Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[N:7]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1nc(Cl)ccc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 6-chloropyridazin-3(2H)-one (600 mg, 4.23 mmol) were added potassium carbonate (1.2 g, 8.46 mmol) and methyl iodide (1.2 g, 8.46 mmol) in DMF (3 mL). The resulting mixture was stirred at 25° C. for 4 h. After the reaction, water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give the residue which was purified by column chromatography to give 6-chloro-2-methylpyridazin-3(2H)-one (550 mg, 91%). 1H NMR (CDCl3): 3.76 (s, 3H), 6.92 (d, 1H), 7.19 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1ccc(C)cc1
Agent: N
Product: Cc1ccc(-c2cc(-c3cncc(Cl)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-4-methylbenzene (Apollo, 35 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 2.40 (s, 3H), 7.41 (d, J=8.1 Hz, 2 H), 7.71 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 8.43 (dd, J=2.4, 1.7 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 271 (M+H)+, 273 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=O)[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:32][CH:31]=1>C(O)C>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:23])([F:24])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:2][OH:3])[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:32][CH:31]=1
Reactant: CC(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)CC(=NO)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 43.6 %

Procedure:
Add hydroxylamine hydrochloride (6.3 mg, 0.091 mmol) and pyridine (15 uL, 0.182 mmol) to a solution of 7-chloro-6-[4-(3-methyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (42 mg, 0.091 mmol) in ethanol (1 mL). Heat the mixture to reflux for 18 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5 to 1:1 gradient over 30 min). Concentrate in vacuo to obtain 7-chloro-6-[4-(1-hydroxyimino-3-methyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (19.1 mg, 44%). MS (ES+) m/z: 482 (M+H)+.
Reaction SMILES: [F:1][C:2]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])([F:19])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[C:11]([O:17][CH3:18])[CH:10]=1.N1CCCCC1.C(O)(=O)C.[C:38]([O:44][CH2:45][CH3:46])(=[O:43])[CH2:39][C:40]([CH3:42])=[O:41]>C1(C)C=CC=CC=1>[CH2:22]([O:21][P:20]([C:2]([F:19])([F:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:39](\[C:40](=[O:41])[CH3:42])/[C:38]([O:44][CH2:45][CH3:46])=[O:43])=[C:11]([O:17][CH3:18])[CH:10]=1)([O:24][CH2:25][CH3:26])=[O:27])[CH3:23]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOc1ccc(C=O)c(OC)c1
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)/C(=C/c1ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc1OC)C(C)=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of diethyl (1,1-difluoro-3-(2-(4-formyl-3-methoxyphenoxy)ethoxy)propyl)phosphonate (1 equiv.) in toluene (0.50 M) was added piperidine (0.10 equiv.), acetic acid (0.50 equiv.) and ethyl acetoacetate (1.2 equiv.). The reaction mixture was then heated to 110° C. for 18 h. At this point additional piperidine (0.10 equiv.), acetic acid (0.50 equiv.) and ethyl acetoacetate (0.50 equiv.) were added to the reaction mixture and heating at 110° C. was continued for 4 h. At this point the reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (78%) as a solid.
Reaction SMILES: [CH2:1]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:27]([C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1OS(C(F)(F)F)(=O)=O)[C:33]([O:35][CH3:36])=[O:34])([O-:29])=[O:28].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:39]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=2[N+:27]([O-:29])=[O:28])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(B(O)O)cc1)Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 71.2 %

Procedure:
To a solution of [4-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]phenyl]boronic acid (3.1 g) in 1,2-dimethoxyethane (45 ml) were added methyl 3-nitro-4-[[(trifluoromethyl)sulfonyl]oxy]benzoate (3.0 g), tetrakis(triphenylphosphine)palladium (800 mg) and aqueous solution of sodium carbonate (2M, 9.1 ml), and the mixture was stirred at 80° C. for 4 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]-2-nitro-4-biphenylcarboxylate (3.05 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[CH3:4])[CH3:2].[CH3:7][O:8][CH2:9][Cl:10]>C1(C)C=CC=CC=1>[Cl-:10].[CH2:1]([N+:3]([CH2:5][CH3:6])([CH3:4])[CH2:9][O:8][CH3:7])[CH3:2]
Reactant: CCN(C)CC
Reactant: COCCl
Solvent: Cc1ccccc1
Product: CC[N+](C)(CC)COC
Product: [Cl-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 30.0 g quantity of N,N diethyl-N-methvlamine (reagent, product of Tokyo Kasei Co., Ltd.) was dissolved in 120 g of toluene, followed by nitrogen replacement. Over a period of 1 hour, 31.2 g of chloromethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd.) was added dropwise to the solution at 5° C. The mixture was stirred at 5° C. for 1 hour, heated to a gradually elevated temperature and stirred at room temperature for 10 hours to complete the reaction. The reaction mixture was filtered, and the solids obtained were washed with 150 g of toluene and 150 g of acetone and then dried in a vacuum, giving 53.7 g of the desired product (white solid).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:37])C(=O)C1.O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[N:8]2[N:26]=[C:27]([CH3:29])[C:28]([Cl:37])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nc(C)cc2n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nc(C)c(Cl)c2n1

Procedure:
5-n-Butyl-2-methyl-7-(3,4,5-trimethoxybenzoyl-amino) pyrazolo[1,5-a]pyrimidine (the compound of Example 53; 0.78 g) was dissolved in 10 ml of chloroform. After addition of 0.28 g of NCS, the mixture was refluxed with heating for 1 hour and allowed to cool. After addition of some water, the reaction mixture was extracted with chloroform. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:2) and recrystallized from ethanol-n-hexane to provide 0.61 g of the object compound as colorless crystals. Table 3 shows the structure and melting point of the compound obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2N=C(C(F)(F)F)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([OH:27])C.O.OOS([O-])=O.[K+]>C1COCC1>[OH:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:27]
Reactant: CSc1ccc(-c2oc(C(F)(F)F)nc2-c2ccc(C)cc2)cc1
Reactant: CCO
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(O)C(=O)c2ccc(C)cc2)cc1
Reaction time: 3 h

Procedure:
4-(4-Methylphenyl)-5-(4-methylthiophenyl)-2-trifluoromethyloxazole from Step 2 (350 mg, 1.0 mmol) was dissolved in THF (20 mL), ethanol (20 mL) and water (20 mL). Oxone® (1.2 g, 2 mmol) was added and the reaction stirred for 3 hours. The reaction mixture was filtered and concentrated to dryness. The residue was dissolved in ethyl acetate (200 mL), washed with water, NaHCO3 and brine, dried and concentrated to yield a white crystalline product (350 mg) which was recrystallized from ethanol and water to yield 4-(4-methylphenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethyl-oxazole (300 mg, 79%): mp 141-142° C. Anal. Calc'd. for C18H14NO3SF3 : C, 56.69; H, 3.70; N, 3.67. Found: C, 56.47; H, 3.79; N, 3.57.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH2:41]([NH:48][C:17]([C@H:14]1[CH2:13][CH2:12][C@H:11]([NH:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:16][CH2:15]1)=[O:19])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1ccccc1)[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid (M) (20 mg, 0.07 mmol) in DMF (0.2 mL) was added EDC (26 mg, 0.14 mmol), HOBt (18 mg, 0.14 mmol), triethylamine (0.019 mL, 0.14 mmol) and benzyl amine (0.007 mL, 0.7 mmol). The reaction mixture was stirred at room temperature for 1 h followed by quenching with aqueous NaHCO3 and EtOAc. The layers were separated and the organic was washed twice with water, dried over Na2SO4, filtered and concentrated. Purification of the crude oil by preparative reverse-phase HPLC gave trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid benzylamide (Example 9) (14 mg): 1H NMR (300 MHz, CD3OD) δ 7.40-7.20 (m, 9 H), 4.39 (s, 2 H), 3.55 (m, 1 H), 2.31 (m, 1 H), 2.20 (br d, 2 H), 1.98 (br d, 2 H), 1.77 (m, 2 H), 1.50 (m, 2 H); mass spectrum m/z 349 [(M+H)+; calcd for C21H25N4O: 349].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:9]=2[N:10]=1.[H][H]>C(O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[NH:7][C:8]=2[CH:14]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccco3)[nH]c2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2nc(-c3ccco3)[nH]c2c1

Procedure:
A solution of 2-(2-furyl)-5-nitrobenzimidazole (52 g, 0.2 mole) in 1 liter of absolute ethyl alcohol is reduced (Parr apparatus) using 5 percent palladium on carbon (50 percent wet) catalyst. An uptake of 44 lbs. (100 percent of theory) of hydrogen in one-half hr is noted. After the reduction is complete the catalyst is removed by filtration. The filtrate is used in part D.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][SH:5].Cl[CH2:8][C@H:9]1[O:13][C@@H:12]([N:14]2[C:23]3[N:22]=[CH:21][N:20]=[C:18]([NH2:19])[C:17]=3[N:16]=[CH:15]2)[C@H:11]([OH:24])[C@@H:10]1[OH:25]>CN(C=O)C>[OH:6][CH2:3][CH2:4][S:5][CH2:8][C@H:9]1[O:13][C@@H:12]([N:14]2[C:23]3[N:22]=[CH:21][N:20]=[C:18]([NH2:19])[C:17]=3[N:16]=[CH:15]2)[C@H:11]([OH:24])[C@@H:10]1[OH:25]
Reactant: OCCS
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CSCCO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a mixture of sodium hydride (1.5 g, 50% dispersion in oil, 31 mmol) in DMF (40 mL) was added 2-thioethanol (1.65 mL, 1.84 g, 24 mmol) dropwise, and the mixture was stirred under argon for 15 min at ambient temperature. 5'Chloro-5'-deoxyadenosine (1a) (4.3 g, 15 mmol) was added portion wise and stirring was continued overnight. The mixture was concentrated under reduced pressure and subjected to flash chromatography (MeOH/CHCl3, 3:7) to give the triol (1b) as a white solid (3.23 g, 66%) that was crystallized from EtOH to give colourless crystals of 1b with mp 198°-201° C.; UV (MeOH) max 259 nm (ε 15 900 ); 1H NMR (Me2SO-d6) δ 8.36 (s, 1, H8), 8.16 (s, 1, H2), 7.29 (br s, 2, NH2), 5.89 (d, J1'-2' =5.9 Hz, 1, H1'), 5.49 (d, JOH-2' =6.0 Hz, 1, OH2'), 5.31 (d, JOH-3' =5.0 Hz, 1, OH3'), 4.76 (t, J=5.5 Hz, 1, CH2OH), 4.75 ("q", J2'-3' =5.5 Hz, 1, H2'), 4.18 ("q", J3'-4' =4.8 Hz, 1, H3'), 4.02 (m, J4'-5'n =6.0 Hz, J4'-5'b =6.8 Hz, 1, H4'), 3.52 ("q", J=6.5 Hz, 2, CH2OH), 2.96 (m, J5'a-5'b =14.0 Hz, 1, H5'a), 2.85 (m, 1, H5'b), 2.60 (t, 2, SCH2); 13C NMR (Me2SO-d6) δ 155.97 (C6), 152.57 (C2), 149.36 (C4), 139.76 (C8), 119.06 (C5), 87.28 (C1'), 83.69 (C4'), 72.60, 72.44 (C3',3'), 60.76 (CH2OH), 34.55 (C5'), 34.19 (SCH2): MS m/z 327.0994 (M+ =327.1001). Anal. Calcd for C12H17N5O4S (327.4): C, 44.03; H, 5.23; N, 21.39; S, 9.79. Found: C, 43.91; H, 5.16; N, 21.52; S, 9.77.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#N)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(=O)(=O)(O)[OH:23].[OH2:27]>>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])=[O:27])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: CCCCCCCc1ccc(-c2ccc(C#N)cc2)cc1
Product: CCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
50 Gram of 4-n-heptyl-4'-cyanobiphenyl and 500 g of 70 weight % sulfuric acid were introduced into a 2 l three neck flask and heated on a mantle heater with stirring under reflux for 2.5 hours, followed by water-cooling adding 500 ml of water, separating the resulting solid by filtration with a glass filter, water-washing and recrystallizing with glacial acetic acid, to give 47.3 g of 4-n-heptyl-biphenyl-4'-carboxylic acid ((II), R=C7H15), which was a colorless crystal having a molecular formula of C20H24O2 (composition: C 81.0%,H 8.2%, O 10.8% as calculated values and C 81.2%, H 8.3%, O 10.5% as observed values) and a melting point of 163° C and formed a smectic liquid crystal at temperatures exceeding the melting point.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CC1c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ester from step 1 in THF-MeOH (4:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 1 h. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The organic was washed with brine, dried and solvent evaporated to afford 2-(4-bromophenyl)cyclopropanecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[NH:11][C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13].ClC(O[C:24](Cl)=[O:25])(Cl)Cl.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:24]([NH:30][CH2:27][CH2:28][CH3:29])=[O:25])=[CH:6][C:5]=1[NH:11][C:12]([NH:14][CH:15]([CH3:16])[CH3:17])=[O:13]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)cc1NC(=O)NC(C)C
Reactant: CCCN
Solvent: CCOC(C)=O
Product: CCCNC(=O)Nc1ccc(C(=O)OC)c(NC(=O)NC(C)C)c1

Procedure:
A solution of methyl-4-amino-2-(3-isopropylureido)benzoate (500 mg), prepared as described in Preparation XVIII, above, in ethyl acetate (10 ml) was added to a solution of trichloromethylchloroformate (0.157 gm) in 5 ml ethyl acetate. After 11/2 hours, 5 ml of n-propylamine was added. The solution was diluted with ethyl acetate, extracted with water, 5% hydrochloric acid and washed with saturated sodium bicarbonate solution. The ethyl acetate layer was dried over magnesium sulphate and evaporated to yield methyl-4-(3-propylureido)-2-(3-isopropylureido)benzoate, as a solid, m.p. 94°-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[CH3:11]/[C:12](/[NH2:16])=[CH:13]\[C:14]#[N:15].[CH2:17]([CH:20]1[CH2:25][C:24](=[O:26])[CH2:23][C:22](=O)[CH2:21]1)[CH2:18][CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:23]3[C:24](=[O:26])[CH2:25][CH:20]([CH2:17][CH2:18][CH3:19])[CH2:21][C:22]=3[NH:16][C:12]([CH3:11])=[C:13]2[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: C/C(N)=C\C#N
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CCCC1CC(=O)CC(=O)C1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1ccc(O)c(Br)c1

Procedure:
The reaction of 3-bromo-4-hydroxy-benzaldehyde (13.07 g) with 3-aminocrotonitril (5.34 g) and 5-propylcyclohexane-1,3-dione (10.02 g) was performed according to the method described in example 1a. Yield: 20.25 g. MS-ESI: [M+H]+=401/403
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([C:24](O)=[O:25])=[N:12][CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:58][O:59][C:60](=[O:63])[CH2:61][NH2:62]>CN(C=O)C>[CH3:58][O:59][C:60](=[O:63])[CH2:61][NH:62][C:24]([C:11]1[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:15][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1)=[O:25]
Reactant: COC(=O)CN
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid HCl, 2, (8.06 g, 21.7 mmol) in DMF (100 mL) at 0° C. under N2 is added diisopropylethylamine (11.35 mL, 65.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (6.23 g, 32.6 mmol) and 1-hydroxybenzotriazole (HOBt) (0.294 g, 2.2 mmol). The solution is stirred for 5 minutes and glycine methyl ester hydrochloride (4.09 g, 32.6 mmol) is added. The reaction is allowed to warm slowly to room temperature and stirred 3 days. The reaction volume is partially concentrated under reduced pressure then diluted with EtOAc and washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to afford a yellow oil that is purified over silica (EtOAc:heptane gradient 1:1 to 1:0) to afford 3.5 g (40% yield) of the desired product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (1 H, t, J=4.9 Hz), 7.95 (1 H, d, J=1.8 Hz), 7.38-7.44 (2 H, m), 7.22-7.35 (8 H, m), 6.85 (1 H, d, J=2.6 Hz), 5.14 (2 H, s), 5.03 (2 H, s), 4.18 (2 H, d, J=5.5 Hz), 3.69 (3 H, s). HPLC-MS: m/z 407 [M+H]+.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([C:15]1[C:39]([OH:40])=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:37]=[CH:36][C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[C:27]([Cl:35])[CH:26]=2)=[CH:21][CH:20]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1(CO)C=CC=CC=1>[Cl:35][C:27]1[CH:26]=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]3[C:15]([C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])=[C:39]([OH:40])[C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=3)=[CH:24][CH:23]=2)[CH:30]=[CH:29][C:28]=1[CH2:31][C:32]([O:34][CH3:1])=[O:33]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)c(Cl)c3)cc2)ccc(C(F)(F)F)c1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: OCc1ccccc1
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1Cl
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A trimethylsilyldiazomethane-0.6M hexane solution (0.20 ml, 0.12 mmol) was added to a solution of (4′-{[2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-3-chloro-1,1′-biphenyl-4-yl)acetic acid (60 mg, 0.11 mmol) obtained in Example (18-4) in a mixture of benzene-methanol (4:1, 2.5 ml), and the mixture was stirred for 1 hour. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: hexane/methylene chloride/ethyl acetate=9/1/1) to give the title compound (45 mg, yield: 73%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)[CH2:8][CH3:9].[C:12](OC=C)(=O)[CH3:13].[O:18]1[CH2:21][C:20]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:19]1>C1(C)C=CC=CC=1>[CH:12]([O:23][CH2:22][C:20]1([CH2:24][O:25][CH:8]=[CH2:9])[CH2:21][O:18][CH2:19]1)=[CH2:13]
Reactant: CCC(=O)O
Reactant: OCC1(CO)COC1
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COCC1(COC=C)COC1
Temperature: 95 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture (280 ml) of 24.9 g (0.23 mol) of sodium carbonate with toluene was raised in temperature to 95° C., 1.4 g of propionic acid was added, and, while maintaining the temperature at 95° C., 16 g of vinyl acetate was added dropwise, and 15 minutes later, 1.27 g (1.9 mmol) of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 was further added. Next, 40 g (0.19 mol) of oxetane-3,3-dimethanol was added dropwise over 3 hours for a reaction. After the completion of the dropwise addition and subsequent stirring for 1 hour, the reaction mixture was analyzed by gas chromatography and found that there were formed 3,3-bis(vinyloxymethyl)oxetane represented by the following formula in a yield of 90% and (3-vinyloxymethyloxetan-3-yl)methanol in a yield of 2%. The reaction mixture was purified by distillation and thereby yielded 31 g of 3,3-bis(vinyloxymethyl)oxetane with a purity of 99%.