Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[C:32]([C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=1)=O.C(OP([CH2:57][C:58]#[N:59])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=2)=[CH:57][C:58]#[N:59])[CH:44]=[CH:45][C:46]=1[O:47][CH3:48]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2)c1
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(OC)c2)c1

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(3′,5′-dimethoxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4,3′,5′-tetramethoxybenzophenone (0.7 g, 2.3 mmol), diethylcyanomethylphosphonate (0.42 mL, 2.5 mmol) and lithium hexamethyldisilazide (1.9 mL, 2.5 mmol, 1.3 M) with a reaction time of 60 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 0.66 g (81%) of a mixture of the E and Z isomers as a white solid: mp 88-90° C.; 1H NMR (CDCl3) δ 7.10-6.80 (m, 6 H), 6.61-6.40 (m, 6 H), 5.66 (s, 1 H), 5.61 (s, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.77 (s, 6 H); 13C NMR (CDCl3) δ 162.7, 162.5, 160.7, 160.6, 151.1, 150.6, 148.8, 148.5, 141.3, 138.9, 131.1, 129.2, 123.2, 122.1, 118.2, 118.0, 112.6, 110.9, 110.7, 110.7, 107.6, 107.0, 102.1, 102.0, 93.4, 93.1, 56.0, 55.9, 55.5, 55.4; Anal. Calcd for C19H19NO4. Theoretical: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.33; H, 5.89; N, 4.03.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.[NH3:12].O>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:12])[C:5]([O:9][CH3:10])=[C:4]([Cl:11])[N:3]=1
Reactant: N
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1c(N)nc(Cl)nc1Cl
Yield: 88 %

Procedure:
2,4,6-Trichloro-5-methoxypyrimidine (1.0 g, 4.7 mmol, see U.S. Pat. No. 3,984,411 for preparation) was dissolved in 15 mL dry dimethyl sulfoxide (DMSO) and treated with a stream of ammonia gas for 30 min. The mixture was poured into 30 mL water and the precipitated product was collected by filtration and washed with water. This solid was dissolved in 40 mL ethyl acetate, washed twice with water, washed once with brine, dried and evaporated to give the title compound (800 mg, 88% yield): mp 155-156° C.: 1H NMR (DMSO-d6+D2O) δ 3.71 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl)(=[O:11])[CH3:10].[OH-].[Na+]>C(O)C>[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)OCCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)OCCCCSc1ccc(Cl)cc1

Procedure:
A mixture of 144.6 g of p-chlorothiophenol, 150.6 g of 4-chlorobutyl acetate, 80 g of 50% aqueous solution of sodium hydroxide and 750 ml of ethyl alcohol was heated under reflux for 5 hours. The alcohol was distilled off and ether was added to the cool mixture. After washing with dilute sodium hydroxide solution and then water, the ether solution was dried, evaporated to dryness and distilled. The product was collected at 110°-116° and 0.01 mm, ND25 1.5480.
Reaction SMILES: [CH:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[O:21][CH2:20][CH2:19][O:18]3)[C:12]2=[O:32])[C@H:7]([CH2:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:6]1)([CH3:3])[CH3:2].C=O.[C:45]([BH3-])#N.[Na+]>CO.CCOC(C)=O>[CH:1]([N:4]([CH3:45])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=4)[O:21][CH2:20][CH2:19][O:18]3)[C:12]2=[O:32])[C@H:7]([CH2:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:35])=[O:36])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)N[C@@H]1CC[C@H](N2CC[C@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
Compound 39i-b (103 mg, 168 μmol) and 37% formaldehyde (50 μL, 1.8 mmol) were dissolved in MeOH (2 mL) and stirred for 3 h at room temperature. Sodium cyanoborohydride (16 mg, 252 μmol) was added and the mixture was stirred for 2 h. The reaction was diluted with EtOAc (400 mL), washed with saturated NaHCO3 (3×150 mL) and brine (100 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by CombiFlash chromatography (silica, 0–10% CH2Cl2/MeOH) and then lyophilized from CH3CN/H2O to give title compound (77 mg, 74%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.90–7.82 (m, 2H), 7.71 (s, 1H), 7.68–7.42 (m, 6H), 4.15–3.92 (m, 3H), 3.80–3.00 (m, 7H), 2.71–2.10 (m, 9H), 1.93–1.40 (m, 9H), 1.17–0.95 (m, 6H); 19F NMR (282 MHz, CDCl3) δ −62.9; ESI MS m/z 623 [C32H41F3N2O5S+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]Br)=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>O.C(O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1Oc1ccc(Br)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccccc1Oc1ccc(Br)cc1

Procedure:
457.8 g of the crude 2-(4-bromophenoxy)benzyl bromide are added over a period of one hour to a mixture that is boiling under reflux of 171.0 g of sodium cyanide in 160 ml of water and 44 ml of ethanol; at the same time 362 ml of ethanol are added dropwise. The mixture is subsequently boiled under reflux for a further 3 hours and then diluted with 1500 ml of water. The aqueous ethanolic phase is washed with 1000 ml of diethyl ether and the ether phase is separated off, washed twice with 200 ml of water, dried over magnesium sulphate and concentrated to dryness under 11 mm Hg. The residue is crystallised from a mixture of diethyl ether and petroleum ether and yields 2-(4-bromophenoxy)phenyl acetonitrile.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][O:15][CH2:14][CH2:13][NH:12]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH3:10][C@@H:11]1[N:12]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:14][O:15][CH2:16]1
Reactant: C[C@H]1COCCN1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1COCCN1c1ccc(C#N)cc1
Temperature: 110 °C
Reaction time: 70 h
Yield: 43.4 %

Procedure:
4-Fluorobenzonitrile (359 mg, 2.97 mmol), (S)-3-methylmorpholine (150 mg, 1.48 mmol) and K2CO3 were suspended in DMSO (1.5 ml). The mixture was stirred for 70 hours at 110° C. in a closed high-pressure flask. The reaction was cooled, diluted with water (50 ml) and extracted with EtOAc (3*20 ml). Combined organics were washed with water (20 ml), dried over MgSO4 and evaporated. The product was purified by flash chromatography using pet.ether/EtOAc (3:1) as eluent to give 130 mg (43%) of the title compound as pale solids.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH2:40]([O:42][C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH3:41]>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[C:30]([C:31]#[N:32])=[CH:44][C:43]([O:42][CH2:40][CH3:41])([CH3:47])[CH3:46])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCOC(C)(C)C=O
Reactant: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(C)(C)C=C(C#N)C(=O)N[C@H](C)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 85 °C
Yield: 7.7 %

Procedure:
To a sealed tube was added N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]-2-cyano-acetamide (105 mg, 0.24 mmol), piperidine (0.01 mL, 0.12 mmol), 2-ethoxy-2-methyl-propanal (0.07 mL, 0.47 mmol) and ethanol (4 mL). The tube was capped, and heated to 85° C. for 60 hrs. The reaction was cooled and evaporated. The resulting crude oil was dissolved in DCM (30 mL) and washed with water (30 mL) and brine, then dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (10 g column, 3%-7% MeOH/DCM) to obtain 10 mg (8%) of the title compound. MS (pos. ion) m/z: 544 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:9]=1[OH:10])=[O:4].[CH2:15](I)[CH3:16]>C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([F:14])([F:12])[F:13])=[CH:8][C:9]=1[O:10][CH2:15][CH3:16])=[O:4]
Reactant: CCI
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)sc1C(=O)OC

Procedure:
The 3-ethoxy-5-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (mp.: 93.6° C.) was prepared from the known adduct 3-hydroxy-5-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (Synthesis 2000, No. 8, 1078-1080) by alkylation with ethyl iodide in the presence of cesium carbonate in DMF as solvent.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([NH2:14])[CH:10]=[CH:11][C:12]=1[CH3:13].O>N1C=CC=CC=1>[CH3:5][O:4][C:2](=[O:3])[NH:14][C:9]1[CH:10]=[CH:11][C:12]([CH3:13])=[C:7]([Br:6])[CH:8]=1
Reactant: Cc1ccc(N)cc1Br
Reactant: COC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Methyl chloroformate (0.202 ml, 2.62 mmol) was added to a solution of 3-bromo-4-methyl-phenylamine (243 mg, 1.31 mmol) in pyridine (2 ml), and the mixture was stirred at room temperature overnight. H2O was added to the reaction mixture, followed by extraction with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane/AcOEt) to give (3-bromo-4-methyl-phenyl)-carbamic acid methyl ester (288 mg, 90%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([NH:26][CH3:27])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:17][C:13]1[CH:12]=[C:11]([CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:18]([N:26]([C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH3:27])=[O:20])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)O
Reactant: CNc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)[C@H](Cc1cccc(Br)c1)NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
Boc-L-3-BromoPhe (5 g, 14.5 mmol) was dissolved in 50 mL of DMF and to it were added 4-chloro-N-methylaniline (2.1 mL, 17.4 mmol) and N,N-diisopropylethylamine (7.6 mL, 43.5 mmol). The reaction mixture was cooled to 0° C. and to it was added HATU portion wise (6.6 g, 17.4 mmol). The reaction mixture was allowed to stir at ambient temperature overnight and then was partitioned between ethyl acetate and water. The organic layer was separated and washed with 5% aqueous LiCl, saturated aqueous NaHCO3 and brine. The mixture was then dried over MgSO4, filtered and concentrated to afford crude product which was purified by silica gel chromatography eluting with ethyl acetate/hexanes to afford 5.6 g of (S)-tert-butyl 3-(3-bromophenyl)-1-((4-chlorophenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate as a white solid. MS (m/z): 469.1 [M+H]+; HPLC retention time 4.39 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[H-].[Na+]>CN(C)C=O>[CH2:21]([O:20][C:18]([CH:17]([N:13]1[CH2:14][CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:15])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)C(Br)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC1CN(C(C(=O)OCc2ccccc2)c2ccc(OCc3ccccc3)cc2)C1=O

Procedure:
3-(2-Phenylacetamido)-2-azetidinone (750 mg.) and benzyl 2-bromo-2-(4-benzyloxyphenyl)acetate (1.51 g.) was added to anhydrous N,N-dimethylformamide (10 ml.), and disdolved in it by warming for a while. The solution was cooled in an ice-water bath, and to the solution was added all at once sodium hydride (50% oily) (178 mg.) under stirring. After removing the cooling bath, the reaction mixture was stirred for 30 minutes to which ethyl acetate was added. The reaction mixture was filtered and the filtrate was washed with water, 2% hydrochloric acid and water respectively, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give an oily material (1.98 g.), which was subjected to column chromatography using silica.gel (40 g.). The fractions, eluted with a mixture of benzene and chloroform were subjected to thin layer chromatography using silica.gel, and the thin layer was developed with a mixture of chloroform and acetone to give two isomers of 1-(α-benzyloxycarbonyl-4-benzyloxybenzyl)-3-(2-phenylacetamido)-2-azetidinone. The isomer A was recrystallized from a mixture of chloroform and ether. Yield: 90 mg. Mp: 129° to 130° C. (dec.). The isomer B is oily material. Yield: 120 mg. The isomer A (90 mg.) obtained above was dissolved in methanol (7 ml.), and to the solution was added 10% palladium carbon (30 mg.). The mixture was reacted in hydrogen atmosphere at ordinary temperature and ordinary atm. until the absorption of hydrogen gas was completed. The catalyst was filtered off from the fraction mixture, and the filtrate was concentrated under reduced pressure. The residue obtained was crystallized from a mixture of ethyl acetate and ether to give crystals of 3-(2-phenylacetamido)lactacillanic acid. The product was identified by comparing an I.R. absorption spectrum and a N.M.R. absorption spectrum and a melting point with an authentic sample synthesized by another method from 3-aminolactacillanic acid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].Cl>CN(C=O)C.CCCCCC>[Cl:16][C:15]1[C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=[CH:13][CH:14]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Cl)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
According to the procedure of J. T. Gupton et al, Can. J. Chem. 63, 3037 (1985), a suspension of hexane-washed sodium hydride (8.4 g, 0.21 mol) in DMF (250 mL) was added to 2,2,2-trifluoroethanol (22.1 mL, 0.3 mol) dropwise in 200 mL of DMF at room temperature over 60 minutes (excessive frothing occurs if added too fast). After stirring an additional 30 minutes 2,3-dichloronitrobenzene (38 g, 0.20 mol) was added in one portion. The resulting mixture was stirred at room temperature for 2 hours. The reaction was then poured into 1N HCl (500 mL) and extracted with Et2O (2×500 mL). The combined Et2O layers were washed first with water (200 mL) and finally with saturated brine (200 mL). After drying (MgSO4), the ether was concentrated to yield 47 g (90% based on dichloronitrobenzene) of 3-chloro-2-(2,2,2-trifluoroethoxy)nitrobenzene as a yellow liquid (b.p. 85° C./0.3 mmHg), which was used without further purification.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH:33]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: Nc1ccc(CN2CCC2)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 4-(azetidin-1-yl-methyl)-aniline.
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][C@@H:8]([C:10]([O:12][CH3:13])=[O:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(O)(=O)C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>CO>[CH2:18]([NH:9][C@H:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:6][C:2]([CH3:5])([CH3:4])[CH3:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](COC(C)(C)C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.5 %

Procedure:
Methyl O-tert-butyl-L-serinate hydrochloride (12 g, 56.7 mmol) was dissolved in methanol (120 ml), acetic acid (6.50 ml, 114 mmol), benzaldehyde (6.25 ml, 61.8 mmol), and sodium cyanoborohydride (1 M tetrahydrofuran solution, 75 ml) were added and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated, diluted with water, and neutralized with sodium bicarbonate under ice cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, then the drying agent was removed by filtration and the solvent was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography [ethyl acetate:n-hexane=1:4 (v/v)] to give the title compound (7.75 g, 52%) as a colorless solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1[SH:9].Cl[C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1[S:9][C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: Sc1c(Cl)cncc1Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
3,5-dichloropyridine-4-thiol sodium salt prepared as in example 17 (0.179 g, 1 mmol), methyl 5-chloro-4-nitro-thiophene-2-carboxylate (221 mg, 1 mmol) was mixed in toluene (5 mL). Then potassium carbonate (0.207 g, 1.5 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 4 hours. After this time, the reaction mixture was filtered and diluted with ethyl acetate. The organic solution was washed with water (2 mL×2), brine (2 mL×2), dried (Na2SO4), and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a 96:4 mixture of hexane and ethyl acetate to afford the title product as a solid (82.5 mg, 23% yield). 1H NMR (300 MHz, d6-DMSO) δ: 9.05 (2H, s), 8.20 (1H, s), 3.82 (3H, s). MS m/z: 365.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>O.CN(C)C=O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(F)c(F)c1Cl
Reaction time: 40 h
Yield: 52.3 %

Procedure:
To a mixture of 2-chloro-3,4-difluorobenzoic acid (2.50 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.99 g), 1-hydroxybenztriazole (2.39 g) and N,N-dimethylformamide (72 mL) was added 28% aqueous ammonia (1.6 mL) at room temperature, and the mixture was stirred for 40 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane). The obtained solid was washed with dichloromethane to give the title compound as a solid (yield: 1.30 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C(OC(C1C(=O)N(CC2C=CC(F)=CC=2)C2C=CSC=2C=1N1CCN(C(C2OC=CC=2)=O)CC1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=2)[C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2[nH]c1=O
Agent: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(Cc2ccc(F)cc2)c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2sccc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (10) and 3-fluoro benzyl bromide by applying a similar method as described for 4-(4-fluoro-benzyl)-7-[4-(furan-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (11). Yield 210 mg, (22%). 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.82 (m, 4H), 4.26 (q, J=7.2 Hz, 2H), 5.38 (s, 2H), 6.65 (m, 1H), 7.07 (m, 4H), 7.34 (d, J=5.6 Hz, 1H), 7.37 (m, 1H), 7.88 (m, 1H), 8.03 (d, J=5.6 Hz, 1H); EIMS m/z 510 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCO2)cc1
Reaction time: 2 h
Yield: 65 %

Procedure:
To (S)-(tetrahydrofuran-2-yl)methanol (2.0 g, 20 mmol) in CH2Cl2 (10 mL) at about 0° C. was added p-toluenesulfonyl chloride (4.2 g, 22.00 mmol), followed by drop-wise addition of triethylamine (5.6 mL, 40.0 mmol). The resulting solution was kept at 0° C. for 2 hours, and then at room temperature for another 2 hours. The reaction mixture was concentrated to dryness and diethylether (200 mL) and water (100 mL) were added. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to yield the title compound (2.3 g, 13.00 mmol, 64%) as a colorless oil, which was used in the next step without purification.