Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:21][CH3:22].[C:23]([C:27]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:16]4[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:21][CH3:22])=[O:34])[N:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1N
Product: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1NC(=O)Nc1cc(C(C)(C)C)nn1-c1ccccc1
Yield: 51 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound (45 mg, 51%) as a white solid.
Reaction SMILES: CC12C3(C)[N:6]4[CH2:7][CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][N:13]1[CH2:14][CH:15]([C:17]([O:19]C)=[O:18])[CH2:16][N:3]2[CH2:4][CH2:5]4.Cl>C(O)C>[NH:6]1[CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH:15]([C:17]([OH:19])=[O:18])[CH2:16][NH:3][CH2:4][CH2:5]1
Reactant: COC(=O)C1CN2CCN3CCCN4CCN(C1)C2(C)C34C
Agent: Cl
Solvent: CCO
Product: O=C(O)C1CNCCNCCCNCCNC1
Temperature: 0 °C

Procedure:
A solution of 0.50 g (1.62 mmol) of compound 3, prepared in example A, stage (b), in 20 ml of absolute ethanol is brought to reflux. 3 ml of a 35% aqueous hydrochloric acid solution are added in small amounts. Reflux is maintained for 48 hours. The mixture is cooled to 0° C. and the precipitate formed is filtered off and washed with ice-cold ethanol. The filtrate is evaporated and then the residue is taken up in the minimum amount of ethanol. The precipitate formed is filtered off and washed with ice-cold ethanol. Compound 6·3HCl is isolated in the form of a white powder (0.57 g, Yield =92%). Overall yield starting from the tetraamine: 87%.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[N:16]1[CH:17]=[CH:18][C:13]([O:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[N:14][CH:15]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccncn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@H](Oc2ccncn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cis/trans-4-(pyrimidin-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (0.90 g, 3.6 mmol) in 1,4-dioxane (18 ml) was added 2 M aqueous sodium hydroxide solution (18 ml, 36 mmol). Stirring at room temperature for 3 h was followed by acidification to pH 2-3 with 1 M aqueous hydrogen chloride solution (42 ml) and extraction with four 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (0.76 g, 95%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][N:13](C)[CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([C:6]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:7]=23)=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([C:6]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:7]=23)=[CH:4][CH:3]=1
Reactant: CN1CCc2c(Cl)ccc3c4c(n(c23)CC1)CCCCC4
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Clc1ccc2c3c(n4c2c1CCNCC4)CCCCC3
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 6-chloro-3-methyl-2,3,4,5,10,11,12,13-octahydro-1H,9H-cyclohepta[b][1,4]diazocino[7,8,1-hi]indole (0.30 g, 0.99 mmole) in dichloroethane (80 mL) was added 1-chloroethyl chloroformate (1.2 mL, 10.8 mmole) and the mixture refluxed for 24 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo and replaced with methanol (25 mL) and refluxed for another 3 hours. The reaction mixture was then cooled to room temperature and the solvent removed in vacuo. The dark residue was dissolved in methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% methanol in dichloromethane) provided 0.28 g of the title compound. 88 mg of this was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 208-210° C. MS (ESI) m/z 289 ([M+H]+).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12]O>>[CH2:5]=[CH:4][CH2:3][CH2:2][CH2:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: OCCCCCO
Reactant: C=CCCC[Mg]Br
Product: C=CCCCCCCCCCCCC=C
Yield: 81 %

Procedure:
The copper catalyzed coupling reaction of a Grignard reagent with an organic halide, which is commonly referred to as a halide displacement reaction, was first reported in 1971 by Kochi and Tamura (J. Am. Chem. Soc. 1971, 93, 1487, Synthesis 1971, 303, J. Organomet. Chem. 1972, 42, 205). In the Synthesis paper the authors reported the coupling reaction of n-butylmagnesium bromide with n-hexyl bromide in the presence of dilithiumtetrachlorocuprate (Li2CuCl4). Since that report the use of Li2CuCl4 in coupling reactions has been quite extensive and is prominent in the synthesis of pheromones as well as in the synthesis of α,ω-olefins. One of the more interesting uses of this copper catalyzed coupling reaction may be found in U.S. Pat. No. 4,912,253 where sorbyl acetate was coupled with the Grignard prepared from the magnesium salt of chlorohexanol to form the codling moth (Laspeyresia pomonella) sex pheromone 8,10-dodecadien-1-ol on a metric ton scale. α,ω-olefins have been formed by coupling 4-pentenylmagnesium bromide with the bis-tosylate of 1,5-pentanediol to form 1,14-pentadecadiene in 81% yield (Tetrahedron 1991, 47, 6287-6292). 1,9-Decadiene has been prepared by the Li2CuCl4 catalyzed coupling reaction of 1,4-dibromobutane with allylmagnesium bromide at 25° C. in 38% yield (Synthetic Communications 1994, 24, 459-463).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[C:3]=1[S:12][CH3:13].[CH3:14][OH:15].[OH-].[K+]>O>[CH3:13][S:12][C:3]1[C:4]([O:10][CH3:11])=[N:5][C:6]([O:8][CH3:9])=[N:7][C:2]=1[O:15][CH3:14]
Reactant: COc1nc(Cl)c(SC)c(OC)n1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1nc(OC)c(SC)c(OC)n1

Procedure:
Charged into a 100-milliliter, 4-necked flask equipped with a reflux condenser, thermometer and stirrer were 2.2 g of 6-chloro-2,4-dimethoxy-5-methylthiopyrimidine and 40 ml of methanol. They were stirred into a homogeneous solution. Subsequent to an addition of 2.0 g of potassium hydroxide, the resultant mixture was heated and refluxed, with thorough stirring, for 3 hours. The liquid reaction mixture was then poured into water and the resultant solid precipitate was collected by filtration. It was recrystallized from isopropyl alcohol, thereby obtaining 5-methylthio-2,4,6-trimethoxypyrimidine (m.p. 90°-91° C.). Yield: 1.96 g(90.7%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21].Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.BrCC1CCCCO1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCC3
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCC3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 198-200° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (d, J=4.8 Hz, 1H), 7.71 (dd, J=7.8, 7.5 Hz, 1H), 7.32-7.15 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.82 (s, 1H), 6.17 (s, 1H), 5.27 (d, J=15.6 Hz, 1H), 5.01 (d, J=15.6 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.49 (td, J=8.7, 0.7 Hz, 2H), 3.15 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.3, 155.2, 154.9, 148.6, 142.1, 138.3, 132.1, 129.1, 128.9, 127.6, 124.0, 123.7, 123.3, 122.3, 109.7, 107.2, 104.0, 80.1, 71.8, 58.6, 45.5, 30.4; MS (ES+) m/z 370.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[Br:21][CH2:22][CH2:23]CBr>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:23][CH2:22][Br:21])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: BrCCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(SCCCBr)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is treated under nitrogen with 1.14 g. sodium borohydride at not greater than 30°. The mixture is stirred for one hour at 15°-20°, then treated with 12 g. of 1,3-dibromopropane at 20°-25°. After a further 3 hours, water is added and the crude product extracted with chloroform. The dried chloroform solution is passed through a column of silica gel to remove polar material. Pure 1-amino-2-nitro-4-(3-bromopropylthio)benzene is obtained from the eluate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>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.O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:17]3[CH:18]=[C:19]([CH3:20])[C:14]([F:13])=[C:15]([CH3:30])[CH:16]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1F
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
Product: Cc1cc(-c2ncnc3cc(Cl)ccc23)cc(C)c1F
Yield: 71.1 %

Procedure:
4,7-dichloroquinazoline (4.0 g, 20.1 mmol), 2-(4-fluoro-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.53 g, 22.1 mmol), sodium carbonate (5.33 g, 50.2 mmol), palladium tetrakis (0.70 g, 0.60 mmol), dimethoxyethane (“DME”) (160 mL), and water (40 mL) were combined in a three neck round bottom flask. A condenser was attached then the system was evacuated and purged with nitrogen three times. The reaction was heated to a vigorous reflux overnight. The reaction was diluted with ethyl acetate, water and brine. The aqueous was partitioned off and the organic was washed once with brine, dried with sodium sulfate, filtered then concentrated down to a yellow solid. The yellow solid was purified with silica gel using DCM to 85/15 DCM/ethyl acetate solvent system to get 4.1 g of light yellow solid for a 71% yield.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][CH2:6][C@:7]1([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]1)[CH3:4].[CH3:31][CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([O:5][CH2:6][C@:7]1([C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:20]2)=[O:14])[CH2:11][CH2:10][C@@H:9]([NH:12][C@@H:37]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[CH3:31])[CH2:8]1)[CH3:4]
Reactant: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N[C@@H]2CCOCC2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a solution of (1R,3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (100.0 mg, 0.211 mmol), 3-methyltetrahydro-4H-pyran-4-one (72.3 mg, 0.634 mmol) and triethylamine (0.118 mL, 0.845 mmol) in dry methylene chloride (5 mL) was added sodium triacetoxyborohydride (134.3 mg, 0.634 mmol). After being stirred at room temperature under N2 overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organics were combined, dried over MgSO4, filtered, purified by silica gel Combi-Flash system (gradient, 0 to 40% MeOH in EtOAc, 12 gram column) to give the desired product (34 mg, 34%). MS calculated for C25H37F3N4O3: (M+H) 499.3; found 499.3.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH3:14].[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25](O)=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([NH:1][C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)=[N:4][C:3]=2[CH3:14])=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1N
Product: Cc1nc(-c2ccc(Cl)cc2)sc1NC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Yield: 30.1 %

Procedure:
Using 5-amino-2-(4-chlorophenyl)-4-methylthiazole (197 mg, 0.877 mmol) and 1-(tert-butoxycarbonyl)nipecotic acid (205 mg, 0.877 mmol), the same procedure was followed as in Step 3a of Example 3 to give 115 mg (30%) of the desired compound as a yellow powder.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:18])=[O:5])=[C:10]([C:16]#[CH:17])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#Cc1cc(Cl)ccc1OCC(=O)O
Reaction time: 8 h

Procedure:
A solution of (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3; 500 mg; 1.87 mmol) in DCM (2.5 ml) was treated with a 4 N solution of HCl in dioxane (14 ml; 56 mmol) and stirred overnight. The solvents were removed under reduced pressure, to give the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1C=O.OO.S([O-])(O)=[O:21].[K+]>CO>[CH3:6][O:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[OH:21]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: O=S([O-])O
Agent: O=S(=O)(O)O
Agent: OO
Agent: [K+]
Solvent: CO
Product: COc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Conc. sulfuric acid (0.4 ml) was added to a mixed solution comprising 3.3 g of 2,4-dimethoxybenzaldehyde and 30 ml of methanol, and under ice-cooling, 2.93 ml of 30% hydrogen peroxide aqueous solution was added to the mixture. After stirring at room temperature for 4 hours, a 5% aqueous potassium hydrogen sulfite solution was added to the mixture and the solvent was removed under reduced pressure. The residue was extracted with diethyl ether, the extract was washed and dried and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 2.1 g of 2,4-dimethoxyphenol (yield: 69%, state: colorless oily product).
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[C:25]([CH2:31][OH:32])[CH:24]=4)[CH:15]=3)=[C:10]([CH2:33][CH2:34][CH3:35])[CH:9]=2)OCC[O:4]1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[OH:32][CH2:31][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:3](=[O:4])[CH2:1][CH3:2])=[CH:9][C:10]=3[CH2:33][CH2:34][CH3:35])[CH:15]=2)[CH:28]=[CH:27][C:26]=1[CH2:29][OH:30]
Reactant: CCCc1cc(C2(CC)OCCO2)ccc1-c1cc(CCc2ccc(CO)c(CO)c2)ccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(CCc2ccc(CO)c(CO)c2)ccc1C
Yield: 49.8 %

Procedure:
640 mg (1.4 mmol) of (4-{2-[4′-(2-ethyl[1,3]dioxolan-2-yl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol are placed in 15 ml of acetone and 15 ml of water in a round-bottomed flask. A spatula-tip of p-toluenesulfonic acid is added and the solution is refluxed for 2 hours 30 minutes. At room temperature, it is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (30/70). 300 mg (50%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][CH:14]([F:31])[C:15]1[N:20]=[CH:19][C:18]([C:21]2([CH2:29][NH2:30])[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]2)=[CH:17][N:16]=1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:21]1([C:18]2[CH:17]=[N:16][C:15]([CH:14]([F:31])[F:13])=[N:20][CH:19]=2)[CH2:26][CH2:25][C:24]([F:27])([F:28])[CH2:23][CH2:22]1)=[O:6]
Reactant: COc1cccc(C(=O)O)c1Cl
Reactant: NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1
Product: COc1cccc(C(=O)NCC2(c3cnc(C(F)F)nc3)CCC(F)(F)CC2)c1Cl

Procedure:
From 2-chloro-3-methoxybenzoic acid and (1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine. LCMS (MH+): m/z=446.1, tR (minutes, Method F)=2.82
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].C(N(CC)CC)C.[OH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:11]
Reactant: Oc1cccnc1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Oc1cccnc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (3.79 g, 0.01 mole) and triethyl amine (1.01 g, 0.01 mole) in toluene (50 ml) was added 3-hydroxypyridine (0.95 g, 0.01 mole). The temperature exothermed to 33° C. and there was an immediate precipitate. The reaction was then refluxed for 24 hours, cooled to room temperature and the triethylamine hydrochloride precipitate collected by filtration. The toluene solution was washed with dilute sodium hydroxide solution and then with saturated sodium chloride solution. After drying and evaporation of the solvent there was obtained 3.1 g of brown oil which solidified. This was triturated with hexane and the solid filtered and dried to give a tan product, m.p. 65°-68° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[O:28]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)c1ccc2ncnc(Oc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
Example 5, Alternative Preparation, Step 1: A sample of 4-chloro-6-(trifluoromethyl)quinazoline (3.25 g, 13.97 mmol) was dissolved in acetonitrile (60 mL) under N2 atmosphere. The resultant cloudy solution was charged with Cs2CO3 (6.83 g, 20.96 mmol) and phenol (1.578 g, 16.77 mmol) and stirred at room temperature. After ˜65 hours, the reaction was filtered to remove the solids. The organic phase was concentrated in vacuo to yield an orange solid. The material was purified by automated flash chromatography (80 g silica gel) using 1:3 EtOAc/Hexanes as the eluant to afford the desired 4-phenoxy-6-(trifluoromethyl)quinazoline as a crystalline solid. LC/MS found (M+H)+=291.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1.[CH3:11][N:12]([CH3:26])[C:13]1[CH:14]=[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]2=[C:17]([CH:25]=1)[C:18](S)=[N:19]3>C(O)C>[CH3:11][N:12]([CH3:26])[C:13]1[CH:14]=[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]2=[C:17]([CH:25]=1)[C:18]([NH:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[N:19]3
Reactant: NCCCc1cccnc1
Reactant: CN(C)c1cc2c3c(cccc3c1)N=C2S
Solvent: CCO
Product: CN(C)c1cc2c3c(cccc3c1)N=C2NCCCc1cccnc1

Procedure:
The reaction of equivalent molar quantities of 3-(3-pyridinyl)propanamine, 4-dimethylaminobenz(cd)indol-2thiol, and mercuric acetate in refluxing ethanol, under the conditions of Example 55 leads to the formation of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-])=[C:6]([CH3:9])[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>C(OCC)(=O)C>[C:15]([O:18][CH2:9][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(Cl)[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cccc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of the 6-chloro-2-methylpyridine-N-oxide prepared in step 1 in 750 mL acetic anhydride was heated at reflux overnight. The reaction was cooled to ambient temperature and poured into saturated aqueous sodium bicarbonate. The mixture was diluted with ethyl acetate and filtered through celite. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated. The residue was azeotroped with benzene to remove any remaining acetic acid. 2-acetoxymethyl-6-chloropyridine was isolated by vacuum distillation (b.p. 105°-110° C./1.3 torr).