Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[C:19]([C:21]1[CH:35]=[CH:34][C:24]([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[C:19]([C:21]1[CH:35]=[CH:34][C:24]([CH2:25][N:26]2[C:30]([CH2:31][CH2:32][NH:33][C:14]([C@@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NCCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 6 h

Procedure:
1 -(t-Butyloxycarbonyl)-piperidine-2(S)-carboxylic acid (0.245 g, 1.07 mmol), 3-(4-cyanobenzyl) histamine dihydrochloride(0.320 g, 1.07 mmol), HOBT (0.137 g, 1.02 mmol), EDC (0.215 g, 1.12 mmol), Et3N (0.374 mL, 2.68 mmol) were dissolved in DMF (3 mL). The solution was stirred for 6 hr, then partitioned between EtOAc (20 mL) and satd NaHCO3 solution (20 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to dryness to give the title compound. 1H NMR (CDCl3); δ7.64 (d, 2H, J=9 Hz), 7.51 (s, 1H), 7.15 (d, 2H, J =9 Hz), 6.91 (s, 1H), 6.27 (br s, 1H), 5.23 (s, 2H), 4.66-4.73 (m, 1H), 3.95-4.16 (m, 1H), 3.41 q, 2H, J=6 Hz), 2.52-2.70 (m, 3H), 2.22-2.30 (m, 1H), 1.46 (s, 9H), 1.33-1.70 (m, 5H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH2:13]Cl)[CH:12]=1>>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH2:13][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:12]=1
Reactant: c1nc[nH]n1
Reactant: ClCc1cncc(Br)c1
Product: Brc1cncc(Cn2cncn2)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates B-1 [B], 1H-1,2,4-triazole has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a white solid. MS: 238.9, 241.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.C(O)(C)(C)C.[N:42]([C:45]1[C:53]([F:54])=[C:52]([F:55])[C:48]([C:49]([OH:51])=[O:50])=[C:47]([F:56])[C:46]=1[F:57])=[N+:43]=[N-:44].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O>[F:55][C:52]1[C:53]([F:54])=[C:45]([N:42]2[CH:36]=[C:35]([CH2:34][NH:33][C:31]([NH:30][C@@:15]([C:4]3[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=3)([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:32])[N:44]=[N:43]2)[C:46]([F:57])=[C:47]([F:56])[C:48]=1[C:49]([OH:51])=[O:50]
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: C#CCNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(NCc1cn(-c2c(F)c(F)c(C(=O)O)c(F)c2F)nn1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a suspension of (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(prop-2-ynyl)urea (5.0 mg, 0.01 mmol), prepared as described in Procedure 3, 4, 5, 6 and 12, in a 1:1 mixture of water and tert-butyl alcohol (100 μl) was added 4-azido-2,3,5,6-tetrafluorobenzoic acid (2.3 mg, 0.01 mmol), followed by sodium ascorbate (1 M solution in H2O, 100 μL) and CuSO4.5H2O (1 mg). The reaction mixture was stirred vigorously overnight in a sealed vial. The reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic portions were concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Onyx Monolithic 10×100 mm; eluting with 10%-90% MeCN/H2O with 0.1% TFA, monitoring at 220 nm) to provide (R)-2,3,5,6-tetrafluoro-4-(4-((3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (Example 319, 5.7 mg, 78% yield). LC/MS: RT=3.610 min [M+H] 742.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm). 1H NMR (500 MHz, MeOH-d4) δ 8.02 (s, 1H), 7.10-6.79 (m, 11H), 6.53 (d, J=5 Hz, 2H), 6.27-6.04 (m, 1H), 4.38-4.31 (m, 2H), 3.81 (d, J=15 Hz, 1H), 3.73 (d, J=10 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH3:28])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO.O>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH3:28])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1n[nH]c2ccc(-c3cc(OC[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)ccc3C=O)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2ccc(-c3cc(OC[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)ccc3CO)cc12
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A solution of Example 247B (225 mg; 0.46 mmol) in EtOH (4 mL) was treated portionwise with NaBH4 (26 mg; 0.70 mmol) and stirred for 30 min., diluted with water, and extracted into EtOAc. The extracts were rinsed with brine, dried (MgSO4), concentrated, and purified by flash chromatography (60% EtOAc/hexane) to provide the desired product (150 mg; 66%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]1([CH2:16][O:17][C:18]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][C:19]=2[C:20](O)=[O:21])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.O>[OH:9][CH2:8][C:3]1[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[C:24]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)[CH:25]=[CH:26][C:18]=2[O:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Reactant: Nc1cccnc1CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccnc1CO)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Neat (3-aminopyridin-2-yl)methanol (may be prepared as described in Description 80; 68 mg, 0.55 mmol) was added in one charge to a stirred suspension of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 120 mg, 0.393 mmol), EDC (151 mg, 0.786 mmol), HOBT (120 mg, 0.79 mmol) and triethylamine (0.11 ml, 0.79 mmol) in N,N-dimethylformamide (1.5 ml) in air at 15° C. The reaction mixture was stirred at 15° C. overnight. Water (30 ml) was added and the reaction mixture extracted with ethyl acetate (30 ml×3). The organic phases were dried with Na2SO4 and concentrated. The residue was purified by pre-HPLC (instrument: Gilson-281, Column: WATERS XBRIDGE 30-100 MM 5 UM, Mobile Phase: A: 0.04% NH3H2O B: CH3CN, Flow rate: 30.0 ml/L, Gradient: 0-10 min, B=30-38% RT=P1: 7.0 min; P2: 9.5 min) to yield the title compound as a white solid. 20 mg.
Reaction SMILES: [CH2:1]([S:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[H-].[Na+].CCCCCC.Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30]>COCCOC.CCOCC>[CH:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][O:14][CH2:13][CH2:12][S:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)([CH3:31])[CH3:30]
Reactant: CC(C)OCCCCBr
Reactant: OCCSCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)OCCCCOCCSCc1ccc2c(c1)OCO2
Reaction time: 3 h

Procedure:
2.12 g (0.01 mol) of 2-piperonylthioethanol are added at room temperature over the course of 10 minutes, to a suspension of 0.48 g (0.01 mol) of 50% sodium hydride dispersion, which had been freed from the mineral oil with hexane, in 40 cc of 1,2-dimethoxy ethane. The mixture is stirred at 50° for 3 hours and a solution of 1.95 g (0.01 mol) of 1-bromo-4-isopropoxybutane in 30 cc of 1,2-dimethoxy ethane is subsequently added. The mixture is stirred at 60° over the course of 48 hours. After cooling to 20°, 100 cc of ether are added to the reaction mixture. The ether solution is extracted with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane/ethyl acetate (5:1), whereupon [2-(4-isopropoxy-butyloxy)-ethyl]-piperonylthioether is obtained as a slightly yellow, clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([NH:8]C(=O)C2C=CC=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>CO>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: CO
Product: Nc1ccc([N+](=O)[O-])cc1

Procedure:
This example illustrates the aminolysis of 4'-nitrobenzanilide, i.e., N-(4-nitrophenyl)benzamide, in methanol to give 4-nitroaniline.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.N1C=CC=CC=1.[C:24]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)([CH3:27])([CH3:26])[CH3:25]>O.ClCCl>[C:24]([C:28]1[N:29]=[C:30]([NH:33][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][N:13]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[S:31][CH:32]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Solvent: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1cc(C(=O)Nc2nc(C(C)(C)C)cs2)ccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
2-(Acetylamino)isonicotinic acid (500 mg, 2.8 mmol) was added dropwise with thionyl chloride (15 ml, 68.5 mmol) at room temperature, warmed to 80° C. and stirred for 30 minutes. The reaction solution was returned to room temperature, concentrated under reduced pressure, and the residue was subjected to azeotropy with toluene to evaporate excessive thionyl chloride. The resulting yellow crystals was added to a mixed solution of pyridine (0.25 ml), dichloromethane (5 ml) and 4-(tert-butyl)-1,3-thiazol-2-amine (525 mg, 3.35 mmol) under ice cooling. The mixture was stirred at 0° C. for 30 minutes, then warmed to room temperature, and further stirred for 2 hours and 30 minutes. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=80:1→50:1) to obtain 545.8 mg (61%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH3:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:25])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(Nc2ccc(OC)cc2OC)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)c(OC)c1
Yield: 97 %

Procedure:
A mixture of 3-(2,4-dimethoxyphenylamino)phthalic acid dimethyl ester (0.85 g, 2.5 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 90 minutes. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.76 g in 97% yield: 1H NMR (CDCl3) δ 3.82 (s, 3H), 3.84 (s, 3H), 6.52 (dd, J=8.6 Hz, J=2.5 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.22-7.26 (m, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.61 (br, 1H).
Reaction SMILES: [C:1]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1C2C(=CC=CC=2)C=[N:22][N:21]=1>>[CH3:20][N:21]1[N:22]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[CH2:19]1
Reactant: Cc1ccc2ccccc2c1C(=O)c1ccccc1
Reactant: c1ccc2cnncc2c1
Product: CN1Cc2ccc3ccccc3c2C(c2ccccc2)=N1

Procedure:
By the procedure described in Example 189, 4.4 g (18 mmol) of the benzoylnaphthalene was converted to 1.73 g of the phthalazine product, which was reduced immediately as shown in Table G.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([F:45])=[CH:32][C:31]=1[N:46]1[CH2:58][CH2:57][N:49]2[C:50]3[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=3[CH:56]=[C:48]2[C:47]1=[O:59])(=[O:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])=[CH:32][C:33]([F:45])=[CH:34][C:35]=1[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CN1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cn3ccnc3c(Nc3ccc(N4CCN(C)CC4)cn3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 90 °C
Yield: 60.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 106c (200 mg, 0.5 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 101l (385 mg, 0.8 mmol), and cesium carbonate (332 mg, 1 mmol). Xantphos (30 mg, 0.08 mmol) and Pd2(dba)3 (55 mg, 0.08 mmol) were added, and the reaction mixture was heated at 90° C. for 4 h. After this time the reaction was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with CH2Cl2/MeOH (10:1) to afford 106d (200 mg, 60%). MS: [M+H]+ 664.
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[CH3:13][C:2]1[O:12][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:4][CH:3]=1
Reactant: CC(=O)CNC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cnc(-c2ccccc2)o1
Yield: 87.8 %

Procedure:
Heat a solution of N-(2-oxopropyl)benzamide (1.0 g, 5.65 mmol) in concentrated H2SO4 (10 mL) at 100° C. for 1 hour. Cool the reaction, pour over ice, neutralize with solid Na2CO3, and extract with ethyl acetate (200 mL). Wash the organic phase with brine (75 mL), dry (Na2SO4), filter, and concentrate to afford a yellow oil. Perform flash chromatography on silica gel, eluting with 100% ethyl acetate, to afford 790 mg (88% yield) of 5-methyl-2-phenyloxazole. MS: m/e=160 (MH+)
Reaction SMILES: [NH2:1][C:2](=[S:17])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]C(C)(C)C)=[O:11])[CH:6]=[N:5]1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=O>>[CH3:9][C:8]1[N:4]([CH2:3][C:2]2[S:17][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[N:1]=2)[N:5]=[CH:6][C:7]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: Cc1c(C(=O)OC(C)(C)C)cnn1CC(N)=S
Product: Cc1c(C(=O)O)cnn1Cc1nc(-c2cccc(C(F)(F)F)c2)cs1
Yield: 81.7 %

Procedure:
A reaction similar to Example 1c was performed using the compound (200 mg, 0.783 mmol) obtained in Example 11b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (209 mg, 0.783 mmol). As a result, the title compound (235 mg, 81%) wherein tert-butyl ester was hydrolyzed by hydrobromic acid produced under the reaction conditions was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[C:23]1(OC)[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([CH2:32][OH:33])[O:24]1)[CH2:2][C:3]#[CH:4].CC#N.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C@H:23]1[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([CH2:32][OH:33])[O:24]1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1C1(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: C#CCCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 4 h
Yield: 31 %

Procedure:
To a cooled solution (−30° C.) of (3R,4S,5S,6R)-2-(2-((but-3-ynyloxy)methyl)-4-chloro-5-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (BW) (12 mg, 0.0238 mmol) in 0.5 mL of 1:1 CH2Cl2:CH3CN was added Et3SiH (16 μL, 0.1 mmol) followed by addition of BF3.OEt2 (10 μL, 0.0789 mmol). After stirring for about 4 h, the reaction was quenched with a saturated solution of NaHCO3. The solution was extracted with ethyl acetate and the extracts were washed with brine, followed by drying over Na2SO4. The solution was concentrated and the resulting residue was purified by preparative HPLC to afford 3.5 mg of title product. 1H-NMR (CD3OD, 400 MHz) δ 7.47 (s, 1H), 7.45 (s, 1H), 7.10 (s, 4H), 4.80 (d, J=12.4 Hz, 1H), 4.61 (d, J=12.4 Hz, 1H), 4.49 (d, J=8.8 Hz, 1H), 4.10 (d, J=15.0 Hz, 1H), 4.05 (d, J=15.0 Hz, 1H), 3.88 (dd, J=12.0, 2.0 Hz, 1H), 3.70-3.64 (m, 3H), 3.50 (t, J=8.4 Hz, 1H), 3.46-3.40 (m, 3H), 2.60 (q, J=7.4 Hz, 2H), 2.53-2.49 (m, 2H), 2.30 (t, J=2.6 Hz, 1H), 1.21 (t, J=7.4 Hz, 3H); LC-MS (m/z): 475 [M+H]+, 519 [M+HCO2]−.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:19])/[CH:7]=[CH:8]/[CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]([CH3:4])[CH3:3]>CO.[Pd]>[CH2:1]([NH:5][C:6](=[O:19])/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNC(=O)/C=C/CCC#Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CNC(=O)/C=C/CCCCc1ccccc1
Yield: 66.9 %

Procedure:
The product of Example 1 (100 mg) was dissolved in dry methanol (3 ml), 5% Pd/C (25 mg) was added, and the mixture was hydrogenated at atmospheric pressure and room temperature. The reaction mixture was diluted with methanol and filtered. The solvent was removed in vacuo, and ether was added then removed in a stream of nitrogen. The last traces of solvent were removed in vacuo to yield N-isobutyl-7-phenylhept-2E-enamide (68 mg). Refractive index 1.39.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])=[N:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:31])([CH3:28])[C:29]#[C:30][C:2]2[C:3]([F:19])=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)=[N:25][CH:26]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1ccc(Cl)cn1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ccc(Cl)cn1
Yield: 28 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(5-chloropyridin-2-yl)but-3-yn-2-ol to give the titled compound as a grey solid (60 mg, 28%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:34]([Cl:35])=[CH:33][C:11]3[N:12]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]([O:15][CH:16]4[CH2:19][CH:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17]4)=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[OH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.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.CN(C=O)C>[Cl:35][C:34]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[OH:36])=[CH:7][CH:6]=2)=[CH:9][C:10]2[N:14]=[C:13]([O:15][CH:16]3[CH2:19][CH:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17]3)[N:12]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:11]=2[CH:33]=1
Reactant: OB(O)c1ccccc1O
Reactant: CCOC(=O)C1CC(Oc2nc3cc(-c4ccc(Br)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
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+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(Oc2nc3cc(-c4ccc(-c5ccccc5O)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Temperature: 120 °C

Procedure:
A 50 mL flask was charged with ethyl 3-{[5-(4-bromophenyl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl]oxy}cyclobutanecarboxylate (150 mg, 0.259 mmol), 2-hydroxybenzeneboronic acid, pinacol ester (60 mg, 0.273 mmol), Pd(PPh3)4 (20 mg, 0.017 mmol), DMF (5 mL), and 1 M aqueous K2CO3 (0.78 ml, 0.780 mmol). The reaction was degassed with N2 and then heated at 120° C. for 1 hour. Then the volatiles were removed in vacuo and the residue partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over (MgSO4), filtered, and concentrated. Chromatography of the resulting residue over silica (preparative TLC) eluting with 45% EtOAc/hexanes afforded the desired product. LC-MS: calculated for C32H37ClN2O5Si 592.22, observed m/e: 593.05 (M+H)+ (Rt 2.67/4 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 4 h
Yield: 80.6 %

Procedure:
5-(4-Aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (1.3 g, 6 mmol) was dissolved in pyridine (10 mL), ethane sulfonyl chloride (0.54 mL, 5.7 mmol) was added, the mixture was stirred for 4 hours, and then water was added. The mixture was diluted with ethyl acetate and washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. Flash chromatography (5%-50% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (1.33 g).