Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[C:4]1[NH:8][C:7](=O)[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].CC(C)=O.N1CC(=O)NC1=[S:17]>N1CCCCC1>[C:1](=[C:4]1[NH:8][C:7](=[S:17])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)=C1NC(=O)NC1=O
Reactant: O=C1CNC(=S)N1
Solvent: CC(C)=O
Solvent: C1CCNCC1
Product: CC(C)=C1NC(=S)NC1=O

Procedure:
Doyle et al, J. Chem. Soc. 1955, 2265-73 (Chemical Abstracts 1956, 50, 8602g at 8603b) teach the preparation of 5-iso-propylidenehydantoin via the reaction of acetone with 2-thiohydantoin in piperdine to yield 5-iso-propylidene-2-thiohydantoin which is then desulfurized with chloroacetic acid to yield 5-iso-propylidenehydantoin.
Reaction SMILES: [K].C1(O)(C)C=CC=CC1C.C([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21])=O>>[C:14]1([OH:13])[C:15]([CH3:21])=[CH:16][CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: Cc1ccc(C)c(OC=O)c1
Agent: CC1C=CC=CC1(C)O
Agent: [K]
Product: Cc1ccc(C)c(O)c1
Reaction time: 1 h
Yield: 41 %

Procedure:
After adding potassium salt of xylenol in an amount of 0.47 weight % based on the separated 2,5-xylyl formate, the thermal decomposition was carried out at 200° C. for one hour to obtain 2,5-xylenol in 41% yield.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[C:19]([C:22](=[N:30][OH:31])[CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)([OH:21])=[O:20].B(F)(F)F.CCOCC.N>C(#N)C.O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:28]3[N:24]([CH2:23][C:22]([C:19]([OH:21])=[O:20])=[N:30][OH:31])[N:25]=[N:26][N:27]=3)[CH2:15][S:14][C@H:9]12
Reactant: O=C(O)C(Cn1nnnc1S)=NO
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: N
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=NO)C(=O)O)CS[C@H]12
Reaction time: 0.83 h
Yield: 75.6 %

Procedure:
To a suspension of 7-aminocephalosporanic acid (12.1 g) and 1-(2-carboxy-2-hydroxyiminoethyl)-1H-tetrazole-5-thiol (9.0 g) in dry acetonitril (60 ml) was added boron trifluoride etherate (25.1 g) and the resulting solution was stirred at 50° for 50 minutes. Water (60 ml) was added and the solution was adjusted to pH 3.5 with conc. aqueous ammonia to give precipitates which were filtered, washed successively with water and acetone, and air-dried to give 7-amino-3-[1-(2-carboxy-2-hydroxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (13.92 g).
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@H:12]([CH3:27])[CH2:11]3)C(C)=CC=1.C(N(CC)CC)C.Cl.NO>O.C(O)C>[NH2:3][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:12]([CH3:27])[CH2:11]2
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2C(=O)OCc1ccccc1
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: C[C@@H]1Cc2cc(N)ccc2N1C(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To a stirred solution of phenylmethyl (2R)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3-dihydro-2-methyl-1H-indole-1-carboxylate (Step 3, 2.11 g, 5.84 mmol) in water/ethanol (1:9, 60 mL) is added triethylamine (6.5 mL, 46.7 mmol) and hydroxylamine hydrochloride (6.49 g, 93.4 mmol). The reaction mixture is stirred at 90° C. for 20 h and is then concentrated under reduced pressure. The residue is taken up in CH2Cl2 (60 mL) and washed with H2O (2×20 mL) and saline (2×20 mL), and the combined aqueous layer is extracted with CH2Cl2 (2×20 mL). The combined organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is purified by chromatography on a Biotage Flash 40M 90 g silica gel cartridge (30-50% EtOAc/Hexanes eluent) to give the title compound, MS (ESI+) for C17H18N2O2 m/z 283 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[CH3:12][S+](C)(C)=O.[H-].[Na+].O>CS(C)=O>[O:10]1[CH:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1
Reactant: C[S+](C)(C)=O
Reactant: O=CCCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCC2CO2)cc1
Reaction time: 1 h

Procedure:
3-Phenylpropionaldehyde (26.8 g) is added under nitrogen to the ylide prepared from trimethylsulfoxonium iodide (48.4 g) and sodium hydride (55% dispersion in oil; 9.6 g) in dry dimethylsulfoxide (200 ml), according to the procedure in J. Am. Chem. Soc., 84, 867 (1962) and ibid., 87, 1353 (1965). After one hour, the solution was poured into 1 liter of water and the product extracted with ether (3×300 ml.). The, extract was washed with water (2×150 ml.) dried (MgSO4) and evaporated to give an oil 1,2-epoxy-4-phenylbutane, used directly in the next step.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[CH2:18][CH2:17]1)C1C=CC=CC=1>C(O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[CH2:20][CH2:21]1
Reactant: Fc1cccc([C@H]2CC[C@H](C=CCCCCCOCc3ccccc3)CC2)c1F
Solvent: CCO
Product: OCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
First, 6.5 g of 1-[trans-4-(7-benzyloxy-1-heptenyl)cyclohexyl]-2,3-difluorobenzene, 1 g of 10% Pd--C, and 50 ml of ethanol were placed in a 300 ml autoclave. The mixture was stirred at room temperature for 2 days under a hydrogen pressure of 10 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=3/1) and recrystallized from hexane to obtain 3.5 g of 1-[trans-4-(7-hydroxyheptyl)cyclohexyl]-2,3-difluorobenzene (Y: 69.6%). The compound thus obtained had a purity of 98.5% by GC.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([C:24](O)=[O:25])=[N:20][NH:21]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7].Cl.CN.C1C=CC2N(O)N=[N:41][C:39]=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:39][NH:41][C:24]([C:19]1[C:18]2[C:22](=[CH:23][C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:27]=[CH:28][CH:29]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[NH:21][N:20]=1)=[O:25]
Reactant: O=C(Nc1ccc(-c2ccc3c(C(=O)O)n[nH]c3c2)cc1)c1cccc(C(F)(F)F)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1n[nH]c2cc(-c3ccc(NC(=O)c4cccc(C(F)(F)F)c4)cc3)ccc12
Temperature: 70 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To a stirred solution of 6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylic acid (26 mg, 61 μmol), methyl amine hydrochloride (6.2 mg, 92 μmol), HOBt (12 mg, 92 μmol), and triethylamine (43 μl, 0.3 mmol) in N,N-dimethylformamide (0.6 Ml), was added EDCI (18 mg, 92 μmol). After the mixture was stirred at 70° C. for 12 h, the mixture was cooled to room temperature, and ethyl acetate and saturated sodium bicarbonate solution were added. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated in ethyl acetate/hexane to give N-methyl-6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxamide (20 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CCCO)cc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(CCCOCCCCCCBr)cc1
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A mixture of 4-(methylthio)benzenepropanol (5.0 g), 1,6-dibromohexane (17.0 g), TAB (0.4 g) and aqueous sodium hydroxide (50% w/v, 20 ml) was stirred for 20 h, diluted with water (30 ml), and extracted with ether (2×100 ml). The dried extract was evaporated and the residue was purified by FCC eluting with cyclohexane followed by System A (19:1) to give the title compound as a colourless oil (7.0 g), T.l.c. (System A 9:1) Rf 0.5.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[O:6][P:7](Cl)[O:8][C:9]3[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH3:20])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1.C(N(CC)CC)C.[NH2:35][CH:36]1[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([CH3:44])[C:38]([CH3:46])([CH3:45])[CH2:37]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[O:6][P:7]([NH:35][CH:36]3[CH2:37][C:38]([CH3:45])([CH3:46])[N:39]([CH3:44])[C:40]([CH3:43])([CH3:42])[CH2:41]3)[O:8][C:9]3[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH3:20])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C)cc1C(C)(C)C)C2
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc2c(c(C(C)(C)C)c1)OP(NC1CC(C)(C)N(C)C(C)(C)C1)Oc1c(cc(C)cc1C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
10.12 g (25.0 mmol) of 2,10-dimethyl-4,8-di-tert-butyl-6-chloro-12H-dibenzo[d,g][1,3,2]-dioxaphosphocine [GB-A-2 250 990, Example 1a, page 17], 10.5 ml (75.0 mmol) of triethylamine and 100 ml of toluene are charged at room temperature and under nitrogen to a 350 ml sulfonation flask. With stirring, a solution of 4.26 g (25.0 mmol) of 4-amino-1,2,2,6,6-pentamethylpiperidine [Beilstein EII, Vol. 22, page 321 (1953)] in 30 ml of toluene is added dropwise to this suspension. The reaction mixture is refiuxed for 2 hours, then cooled to room temperature and filtered. The filtrate is concentrated on a vacuum rotary evaporator. Crystallisation of the residue from hexane yields 7.7 g (57%) of 2,10-dimethyl-6-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)-4,8-di-tert-butyl-12H-dibenzo-[d,g][1,3,2]dioxaphosphocine (57%) (compound (101)) as a white powder, m.p. 207°-216° C. Analysis: calcd: C 73.57%; H 9.54%; N 5.19%; found: C 74.38%; H 10.03%; N 4.68%.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12]
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Reactant: OB(O)c1ccccc1F
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: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(F)c1-c1ccccc1F
Temperature: 110 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-bromo-3-fluoronitrobenzene (1.500 g, 6.8 mmol), 2-fluorophenylboronic acid (1.145 g, 8.2 mmol), N,N-dimethylformamide (50 mL), and 2.0 M aqueous potassium carbonate (10 mL) under argon was added tetrakis(triphenylphosphine)palladium (0) (0.394 g, 0.3 mmol). The mixture was stirred at 110° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% methylene chloride/hexanes) to afford a pale yellow solid (0.780 g, 49%). 1H NMR (300 MHz, CDCl3) δ 7.86 (dt, 1H, J=7.8, 1.2 Hz), 7.56 (td, 1H, J=8.1, 5.7 Hz), 7.52-7.40 (m, 2H), 7.35-7.15 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(#N)C>[S:17]([C:15]1[S:16][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:13][N:14]=1)(=[O:18])(=[O:19])[NH2:20]
Reactant: Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
5-(4-Aminophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide (7, 50 mg, 0.15 mmol) was suspended in anhydrous acetonitrile (5 mL). Triethylamine (17.1 mg, 0.17 mmol) was added with stirring at 0° C. A solution of decanoyl chloride (32.4 mg, 0.17 mmol) dissolved in anhydrous acetonitrile (1 mL) was added dropwise, and the reaction mixture was stirred at 0° C. for 2 h and overnight at room temperature. Volatiles were removed in vacuo and the residue was washed with water (5 mL). The residue was subjected to chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1, giving the pure product as a solid (42 mg, 0.09 mmol, 60% yield), mp 242-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, 3H, J=6.9 Hz), 1.24 (m, 12H), 1.56 (m, 2H), 2.32 (t, 2H, J=7.5 Hz), 7.66 (s, 4H), 7.91 (s, 2H), 10.13 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.1, 22.3, 25.2, 28.8, 29.0, 31.5, 36.6, 118.6, 127.0, 137.4, 142.2, 157.8, 170.8, 172.1; LRMS (LCQ, ESI) calcd for C18H26N5O5S3 488.1, found 488.1 (M−H)−; HRMS (ESI−, m/z) calcd for C18H26N5O5S3 488.1102, found 487.1101 (M−H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]([CH2:26][C@H:27](O)[CH3:28])[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([O:13][C@H:27]([CH3:28])[CH2:26][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.1 %

Procedure:
To a solution of 2-(phenylmethoxy)benzoic acid (4.0 g, 17.5 mmol), (2R)-1-(tert-butyldimethylsiloxy)propan-2-ol (2.78 g, 14.6 mmol), and 4-(dimethylamino)pyridine (183 mg) in 100 mL of anhydrous dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (4.2 g, 17.5 mmol) was slowly added. The resulting mixture was stirred at room temperature for 48 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl twice followed by the addition of saturated NaHCO3 solution and brine. The organic layer was separated, dried through a MgSO4 pad, and concentrated under reduced pressure. Chromatography (silica gel, 1:12 ethyl acetate/hexane) of the residue afforded 1.7 g (29%) of (1R)-1-Methyl-2-(tert-butyldimethylsiloxy)ethyl 2-(phenylmethoxy)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[C:4]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[C:3]=1[F:20].[Cl:21]N1C(C)(C)C(=O)N(Cl)C1=O>CC#N>[NH2:1][C:2]1[C:7]([Cl:21])=[C:6]([CH:8]=[O:9])[N:5]=[C:4]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=2)[C:3]=1[F:20]
Reactant: Nc1cc(C=O)nc(-c2ccc(C(F)(F)F)nc2)c1F
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC#N
Product: Nc1c(F)c(-c2ccc(C(F)(F)F)nc2)nc(C=O)c1Cl
Yield: 147.5 %

Procedure:
Using the procedure for Example 15, 4-amino-3-fluoro-6′-(trifluoromethyl)-[2,3′-bipyridine]-6-carbaldehyde (200 mg, 0.701 mmol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (76 mg, 0.386 mmol) and CH3CN (7 mL) gave 4-amino-5-chloro-3-fluoro-6′-(trifluoromethyl)-[2,3′-bipyridine]-6-carbaldehyde (182 mg, 69.8%) as a yellow solid: mp 147-149° C.; 1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 9.34 (d, J=2.0 Hz, 1H), 8.54 (m, 1H), 7.84 (m, 1H), 5.13 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −68.02, −137.62.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)butyl]piperazine-1-carboxylate (0.0860 g, 0.212 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0282 g, 0.193 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}butyl)piperazine-1-carboxylate (0.0945 g, 91%).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:40]([O:41]CC2C=CC=CC=2)[C@H:39]([O:49][C@@H:50]2[O:79][C@H:78]([CH3:80])[C@@H:69]([O:70]CC3C=CC=CC=3)[C@H:60]([O:61]CC3C=CC=CC=3)[C@H:51]2[O:52]CC2C=CC=CC=2)[C@@H:38]([CH2:81][O:82]CC2C=CC=CC=2)[O:37][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17]CC2C=CC=CC=2)[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@H:13]1[CH2:35][F:36])C1C=CC=CC=1>CO.Cl.[OH-].[Pd+2].[OH-].[C]>[C@@H:50]1([O:49][C@@H:39]2[C@@H:38]([CH2:81][OH:82])[O:37][C@H:10]([O:11][C@H:12]3[C@H:16]([OH:17])[CH2:15][NH:14][C@H:13]3[CH2:35][F:36])[C@H:9]([OH:8])[C@H:40]2[OH:41])[O:79][C@H:78]([CH3:80])[C@@H:69]([OH:70])[C@H:60]([OH:61])[C@H:51]1[OH:52]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@H]3[C@H](OCc4ccccc4)CN(C(=O)OCc4ccccc4)[C@H]3CF)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)CN[C@H]3CF)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 0 %

Procedure:
The compound (53 mg, 43.9 mmol) synthesized in Example 10 (10d) was dissolved in 1% hydrochloric acid methanol solution (5 mL) and 20% palladium hydroxide-carbon (30 mg) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 3 hours. After the catalyst was removed by celite filtration, 28% ammonia water (0.2 mL) was added thereto and the mixture was stirred for 10 minutes. After the solvent was distilled off under reduced pressure and it was passed through ion exchange resin column with water (30 mL), 1% ammonia water (30 mL) was flowed through. The ammonia water containing the desired compound was concentrated under reduced pressure and the residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (1.6 mg, 8%) as a colorless solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:31]([CH2:40][CH3:41])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:43].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:31]([CH2:40][CH3:41])=[N:30][C:25]=3[C:26]([NH2:43])=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
mCPBA (2.0 g of 60%, 6.97 mmol) was added to a solution of 7-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (2.8 g, 6.97 mmol) in chloroform (50 mL). After 30 minutes an additional equivalent of mCPBA was added and the reaction mixture was stirred for an additional hour. Ammonium hydroxide (20 mL) was added and the reaction mixture was stirred for 10 minutes. p-Toluenesulfonyl chloride (1.33 g, 6.97 mmol) was added in a single portion and the reaction mixture was stirred for 16 hours. The layers were separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The organics were combined, washed with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (40+M cartridge eluting with a gradient of 2 to 25% CMA in chloroform). The residue was combined with acetonitrile and allowed to stand overnight. A solid was isolated by filtration and rinsed with acetonitrile to provide 1.96 g of 7-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 193.9 %

Procedure:
To a solution of 1-bromo-4-(trifluoromethoxy)benzene (0.90 g, 3.7 mmol) in tetrahydrofuran (20 ml) was added a solution of 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.36 g, 1.54 mmol) in tetrahydrofuran (10 ml), potassium carbonate (0.42 g, 3.0 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (40 mg, 0.077 mmol) and water (0.20 ml) and the mixture refluxed under nitrogen for 19 h. The reaction mixture was tipped into water (150 ml) and extracted with ether (2×50 ml), the ether extract then dried (MgSO4) and evaporated to give a tan semi-solid (0.801 g). Purification by column chromatography (silica gel, 4:1 hexane/chloroform) afforded 4-methoxy-4′-(trifluoromethoxy)-1,1′-biphenyl (36) as a white solid (0.33 g, 80%). 1H nmr (CDCl3, 300 MHz) 3.86, s, 4-OMe; 6.99, d (8.7 Hz), H3,5; 7.26, d (8.1 Hz), H3′,5′; 7.49, d (8.7 Hz), H2,6 or H2′,6′; 7.55, d (8.7 Hz), H2′,6′ or H2,6. APCI (+ve) MS m/z 268 (M+, 80%).