Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[C:11]2[CH2:12][CH:13]([CH2:15][O:16][CH3:17])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C1C=C(O[C:47]2[CH:52]=[CH:51][C:50]([C:53](=[O:57])[N:54]([CH3:56])[CH3:55])=[CH:49][CH:48]=2)C2CC(CO)OC=2C=1)=O)(C)(C)C.CI>>[C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:47]2[CH:52]=[CH:51][C:50]([C:53](=[O:57])[N:54]([CH3:55])[CH3:56])=[CH:49][CH:48]=2)[C:11]2[CH2:12][CH:13]([CH2:15][O:16][CH3:17])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCC1Cc2c(OCc3ccccc3)cc(C(=O)OC(C)(C)C)cc2O1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(CO)O3)cc1
Solvent: CI
Product: COCC1Cc2c(Oc3ccc(C(=O)N(C)C)cc3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 204b, from 4-(4-dimethylcarbamoyl-phenoxy)-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (211a) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.40-7.43 (m, 2 H) 7.24 (d, J=1.26 Hz, 1 H) 7.17 (d, J=1.26 Hz, 1 H) 6.92-7.01 (m, 2 H) 4.92-5.05 (m, 1 H) 3.51-3.59 (m, 2 H) 3.41 (s, 3 H) 2.99-3.15 (m, 7 H) 2.81-2.90 (m, 1 H) 1.54 (s, 9 H); LCMS for C24H29NO6 m/z 428.20 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][CH2:10][CH2:11]O.[ClH:14]>O>[ClH:14].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Cl:14]
Reactant: Nc1ccccc1C(=O)CCCO
Agent: Cl
Solvent: O
Product: Nc1ccccc1C(=O)CCCCl
Yield: 73 %

Procedure:
A mixture of 9.3 g (5.1 mmol) of 1-(o-aminophenyl)-4-hydroxy-1-butanone, 26 mL of water and 90 mL of 37% HCl is refluxed for about 6.5 hours, cooled and filtered to afford 8.0 g of 1-(o-aminophenyl)-4-chloro-1-butanone hydrochloride. Extraction of the aqueous mother liquor with methylene chloride gives an additional 1.10 g of the title product for an overall yield of 73% (mp 142-145° C.). The product is identified by NMR and MS analyses.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].[CH3:13][S:14][CH2:15]Cl.C(N(CC)CC)C>>[C:1]([O:12][CH2:13][S:14][CH3:15])(=[O:11])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[CH3:4]
Reactant: CSCCl
Reactant: CC(C)=CCCC(C)CC(=O)O
Solvent: CCN(CC)CC
Product: CSCOC(=O)CC(C)CCC=C(C)C

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting citronellic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 110° C./2 mm Hg, n20 1.4760.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10]2[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.O>CS(C)=O>[CH3:16][O:15][C:13]([C:11]1[C:10]2[C:17](=[O:22])[CH:18]([Br:23])[CH2:19][CH2:20][CH2:21][C:9]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=1)=[O:14]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a solution of 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole 1,3-dicarboxylic acid 3-methyl ester 1-tert-butyl ester(1.1 g, 3.6 mmol) in DMSO(20 mL) is added 1,3-dibromo-5,5-dimethylhydantoin(1.5 g, 5.4 mmol) portion wise with the aid of a cooling bath and the resulting mixture is stirred for 18 h at RT. Water is added and the reaction mixture is extracted with ether. The combined ether layers are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (10% EtOAc/Hex to 25% EtOAc/Hex) to yield 915 mg of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a bright yellow oil (66%). 1H NMR (CDCl3) 1.59 (s, 9H), 1.72-1.84 (m, 1H), 2.12-2.25 (m, 2H), 2.43-2.58 (m, 1H), 3.05-3.14 (m, 1H), 3.40-3.49 (m, 1H), 3.80 (s, 3H), 4.75 (m, 1H), 7.79 (s, 1H) Step 2: A mixture of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(467 mg, 1.2 mmol), 4-Amidinopyridine hydrochloride(953 mg, 6.1 mmol), and NaHCO3(813 mg, 9.7 mmol) in dioxane(20 mL) is refluxed for 20 h. After cooling to RT, MeOH(5 mL) is added and the mixture is filtered. The filtrate is concentrated in vacuo and the brown residue is purified by flash chromatography on silica gel (10% MeOH/CH2Cl2) to yield 197 mg of 2-Pyridin-4-yl-4,5,6,7-tetrahydro-3H-1,3,7-triaza-cyclopenta[e]azulene-9-carboxylic acid methyl ester as a yellow solid (53%). 1H NMR (CDCl3) 2.06 (quint, 2H), 2.98 (t, 2H), 3.04 (t, 2H), 3.91 (s, 1H), 7.46 (s, 1H), 7.76 (d, 2H), 8.28 (br s, 1H)8.56 (d, 2H)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.CCN(CC)CC.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:9][CH2:8][CH:5]2[CH2:6][O:7][C:2]([CH3:10])([CH3:1])[O:3][CH2:4]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 1.5 g (10.26 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methanol and 1.71 mL of Et3N in 15 mL of DCM, cooled to 0° C., are added 2.15 g (11.3 mmol) of tosyl chloride. The medium is allowed to warm to room temperature, and stirring is continued for 1 hour. The medium is taken up in 100 mL of DCM, washed successively with 0.1N HCl (2×20 mL) and brine (20 mL), dried over Na2SO4, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 3 g of (2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate are obtained in the form of a colourless oil.
Reaction SMILES: [I-:1].O[CH2:3][P+:4]([CH2:9]O)([CH2:7]O)[CH2:5]O.[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14]>C1(C)C=CC=CC=1>[I-:1].[CH3:11][N:12]([CH2:9][P+:4]([CH2:3][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])([CH2:5][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[CH2:7][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: [I-]
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 97.1 %

Procedure:
Reaction of tetrakis(hydroxymethyl)phosphonium iodide (7.05 g, 0.025 mol) with 1,3-dimethylurea (8.81 g, 0.1 mol) in toluene (25 ml), following Example 1, gave 13.65 g (97.1%) of tetrakis(1,3-dimethylureidomethyl)phosphonium iodide (I, R=R'=CH3, R"=H, X=I) as a white, crystalline solid, mp 194° C. dec after two recrystallizations from ethanol (10 ml/g). The product suffered no weight loss when dried under vacuum for 2 hr at 100° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:14]=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:14]=[N:13][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:16]=2)=[CH:22][CH:21]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)nn1
Product: Fc1ccc(-c2cn(CCC#Cc3ccccn3)nn2)cc1
Yield: 25945.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-[1,2,3]triazole (80 mg, 0.37 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography DCM/MeOH 98.5:1.5) to yield 28 mg (96 mmol, 26%) of 2-(4-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a brown solid (M.P.=120-122° C.).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[C:30]1([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>ClCCl.C(OCC)C>[C:30]1([C:36]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=2)([OH:40])[CH2:37][CH2:38][CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCC(=O)c1ccccc1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC(O)(c1ccccc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 200 mg (0.46 mmol) 4-iodo-1-trityl-imidazole in 3 ml anhydrous dichloromethane was added at ambient temperature 0.16 ml (0.48 mmol) 3M ethyl magnesium bromide in diethyl ether. The mixture was stirred for 1 hour then a solution of 55 mg (0.37 mmol) 1-phenyl-butan-1-one in 0.1 ml anhydrous dichloromethane was added in one portion and the reaction mixture was stirred for 16 hours. Saturated aqueous ammonium chloride (5 ml) was then added to the reaction mixture and the whole was extracted with dichloromethane (3×5 ml). The organic phase was washed with water (3×5 ml) then brine (3×5 ml), dried over MgSO4, concentrated and purified by preparative HPLC to give 90 mg rac-1-phenyl-1-(1-trityl-1H-imidazol-4-yl)-butan-1-ol as colourless oil: MS (ISP): 459.0 ((M+H)+.); 1H-NMR (CDCl3): 0.80 (3H, t, CH3), 1.30 (2H, m), 2.05 (2H, m, CH2), 3.45 (1H, s, br, OH), 6.70 (1H, s), 7.05-7.45 (21H, m).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1c(Br)cnn1C
Yield: 66.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with α,α,α-trifluoro-m-tolylisocyanate (0.025 g, 18.0 μL, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 11 (0.038 g, 0.080 mmol, 65%) as a white solid. LCMS m/z (%)=469 (M+H79Br, 91), 471 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.42 (s, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.64-7.73 (m, 2H), 7.45-7.53 (m, 2H), 7.44 (s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.15 (d, J=8.9 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:33]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:26])[NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:8]=1)(=[S:33])[NH2:2]
Reactant: S
Reactant: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C#N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C(N)=S)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of step (a) (600 mg), pyridine (56 ml) and triethylamine (8 ml) was covered with a blanket of H2S gas and stirred at ambient temperature overnight. The dark green reaction mixture was evaporated to dryness and the residue was stirred with dry ether for 1 hour. The resultant solid was collected and washed thoroughly with ether to give methyl 4-[4-(4-thiocarbamoylphenyl)allophanoyl]phenoxyacetate (593 mg) as a yellow solid; m.p. 215°-218° C. (decomposes); NMR Spectrum (DMSO-d6 +CD3CO2D) 3.73 (3H, s), 4.90 (2H, s), 7.08 (2H, d), 7.64 (2H, d), 7.98 (2H, d), 8.06 (2H, d); Mass Spectrum m/Z 388 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][N:11]=[C:5]2[N:4]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]1=[O:17].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)[N:11]=[C:5]2[N:4]([CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:3]1=[O:17]
Reactant: Cn1c(=O)c2c[nH]nc2n(CC(C)(C)C)c1=O
Reactant: ClCc1ccc(-c2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2cn(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.4 %

Procedure:
5-methyl-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (236 mg, 1.0 mmol), 4-(4-(chloromethyl)phenyl)pyridine (305 mg, 1.5 mmol) and potassium carbonate (414 mg, 3.0 mmol) are suspensed in 3 mL of DMF. The reaction mixture is stirred at room temperature overnight, and then diluted with 100 mL of water. The mixture is extracted with methylene chloride four times (40 mL×4). The combined organic phase is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated to dryness to give 510 mg of crude product, which is used in the next step without further purification. MS (ESI) m/z 404.2 [M+H]+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[CH3:25][C@@H:26]([CH2:35][CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>C(O)C>[CH3:25][C@@H:26]([CH2:35][CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:3][C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: CC[C@H](C)CCCCCCCBr
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ncc(OCCCCCCC[C@@H](C)CC)cn2)cc1
Yield: 29.7 %

Procedure:
KOH (0.8 g) was added to a solution of 5-hydroxy-2-(4-octyloxyphenyl)pyrimidine (4 g) dissolved in ethanol (20 ml), followed by adding (S)-8-methyldecyl bromide (3.2 g) prepared according to the method disclosed in the literature (Mol. Cryst. Liq. Cryst., 1984, Vol. 114, pp. 237-247), keeping the mixture under reflux for 6 hours, allowing the resulting material to cool down, extracting it with toluene, washing the resulting organic layer with 2N-NaOH aqueous solution, further washing with water until the washing water became neutral, distilling off low-boiling components in the organic layer and recrystallizing the residue from ethanol to obtain the captioned compound, (S)-5-(8-methyldecyloxy)-2-(4-octyloxyphenyl)pyrimidine (1.8 g). Its phase transition points were as follows: ##STR12##
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][C:18](=[O:23])[C:17]([C:24]([OH:26])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12>CN(C=O)C>[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH:68][C:24]([C:17]3[C:18](=[O:23])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][C:13]([O:12][C:11]([F:10])([F:28])[F:27])=[CH:22][CH:21]=4)=[O:26])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)ccc2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(OC(F)(F)F)ccc2oc1=O
Temperature: 25 °C
Yield: 36.4 %

Procedure:
DIEA (34.9 μL, 0.20 mmol) was added to 6-trifluoromethoxy-3-carboxy-coumarin (50.0 mg, 0.18 mmol) and HATU (76.3 g, 0.20 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.2 mg, 0.18 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 30.5 mg of product in 36% yield: LCMS (ESI) m/z 466 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:36]([O:38]C)=[O:37])[CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:12]=1
Reactant: COC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(Cl)c3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCC2(C(=O)O)CC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
In methanol (7 mL) and tetrahydrofuran (7 mL) was dissolved methyl 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylate (236 mg), 2N aqueous sodium hydroxide solution (1.98 mL) was added to the solution and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and acetic acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1-{[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclopropanecarboxylic acid (221 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][N:6]2[CH:13]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C1COCC1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][N:6]3[CH:13]=2)[CH2:26][CH2:27]1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Reactant: COc1ccc2nc(CCl)cn2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2nc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)cn2c1
Temperature: 75 °C
Yield: 47.7 %

Procedure:
A mixture of 2-(chloromethyl)-6-methoxyimidazo[1,2-a]pyridine (0.1392 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.1662 g), triethylamine (Aldrich; 0.11 mL), and THF (2 mL) is stirred at 75° C. until the reaction is complete by thin layer chromatography. The cooled mixture is concentrated under reduced pressure and partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and crystallized from ethyl acetate/ether to give 0.132 g of the title compound in two crops; mp 129.5-130.5° C.; MS m/z 390, 392; IR (mineral oil) 1479, 1166, 799, 1510, 1219 cm-1 ; 1H NMR (CDCl3) δ2.76, 3.08, 3.77, 3.81, 6.93, 6.97, 7.17, 7.34, 7.45, 7.49, 7.60.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:27])=[C:15]([CH:26]=1)[C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH3:25])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:27][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:26][C:15]=1[C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH3:25])=[O:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1CCCCC1OC(=O)c1cc(N)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCCC1OC(=O)c1cc(NC(=O)c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.3 %

Procedure:
Benzoyl chloride (5.2 g, 0.037 mole) was added slowly at room temperature to a stirred mixture of 2-methylcyclohexyl 5-amino-2-chlorobenzoate (10 g, 0.037 mole), triethylamine (4.0 g, 0.04 mole) dissolved in methylene chloride (100 ml). This reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then washed with water (200 ml), 3% HCl solution (100 ml), 2% NaOH solution (100 ml) and water (100 ml), dried (magnesium sulfate) and filtered. The solvent was evaporated off to give a brown oil which was crystallized with ethyl/hexane to give 2-methylcyclohexyl 2-chloro-5-(benzoylamino)benzoate as a white solid (5 g, m.p. 121°-122° C.)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C.C(Cl)(Cl)(Cl)Cl>[Br:10][C:8]1[CH:9]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH2:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ccc(N)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CSc1ccc(N)c(Br)c1
Temperature: 25 °C

Procedure:
To a solution containing 1.0 mL (8.0 mmol) of 4-(methylthio)aniline in 40 mL of a 3:1 solution mixture of acetonitrile/carbon tetrachloride was added 1.6 g (8.8 mmol) of N-bromosuccinimide. The reaction mixture was heated to reflux for 30 min, then cooled to ambient temperature and concentrated in vacuo. To the residue was added 100 mL of ethyl acetate and the organic solution was washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous brine (100 mL each), dried over sodium sulfate, filtered and evaporated in vacuo to yield a viscous oil. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 30% ethyl acetate/hexanes gradient) to give the title compound. 1H NMR (CDCl3): δ 7.45 (s, 1H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 6.72 (d, 8.5 Hz, 1H), 4.08 (bs, NH2), 2.44 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]([N+:17]([O-])=O)[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=1)[CH3:2].[Sn](Cl)Cl>C(O)(=O)C.Cl>[CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]([NH2:17])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2cc3ccccc3c([N+](=O)[O-])c2c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Product: CCc1ccc2cc3ccccc3c(N)c2c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
2-Ethyl-9-nitroanthracene (2.55 g; 0.01 mole) (See Example 1) was dissolved in acetic acid (20 ml). To the clear solution at 50° C., there was slowly added tin (II) chloride (9.6 g; 0.051 mole) in concentrated HCl (25 ml). The solution was stirred at 50° C. for 15 minutes and allowed to cool to room temperature. The yellow solid which precipitated was filtered off, washed with water and then neutralised with 10% NaOH solution. The amino derivative was thoroughly washed with water, dried in air overnight and then under vacuo at 50° C. for 5 hours. Yield 1.98 g (88%). The product became brown in colour and was slightly sticky.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][NH:4][C:5]([C:7]1([NH:10]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1)=[O:6].[ClH:20]>C(Cl)Cl.O1CCOCC1>[ClH:20].[C:7]([CH:9]1[CH2:8][C:7]1([NH2:10])[C:5]([NH:4][CH2:3][C:2]([F:1])([F:18])[F:19])=[O:6])([CH3:9])([CH3:8])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NCC(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)C1CC1(N)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To tert-butyl (1-((2,2,2-trifluoroethyl)carbamoyl)cyclopropyl)carbamate (3.2 g, 11 mmol) in CH2Cl2 (20 mL) was added 4 M HCl in dioxane (20 mL). The solution was stirred for 18 h at ambient temperature. The reaction mixture was concentrated in vacuo and the residue placed in a 60° C. vacuum oven (24 h) to afforded the title compound as an off-white solid (2.3 g, 93%): 1H NMR (400 MHz, DMSO-d6) δ 8.77 (bs, 3H), 8.50 (t, J=6.3 Hz, 1H), 3.90 (qd, J=9.7, 6.1 Hz, 2H), 1.52-1.15 (m, 4H); 19F NMR (376 MHz, DMSO-d6) δ −70.54; 13C NMR (101 MHz, DMSO-d6) δ 175.33, 132.46 (q, J=280.8 Hz), 45.13 (q, J=34.34 Hz), 40.06, 17.57.