Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[N:5]=[C:6]([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[NH:7][CH:8]=1)[CH3:2].[CH3:31]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[CH2:1]([C:3]1[C:4](=[O:30])[N:5]=[C:6]([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[N:7]([CH3:31])[CH:8]=1)[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(SCc2ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c2)nc1=O
Solvent: CI
Solvent: ClCCl
Product: CCc1cn(C)c(SCc2ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c2)nc1=O
Yield: 38.8 %

Procedure:
The same procedure as E64 from 5-{[(5-ethyl-4-oxo-1,4-dihydro-2-pyrimidinyl)thio]methyl}-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (250 mg, 0.579 mmol), DIPEA (0.202 mL, 1.159 mmol) and MeI (0.054 mL, 0.869 mmol) in DCM (2 mL). to afford the title compound (100 mg, 38.7% yield). LCMS: rt=3.25 min, [M+H+]=446
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[OH:9][CH2:10]C1C(O)=C(CO)C=C(C)C=1.O.O.C(O)(=O)C(O)=O.CCOCCOC(C)=O.C=O>O>[C:1]1([CH:10]=[O:9])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: Cc1cccc(O)c1
Reactant: Cc1cc(CO)c(O)c(CO)c1
Agent: C=O
Agent: O=C(O)C(=O)O
Solvent: CCOCCOC(C)=O
Solvent: O
Product: Cc1cccc(O)c1C=O
Temperature: 70 °C

Procedure:
A phenolic resin rich in alternating phenolic copolymer block segments was formed by reacting a mixture of 519.Og of 99 percent pure m-cresol, 538.2 g 97 percent pure 2,6-bis(hydroxymethyl)-p-cresol and 20 g oxalic acid dihydrate in a solvent mixture of 40 ml deionized water and 200 ml ethyl cellosolve acetate. The reaction mixture was heated to about 70° C. to initiate the reaction forming the copolymer block segments. At 102° C., 32.6 g of 36.9 percent formaldehyde was added in 8 minutes to the reaction mixture to form substantially m-cresol formaldehyde block segments and to chemically bond these segments to the previously formed copolymer blocks. After heating the mixture at reflux for three hours, the amount of heat was increased to remove the water and solvent by distillation. Partial vacuum was applied at about 220° C. and gradually increased to 4 mm Hg to remove the unreacted monomers. Maximum mixture temperature during vacuum stripping was about 226° C. The copolymer was poured from the reaction kettle and allowed to cool. About 840 g of product having a Tg of 112° C. was obtained.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:31]([NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]>C(O)(=O)C>[CH2:31]([N:34]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=23)=[N:4][CH:1]=1)[CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)o1
Temperature: 25 °C
Reaction time: 46 h
Yield: 25.4 %

Procedure:
A solution of 2.94 g (0.010 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 60 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 46 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark brown solid residue was dissolved in 100 ml of THF, treated with 13.7 ml (0.10 mol) of dipropylamine and stirred at room temperature for 3 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 1.0 g (25%) of 3-(5-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 133-135°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([NH2:17])=[O:16])=[C:6]2[C:11]=1[O:10][CH2:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7]2.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([NH2:17])=[O:16])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([N+:12]([O-:14])=[O:13])[CH2:7]2
Reactant: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: NC(=O)c1ccc(F)c2c1CC([N+](=O)[O-])CO2
Reaction time: 0.33 h

Procedure:
8-Fluoro-3-nitro-2H-1-benzopyran-5-carboxamide (730 mg, 3.1 mmol) was slurried in chloroform (75 mL) and isopropyl alcohol (25 mL). To the stirred mixture, silica gel (2.2 g, 230-400 mesh ASTM) was added followed by powdered sodium borohydride (255 mg, 6.2 mmol) portionwise over a period of 15 min. After the addition was complete, the reaction was stirred for 20 min. and the reaction was then quenched by the addition of acetic acid (2 mL) and stirred for an additional 30 min. The insoluble material was filtered off and the solvent removed in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined ethyl acetate phases were treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give 0.67 g (91% yield) of an off-white solid as the title compound (mp 191.0-191.5° C.). EIMS (70 eV) m/z (relative intensity) 240 (1, M+), 195 (17), 194 (100), 193 (17), 177 (26), 151 (44), 149 (27), 148 (18), 123 (23), 103 (48), 102 (11), 101 (29), 96 (13), 95 (15), 94 (11), 88 (41), 83 (14), 77 (25), 76 (11), 75 (39), 74(23), 70 (10), 63 (11), 60 (11), 51 (17), 50 (10).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([N:22]=[C:23]=[O:24])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].N1C=CC=CC=1>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:22][C:23]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])=[O:24])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)n2cc(F)c(=O)[nH]c2=O)cc(OC)c1OC
Temperature: 90 °C
Yield: 47.2 %

Procedure:
A mixture of 3.9 g of 5-fluorouracil, 6.27 g of 3, 4, 5-trimethoxyphenylisocyanate and 15 ml of pyridine was heated at 90° C. for 2 hr and, after evaporating pyridine, 100 ml of dichloromethane and 200 ml of hydrochloric acid water were added to it. The insoluble substance produced was combined with the substance dissolved in the dichloromethane. The combined substances were washed with water and then with ethanol, and 4.8 g of 1-(3, 4, 5-trimethoxyphenylcarbamoy)-5-fluorouracil (melting point: 168°-170° C.) was obtained (Compound No. 6). NMR: 3.76 (3H s OCH3) 3.84 (6H s OCH3) 6.64-7.0 (2H b C6H2).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C([O-])(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=Cc1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 0 °C
Yield: 55.2 %

Procedure:
The 1-aryl-2-nitropropenes were prepared according to the procedure of Koremura, Oku, Shono and Nakanishi (6). The starting aldehydes, commercially available, were used without further purification. To prepare 1-(2,4-dichlorophenyl)-2-nitropropene, a mixture of 43.5 g (0.25 mol) of 2,4-dichlorobenzaldehyde, 18.75 g (0.25 mol) of 1-nitroethane, and 20 g of ammmonium acetate, dissolved in 100 ml of glacial acetic acid, was refluxed for two hours, and then poured onto 200 g of ice. The yellow precipitate was collected and recrystallized from absolute ethanol to give 32 g (60%) of 1-(2,4-dichlorophenyl)-2-nitropropene mp 75°; ir (KBr) 1661 (C=C), 1520 and 1319 cm-1 (NO2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:15]([Cu])#[N:16]>CN1C(=O)CCC1.CCOC(C)=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([CH3:14])([C:10](=[O:12])[CH3:11])[CH3:13])=[CH:3][C:2]=1[C:15]#[N:16]
Reactant: N#C[Cu]
Reactant: CC(=O)C(C)(C)c1ccc(F)c(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)C(C)(C)c1ccc(F)c(C#N)c1
Temperature: 160 °C
Yield: 69.2 %

Procedure:
To a solution of 3-(3-bromo-4-fluorophenyl)-3-methylbutan-2-one (13 g, 50 mmol) in NMP (100 mL) was added CuCN (17.9 g, 200 mmol, 4 eq). The mixture was heated 24 h at 160° C. After cooling, the reaction was diluted with EtOAc, washed with 2N HCl (200 mL), satd NaHCO3 (200 mL) and brine (200 mL) successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc=4:1) to give 2-fluoro-5-(2-methyl-3-oxobutan-2-yl)benzonitrile (7.1 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.56-7.54 (m, 1H), 7.49-7.45 (m, 1H), 7.20 (t, J=8.4 Hz, 1H), 1.96 (s, 3H), 1.50 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.Cl.[CH3:15][C:16]1([CH3:35])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[N:25][N:26]([C:28]3([CH2:32][C:33]#[N:34])[CH2:31][NH:30][CH2:29]3)[CH:27]=2)[O:17]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:33]([CH2:32][C:28]1([N:26]2[CH:27]=[C:23]([B:18]3[O:19][C:20]([CH3:22])([CH3:21])[C:16]([CH3:35])([CH3:15])[O:17]3)[CH:24]=[N:25]2)[CH2:31][N:30]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=2)[CH2:29]1)#[N:34]
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Reactant: CC(C)NC(=O)c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
A mixture of 5-chloro-N-isopropylpyrazine-2-carboxamide (200 mg, 1.00 mmol), {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (325 mg, 1.00 mmol, from Example 1, step 3) and N,N-diisopropylethylamine (401 μL, 2.30 mmol) in 1,4-dioxane (5.0 mL) was heated at 100° C. for 2 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 20-80%) to afford the desired product (0.26 g, 58%). LCMS cacld. for C22H31BN7O3 (M+1)+: m/z=452.3. Found: 452.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:23])[CH2:10][CH2:9][C:8]2[C:11]([CH3:22])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[CH3:24][S:25](Cl)(=[O:27])=[O:26].S(=O)(=O)(O)O>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1([CH3:23])[CH2:10][CH2:9][C:8]2[C:11]([CH3:22])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][O:21][S:25]([CH3:24])(=[O:27])=[O:26])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)C1(C)CCc2c(C)c(OCCCO)c(C)c(C)c2O1
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(C)CCc2c(C)c(OCCCOS(C)(=O)=O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.3 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-hydroxypropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester in 5 ml of anhydrous methylene chloride and 0.33 ml of triethylamine was added 0.17 ml of methanesulfonyl chloride. The mixture was stirred at room temperature for 45 minutes then treated with 1N sulfuric acid and worked-up with methylene chloride in the usual manner. There was obtained 0.461 g of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-methanesulfonyloxypropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester as an oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12](Br)=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5](Br)[CH:4]=2.F[C:20]1(F)[C:33](F)(F)[C:32]2C=C(Br)C=CC=2C2[C:21]1=[CH:22][C:23](Br)=CC=2>>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([CH2:4][CH2:3][CH2:2][CH2:15][CH2:14][CH3:9])=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5]([CH2:32][CH2:33][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=2
Reactant: Fc1c(F)c2cc(Br)ccc2c2ccc(Br)cc12
Reactant: FC1(F)c2cc(Br)ccc2-c2ccc(Br)cc2C1(F)F
Product: CCCCCCc1ccc2c(c1)c(F)c(F)c1cc(CCCCCC)ccc12

Procedure:
In analogy to Examples 1 and 2, 9,10-difluoro-2,7-dibromophenanthrene and 9,9,10,10-tetrafluoro-2,7-dibromo-9,10-dihydrophenanthrene can be reacted with other Grignard reagents to give symmetrically substituted compounds of the formula (Ia1) and (Ia2).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[CH:4]=[C:5]([C:8]([NH:10][NH:11][C:12](=[O:28])[C:13]([CH3:27])([O:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[CH3:14])=[O:9])[NH:6][CH:7]=1.CNN.C(O)C>CN(C)C=O>[NH2:16][O:15][C:13]([CH3:27])([CH3:14])[C:12]([NH:11][NH:10][C:8]([C:5]1[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:29])[CH:4]=1)=[O:9])=[O:28]
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)NNC(=O)c1cc(=O)c(O)c[nH]1
Agent: CNN
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(ON)C(=O)NNC(=O)c1cc(=O)c(O)c[nH]1

Procedure:
0.670 g (1.675 mmol) of 1-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridyl)carbonyl]-2-[2-methyl-2-(phthalimidooxy)propionyl]hydrazine was dissolved in 1.5 ml of dimethylformamide and treated with 0.077 g (1.675 mmol) of methylhydrazine. After stirring for 21/2 hours at room temperature about 2 ml of ethanol were added. The crystals obtained were filtered off and discarded. The filtrate was evaporated under strongly reduced pressure and the product was crystallized from ethanol. 1-[2-(aminooxy)-2-methylpropionyl]-2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridyl)carbonyl]hydrazine was obtained as white crystals melting at 234° (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH:15]([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]>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>[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:19])[CH:15]([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1)=[O:24])[CH3:21]
Reactant: C=CC(C)C(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CC(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-methyl-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[CH:12][C:13]([F:27])=[C:14]([C@:16]2([CH:24]([F:26])[F:25])[C@@H:22]3[C@@H:20]([CH2:21]3)[O:19][C:18]([NH2:23])=[N:17]2)[CH:15]=1.[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1)#[C:29][CH3:30]>O1CCOCC1.O.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:25][CH:24]([F:26])[C@@:16]1([C:14]2[CH:15]=[C:10]([C:33]3[CH:34]=[N:35][CH:36]=[C:31]([C:28]#[C:29][CH3:30])[CH:32]=3)[CH:11]=[CH:12][C:13]=2[F:27])[C@@H:22]2[C@@H:20]([CH2:21]2)[O:19][C:18]([NH2:23])=[N:17]1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Reactant: CC#Cc1cncc(B(O)O)c1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC#Cc1cncc(-c2ccc(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)c1
Temperature: 110 °C
Yield: 73.9 %

Procedure:
A microwave vial was charged with mixture of potassium phosphate (0.19 g, 0.90 mmol), (1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16f-B, 0.10 g, 0.30 mmol), (5-(prop-1-yn-1-yl)pyridin-3-yl)boronic acid (0.12 g, 0.75 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (10.56 mg, 0.015 mmol) in dioxane/water (2.0/0.5 mL). The reaction mixture was heated to 110° C. for 30 min in the microwave. The reaction mixture was then diluted with water and extracted with DCM three times. The combined organic extracts were washed with brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the crude material was purified by silica gel chromatography (0-100% EtOAc-DCM) to obtain the title compound as a white solid (82.3 mg, 74% yield). MS m/z=372 [M+H]+. Calculated for C20H16F3N3O: 371.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12].[Sn](Cl)(Cl)(Cl)Cl.[K+].[Br-]>ClCCl>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:11](=[O:12])[CH:10]=[C:9]([CH3:14])[CH3:8]
Reactant: CC(C)=CC(=O)Cl
Reactant: COc1ccsc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccsc1C(=O)C=C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-methoxythiophene (21.3 g, 0.187 mol) [S. Gronowitz, Arkiv. Kemi., 1958, 12, 239] in dichloromethane (50 mL) was slowly added to a solution of 3,3-dimethylacryloyl chloride (22 mL, 0.195 mol) and tin(IV) chloride (23 mL, 0.195 mol) in dichloromethane (350 mL) at 0°-5° C. After stirring at 0°-5° C. an additional 1 h, the solution was poured into ice water (1 L). The organic layer was separated, washed with water, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The resulting oil was purified by flash chromatography using dichloromethane as the eluant to give the product, 29.6 g (81%): mp 49°-51° C.; IR (KBr): 1671, 1628 and 1430 cm-1 ; MS: m/z 197 (MH+); 1H NMR (CDCl3): δ1.98 (d, J=1.2 Hz, 3H), 2.23 (d, J=1.1 Hz, 3H), 3.98 (s, 3H), 6.85 (d, J=5.5 Hz, 1H), 6.89 (dd, J=1.1 Hz, J=1.2 Hz, 1H) and 7.47 (d, J=5.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([O:9][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-4-hydroxyproline methyl ester (30.2 g, 123 mmol) in methylene chloride (300 ml) were dropwise added successively triethylamine (41.2 ml, 0.295 mmol) and methanesulfonyl chloride (17.1 ml, 0.221 mol) at 0° C. in a nitrogen atmosphere. The mixture was stirred at 0° C. for 2 h, and saturated aqueous sodium hydrogencarbonate was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was subjected to silica gel flash column chromatography (heptane-ethyl acetate=5:5) to give (2S,4R)-N-tert-butoxycarbonyl-4-methanesulfonyloxyproline methyl ester (39.5 g, yield: 99.1%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)=O>C(O)C>[N+:20]([C:16]1[CH:15]=[C:14]([C:12]2[N:1]=[C:2]([NH2:4])[S:3][CH:11]=2)[CH:19]=[CH:18][CH:17]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiourea (0.31 g, 4.1 mmol) and sodium acetate (0.44 g, 5.3 mmol) were combined in 30 mL of dry ethanol. To this suspension was added 2-bromo-1-(3-nitro-phenyl)-ethanone (1.0 g, 4.1 mmol). Reaction mixture was stirred at room temperature overnight. Reaction mixture was evaporated to dryness to yield 4-(3-nitro-phenyl)-thiazol-2-ylamine, which was used in the next step without any further purification. MS: 222.0 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:10])C=O.[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])CCC1C=CC=CC=1Cl)([CH3:14])([CH3:13])[CH3:12].ClC1C=CC=CC=1C=CC=O>>[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH2:10][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Reactant: CC(C=O)c1ccccn1
Agent: O=CC=Cc1ccccc1Cl
Product: CC1CCN(C(=O)C(CCc2ccccn2)NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-2-ylpropyl}carbamate is prepared from pyridin-2-yl propionaldehyde (Kitbunnadaj, R. et al. J. Med. Chem, 2004, 47, 2414-2417) in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is prepared from 3-(2-chlorophenyl)propenal in Example 5.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[OH-].[CH2:11]([N+:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>O.CC(O)C>[CH2:2]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O-:6])=[O:5])[OH:1].[CH2:24]([N+:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CC(CO)(CO)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(CO)(CO)C(=O)[O-]

Procedure:
To a flask were added 3.0 g 2,2-bis(hydroxymethyl)propionic acid, 9.5 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 40 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 40 ml of 2-propanol were added and removed by distillation under reduced pressure. After drying, a pale yellow oil was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(C(F)(F)F)cc2Br)c(F)c1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromo-4-fluorobenzotrifluoride (0.5 mL, 3.52 mmol), 2,4-difluorophenol (0.337 mL, 3.52 mmol), and potassium carbonate (0.486 g, 3.52 mmol) in dimethylformamide (7 mL) was heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude material was purified by flash chromatography (ethyl acetate/hexanes) to provide the title compound (1.0 g, 80% yield).