Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:27]#[N:28])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=1)[CH:9]=2)=O.[NH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CCO>[CH2:35]([O:34][C:32](=[O:33])[C:31]([CH3:38])([CH3:37])[CH2:30][NH:29][C:3]([C:5]1[N:6]=[C:7]([C:27]#[N:28])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=1)[CH:9]=2)=[O:2])[CH3:36]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O

Procedure:
1-Cyano-4-hydroxy-7-(naphthalen-2-yloxy)-isoquinoline-3-carboxylic acid methyl ester (15 mg, 0.04 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (24 mg, 0.16 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 18 mg. MS: (−) m/z 482.36 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C(NCC)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:21][N+:18]([O-:20])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccccc1)c1ccc(F)cc1
Reactant: C[N+](=O)[O-]
Solvent: CO
Solvent: CCNCC
Product: O=C(CC(C[N+](=O)[O-])c1ccccc1)c1ccc(F)cc1
Yield: 95.1 %

Procedure:
In a 1 L flask, 138.8 g (613 mmol) of (2E)-1-(4-fluorophenyl)-3-phenylprop-2-en-1-one were dissolved in 825 g of methanol, admixed with 187.0 g (3.06 mol) of nitromethane and 224.1 g (3.06 mol) of diethylamine and refluxed for 16 h. The solvent was half distilled off in vacuo and the precipitated solid was separated off and dried to constant weight in vacuo to obtain 167.7 g (583 mmol) of 1-(4-fluorophenyl)-4-nitro-3-phenylbutan-1-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:14]C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])[CH3:2].C(OCC)=[O:18].[Na].C(O)C>O>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([CH:14]=[O:18])[C:4]([O:3][CH2:1][CH3:2])=[O:16]
Reactant: CCOC(=O)C(CC)c1ccccc1OC
Reactant: CCOC=O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 2-methoxy-phenylacetic acid ethyl ester (11 g), ethyl formate (8.2 ml) and sodium (1.5 g) was added drop by drop with ethanol (5 ml) at 0° C., and the resulting mixture was stirred for 2 days at room temperature. Water was added, the organic layer was separated, the aqueous phase was washed with diethyl ether and extracted three times with ethyl acetate. The combined extracts were washed with water, dried and evaporated, to give 2 g of ethyl 2-(2-methoxy-phenyl)-3-oxo-propionate. The compound described above (2 g) was dissolved in water (50 ml), added with sodium carbonate (0.95 g), and the resulting mixture was added drop by drop with a solution of benzydamine (1.1 g) in water. The mixture was then heated under stirring for 10 hours at 60° C., acidified and extracted 3 times with methylene chloride. The combined extracts were washed with an 8% sodium bicarbonate aqueous solution, with water, dried and evaporated. The solid residue was crystallized from diethyl ether, to give the title product as a white solid (0.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:8][C:9]3[C:10]([N:24]=2)=[CH:11][C:12]2[C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=2[CH:17]=3)=[N:4][NH:5][CH:6]=1.[CH3:25][C:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1>>[CH:18]([N:15]1[C:16]2[CH:17]=[C:9]3[NH:8][C:7]([C:3]4[C:2]([NH:1][C:29]([C:26]5([CH3:25])[CH2:28][CH2:27]5)=[O:30])=[CH:6][NH:5][N:4]=4)=[N:24][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:23])[C:14]1=[O:21])([CH3:19])[CH3:20]
Reactant: CC(C)N1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Reactant: CC1(C(=O)O)CC1
Product: CC(C)N1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4NC(=O)C4(C)CC4)[nH]c3cc21
Yield: 55.9 %

Procedure:
Methyl-cyclopropanecarboxylic acid[3-(5-isopropyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-isopropyl-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one (300 mg. 0.925 mmol) and 1-methyl-cyclopropanecarboxylic acid (101.8 mg, 1.017 mmol). 210 mg (56%) of the title compound were obtained.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:18]([Sn:22]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])Cl)[CH2:19][CH2:20][CH3:21]>C1COCC1>[C:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Sn:22]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=2)[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cc(C2=CCCC2)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C2=CCCC2)ccn1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-iodo-4-cyclopent-1-enyl-pyridine (150 mg, 0.55 mmol) in THF (3 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 0.38 mL, 0.61 mmol). The resulting deep orange-brown solution was stirred at −78° C. for 15 min then tributylchlorostannane (0.17 mL, 61 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min then warmed to room temperature over 30 min, quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to provide 4-cyclopent-1-enyl-2-tributylstannanyl-pyridine as an orange oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[NH:11][N:10]=1.[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]([CH2:25][CH3:26])[N:10]=1
Reactant: CCI
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc2c1=O
Yield: 77.9 %

Procedure:
A suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-2H-phthalazin-1-one (0.52 g, 1.55 mmoles), prepared as described in example 38, in DMF (10 ml) was added with NaH (0.057 g, 1.55 mmoles) and, after 1 hour, with ethyl iodide (0.125 ml, 1.55 mmoles). After 1 night the mixture was diluted with water (10 volumes) and extracted twice with ethyl acetate. The organic phase was anhydrified and concentrated to give a solid which was purified by flash chromatography (eluent: ethyl acetate/petrolatum 3:7). There was thus obtained 0.44 g of the title compound (yield: 78%). m.p.: 150.2-151.2° C.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([O:7][P:8]([CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1)[OH:9])[CH3:6].[O-]CC.[Na+].C(O)(=O)C>C(O)C>[C:1]([CH2:2][CH2:3][P:8]([CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1)(=[O:9])[O:7][CH2:5][CH3:6])#[N:4]
Reactant: C=CC#N
Reactant: CCOP(O)C1CCCO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOP(=O)(CCC#N)C1CCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.68 g of acrylonitrile and 2.11 g of tetrahydrofuran-2-yl phosphonous acid ethyl ester in 5 ml of absolute ethanol is cooled to 0° under argon and treated, dropwise, with an ethanolic solution of sodium ethoxide (from 0.15 g of sodium metal and 15 ml of absolute ethanol) at such a rate so that the temperature does not exceed 5° (extremely exothermic). After the addition is completed the reaction mixture is stirred at room temperature for 30 minutes and 0.4 g of glacial acetic acid are added. The solvent is removed in vacuo and the residue partitioned between dichloromethane water. The organic layer is dried with anhydrous magnesium sulphate and removed in vacuo to afford ethyl 2-cyanoethyl(tetrahydrofuran-2-yl)-phosphinate; 1H-NMR (CDCl3): δ 4.15 (3 H, m), 3.90 (2 H, m), 2.72 (2 H, m, CH2CN), 2.34-1.87 (6 H, m), 1.32 (3 H, m, CH3 ).
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])C=C[S:10]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)(Cl)(=O)=O.[CH2:21]([Cl:24])[CH2:22][Cl:23]>>[Cl:23][CH:22]1[CH:21]([Cl:24])[S:10](=[O:15])[N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:13]1=[O:14]
Reactant: CCCCCCCCN1C(=O)C=CS1=O
Reactant: ClCCCl
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCCCN1C(=O)C(Cl)C(Cl)S1=O
Temperature: 25 °C

Procedure:
To a solution of 2.29g. (0.01 mole) of 2-n-octyl-4-isothiazolin-3-one 1-oxide in 3 ml. of EDC is added 1.2g. (0.01 mole) of sulfuryl chloride in 3 ml. of EDC. The mixture is stirred at room temperature over a weekend. The solution is filtered and concentrated to give an oil. The oil is further purified via column chromatography (100% benzene: silica) to give 1.0g. (33%) of product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][O:3]1.[CH3:5][NH:6][CH2:7][CH:8]=[CH2:9].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>O1CCOCC1>[CH2:7]([N:6]([CH3:5])[CH2:4][C@H:2]([OH:3])[CH3:1])[CH:8]=[CH2:9]
Reactant: C=CCNC
Reactant: C[C@@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1COCCO1
Product: C=CCN(C)C[C@@H](C)O
Temperature: 140 °C
Yield: 29 %

Procedure:
(2R)-2-methyloxirane (13.76 g) was added to a suspension of N-methylprop-2-en-1-amine (25 ml) and ytterbium(III) trifluoromethanesulfonate (100 mg) in dioxane (100 ml) and heated to 140° C. for 1 hour under microwave irradiation. The solution was concentrated in vacuo and the residue partitioned between water (100 ml) and ethyl acetate (200 ml). The organic extract was dried and solvent removed in vacuo yielding (2R)-1-[allyl(methyl)amino]propan-2-ol as a yellow oil (8.8 g, 29%); NMR spectrum (CDCl3) 1.20 (d, 3H), 2.33 (s, 3H), 2.27-2.46 (m, 2H), 3.05 (m, 1H), 3.23 (m, 1H), 3.88 (m, 1H), 5.19-5.29 (m, 2H), 5.90 (m, 1H); Mass spectrum M+ 129.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:6][C:5]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:4][CH:3]=1.NC1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)=[O:18])[CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Cl)c(-c2cccc([N+](=O)[O-])c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: CO
Product: Nc1cccc(-c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc2Cl)c1
Reaction time: 20 h
Yield: 76.8 %

Procedure:
6-Chloro-3′-nitro-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide (0.46 g, 0.0011 mol) was dissolved in methanol (40 mL), and palladium hydroxide on carbon (20%; 88 mg; 50% wet; 0.000063 mol) was added. The resulting mixture was hydrogenated at 60 psi and 20° C. for 20 h, at which time LCMS showed near complete conversion to the aniline (accompanied by 3% de-chlorination). The reaction mixture was filtered; and rinsed thoroughly. The filtrate was concentrated in vacuo to give 0.33 g of product. The product was purified by prep HPLC/MS using a 30 mm×100 mm C18 column; 35% CH3CN—H2O (0.1% TFA), 1 min, to 55% at 6 min; 60 mL/min; detector set at m/z 391; retention time, 5.5 min. The resulting mixture was freeze dried to yield 258 mg white solid TFA salt. 1H NMR (DMSO-d6) δ 10.62 (br s, 1H, amide NH); 8.20 (s, 1H); 8.04 (d, 1H); 8.00 (m, 2H); 7.75 (d, 1H); 7.59 (t, 1H); 7.45 (d, 1H); 7.35 (t, 1H); 7.00 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:5][N:6]=1.[CH3:11][C:12]1[C:13]([O:15][C:16](=O)[C:17]=1[CH3:18])=[O:14]>C(O)(=O)C>[C:7]([C:4]1[S:3][C:2]([N:1]2[C:13](=[O:14])[C:12]([CH3:11])=[C:17]([CH3:18])[C:16]2=[O:15])=[N:6][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)N(c2nnc(C(C)(C)C)s2)C1=O
Yield: 91 %

Procedure:
2-Amino-5-tert-butyl-1,3,4-thiadiazole (1.57 g) and 2,3-dimethylmaleic anhydride (1.51 g) were refluxed for 5 hours in glacial acetic acid (30 ml). After the reaction, acetic acid and the excess of the 2,3-dimethylmaleic anhydride were evaporated. The residue was dissolved in dichloromethane (50 ml), and the solution was washed with a 10% aqueous solution of potassium carbonate (20 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the desired N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2,3-dimethyl-maleinimide (2.41 g). mp. 87°-91° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[O:21]=[N+:22]=[O:23]>C(Cl)Cl.S1(CCCC1)(=O)=O>[C:11]([C:7]1[CH:8]=[C:9]([N+:22]([O-:23])=[O:21])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: F[B-](F)(F)F
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Product: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: -60 °C

Procedure:
Dissolve 2,6-di-t-butylphenol (721 mg, 3.5 mmol) in methylene chloride (10 mL) and cool to -60° C. Add, by dropwise addition, a solution of nitronium tetrafluoroborate (25 mL of a 0.5M solution in sulfolane, 12.5 mmol) in methylene chloride (15 mL). Warm slowly to 10° C. and partition between methylene chloride (75 mL) and water (75 mL). Separate the aqueous phase and extract with methylene chloride (50 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify and separate by flash silica gel chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22]C=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.CC1[O:40][N:39]=C(CO)C=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][C:25]4[CH:24]=[C:23]([CH3:22])[O:40][N:39]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc(CO)no1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1cc(C)on1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed with (5-methyl-3-isoxazolyl)methanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give (5-methyl-3-isoxazolyl)methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (18 mg, 0.038 mmol). 1H NMR (CDCl-d) δ 2.06(m, 4H), 2.44 (s, 3H), 3.64 (m, 2H), 3.91 (s, 3H), 4.13 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 6.12(s, 1H), 6.95 (s, 1H), 7.06 (m, 2H), 7.39 (s, 1H), 8.17 (bs, 1H), 8.21(s, 1H). LC/MS: MH+479.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.O.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>[Cl:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:3][N:4]=[C:5]2[CH2:10]1)=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ccccc2)C1

Procedure:
To 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.150 g, 0.366 mmol, e.g. see Example 1 for methods of preparation) in 1,2-dimethoxyethane (DME) (3 mL) was added aqueous sodium carbonate solution (1.9 mL, 1 M) followed by phenylboronic acid (0.067 g, 0.549 mmol, commercially available e.g. from Sigma-Aldrich or Strem Chemicals) and dichlorobis(triphenylphosphine)palladium(II) (0.013 g, 0.018 mmol). The reaction mixture was heated at reflux for 7 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (twice). The combined organic fractions were dried, filtered and evaporated. An attempt to purify the crude material on silica gel chromatography using methanol in Dichloromethane (0-20%) as eluent was unsuccessful. The residue was then purified using mass-directed automated (preparative) HPLC (MDAP) to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.076 g) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.[NH3:11]>>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:11])=[O:9])[CH2:3][CH2:2]1
Reactant: N
Reactant: COC(=O)C1CCOCC1
Product: NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 43.5 h
Yield: 74.6 %

Procedure:
Concentrated aqueous ammonia (50 mL) was added to methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) and the reaction mixture was stirred for 43.5 hours at room temperature. The reaction mixture was then cooled in an ice water bath, after which the precipitate was filtered out and dried under reduced pressure at 40° C. to afford 33.4 g of the title compound (74.6% yield).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@@H:43]1[C:50](=[O:51])[N:49]2[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]2[CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:42][C@@H:43]1[C:50](=[O:51])[N:49]2[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]2[CH2:47][CH2:46][CH2:45][CH2:44]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCCC[C@H]2CCCCN2C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCC[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((7S,11aS)-6-oxodecahydro-1H-pyrido[1,2-a]azocin-7-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 56 (5.0 mg, 0.021 mmol) to give a white solid (11 mg, 80% yield). Anal. Calcd. for C42H56N4O6S m/z 744.4. found: 745.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.08 (11H, m), 7.05 (1H, d, J=7.1 Hz), 5.33 (1H, t, J=4.7 Hz), 5.15-5.09 (1H, m), 5.04-4.95 (1H, m), 4.82-4.73 (1H, m), 4.39 (1H, d, J=13.2 Hz), 4.16 (1H, d, J=12.6 Hz), 3.68 (3H, s), 3.16 (1H, t, J=11.5 Hz), 2.87-2.69 (5H, m), 2.52 (1H, td, J=13.2, 2.7 Hz), 2.46-2.34 (3H, m), 2.15 (1H, t, J=13.5 Hz), 2.07-1.99 (2H, m), 1.94-1.77 (2H, m), 1.76-1.37 (16H, m), 1.36-1.19 (2H, m), 1.08-0.94 (1H, m), 0.89-0.76 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[CH:27]([Mg]Br)=[CH2:28]>C(OCC)C>[CH3:25][O:24][C:4]1[C:5]2[CH:6]([CH:27]=[CH2:28])[N:7]3[CH2:20][CH2:19][C:18]4[C:13]([C:8]3=[CH:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=4
Reactant: C=C[Mg]Br
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Agent: [Cl-]
Solvent: CCOCC
Product: C=CC1c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
To a suspension of berberine hydrochloride (500 mg, 1.3 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added vinylmagnesium bromide solution (1.0 M in tetrahydrofuran, 13 mL, 13 mmol) dropwise. After stirring at 0° C. for 2 h, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-8-vinyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (480 mg, 98%). LC/MS m/e calcd for C22H21NO4 (M+H)+: 364.32, observed: 364.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.74-2.84 (m, 2 H) 3.16-3.24 (m, 2 H) 3.75 (s, 3 H) 3.77 (s, 3 H) 4.97 (d, J=10.11 Hz, 1 H) 5.06 (dd, J=4.55, 2.53 Hz, 2 H) 5.85-5.93 (m, 1 H) 5.95 (s, 1 H) 6.00 (d, J=5.31 Hz, 2 H) 6.72 (d, J=8.34 Hz, 1 H) 6.77 (s, 1 H) 6.86 (d, J=8.34 Hz, 1 H) 7.25 (s, 1 H).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[N:26]=2)=[C:5]([C:7]2[CH:8]=[C:9]([NH:13][S:14]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[N:6]=1.C(ON=O)(C)(C)C>C1COCC1.CCOC(C)=O>[Cl:31][C:27]1[N:26]=[C:25]([C:4]2[S:3][CH:2]=[N:6][C:5]=2[C:7]2[CH:8]=[C:9]([NH:13][S:14]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Nc1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc(-c2ncsc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To N-{3-[2-amino-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzene sulfonamide (0.8 g, 1.67 mmol) in 10 mL THF was added t-butylnitrite (0.4 mL, 4 mmol) by syringe. The mixture stirred at rt for 1 h. More t-butylnitrite (0.2 mL, 2 mmol) was added and the mixture heated to 80° C. for 1 h. The mixture was cooled, diluted with 100 mL EtOAc, washed with 20 mL water, filtered through Whatman 1 PS (phase separating) paper and concentrated under vacuum. The crude product was then purified by flash chromatography to give the title compound of Step B (0.53 g, 1.14 mmol, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (s, 1H), 9.37 (s, 1H), 8.55 (d, J=5.3 Hz, 1H), 7.65-7.75 (m, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.23-7.32 (m, 5H), 7.03 (d, J=5.3 Hz, 1H).