Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH2:14])[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:21](=[O:22])[C:20]2[CH:24]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:25][CH3:26])[CH:6]=1)=[O:4]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: COC(=O)c1ccc(=O)n(CCN)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(=O)n(CCNC(=O)c2cc(Cl)ccc2OC)c1

Procedure:
1-(2-aminoethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester (0.985 g, 5.0 mmol) was reacted with 5-chloro-2-methoxybenzoyl chloride (1.04 g, 5.1 mmol) in dichloromethane (25 ml) and pyridine (10 ml). After an aqueous work-up, purification via flash column chromotography (silica gel, 8% methanol/dichloromethane) gave the product, MP: 149°-150° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH:19]2[O:23][CH:22]([CH2:24][CH2:25][CH2:26][CH2:27]O)[CH2:21][O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12>C1COCC1>[C:13]1([CH:19]2[O:23][CH:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:52]3[C:51](=[O:53])[C:50]4=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]4[C:48]3=[O:58])[CH2:21][O:20]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCCC1COC(c2ccccc2)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCC1COC(c2ccccc2)O1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A solution of diethyl azodicarboxylate (8.6 g, 49.4 mmol) in 40 mL of THF was slowly added to a cold (ice bath) solution of 17 (10.0 g, 45.0 mmol), triphenylphosphine (13.0 g, 49.5 mmol) and phthalimide (7.3 g, 49.7 mmol) in 60 mL of THF. After being kept at ambient temperature overnight, the solution was concentrated and the residue was triturated with ether (˜150 mL) to precipitate triphenylphosphine oxide which was then removed by filtration. The filtrate was concentrated to give an oily residue which was chromatographed on silica eluting with 33% ethyl acetate in hexane. Concentration of the pure product fractions followed by drying under vacuum afforded 14.6 g (92%) of the desired product as a semi-solid (a mixture of diastereomers): 1H NMR (CDCl3, 300 MHz, ppm) 7.85 (m, 2H), 7.71 (m, 2H), 7.46 (m, 2H), 7.36 (m, 3H), 5.90 (s, 0.4H), 5.78 (s, 0.6H), 4.3-4.0 (m, 2H), 3.68 (m, 3H), 1.9-1.3 (m, 6H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[C:11](=[O:12])[C:10]([F:13])=[CH:9][NH:8][C:7]1=[O:14].ClC1C(=O)NC(=O)NC=1.CC1C=CC(S(O[CH:35]([I:38])[C:36]#[CH:37])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[I:38][C:35]#[C:36][CH2:37][C:9]1[NH:8][C:7](=[O:14])[N:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:11](=[O:12])[C:10]=1[F:13]
Reactant: O=c1[nH]cc(F)c(=O)n1-c1ccco1
Reactant: C#CC(I)OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cc(Cl)c(=O)[nH]1
Agent: [K+]
Product: O=c1[nH]c(CC#CI)c(F)c(=O)n1-c1ccco1

Procedure:
The procedure in Example 1 was repeated, except that 2.0477 g of 3N-(2-furanyl)-5-fluorouracil (ftorafur) (10.23 mmole) available from Aldrich Chemical Co. was used instead of 5-chlorouracil and 3.6089 g of iodopropargyl 4-methylbenzenesulfonate (10.741 mmole) and 1.060 g (7.67 mmole) of potassium carbonate were used.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH2:21][OH:22])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.[O-2].[Mn+2]>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH:21]=[O:22])=[CH:8][CH:7]=1
Reactant: CN(C)CCNc1ccc(CO)c2sc3ccccc3c(=O)c12
Agent: [Mn+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CN(C)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Temperature: 60 °C
Yield: 86.4 %

Procedure:
A mixture of 1-[[2-(dimethylamino)ethyl]amino]-4-(hydroxymethyl)thioxanthen-9-one (9.2 g, 0.028 mol) in toluene (322 mL) was heated to about 60° C. and then manganese oxide (MnO2, 16 g) was added and the mixture was heated at 60° C. for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to afford 7.9 g (87%) of 1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-carboxaldehyde (Formula II: R1 =R2 =Me; R8 =H; n=2).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[CH:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)=[CH2:25].C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([CH:24]=[CH2:25])=[CH:27][CH:28]=2)[CH2:12]1)=[O:9])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: C=Cc1ccc(CCl)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-vinylbenzyl chloride (9.9mg, 0.065 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.30 mL) was stirred at 50° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with CH3OH (15 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]-1-(4-vinylbenzyl)pyrrolidine (Compound No. 1701) (19.6 mg, 88%): The purity was determined by RPLC/MS (92%); ESI/MS m/e 547.2 (M++H, C23H25ClF3N4O2).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:38])[N:7]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:8]([C@H:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][C:14]#[CH:15])=[N:9]2)=[CH:4][CH:3]=1.[CH3:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1>ClC(Cl)C.ClCCCl>[NH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:39][C:40]1[CH:47]=[CH:46][C:43]([CH3:44])=[CH:42][CH:41]=1)[C@@H:12]([C:8]1[N:7]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:6](=[O:38])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][C:14]#[CH:15]
Reactant: C#CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Reactant: Cc1ccc(C=O)cc1
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (52.6 mg, 0.10 μmol) in dichloroethane (0.5 mL) was treated with respective aldehydes (in this case 4-methyl benzaldehyde, 0.25M solution in DCE, 0.8 mL, 0.2 μmol). The mixture was stirred at room temperature for 16 h. Solvent was removed under reduced pressure. Residue was taken in MeOH (1.0 mL) and treated with hydrazine (0.25 mL). Reaction mixture was stirred at room temperature for 16 h and solvent removed under reduced pressure. The product was purified with reverse phase chromatography to give final product. Yield (14 mg, 24%). LCMS: m/e 500 [M+H].
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.Cl.[C:12]1(C)[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1>C(O)(=O)C>[CH:13]1[CH:12]=[CH:17][CH:16]=[C:15]2[C:14]=1[C:1]1[C:2]([CH:3]=[C:4]3[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]3)=[N:18]2
Reactant: Cc1ccc(NN)cc1
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Solvent: CC(=O)O
Product: C1=c2ccccc2=C2C1=Nc1ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-indanone (51.0 g, 0.39 mol) and p-tolylhydrazine hydrochloride (61.4 g, 0.39 mol) is dissolved in glacial acetic acid (525 mL) and is vigorously stirred and heated to reflux. The mixture turns red and is heated for 2 h. After cooling to room temperature, it is poured into ice water (1 L). The precipitate is filtered to afford a solid, which is washed with water (about 1 L). The solid is dissolved in ethyl acetate (1.4 L), activated charcoal is added, and the mixture is gently warmed. The mixture is then cooled and filtered over a pad of Celite. The filtrate is dried over Na2SO4 filtered, and is then concentrated to 450 mL and cooled to −30° C. for 3 days. The crystalline solid is filtered and washed with chilled (−78° C.) hexanes (2×500 mL). The beige solid is collected and dried under vacuum (47.1 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].CC(N(C)C)=O>O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:14][C:12](=[O:13])[C:3]2[N:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=2[N:1]=1)[CH3:16]
Reactant: CCSc1ccccc1C=O
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 20 h
Yield: 54.1 %

Procedure:
A mixture of 1.0 g of 3-amino-5-trifluoromethylpyridine-2-carboxylic acid amide, 850 mg of 2-ethylsulfanylbenzaldehyde, 1.60 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 20 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:19]=1)[NH:7][C:8](=[O:18])[CH2:9][N:10]=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>CN(C=O)C.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]>[O:18]=[C:8]1[NH:7][C:6]2[CH:19]=[C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])[CH:3]=[CH:4][C:5]=2[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH2:9]1
Reactant: C=CC(=O)OC
Reactant: O=C1CN=C(c2ccccc2)c2ccc(Br)cc2N1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2c(c1)NC(=O)CN=C2c1ccccc1
Yield: 32.9 %

Procedure:
Title compound 354 (400 mg, 1.28 mmol), methyl acrylate (132 mg, 1.54 mmol), Pd2(dba)3 (16 mg, 0.038 mmol), POT (24 mg, 0.07 mmol) and triethylamine (0.446 mL, 3.2 mmol) were mixed in DMF (15 mL). The mixture was degassed with nitrogen for 5 minutes and the reaction mixture was heated to 100 oC for 2 hours. The DMF was removed and the residue was partitioned between ethyl acetate and water. The 2 layers were split and the aqueous layer was extracted with 2 other portions of ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (50% to 65% ethyl acetate in hexanes) to afford title compound 355 (135 mg, 33%) as a light yellow solid. 1H NMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.68 (d, J=16.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.24 (d, J=6.4 Hz, 2H), 7.16 (td, J=7.5, 1.0 Hz, 1H), 6.70 (d, J=16.2 Hz, 1H), 4.12 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.S(=[N:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)=O>N1C=CC=CC=1>[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]2=[O:8])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C1CCCCCN1
Reactant: O=S=Nc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)N2CCCCCC2=O)cc1

Procedure:
Into a 3000 mL three-neck reactor were charged caprolactam (150 g, 0.703 mol), toluene (1300 mL), and pyridine (680 mL); the reactor was then purged with nitrogen. Under ice bath, p-sulfinylaminobenzoyl chloride (147.1 g, 0.730 mol) was added with stirring to the above mixture. After removing the ice-bath, the reaction mixture was stirred at room temperature for 14 hours. After this, pyridine chloride was removed by filtration and the filtrate was washed with 5% sodium bicarbonate solution two times, and then concentrated to remove the solvent. The residue was recrystallized from ethyl acetate to give N-(p-aminobenzoyl)caprolactam, a polymerizable lactam monomer.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([NH:13][NH:14][C:15](=[S:17])[NH2:16])=O)=[C:9]([F:20])[CH:8]=1.N.O>C(O)(=O)CCCC>[Br:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]2[S:17][C:15]([NH2:16])=[N:14][N:13]=2)=[C:9]([F:20])[CH:8]=1
Reactant: NC(=S)NNC(=O)c1ccc(Br)cc1F
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCC(=O)O
Product: Nc1nnc(-c2ccc(Br)cc2F)s1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
H2SO4 (2 mL) was added to a solution of 2-(4-bromo-2-fluorobenzoyl)-hydrazinecarbothioamide (2.9 g, 10.0 mmol) in pentanoic acid (5 mL) and the resulting mixture was stirred at 110° Celsius for 2 hours. After cooling to rt, the reaction mixture was poured into ice-water (20 mL) and treated with NH3.H2O (15 mL). 5-(4-Bromo-2-fluorophenyl)-1,3,4-thiadiazol-2-amine was then isolated via vacuum filtration and air dried. MS (ESI): mass calcd. for C8H5BFN3OS, 272.94, m/z found, 274.1 [M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[I:20].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[I:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:13]1[O:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=2[N:12]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1I
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2oc(-c3ccncc3I)nc2c1
Temperature: 50 °C
Yield: 80.9 %

Procedure:
To a mixture of 1.81 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-iodoisonicotinamide, 20 ml of tetrahydrofuran and 1.34 g of triphenylphosphine, 2.22 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred while heating at 50° C. for one hour. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.40 g of 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 29”).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:16])[CH:8]=2)[N:3]=1.[C:17]([C@@H:21]1[CH2:26][CH2:25][C@H:24](O)[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.C1COCC1>[C:17]([C@H:21]1[CH2:26][CH2:25][C@H:24]([O:16][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[C:12]([F:13])([F:15])[F:14])[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cc(C(F)(F)F)c2cc(O)ccc2n1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(F)(F)F)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-Methyl-4-trifluoromethyl-quinolin-6-ol (0.771 g, 0.00339 mol, cis-4-tert-Butyl-cyclohexanol (0.8570 g, 0.005484 mol) and Triphenylphosphine (1.423 g, 0.005425 mol) were placed in a flask, and dissolved in Toluene (25 mL). For the Mitsunobu reaction of certain analogs, THF was substituted for toluene as solvent. Diisopropyl azodicarboxylate (1.137 mL, 0.005430 mol) was then added dropwise. After 3 d stirring at RT, the reaction was evaporated to dryness. The residue was purified by silica gel chromatography using 0-30% ethyl acetate in hexanes as eluent (Rf=0.38 in 3:1 hexanes/ethyl acetate). Isolated was 0.739 g of product (60%). ESI-MS(M+H+): 366.20.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([OH:13])=O.[Cl-].[CH2:19]([O:21][C:22](=[O:34])[CH:23]([OH:33])[CH:24]([NH3+:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:20]>>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:32][CH:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:23]([OH:33])[C:22]([O:21][CH2:19][CH3:20])=[O:34])=[O:13]
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1Cl
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1Cl

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting (R)-1-(2-chlorobenzyl)-5-oxopyrrolidine-2-carboxylic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+=459.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([OH:12])[C:4]([CH3:13])=[N:3]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:12][C:5]1[C:4]([CH3:13])=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(O)c(C)nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(OCc2ccccc2)c(C)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a 5 ml solution of ethyl 1,3-dimethyl-4-hydroxypyrazole-5-carboxylate (2 g, 11.6 mmol) in anhydrous dimethylformamide (hereinafter, referred to as DMF) was added sodium hydride (60% dispersion in oil) (0.47 g, 11.8 mmol) under ice-cooling. Benzyl bromide (2 g, 11.7 mmol) was then added dropwise thereto, and the resulting mixture was stirred at room temperature for one hour and poured into water. The mixture was extracted with ethyl acetate. The extract was washed with water, and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel (eluent; ethyl acetate/n-hexane=1:4) to give ethyl 4-benzyloxy-1,3-dimethylpyrazol-5-carboxylate (2.5 g, 9.1 mmol, 78%).
Reaction SMILES: [CH3:1][C:2]([O:4][CH:5]1[CH:9]([O:10][C:11]([CH3:13])=[O:12])[CH:8]2[CH:14]([O:19][C:20]([CH3:22])=[O:21])[CH:15]=[CH:16][C:17](=[O:18])[N:7]2[CH2:6]1)=[O:3].[H][H]>C(O)C>[CH3:22][C:20]([O:19][C@H:14]1[C@@H:8]2[C@H:9]([O:10][C:11]([CH3:13])=[O:12])[C@H:5]([O:4][C:2]([CH3:1])=[O:3])[CH2:6][N:7]2[CH:17]([OH:18])[CH2:16][CH2:15]1)=[O:21]
Reactant: [H][H]
Reactant: CC(=O)OC1C=CC(=O)N2CC(OC(C)=O)C(OC(C)=O)C12
Solvent: CCO
Product: CC(=O)O[C@H]1[C@H]2[C@H](OC(C)=O)CCC(O)N2C[C@H]1OC(C)=O
Reaction time: 8 h

Procedure:
14. (1S,2R,8R,8aR)-1,2,8-triacetoxy-1,2,3,5,8,8a-hexahydro-5-oxyindolizine, 13, 22 g (0.070 mole), was hydrogenated at atmospheric pressure of hydrogen in 400 mL ethanol containing 3 g 10% Pd on carbon. The reaction was allowed to proceed overnight. The catalyst was filtered, and the filtrate was evaporated to dryness. The crystalline residue was taken up in ether and hexane and filtered to afford (1S,2R,8R,8aR)-1,2,8-triacetoxy-octahydro-5-oxyindolizine, 14, 21.4 g (0.068 mole; 97%) as a white crystalline solid of m.p. 146°-147° C. (lit. 143-145 ; A. C. Richardson et. al., Carb. Res., 136: 225(1985)).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])[O:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][S:18]([CH3:17])(=[O:20])=[O:19])[O:5]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 5 mmol) in pyridine (20 mL) was added methanesulfonyl chloride (627 mg, 5.5 mmol) and the mixture stirred at rt for 24 hours. The solvent was then removed under reduced pressure, and the resulting residue redissolved in DCM (200 mL), washed with 1 N HCl (1×100 mL) and 20% NaHCO3 (1×100 mL). The organic layer was then isolated, dried (Na2SO4) and concentrated to dryness. The crude product was purified by crystallization from DCM/hexanes to give the title compound (700 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.82-7.77 (m, 1H), 7.59 (d, J=8.2, 1H), 7.51-7.43 (m, 1H), 7.17-7.10 (m, 1H), 2.95 (s, 3H), 1.37 (s, 12H).
Reaction SMILES: CS[C:3]1[CH:8]=[C:7]([C:9]2[N:10]([C:14]([F:17])([F:16])[F:15])[N:11]=[N:12][CH:13]=2)[C:6]([F:18])=[CH:5][C:4]=1[Cl:19].ClC1C=C(F)C(C2N(C(F)(F)F)N=NC=2)=CC=1S>>[Cl:19][C:4]1[CH:5]=[C:6]([F:18])[C:7]([C:9]2[N:10]([C:14]([F:16])([F:17])[F:15])[N:11]=[N:12][CH:13]=2)=[CH:8][CH:3]=1
Reactant: CSc1cc(-c2cnnn2C(F)(F)F)c(F)cc1Cl
Agent: Fc1cc(Cl)c(S)cc1-c1cnnn1C(F)(F)F
Product: Fc1cc(Cl)ccc1-c1cnnn1C(F)(F)F
Yield: 85.7 %

Procedure:
2.2 g (7.1 mmol) of [2-chloro-4-fluoro-5(3-trifluoromethyltriazolyl)phenyl] methyl sulfide was converted to 2-chloro-4-fluoro-5(3-trifluoromethyltriazolyl)thiophenol in the same manner as in Reference Example 1 and then to 1.8 g of 1,1′-thiodi-[2-chloro-4-fluoro-5-(3-trifluoromethyltriazolyl)benzene (yield 85.7%) in the same manner as in Reference Example 5 (1), which was used in Example 2 (4) as the starting material.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12](C(O)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.ClC(OCC)=O.[NH2:31][C:32]1[C:41]([NH2:42])=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35].C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:31][C:32]1[C:41]([NH:42][C@H:12]2[CH2:13][CH2:14][C@@H:9]([NH2:8])[CH2:10][CH2:11]2)=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: COC(=O)c1cccc(N)c1N
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N[C@H]2CC[C@@H](N)CC2)c1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.4 g (9.9 mmol) of cis-4-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid and 2.7 ml (19.7 mmol) of triethylamine were dissolved in 70 ml of anhydrous tetrahydrofuran and, at −10° C., a solution of 0.94 ml (9.9 mmol) of ethyl chloroformate in 25 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was then stirred at 0° C. for 1 hour. After this, 1.6 g (9.9 mmol) of methyl 2,3-diaminobenzoate were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water and made alkaline with aqueous sodium bicarbonate solution. This aqueous phase was extracted with ethyl acetate. The organic phase was then washed with aqueous sodium bicarbonate solution and water, dried and concentrated in vacuo. 2.7 g of the product were obtained.