Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][C:22]=1[F:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33]N1C(=O)CCC1=O>CC#N.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:33])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([C:28]([F:30])([F:31])[F:29])=[CH:23][C:22]=1[F:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)cc1F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)cc1F
Temperature: 70 °C

Procedure:
To a yellow homogeneous solution of 8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.400 g; 3.047 mmol) in anhydrous MeCN (50 ml) was added dropwise, at rt, a solution of N-chlorosuccinimide (0.407 g; 3.047 mmol; 1 eq.) in anhydrous MeCN (25 ml). The resulting solution was then heated to 70° C., under nitrogen, for 3 h30. Concentration to dryness afforded a yellow oily residue which was dissolved in EA (150 ml), and this organic layer was successively washed with aq. sat. NaHCO3 (2×50 ml), and brine (50 ml), and was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=50/1) gave the expected 1-chloro-8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.711 g; 47%). LC-MS: tR=1.10 min.; [M+H]+=493.93 g/mol.
Reaction SMILES: C(OC([N:8]1[CH2:39][CH2:38][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](=[O:37])[NH:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]4)[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:34]([CH3:36])=[CH:33][CH2:32][N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:24]([CH:22]2[CH2:23][N:20]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:39][CH2:38][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:21]2)=[O:37])[CH2:27][CH2:28]1
Reactant: CC(C)=CCN1CCC(NC(=O)C2CN(c3c4c(nc5ccnn35)CCN(C(=O)OC(C)(C)C)CC4)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCN1CCC(NC(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)CC1
Reaction time: 2.5 h

Procedure:
To 70 mg (0.13 mmol) 10-{3-[1-(3-Methyl-but-2-enyl)-piperidin-4-ylcarbamoyl]-azetidin-1-yl}-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester in 2 mL of DCM was added 0.13 mL TFA and stirring was continued for 2.5 h at room temperature. The reaction mixture was concentrated and the residue, after addition of small amounts of 1N NaOH and MeOH, purified by HPLC.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)([OH:7])[CH3:6])[CH3:2].[Cl-].[NH4+].[In]>C(O)C.ClCCl>[NH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[C:20]([F:23])([F:21])[F:22])[NH:9][C:8]([C:5]([OH:7])([CH3:6])[CH2:4][S:3][CH2:1][CH3:2])=[CH:16]2
Reactant: CCSCC(C)(O)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: CCSCC(C)(O)c1cc2cc(N)c(C(F)(F)F)cc2[nH]1

Procedure:
A solution of 1-ethylsulfanyl-2-(5-nitro-6-trifluoromethyl-1H-indol-2-yl)-propan-2-ol (0.35 g, 1.0 mmol) in ethanol. (20 mL) was prepared. To the solution was then added saturated ammonium chloride solution (20 mL). Indium was added (1.15 g, 10 mmol) and the reaction heated to reflux. After one-half hour the reaction was complete. The reaction mixture was filtered through Celite and the Celite washed with water and diethyl ether. The layers were separated and the aqueous layer extracted with diethyl ether. The organic layers were dried over magnesium sulfate, filtered, and evaporated to yield a residue. The residue was dissolved in dichloromethane and purified by column chromatography eluting with 1:1 diethyl ether/hexanes to yield the title compound as a solid.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][CH2:10][OH:11]>C(O)C>[OH:11][CH2:10][CH2:9][NH:8][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: NCCO
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NCCO)CS1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of 4-thioxothiazolidin-2-one (2.66 g) in ethanol (50 mL) was added 2-aminoethanol (1.22 g) at room temperature. The reaction mixture was stirred at room temperature for 4 hr, and the precipitate was collected by filtration and washed with ethanol to give the title compound (2.24 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:17][C:18]1[CH:19]=[N:20][NH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:20]2[CH:19]=[C:18]([I:17])[CH:22]=[N:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)cn2)C1
Temperature: 85 °C

Procedure:
A mixture of 3-methanesulfonyloxyazetidine-1-carboxylic acid tert-butyl ester (4.00 g, 15.9 mmol), 4-iodopyrazole (3.1 g, 15.9 mmol), potassium carbonate (2.85 g, 20.6 mmol) and 18-crown-6 (400 mg) in dry DMF (15 mL) was heated at 85° C. for 24 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes/dichloromethane/ethyl acetate (8:1:1) to give the pure title compound. 1H NMR (300 MHz, CDCl3): δ=1.47 (s, 9H), 4.29 (m, 2H), 4.36 (m, 2H), 5.05 (m, 1H), 7.59 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1)#[N:2].C(/C=C\C1CCN(C(OCC2C=CC=CC=2)=O)C1)#N.C1CCN2C(=NCCC2)CC1.[NH:50]1[CH:54]=[C:53]([C:55]2[C:56]3[CH:63]=[CH:62][N:61]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:57]=3[N:58]=[CH:59][N:60]=2)[CH:52]=[N:51]1>C(#N)C>[C:1]([CH2:3][CH:4]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:6]1)[N:50]1[CH:54]=[C:53]([C:55]2[C:56]3[CH:63]=[CH:62][N:61]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:57]=3[N:58]=[CH:59][N:60]=2)[CH:52]=[N:51]1)#[N:2]
Reactant: N#C/C=C/C1CCN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: N#C/C=C\C1CCN(C(=O)OCc2ccccc2)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCN(C(=O)OCc5ccccc5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of benzyl 3-[(E)-2-cyanovinyl]pyrrolidine-1-carboxylate and benzyl 3-[(Z)-2-cyanovinyl]pyrrolidine-1-carboxylate (241 mg, 0.940 mmol) and DBU (234 μL, 1.57 mmol) in ACN (13 mL) was added 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (250 mg, 0.78 mmol). The mixture was stirred at ambient temperature for 3 hours. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, and the organic layer was washed sequentially with 1N HCl, water, saturated NaHCO3, and brine. The washed solution was dried over sodium sulfate and the solvent was removed in vacuo. Purification via flash column chromatography (eluting with a gradient of 0-100% [5% MeOH/DCM] in hexanes) afforded the product as a mixture of diastereomers (400 mg, 89%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C:8]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[SH:34].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH:1]1([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]([S:34][C:28]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=3[Cl:26])[C:8]2=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OC2C(=O)N(C3CCCCC3)CC2(C)C)cc1
Reactant: Sc1ccc(Cl)cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC1(C)CN(C2CCCCC2)C(=O)C1Sc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
Place toluene-4-sulfonic acid 1-cyclohexyl-4,4-dimethyl-2-oxo-pyrrolidin-3-yl ester (0.102 g, 0.28 mmol), 2,4-dichloro-benzenethiol (0.073 ml, 0.56 mmol) and DBU (0.130 ml, 0.84 mmol) in DMF (3 mL). Stir for 5 hours at 50° C. Quench with water and extract with ethyl acetate. Wash the extract brine and dry over magnesium sulfate, filter, and concentrate. Flash chromatography affords 0.030 g (29%) of the title compound: Mass spectrum (apci) m/z=372 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2nc(-c3ccc(OCc4ccccc4)cc3)oc2c1
Reactant: CCCC(=O)N(C)OC
Product: CCCC(=O)c1ccc2nc(-c3ccc(OCc4ccccc4)cc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 29a from 2-(4-benzyloxy-phenyl)-6-bromo-benzoxazole and N-methoxy-N-methyl-butyramide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:20]([NH:27][C:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1

Procedure:
A solution of 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperidin-4-one (prepared from 3-ethoxycarbonylpiperidin-4-one and di-tert-butyl-dicarbonate in dichloromethane and triethylamine) (25 g) and benzylamine (10.85 g) in toluene was heated under reflux in a Dean and Stark apparatus for 18 hours and then evaporated to dryness to give an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH:8]=[CH:9][C@:10]2([N:22]=[N+]=[N-])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH:8]=[CH:9][C@:10]2([NH2:22])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1[C@@H]2C=C[C@](N)(C(=O)OCc3ccccc3)[C@@H]21
Temperature: 60 °C
Reaction time: 19 h
Yield: 31.2 %

Procedure:
To a solution of (1S,2R,5R,6S)-2-azido-bicyclo [3.1.0]hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXVI) (66 mg, 0.202 mmol) in THF (4.5 mL) and H2O (0.5 mL) was added polymer supported PPh3 (130 mg, 0.404 mmol, 3.1 mmollg) and the mixture was stirred at 60° C. for 19 h. The resin was filtered off and washed with DCM. Removal of the solvent in vacuum left a yellow oil which was purified by silica gel column chromatography with hexane/ethyl acetate 1:3 to give (1S,2R,5R,6S) -2-amino-bicyclo [3.1.0] hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXVII) (19 mg, 31%) as a colorless oil. 1H-NMR (250 MHz, CDCl3) □1.25 (3H, t, J=7.2 Hz), 1.55 (1H, t, J=2.9 Hz), 1.78 (2H, bs), 2.53 (2H, m),4.12 (2H, q,J=7.2 Hz), 5.21 (2H, s), 5.37 (1H, d,J=5.3 Hz), 6.07 (1H, dd,J=5.3, 2 Hz), 7.35 (5H, s); MS[ISP] 302 (M+H+); □D20 -322.98 (c=0.77, CHCl3).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:29]1([P:35](Cl)(Cl)=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCCC.C1CCCCC1>[C:29]1([P:35]2(=[O:36])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: O=P1(c2ccccc2)c2ccccc2CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8.0 g, 0.125 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature at 0° C., a solution of dibenzylamine (11.8 g, 0.06 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to -76° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 30 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to 0° C. The reaction mixture was allowed to cool to -76° C., after which time the reaction mixture was stirred for 0.25 hours. The solid carbon dioxide-acetone bath was then removed and the reaction mixture was stirred for an additional 2 hours at 26° C. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. The cyclohexane was removed on a rotary evaporator, and the resulting residue partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried and concentrated in vacuo to yield an orange glass. The orange glass was distilled at 220° C. and 0.25 torr and the resulting solid residue was chromatographically separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was crystallized from diethyl ether and petroleum ether to yield 1-phenyl-2-(phenylmethyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (6.15 g, 32% yield) as a white solid having a melting point of 99°-101° C. and the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1Cl.[F:17][C:18]1([F:23])[CH2:22][CH2:21][NH:20][CH2:19]1.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:20]1[CH2:21][CH2:22][C:18]([F:23])([F:17])[CH2:19]1
Reactant: FC1(F)CCNC1
Reactant: CNc1cc(Cl)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N2CCC(F)(F)C2)c(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from methyl-2-chloro-4-methylamino-5-nitro-benzoate (1.00 g, 4.09 mmol), 3,3-difluoro-pyrrolidine×HCl (880 mg, 6.13 mmol), DIPEA (2.8 mL, 16 mmol) and dioxane (10 mL).
Reaction SMILES: [CH3:1][C:2]1[C:6](=[CH:7][NH2:8])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.FC(F)(F)C(O)=O.[CH2:23]([O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1N)[CH2:24][CH3:25]>C(O)C>[CH3:1][C:2]1[C:6](=[CH:7][NH:8][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:23][CH2:24][CH3:25])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: CC1=NN(c2ccccc2)C(=O)C1=CN
Reactant: CCCOc1ccccc1N
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCOc1ccccc1NC=C1C(=O)N(c2ccccc2)N=C1C

Procedure:
2 g of 3-methyl-4-aminomethylene-1-phenyl-4,5-dihydro-5-pyrazolone and 1.6 g of 2-propoxyaniline trifluoroacetate are added to ethanol and boiled under reflux for 1.5 hours. The reaction solution is concentrated. The reaction product is then separated by chromatography on silica gel using a solvent mixture consisting of methyl butyl ketone/hexane 4:1 as eluent and is recrystallized from a methyl butyl ketone/hexane mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][CH2:21][F:22])[CH:3]=1.CN.[C:25]([BH3-])#[N:26].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:26][CH3:25])[C:12]=2[O:19][CH2:20][CH2:21][F:22])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCF
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1OCCF
Yield: 43 %

Procedure:
4-Chloro-2-[2-(2-fluoroethoxy)-3-formylphenoxy]benzonitrile (0.35 g, 1.1 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 16 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration and dried to give 4-chloro-2-[2-(2-fluoroethoxy)-3-(methylaminomethyl)phenoxy]benzonitrile fumarate (194 mg, 40%) as a beige solid.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH3:13][C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[O:15].[OH-].[K+].O>C(O)C>[CH3:18][O:17][CH:16]([O:19][CH3:20])[C:14](=[O:15])[CH:13]=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: COC(OC)C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(OC)C(=O)C=Cc1ccc(-c2cccs2)s1

Procedure:
To a solution of 5-formyl-2,2'-bithiophene (4.0 g) in ethanol (120 ml) was added dimethoxymethyl methyl ketone (3 ml). Potassium hydroxide aqueous solution (50%) was added dropwisely into the solution mixture at 16° C. Color changed from yellowish brown into dark green, then dark brown. Yellow solid was formed during the reaction. Water was added. Solid residue was filtered and washed with water, redissolved in acetone and separated by silica gel chromatography eluted with ethyl acetate/n-hexane (1:9). Yellowish crystals 1.88 g were obtained, melting point 74° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C@H:3]1[C:13]([OH:15])=[O:14].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([N:4]1[C@@H:3]([C:13]([OH:15])=[O:14])[C:2]([CH3:16])([CH3:1])[S:6][C@H:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:19])[CH3:18]
Reactant: CC1(C)S[C@@H](c2ccccc2)N[C@H]1C(=O)O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccccc1
Temperature: 0 °C

Procedure:
0.47 g (2 mmoles) of 5,5-dimethyl-2(S)-phenylthiazolidine-4(S)-carboxylic acid is suspended in 5 ml of pyridine while stirring. The temperature of the suspension is adjusted to 5° C. by cooling with ice-water and 0.17 g of acetyl chloride is dropped in. The mixture is stirred for 1 additional hour, then poured in 60 ml of ice-cold 2N sulphuric acid. After several hours, the precipitated product is filtered out, washed with water and dried. The product is dissolved in ethanol and water is added to precipitate the title compound in a yield of 0.38 g (70.3%), m.p.: 216°-217° C., [α]D20 =-109° (c=0.686, methanol).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[CH:4]=[N:3][CH:2]=1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[Br:15][C:7]1[C:6]2[N:1]=[CH:2][N:3]=[CH:4][C:5]=2[S:9][CH:8]=1
Reactant: c1ncc2sccc2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1csc2cncnc12
Temperature: 90 °C
Yield: 58.9 %

Procedure:
Thieno[3,2-d]pyrimidine (0.163 g, 1.20 mmol) was dissolved in acetic acid (3 mL). Sodium acetate (0.196 g, 2.39 mmol) was added while stirring, followed by bromine (0.38 g, 2.4 mmol). The reaction mixture was heated in a microwave reactor at 90° C. for 90 min. Solvent was removed by rotary evaporation, then under high vacuum. Purification by ISCO chromatography (0 to 10% methanol:DCM) afforded 0.152 g (59%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.36 (s, 1 H), 9.30 (s, 1 H), 8.05 (s, 1 H); MS (ESI): 214.97, 216.99 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([F:17])=[C:9]([NH:15][NH2:16])[C:10]([F:14])=[C:11]([F:13])[CH2:12][C:6]=2[C:5]([F:18])=[C:4]([F:19])[C:3]=1[F:20].[CH3:21][CH:22]([CH3:26])[C:23](=O)[CH3:24]>C(O)C>[F:1][C:2]1[C:7]2[C:8]([F:17])=[C:9]([NH:15][N:16]=[C:23]([CH:22]([CH3:26])[CH3:21])[CH3:24])[C:10]([F:14])=[C:11]([F:13])[CH2:12][C:6]=2[C:5]([F:18])=[C:4]([F:19])[C:3]=1[F:20]
Reactant: CC(=O)C(C)C
Reactant: NNC1=C(F)c2c(F)c(F)c(F)c(F)c2CC(F)=C1F
Solvent: CCO
Product: CC(=NNC1=C(F)c2c(F)c(F)c(F)c(F)c2CC(F)=C1F)C(C)C
Yield: 81.4 %

Procedure:
To (1,2,3,4,6,7,9-heptafluoro-5H-benzo[7]annulen-8-yl)hydrazine (1 g) was added ethanol (20 ml) and 3-methyl-2-butanone (0.38 g). The mixture was heated to reflux for 3 hours after which time the volatiles were removed on a rotary evaporator to give a solid (1 g) which was used in the next step. M+=352
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].O=[C:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:41][CH:40]([CH2:42][O:43][CH3:44])[O:39][C:38]3=[O:45])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.O>O1CCCC1>[CH3:44][O:43][CH2:42][CH:40]1[O:39][C:38](=[O:45])[N:37]([C:34]2[CH:35]=[CH:36][C:31]([CH:28]3[CH2:29][CH2:30][C:25](=[CH2:2])[CH2:26][CH2:27]3)=[CH:32][CH:33]=2)[CH2:41]1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCC1CN(c2ccc(C3CCC(=O)CC3)cc2)C(=O)O1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCC(c2ccc(N3CC(COC)OC3=O)cc2)CC1
Yield: 83.4 %

Procedure:
5.76 g (13.8mmol) of methyltriphenylphosphonium bromide/sodium amide mixture were stirred at room temperature under argon in 170 ml of tetrahydrofuran for 1 hour. Then, a solution of 4.20 g (13.8 mmol) of (RS)-3-[4-(4-oxo-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one was added dropwise within 5 minutes. After boiling under reflux overnight the mixture was poured into water and extracted with methylene chloride. After drying with sodium sulfate and concentrating the residue was chromatographed over silica gel with ethyl acetate/n-hexane (1:2). 3.47 g (83%) of a solid were obtained. A small sample was recrystallized from hexane. M.p.: 63°-65°.