-[(4-bromophenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (ee 78% determined by both chiral HPLC and Mosher ester) as a crystalline solid (2.22 g, 54%). This material was recrystallized (CH2Cl2/hexane) three times to provide (S)-4-[(4-bromophenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.29 g, 35%) with ee of 96%.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:32])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:23]5C=CC(C(=O)C)=C[CH:24]=5)[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[OH2:35]>CCO>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:32])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH:23]([OH:35])[CH3:24])[CH:19]=4)[CH2:14]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O
Reactant: CC(=O)c1ccc(-c2ccc3c(c2)CCN(CC(=O)N2CCN(C4CCC4)CC2)C3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc2c(c1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(4-{2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}phenyl)ethanone (153 mg) in EtOH (10 mL) is added sodium borohydride (20 mg). The resulting mixture is stirred at rt for 2 hr. Water (10.0 ml) is added to quench the reaction, and then the EtOH is evaporated. The residue is extracted with DCM (10 ml×3). The combined organic phase is dried over sodium sulfate, and the solvent is removed under reduced pressure to give a residue that is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.08˜7.14 (2H, m), 6.92-6.98 (1H, m), 4.82 (1H, q), 3.58-3.64 (6H, m), 3.28 (2H, s), 2.60-2.84 (6H, m), 2.20-2.28 (4H, m), 1.60-2.20 (6H, m), 1.42 (3H, d); MS (+VE) m/z 358.2 (M++1).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)#[N:3].ClC1C=C(N2[C:24]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:23][C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=N2)C=CC=1F>>[Cl:32][C:27]1[CH:26]=[C:25]([C:24]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:2]#[N:3])[CH:5]=3)[N:11]=[C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=2)[CH:30]=[C:29]([F:31])[CH:28]=1
Reactant: N#Cc1cccc(NN)c1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(C#N)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 1A and 3-cyanophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 1.96 g of the title compound with 55% purity (86% of theory) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](I)[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CCI
Product: CCOc1ccc(C=O)cc1Cl

Procedure:
Following a similar procedure to that described in reference example 3, but starting from 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde and using ethyl iodide instead of 2-iodopropane, the title compound of the example was obtained as an oil (98% yield).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[CH:14][C:15]([OH:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]32[CH2:14][C:15](=[O:17])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)C=C1CCCCC1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC2(CCCCC2Cc2ccccc2)Sc2ccccc2N1
Temperature: 0 °C
Yield: 50 %

Procedure:
A mixture of 2-phenylmethyl-1-carboxymethylenecyclohexane (3.0 g) and 2-aminothiophenol (5.0 g) in N,N-dimethylformamide (3 ml) was refluxed for 20 hours under nitrogen atmosphere. The mixture was cooled to 0° C. and diluted with ethyl acetate (30 ml) and the mixture was washed with 1N hydrochloric acid (30 ml), water (30 ml), a saturated aqueous solution of sodium bicarbonate (30 ml) and brine (30 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 2'-phenylmethyl-4,5-dihydro-4-oxospiro[1,5-benzothiazepine-2(3H), 1'-cyclohexane] (2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([OH:21])=O.C1C=CC2N(O)N=[N:28]C=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[OH-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([NH2:28])=[O:21]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.6 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (64.0 mg, 0.16 mmol) in anhydrous THF (3.6 mL) was added HOBt (56.5 mg, 0.42 mmol, 2.6 eq), DIPEA (0.073 mL, 0.42 mmol, 2.6 mmol), and EDCI (67.8 mg, 0.35 mmol, 2.2 eq), and the reaction mixture was stirred at room temperature under N2 for 2 h. Concentrated aqueous ammonium hydroxide solution (0.50 mL) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with a saturated aqueous solution of ammonium chloride, water and brine. The organic layer was isolated and dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 20% methanol in dichloromethane) to give an oil. Crystallization from DCM-ether-hexane afforded the title compound as a beige solid (9.9 mg, 16.0%). 1H NMR (MeOD, 400 MHz) δ ppm 8.74 (s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.62 (dd, J=10.4 Hz, 2.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 6.59 (t, J=8.4 Hz, 1H); LCMS (method D1): RT=0.84 min, [M+H]+=398.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.Cl.C[O:16][C:17]([CH:19]1[C:24](=O)[CH2:23][CH2:22][NH:21][CH2:20]1)=O.[OH-].[NH4+]>>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]2[C:24]3[CH2:23][CH2:22][NH:21][CH2:20][C:19]=3[C:17](=[O:16])[O:13][C:9]=2[CH:8]=1
Reactant: Cc1cccc(O)c1
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Temperature: 5 °C
Yield: 20.9 %

Procedure:
An 80% sulfuric acid solution (80 ml) is stirred and cooled to 5° C. in an ice bath and 3-methylphenol (10.8 ml, 0.10 moles) is added, followed by methyl-4-oxo-3-piperidine carboxylate hydrochloride (20.0 g, 0.10 moles). The mixture is allowed to warm gradually to room temperature. After 48 hours the solution is poured into ice water (400 ml) and stirred until a crystalline precipitate forms. Concentrated ammonium hydroxide is added until the mixture is strongly basic. After one hour the precipitate is filtered off, rinsed with concentrated ammonium hydroxide, then water, and dried. Recrystallization from acetonitrile gave the product (4.5 g), mp 128°-130° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>CN1C(=O)N(C)CCC1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CCOC(COc1ccccc1)OCC
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (5.83 g of a 55% dispersion in mineral oil) was added to a solution of phenol (12.56 g) in DMPU (25 ml) at 5° C. and the mixture was stirred for 30 minutes. Bromoacetaldehyde diethyl acetal (10.05 ml) was added and the mixture was heated at 110° C. for 5 hours, then allowed to cool. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic phase was separated and washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml). The aqueous fractions were combined and re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried (MgSO4) and concentrated. The resultant oil was purified by flash column chromatography, eluting with ethyl acetate/hexane (1:10 v/v) to give 2-phenoxyacetaldehyde diethyl acetal (9.43 g) as an oil; NMR: 1.25(6H,t, J=7.0 Hz), 3.6-3.85(4H,m), 4.05(2 H,d, J=6.0 Hz), 4.85 (1H,t, J=6.0 Hz) and 6.9-7.35(5H,m).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH3:2].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]1[S:12][C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:30][CH2:31][N:32]([S:35]([CH2:38][CH3:39])(=[O:36])=[O:37])[CH2:33][CH2:34]2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 7 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [2-(ethyloxy)ethyl]amine (30 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown for preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide to give 6 mg of the title compound (7%).
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:2]([NH:1][C:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (614 mg, 91%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[N:4][S:5][N:6]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:7]([C:3]1[C:2]([CH3:1])=[N:6][S:5][N:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nsnc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nsnc1C(=NO)c1ccccc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a stirred solution of (4-Methyl-[1,2,5]thiadiazol-3-yl)-phenyl-methanone (20 g, 98 mmol) in dry pyridine (70 mL) was added hydroxylamine hydrochloride (17 g, 245 mmol). The reaction mixture was stirred at 70° C. for 3 h, then concentrated in vacuo and diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water (2×100 mL) and dried over MgSO4. Evaporation of the solvent in vacuo afforded N-hydroxy-1-(4-methyl-1,2,5-thiadiazol-3-yl)-1-phenylmethanimine as an orange oil [24.3 g, yield 99.6%; HPLC/MS: m/z=220 (M+H); log P(HCOOH)=2.26].
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]([OH:19])[C:16](O)=[O:17])=[O:12].[CH3:31][O:32][NH2:33]>>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH:15]([OH:19])[C:16]([NH:33][O:32][CH3:31])=[O:17])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: CON
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F

Procedure:
The reaction can be carried out in analogy to reaction step 1.3 by reacting 3-((R)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[CH3:21])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([N:20]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[CH3:21])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1)C1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cnc2c(n1)OCCN(Cc1ccccc1)C2)C1CCC1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of 2-[benzyl({3-chloro-5-[cyclobutyl(methyl)amino]pyrazin-2-yl}methyl)amino]ethanol (0.74 g) in DMF (4 mL) was added potassium tert-butoxide (0.28 g) at 0° C., and the mixture was stirred for 2 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→40% ethyl acetate/hexane) to give the title compound (0.48 g, 71%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:3]1=[O:20]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H](NC(=O)C=Cc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, cinnamoyl chloride, and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white solid after removal of the solvent: m.p. 126°-140° C.
Reaction SMILES: N1N[N:3]=[N:4][C:5]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.O>N1C=CC=CC=1>[N:11]1[C:6]([C:5]2[O:28][C:18]([C:19]3[CH:27]=[CH:26][C:22]([C:23]4[O:24][C:5]([C:6]5[N:11]=[C:10]([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=6)[CH:9]=[CH:8][CH:7]=5)=[N:4][N:3]=4)=[CH:21][CH:20]=3)=[N:3][N:4]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)nc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: c1ccc(-c2cccc(-c3nnc(-c4ccc(-c5nnc(-c6cccc(-c7ccccn7)n6)o5)cc4)o3)n2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
0.67 g of 6-(2H-tetrazol-5-yl)-2,2′-bipyridine was dissolved in 10 ml of dehydrated pyridine, and 0.32 g of terephthaloyl dichloride was added. Temperature was elevated to 110° C., and stirring was conducted for 5 hours under reflux. After cooling to room temperature, the reaction solution was poured into water, and a precipitated white solid was taken out by suction filtration, and washed with water. The solid was vacuum dried at 80° C. for 20 hours to obtain a while crude product. By purifying with column chromatography, 0.58 g (yield 74%) of BpyOXDp was obtained. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 8.736 ppm (2H), 8.640 ppm (4H), 8.463 ppm (3H), 8.260-8.384 ppm (4H), 8.060 ppm (2H), 7.932 ppm (2H), 7.380 ppm (1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[CH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][C:38]([Cl:44])=[CH:39][CH:40]=3)[N:35]=2)[CH:27]=1)[OH:25])(=[O:15])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]2[C:41]([CH:42]=[CH:43][C:34]([CH:33]=[CH:32][C:28]3[CH:27]=[C:26]([C@H:24]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23][CH2:22][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:13](=[O:15])[CH3:14])[CH:31]=[CH:30][CH:29]=3)=[N:35]2)=[CH:40][CH:39]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccccc1CC[C@@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccccc1CC[C@@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
At -40° C., methanesulfonyl chloride (1.25 mL, 16.2 mmol) and Et3N (2.8 mL, 20 mmol) were added successively to a solution of the hydroxyketone of Step 4 (6.157 g, 13.44 mmol) in 135 mL of CH2Cl2 and the mixture was stirred at -40° C. for 30 min., then at 0° C. for an hour. A saturated solution of NaHCO3 was added and the title mesylate was extracted into CH2CL2, dried over Na2SO4, concentrated and the remaining traces of water were co-evaporated twice with toluene. This mesylate was used as such in Step 7.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:35](=O)([O:41]C(C)(C)C)[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3.03 g (8.70 mmol) of Compound 27 obtained in Example 27 was dissolved in 200 ml of dimethylformamide, 109 mg of dimethylaminopyridine and 3.0 ml of di-tert-butyl carbonate were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 3.44 g (88%) of 2-[4-[N-acetyl-N-(tert-butoxycarbonyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:14][CH:15]([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1>>[F:14][CH:15]([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH:9]3[O:10][CH2:11][CH2:12][O:13]3)[CH:6]=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#Cc1cccc(C2OCCO2)c1
Product: FC(F)Oc1ccc(C#Cc2cccc(C3OCCO3)c2)cc1
Yield: 85 %

Procedure:
Using essentially the same procedure described in Example 1, step a, and employing 2-(3-ethynylphenyl)-1,3-dioxolane and 1-(difluoromethoxy)-4-iodobenzene, the coupled product was obtained. This product was purified on silica gel (ISCO) using hexanes/EtOAc 5/1 as the eluting solvents to give 2-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,3-dioxolane as a yellow oil (7.9 g, 85% yield), MS m/e (M+H)+ 317; 1H NMR (400 MHz, DMSO-d6) 3.9-4.05 (m, 4H), 5.72 (s, 1H), 7.1-7.3 (m, 3H), 7.4 (m, 2H), 7.5-7.6 (m, 4H).