Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:14][C:15]1[C:22]([CH3:23])=[C:21](I)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>O1CCOCC1.[Cu]I>[Cl:14][C:15]1[C:22]([CH3:23])=[C:21]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)c(Cl)c1C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a pressure reaction flask containing diethyl malonate (4.1 mL, 27 mmol) in 50 mL of anhydrous dioxane was added NaH (1.1 g, 27.5 mmol, ˜60% in mineral oil) in several portions at RT, and stirred for 30 min. Compound 1E (2.5 g, 9 mmol) and CuI (5.1 g, 26.8 mmol) were added, sealed and heated at 100° C. for 3 days. The reaction was cooled to RT and filtered through a pad of celite. The celite pad was washed with EtOAc. The organics were washed twice with water, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (silica gel, 110 g ISCO, 10% EtOAc in hexane) gave the title compound (2.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Br)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A 500 mL round-bottom flask was charged with 4-bromo-2-methylbenzaldehyde (8.00 g, 40.2 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (9.40 g, 50.5 mmol, 1.26 equiv), triethylamine (6.50 g, 64.2 mmol, 1.60 equiv) and dichloroethane (200 mL). The resulting solution was stirred for 30 min at room temperature. Solid sodium triacetoxyborohydride (27.0 g, 127 mmol, 3.17 equiv) was added. The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with dichloromethane (3×200 mL) and the organic layers were combined, washed with brine (2×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/3) to yield 10.0 g (67% yield) of tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 369 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13]
Reactant: O=C1Nc2cccc3c2C1CCC3
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCBr)CCC3
Temperature: 60 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
2a, 3,4,5-Tetrahydrobenz [cd]indole-2(1H) -one (1.0 g, 5.8 mmol) was dissolved in anhydrous N,N-dimethylformamide (40 ml). Thereto was added sodium hydride (230 mg, 5.8 mmol), and the resulting solution was stirred at 60° C. for 1 hour. The reaction solution was mixed with 1,3-dibromopropane (1.8 ml, 17 mmol) and again stirred for 2 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 150 mg of the title compound (0.51 mmol, 8.8% in yield).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CC1(c2ccc(O)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.5 %

Procedure:
To a solution of 1-(4-methoxyphenyl)cyclohexanecarbonitrile (2 g, 9.29 mmol) in DCM (40 mL) at 0° C. under N2 was added dropwise BBr3 (2.63 mL, 27.87 mmol). The reaction was allowed to warm to room temperature and stirred for 48 hours. The mixture was stirred for 3 hours at 0° C. and quenched with water (30 mL). The mixture was separated and the organic layer was washed with a saturated aqueous solution of NaHCO3 then water. The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel eluting with DCM:acetone (97:3) to give the title compound (1.71 g, 91%).
Reaction SMILES: C1(S([CH:10]([F:27])/[C:11](=[N:19]\S(C(C)(C)C)(=O)=O)/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)(=O)=O)C=CC=CC=1.OP([O-])([O-])=O.[Na+].[Na+].[ClH:35].O1CCOCC1>CO>[ClH:35].[Br:18][C:14]1[CH:13]=[C:12]([C@H:11]([NH2:19])[CH2:10][F:27])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)S(=O)(=O)/N=C(/c1cccc(Br)c1)C(F)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H](CF)c1cccc(Br)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methyl-propane-2-sulfonic acid [2-benzenesulfonyl-1-(3-bromo-phenyl)-2-fluoro-eth-(Z)-ylidene]-amide (1.74 g, 3.76 mmol) and sodium phosphate dibasic (4.27 g, 30.1 mmol) in methanol (50 mL), cooled to −20° C., was added Na/Hg amalgam (6.92 g, 30.1 mmol). The reaction mixture was stirred for 1 h at −20° C., followed by filtration. To the filtrate was added a 4N HCl solution in dioxane (9.41 mL, 37.6 mmol), followed by stirring for 30 min at 25° C. After evaporation of volatiles, Et2O was added to the residue and the resulting precipitate was filtered off. The title compound thus obtained was used in the next reaction step without further purification. MS (LC/MS): 218/220 [M+H]+; tR (HPLC conditions f): 1.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[O:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1>C(O)=O.[Zn]>[CH:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]1[C:17](=[O:19])[C:18]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:10]([O:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[CH:11]=[N:12][C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[O:25]
Reactant: Cc1ccc(Oc2cnc3c(c2C(O)c2ccc(Cl)cc2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)cn1
Agent: [Zn]
Solvent: O=CO
Product: Cc1ccc(Oc2cnc3c(c2Cc2ccc(Cl)cc2)c(=O)n(CCCOC=O)c(=O)n3C)cn1
Temperature: 70 °C
Yield: 43.9 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (25 mg, 0.046 mmol) in HCOOH (3 mL) was added Zn dust (30.4 mg, 0.46 mmol). The reaction was heated at 70° C. for 40 min, cooled to RT and filtered. The filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give 3-(5-(4-chlorobenzyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (10 mg, 45.8% yield) as a solid. LCMS: MH+ 495 and TR=1.316 min.
Reaction SMILES: [CH:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[O:21])=[N:18][CH:19]=1)=O.[Cl:30][C:31]1[CH:36]=[C:35]([NH2:37])[CH:34]=[CH:33][C:32]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1.C(C1C(OC)=CC(C(F)(F)F)=CC=1C1C=CC(C(NCCC(OCC)=O)=O)=NC=1)=O.ClC1C=C(N)C=CC=1C1C=CC(C(F)(F)F)=CC=1>>[Cl:30][C:31]1[CH:36]=[C:35]([NH:37][CH2:1][C:3]2[C:8]([OH:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[N:18][CH:19]=2)[CH:34]=[CH:33][C:32]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(O)c2C=O)cn1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Agent: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2C=O)cn1
Agent: Nc1ccc(-c2ccc(C(F)(F)F)cc2)c(Cl)c1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(O)c2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1

Procedure:
The title compound was prepared as described in Example 159 substituting ethyl 3-(5-(2-formyl-3-hydroxy-5-(trifluoromethyl)phenyl)picolinamido)propanoate and 2,4′-dichloro-[1,1′-biphenyl]-4-amine for ethyl 3-(5-(2-formyl-3-methoxy-5-(trifluoromethyl)phenyl)picolinamido)propanoate and 2-chloro-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-amine, respectively.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][C@@H:32]1[O:36][C:35](=[O:37])[NH:34][CH2:33]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:33][C@H:32]([CH3:31])[O:36][C:35]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: C[C@H]1CNC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 62.9 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (493 mg) described in Preparation Example 118 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (323 mg) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:31])[CH2:29][NH2:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](=[O:31])[CH2:29][NH:30][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)CN)cc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCC(=O)c3ccc(OC)cc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and [2-(4-methoxy-phenyl)-2-oxo-ethyl]-amine to afford the title compound. MS: m/e=406 (M+H).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[C:4]1[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)C(C)C)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].[O-]CC.[Na+].Cl>C(#N)C>[CH2:16]([O:15][C:13]([CH:12]([C:4]1[NH:3][C:11]2[CH2:10][CH2:9][N:8]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:7][C:6]=2[N:5]=1)[CH3:18])=[O:14])[CH3:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(C)c1nc2c([nH]1)CCNC2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(C)c1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Yield: 72.7 %

Procedure:
A solution comprising ethyl 2-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)propionate dihydrochloride (60.2 g, 0.20 mol) in acetonitrile (400 mL) was cooled to 0° C. under nitrogen, treated with N,N-diisopropylethylamine (35 mL, 0.20 mol), further cooled to ˜−5° C. (ice/acetone) and then treated with benzyl chloroformate (58 mL, 0.41 mol) and N,N-diisopropylethylamine (70 mL, 0.40 mol) in alternating portions over 30 minutes. The mixture was cooled at −5° C. for 1 hour and allowed to warm to 20° C. and, after 16 hours, concentrated under reduced pressure. The residue was suspended in ether and the suspension was washed successively with sodium bicarbonate, sodium chloride, 0.1M hydrochloric acid and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (320 mL) and the solution was cooled to −5° C. under nitrogen and then sodium ethoxide (21 wt %, 85 mL, 0.22 mol) was added dropwise over 1 hour while the reaction temperature was maintained below 0° C. The mixture was cooled at −5° C. for 1 hour, adjusted to neutral pH with 50 mL of 4M hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with sodium bicarbonate and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes/ethyl acetate) to provide benzyl 2-(1-ethoxycarbonylethyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (52 g, 72%) as a pale yellow oil; 1H-NMR (300 MHz, DMSO-d6) d ppm: 11.72 (br s, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (br s, 2H), 4.02 (q, 2H, J=9.3 Hz), 3.77 (q, 1H, J=8.3 Hz), 3.66 (s, 2H), 2.55 (s, 2H), 1.38 (d, 3H, J=8.3 Hz), 1.13 (t, 3H, J=9.3 Hz).
Reaction SMILES: CON(C)[C:4](=O)[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.[CH3:30][S:31]([CH2:34]P(=O)(OCC)OCC)(=[O:33])=[O:32].[H-].[Na+]>C1COCC1.CC(C)=O>[CH3:30][S:31](/[CH:34]=[CH:4]/[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)(=[O:33])=[O:32]
Reactant: CCOP(=O)(CS(C)(=O)=O)OCC
Reactant: CON(C)C(=O)[C@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](/C=C/S(C)(=O)=O)Cc1ccncc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Weinreb amide 76 (0.33 g, 1.08 mmol) was dissolved in THF (15 mL), put under an argon atmosphere and cooled to 0° C. LiAlH4 (1.5 eq., 1.68 mmol, 1.68 mL of a 1 M solution in THF) was added slowly and the mixture was stirred at 0° C. for 1 hour after which TLC analysis indicated complete conversion of the starting compound. 0.1 M aq. HCl (1 mL) was slowly added and the mixture was stirred vigorously for 5 minutes. The organic layer was extracted with sat. aq. NaHCO3 (2×) and brine, dried over MgSO4 and concentrated under reduced pressure. Diethyl ((methylsulfonyl)methyl)phosphonate (1.5 eq., 1.68 mmol, 0.39 g) was dissolved in THF (20 mL) and cooled to 0° C. under an argon atmosphere. NaH (1.3 eq., 1.46 mmol, 58.0 mg, 60% w/w in mineral oil) was slowly added and the mixture was stirred at 0° C. for 30 minutes. Next, the freshly obtained aldehyde (in THF (2 mL)) was slowly added and the mixture was stirred for 2 hours while slowly warming it to room temperature. After this time, TLC analysis indicated complete conversion of the aldehyde. The reaction was quenched by addition of 1 M aq. HCl (1 mL) after which the mixture was diluted with EtOAc and extracted with sat. aq. NaHCO3 (2×) and brine, dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained after column chromatography (40%->80% Acetone/PE) as a colorless solid (yield: 117 mg, 0.36 mmol, 32%). 1H NMR (400 MHz, CDCl3): δ=8.50 (d, J=5.28 Hz, 2H), 7.15 (d, J=5.90 Hz, 2H), 6.92 (dd, J=15.10, 4.76 Hz, 1H), 6.53 (d, J=15.10 Hz, 1H), 5.56 (d, J=8.99 Hz, 1H), 4.80-4.72 (m, 1H), 3.02-2.84 (m, 2H), 2.93 (s, 3H), 1.39 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=154.87, 149.59, 146.40, 145.41, 130.04, 124.51, 80.10, 51.10, 42.58, 39.48, 28.06 ppm. [α]D23=−6.0 (c=1, MeOH). HRMS: calcd. for C15H22N2O4S [M+H]+327.13730. found 327.13741.
Reaction SMILES: [O:1]=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1>[Ni].C(O)C>[O:1]=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Agent: [Ni]
Solvent: CCO
Product: O=C(O)c1ccc(CCC(=O)c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
4-(3-Oxo-3-phenyl-propenyl)-benzoic acid (7.64 g, 30 mmol) is combined with Raney nickel (2 g) in ethanol (140 mL). The mixture is hydrogenated at room temperature and 50 psi for 1.5 h. The reaction is filtered evaporated in vacuo. The resulting residue is recrystallized from ethyl acetate to obtain 4.57 g (59%) of the titled compound. m.p.=145-147° C.; Anal. Calcd for C16H14O3: C, 75.58; H, 5.55. Found: C, 75.60; H, 5.32.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9]C)[C:3]=1[CH2:11][CH2:12][OH:13].O>C(Cl)Cl>[F:1][C:2]1[C:3]([CH2:11][CH2:12][OH:13])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(F)c(F)c1CCO
Solvent: O
Solvent: ClCCl
Product: OCCc1c(O)ccc(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
To a solution of 2-(2,3-difluoro-6-methoxyphenyl)ethanol (800 mg, 4.25 mmol) in DCM (25 mL) at 0° C. was added 1M BBR3 (17.01 mL, 17.01 mmol) solution and the resulting mixture was allowed to warm to room temp and stir for 4 h. Water (dropwise) was then added and after the bubbling stops mixture was diluted with DCM and washed with water, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-50%, EtOAc/hexane) to afford 3,4-difluoro-2-(2-hydroxyethyl)phenol (500 mg, 2.87 mmol, 67.5% yield) as clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.85 (br. s., 1H), 7.04-6.93 (m, 1H), 6.71-6.60 (m, 1H), 4.07-4.01 (m, 2H), 3.04-2.95 (m, 2H), 2.38 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([OH:22])([C:18]([F:21])([F:20])[F:19])[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])=[CH2:8])[CH3:2].II.I[CH2:27]I>CCOCC.CCOC(C)=O.[Cu].[Zn]>[CH2:1]([O:3][C:4](=[O:23])[C:5]([CH2:6][C:7]1([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[CH2:27][CH2:8]1)([OH:22])[C:18]([F:19])([F:20])[F:21])[CH3:2]
Reactant: ICI
Reactant: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cc(F)ccc1OC
Agent: [Cu]
Agent: II
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(O)(CC1(c2cc(F)ccc2OC)CC1)C(F)(F)F
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of 620 mg (1.84 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester, 475 mg zinc copper couple, and an iodine crystal in anhydrous ether in a sealed tube warmed to 55° C. was added dropwise 500 μL (6.20 mmol) of diiodomethane. The reaction was monitored by TLC in dichloromethane-hexanes (1:1) or ether-hexanes (2:8). After 18 hours, the mixture was cooled, diluted with EtOAc, and filtered through diatomaceous earth. The filtrate was washed with three 10 mL portions of 1 N aqueous HCl, 10 mL of brine, three 10 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The crude material was adsorbed onto silica gel and chromatographed on silica gel using ether-hexanes (0:100, then 1:99, then 2:98) to afford 494 mg (76%) of 3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]-2-hydroxypropionic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1(=O)[O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13]1.C(OC(=O)C)(=O)C.C([O-])(=O)C>O1CCCC1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]2[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C:12]2=[O:18])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CCCC(=O)O1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCCC(=O)N1Nc1ccc([N+](=O)[O-])cc1
Temperature: 120 °C

Procedure:
3 g of p-nitrophenylhydrazine and 2 g of glutaric anhydride in 20 ml THF ("tetrahydrofuran") were stirred for 15 min at room temperature. Analysis by infrared spectroscopy showed high conversion to amide-acid. To the reaction mixture was added 2 g of acetic anhydride, 1 ml of triethylamine which as then heated to near reflux. 50 mg of colbalt(II) acetate was added which induced an exothermic reaction. Analysis (IR) after a few minutes showed high conversion to imide. The mixture was evaporated under nitrogen and then slurried with ethanol. The ethanol soluble fraction (main product) was removed and concentrated to 3.4 g of brown solid. This solid was washed twice with benzene to remove 0.2 g and then crystalized from methanol to yield yellow needles, mp=197-198° C. The structure was confirmed by elemental analysis, IR and NMR. DSC analysis showed no crystallization when the melt was cooled at 20° C./min. On reheating a Tg was detected at 65° C., a Tc was detected at 120° C. and a Tm was detected at 204° C. Thin films cast from THF were glassy (noncrystalline) with Tg of 65° C. and were shown, by IR, to contain hydrogen bonds involving the carbonyl and N-H groups. On heating to 120° C., crystallization occured and the H-bonding was lost. High viscosity above Tg was observed by the resistance to sliding of two glass plates sandwiching a thin film of the compound. The μβ, determined by EFISH in dioxane, was 26×10-48 esu. Thin films were prepared on a conducting glass by spin coating using Film Forming Procedure 1 and were poled using Poling Procedure 1. The resulting material retained a substantial portion of the induced molecular ordering for more than 6 months. The induced d33 determined from SHG Measurements was ≈4×10-12 m/V.
Reaction SMILES: [F:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC.CCOC(C)=O.CCCCCC>CC(C)=O.C(OCC)C>[CH3:11][O:9][C:5]1[CH:6]=[C:7]([I:8])[C:2]([F:1])=[CH:3][C:4]=1[CH3:10]
Reactant: Cc1cc(F)c(I)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(I)c(F)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To 122C (1 g, 4 mmol) in acetone (20 mL) was added K2CO3 (1.64 g) and iodomethane (0.75 mL). The mixture was stirred at rt for 3 h. After TLC (10% EtOAc/Hexane) indicated the reaction was complete, the mixture was diluted with diethyl ether, washed with water and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography to give 122D (0.75 g, 70% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.16 (s, 3H) 3.78 (s, 3H) 6.85 (d, J=8.79 Hz, 1H) 7.05 (d, J=5.27 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:26]([NH:25][C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[O:27])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Fc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(F)ccc23)CC1

Procedure:
7-Fluoro-4-(piperazin-1-yl)quinoline (0.29 g, 1.25 mmol) and 4-fluorophenyl isocyanate (142 μL, 1.25 mmol) in THF (10 mL) are reacted according to method C yielding the product as colorless crystals after column chromatography with hexane-EtOAc.