Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C1([C:14]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:15]=2[CH:16]=CC(O)=O)C=CC=CC=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:34])C=CC=CC=1.[C:44]1([CH3:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:44]1([C:50]([CH2:16][C:15]2[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[CH:14]=2)=[O:34])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1cccc(C=CC(=O)O)c1-c1ccccc1
Reactant: Cc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(CC(=O)c2ccccc2)c1
Reaction time: 24 h
Yield: 38 %

Procedure:
A mixture of m-anisaldehyde (29.37 g, 21.57 mmol) and phenylacetic acid (29.37 g, 21.57 mmol) in acetic anhydride (200 mL) was stirred with triethylamine (30 mL). The reaction mixture was heated at reflux for 4 h, then cooled to 80-90° C., then water (500 mL) was added slowly. Oil separated, which upon stirring and cooling produced a light orange solid. The solid was filtered, washed with water and dried to afford 35 g (64%) of the desired 2-phenyl-m-methoxycinnamic acid. Triethylamine (17 mL) was added to a mixture of 2-phenyl-m-methoxycinnamic acid (30.0 g, 118.0 mmol) and diphenylphosphorylazide (28 mL) in toluene (200 mL) at 0° C. After the reaction had been complete (3 h), the reaction mixture was quenched with concentrated HCl (20 mL) and extracted with ether (200 mL). The organic layer was concentrated and the residue was stirred further with Conc. HCl (100 mL) and dioxane (100 mL) for 24 h. The reaction mixture was diluted with water (400 mL) and was extracted with ether (3×300 mL). The ether layer was dried and concentrated to afford 10 g (38%) of the desired product. 1H NMR (CDCl3) δ 7.99-8.01 (m, 2H), 7.42-7.54 (m, 5H), 6.77-6.85 (m, 3H), 4.24 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[C:6]([CH3:17])[C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@@H:30]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33])(=O)=O.O>CC1CCCO1>[CH3:17][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1)[O:18][C@H:30]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCC[C@@H](OS(C)(=O)=O)c1ccc(C(=O)OC)cc1
Reactant: Cc1cc(O)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC1CCCO1
Solvent: O
Product: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)OC)cc1
Temperature: 65 °C

Procedure:
To a solution of 3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (intermediate 26) (12.6 g, 49 mmol) in 2-methyltetrahydrofuran (70 mL) was added cesium carbonate (23.5 g, 72 mmol) and the solution of mesylate from step 2. The reaction was heated to 65° C. for 5 h. The reaction was then cooled to room temperature and water (80 mL) was added. The aq. layer was split and the organic solution was used in the next step without isolation.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:9])[CH2:7][CH3:8].C(O[CH:15]([N:19]([CH3:21])[CH3:20])N(C)C)(C)(C)C>>[CH3:21][N:19]([CH3:20])[CH:15]=[C:7]([CH3:8])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCC(=O)c1cccs1
Product: CC(=CN(C)C)C(=O)c1cccs1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
1-(Thiophen-2-yl)propan-1-one (0.15 g, 1.069 mmol) was treated with tert-butoxybis-(dimethylamino)methane (0.5 mL) and the mixture stirred at 55° C. overnight. The volatiles were removed in vacuo and the residual liquid was azeotroped with toluene. The resulting residue was dissolved in ethyl acetate and passed through a plug of silica gel. The filtrate was concentrated and placed under vacuum to afford a thick yellow oil. Yield=0.2 g. MS (M+H)+ 196.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:34]([Cl:35])=[CH:33][C:11]3[N:12]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]([O:15][CH:16]4[CH2:19][CH:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17]4)=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[OH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[Cl:35][C:34]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[OH:36])=[CH:7][CH:6]=2)=[CH:9][C:10]2[N:14]=[C:13]([O:15][CH:16]3[CH2:19][CH:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17]3)[N:12]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:11]=2[CH:33]=1
Reactant: CCOC(=O)C1CC(Oc2nc3cc(-c4ccc(Br)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Reactant: OB(O)c1ccccc1O
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: CN(C)C=O
Product: CCOC(=O)C1CC(Oc2nc3cc(-c4ccc(-c5ccccc5O)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Temperature: 120 °C

Procedure:
A 50 mL flask was charged with ethyl 3-{[5-(4-bromophenyl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl]oxy}cyclobutanecarboxylate (150 mg, 0.259 mmol), 2-hydroxybenzeneboronic acid, pinacol ester (60 mg, 0.273 mmol), Pd(PPh3)4 (20 mg, 0.017 mmol), DMF (5 mL), and 1 M aqueous K2CO3 (0.78 ml, 0.780 mmol). The reaction was degassed with N2 and then heated at 120° C. for 1 hour. Then the volatiles were removed in vacuo and the residue partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over (MgSO4), filtered, and concentrated. Chromatography of the resulting residue over silica (preparative TLC) eluting with 45% EtOAc/hexanes afforded the desired product. LC-MS: calculated for C32H37ClN2O5Si 592.22, observed m/e: 593.05 (M+H)+ (Rt 2.67/4 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Aldrich, 2.01 g, 10 mmol) in tetrahydrofura n (15 mL) at —78° C., n-BuLi (2.5 M in hexanes, 11 mmol, 4.4 mL) was added dropwise. After the addition, 4-fluoro nitrobenzene (1.41 g, 10 mmol) was added and the solution was gradually warmed to room temperature and stirred for 2 hours. The solution was poured into water and the mixture was extracted with ether. The extract was dried (Na2SO4) and concentrated to give the crude which was chromatographed (20% ethyl acetate/hexanes) to yield a pale yellow oil. 1.34 g.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: Nc1ccccc1
Reactant: Cc1ncc([N+](=O)[O-])cc1C(=O)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: Cc1ncc([N+](=O)[O-])cc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-5-nitronicotinic acid (364 mg, 2 mmol), aniline (186 mg, 2 mmol) and DIEA (774 mg, 6 mmol) in DMF (6 mL) is added HATU (798 mg, 2.1 mmol). The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed by rotary evaporation and the crude product is purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to afford -methyl-5-nitro-N-phenylnicotinamide as a light green solid. MS m/z 258.1 (M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH:20]([OH:24])[CH2:21][CH2:22][OH:23])[CH:13]=1.C(N(CC)CC)C.CO>ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCCC(O)CCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(O)CCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.4 %

Procedure:
Solid para-toluenesulfonyl chloride (1.26 g) was added to a solution of (±)-5-(3-pyridyl)-1,3-pentanediol (1.20 g) and triethylamine (1.11 ml) in anhydrous dichloromethane (20 ml) at -30° C. under nitrogen. The solution was allowed to warm to room temperature over 1 hour and stirring was continued for 24 hours. Methanol (1 ml) was added and the solution concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexane:acetone (3:2) to give the sub-title compound as an oil (1.05 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:19]([C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C(CBr)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
1-[5-Bromo-2-hydroxyphenyl]ethanone (13.4 g) was dissolved in N,N-dimethylformamide (300 mL). To the reaction mixture were added potassium carbonate (25.8 g) and 2-bromo-1-cyclohexylethanone (19.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was filtered through celite, water (200 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (150 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (9.3 mL) was added to the solution at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid (70 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitate was washed with diisopropyl ether to give the title object compound (15.4 g, 77%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BrH:12]>CS(C)=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: Br
Solvent: CS(C)=O
Product: Cc1cc(Br)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (10.0 g, 66 mmol) in DMSO was added 48% aqueous hydrogen bromide (18.0 ml). The reaction solution was stirred at room temperature overnight and then quenched with saturated sodium bicarbonate. The resultant mixture was stirred overnight. Precipitation was collected by filtration and dried in vacuo to give 2-amino-5-bromo-3-methylbenzoic acid (13.0 g, 85%) as a pink solid: 1H NMR (500 MHz, DMSO) δ 7.69 (d, J=1.0 Hz, 1H), 7.33 (d, J=1.0 Hz, 1H), 2.10 (s, 3H); MS (ESI+) m/z 231 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)/[C:7](=[O:19])[N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si](C)(C)C)=[CH:4][CH:3]=1.[CH2:28]([O:31][C:32]1[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=1[CH:39]=[N:40][C:41]([O:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[CH2:42])[CH:29]=[CH2:30]>C1(C)C=CC=CC=1>[CH2:28]([O:31][C:32]1[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=1[CH:39]1[C:6]2([C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:19])[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH2:42][C:41](=[O:43])[NH:40]1)[CH:29]=[CH2:30].[CH3:11][O:12][CH:13]([Si:44]([CH3:45])([CH3:46])[CH3:47])[CH3:14]
Reactant: C=CCOc1ccc(I)cc1C=NC(=C)O[Si](C)(C)C
Reactant: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: C=CCOc1ccc(I)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: COC(C)[Si](C)(C)C
Yield: 44.4 %

Procedure:
In a manner similar to the method described in example 1d, E/Z-6-chloro-3-(3-chlorobenzylidene)-1-(2-trimethylsilanyl-ethoxymethyl-1,3-dihydro-indole-2-one (6 g, 15 mmol) prepared in example 1b was reacted with 1-(2-allyloxy-5-iodo-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (26 g, 65 mmol) prepared in example 18b in toluene (100 mL) to give racemic (2′R, 3R, 4′S)-2′-(2-allyloxy-5-iodo-phenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxo spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (5 g, 44%)
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[O:7])[CH2:3]1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>>[CH3:17][S:14]([C:12]1[CH:11]=[CH:10][C:9]([O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[C:8]([C:6]([N:4]2[CH2:3][CH:2]([O:1][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:5]2)=[O:7])[CH:13]=1)(=[O:15])=[O:16]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1)C(F)(F)F
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Yield: 5 %

Procedure:
Prepared in analogy to Example 21(b) from (3-hydroxy-azetidin-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone and 4-fluorobenzotrifluoride. The crude material was purified by flash chromatography (methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 5%). MS (m/e): 512.5 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:12])[NH:9][CH:10](O)[C:6]=2[C:5]([F:13])=[C:4]([F:14])[N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CC(OC)(C)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:12])[NH:9][CH2:10][C:6]=2[C:5]([F:13])=[C:4]([F:14])[N:3]=1
Reactant: O=C1NC(O)c2c(F)c(F)nc(Cl)c21
Agent: CC[SiH](CC)CC
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(F)c(F)nc(Cl)c21
Temperature: 60 °C
Yield: 82 %

Procedure:
To an inert 50 mL round bottom flask with magnetic stirring was added 4-chloro-6,7-difluoro-1-hydroxy-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (4.39 g, 19.90 mmol) and trifluoroacetic acid (18.40 mL, 239 mmol). The solids were suspended with stirring and triethylsilane (7.95 mL, 49.8 mmol) was added. The reaction mixture was heated to 60° C. and stirred for 30 minutes at that temperature. The reaction mixture was subsequently cooled to room temperature and added dropwise to MTBE (88 mL) to produce a white precipitate. The suspension was cooled to 5° C. for 45 minutes. The solids were filtered, washed with MTBE (20 mL) and air dried on the filter to afford the title compound (3.336 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.58 (s, 2H), 9.13 (s br, 1H).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3]1.[C:13]12([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:13]12([CH2:23][C:24]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[CH:3]3)=[O:25])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1cnc2ccccc2c1=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.8 %

Procedure:
3-Amino-4(3H)-quinazolinone (158.7 mg, 0.99 mmol) was dissolved in chloroform (5 mL). 1-Adamantaneacetyl chloride (204.1 mg, 0.96 mmol) and pyridine (100 μL, 1.24 mmol) were added, and the reaction was allowed to stir at ambient temperature for 22 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white solid (264.9 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.69 (m, 12H), 1.96 (br s, 3H), 7.58-7.63 (m, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.87-7.93 (m, 1H), 8.18-8.20 (m, 2H), 11.12 (s, 1H) ppm; MS (DCI/NH3) m/z 338 (M+H)+; Elemental Analysis: Calculated for C20H23N3O2: C, 71.19; H, 6.87; N, 12.45. Found: C, 71.11; H, 6.85; N, 12.43.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH3:23])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[S:15][C:16]=1[CH2:17][OH:18].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]1([CH3:23])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[S:15][C:16]=1[CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1-c1c(CO)sc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1c(COS(C)(=O)=O)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Methanesulfonyl chloride (158 μL, 2.04 mmol) was added dropwise to a solution of (3-o-tolylbenzo[b]thiophen-2-yl)methanol (432 mg, 1.70 mmol) and DIPEA (385 μL, 2.21 mmol) in anhydrous DCM (10 mL) at RT. Stirring at RT was continued for 18 h then the reaction mixture was washed with water, dried (Na2SO4) and concentrated in vacuo affording the title compound as a brown oil (424 mg, 75%). 1H NMR (DMSO-d6, 400 MHz): δ 8.05 (1H, d, J=8.04 Hz), 7.45-7.40 (3H, m), 7.38-7.32 (2H, m), 7.21 (1H, d, J=7.40 Hz), 7.12 (1H, d, J=7.98 Hz), 4.82 (1H, d, J=12.41 Hz), 4.76 (1H, d, J=12.41 Hz), 3.32 (3H, s), 1.99 (3H, s)
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2O1.[Cl:64]C1C=CC(B(O)O)=CC=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][C:32]([Cl:64])=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Product: Clc1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and 4-chlorophenylboronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-chlorophenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.99 (bs, 1H), 8.05 (bs, 1H), 7.85 (s, 1H), 7.50-7.42 (m, 4H), 7.23 (bs, 1H), 7.10 (dd, 1H, J=2.4 and 8.7 Hz), 7.06 (t, 1H, J=2.4 Hz), 7.00-6.94 (m, 1H), 6.73 (d, 1H, J=8.7 Hz), 6.63 (d, 1H, J=8.7 Hz); LCMS: ret. time: 16.12 min.; purity: 86%; MS (m/e): 490 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:15][CH:14]([NH:16][CH3:17])[CH2:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:18][C:19]1[N:20]=[C:21]([C:26]([OH:28])=O)[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([N:16]([CH3:17])[CH:14]2[CH2:13][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[CH2:15]2)=[O:28])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1sc(N2CC(NC)C2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC(N(C)C(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 90.1 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 4-methyl-2-[3-(methylamino)azetidin-1-yl]-1,3-thiazole-5-carboxylate obtained in Example (226b) (114 mg, 0.45 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (78 mg, 0.45 mmol), WSC hydrochloride (256 mg, 1.34 mmol), 1-hydroxybenzotriazole (60 mg, 0.45 mmol) and N-methylmorpholine (0.10 mL, 0.89 mmol), to obtain 167 mg of the title compound as a white solid (91%).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([CH2:24]O)=[N:20]3)[CH:13]=[N:14][C:15]=2[O:16][CH3:17])[CH:7]=[CH:8][CH:9]=1.COCCN(S(F)(F)[F:37])CCOC>C(Cl)Cl>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH3:17])=[N:14][CH:13]=[C:12]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([CH2:24][F:37])=[N:20]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ncc(Cn2cnc(CO)n2)cc1-c1cccc(OC(F)F)c1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: COc1ncc(Cn2cnc(CF)n2)cc1-c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of (1-((5-(3-(difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol (Example 202, 40.0 mg, 0.11 mmol) in DCM (3 mL) was added Deoxo-Fluor® (36.64 mg, 0.17 mmol). The mixture was stirred at room temperature for 2 h. The material was adsorbed on silica and purified (FCC, SiO2, 20-100% EtOAc/hexanes) to afford the title compound (11 mg, 27%). 1H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.49-7.36 (m, 2H), 7.33 (t, J=2.2 Hz, 1H), 7.16-7.11 (m, 1H), 7.04-6.65 (m, 1H), 5.44 (s, 2H), 5.41-5.28 (m, 2H), 3.96 (s, 3H). [M+H]=365.21.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].[H-].[Na+].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>C1(C)C=CC=CC=1.C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[C:12]#[N:13]
Reactant: N#CCc1ccc2ccccc2n1
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC(c1ccc2ccccc2n1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
To a solution of 2-quinolylacetonitrile (14.5 g, 86.2 mmol) in toluene (200 mL) was added slowly NaH (6.9 g of 60% oil dispersion, 172 mmol). The reaction mixture was stirred at ambient temperature for 15 min at which point H2 evolution was no longer evident. A solution of 2-chloroquinoline (14.1 g, 86.2 mmol) in toluene (150 mL) was added to the reaction flask, and the reaction mixture was then heated at reflux for 18 h. The reaction mixture was cooled to ambient temperature, diluted with THF, and quenched with H2O. The organic solution was washed with 1N HCl (200 mL), saturated aqueous solution of NaHCO3, and brine. An orange solid precipitated from the organic layer and was isolated via vacuum filtration. The mother liquor was dried over MgSO4 and the volatile components were removed with a rotary evaporator. The resulting solid was combined with the orange powder isolated via filtration. The solid was washed with a mixture of ether and heptane to afford 14.7 g (57.6%) of product. Results of 1H NMR spectroscopy and electrospray mass spectroscopy are consistent with the product. 1H NMR (300 MHz, CDCl3): δ 7.36 (m, 2H), 7.57 (d, J=9.1 Hz, 2H), 7.64 (m, 4H), 7.73 (d, J=8.8 Hz, 2H), 7.86 (d, J=9.1 Hz, 2H).