Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH:21]([CH3:23])[CH3:22])[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.[OH-].[Li+].O>C1COCC1>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C@@H:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH:21]([CH3:23])[CH3:22])[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:3]([OH:35])=[O:2])=[O:34]
Reactant: COC(=O)[C@H](C/C=C/c1ccc(N(c2ncccn2)C(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(c1ccc(/C=C/C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1)c1ncccn1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 0.1 %

Procedure:
A solution of (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (526.2 g) in THF (15 ml) was cooled to 0° C. To the solution, 0.1N aqueous lithium hydroxide solution (15.4 ml) was added, and the resulting mixture was stirred at 0° C. for 40 minutes. Water (20 ml) was added to the reaction solution and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid in small portions thereto, and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (420.7 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])[C@H:3]1[C:14]([O:16]C(C)(C)C)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(=C)C>C1(C)C=CC=CC=1>[CH3:21][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])[C@H:3]1[C:14]([OH:16])=[O:15]
Reactant: CCCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: C=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Yield: 74.8 %

Procedure:
A mixture of 3.3 g of the product of Step B, 350 mg of p-toluene sulfonic acid and 40 ml of toluene was stirred at reflux until isobutylene evolution ceased (about 40 minutes) and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 75-25-1 cyclohexane-ethyl acetate-acetic acid mixture to obtain 2 g of (1R,cis)2,2-dimethyl-3-[Z-2-(n-butoxycarbonyl)-ethenyl]-cyclopropane-carboxylic acid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.[N:24]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25]1.C1(S(N)(=O)=O)CC1>>[N:24]1([S:28]([NH:31][C:9](=[O:10])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([O:14][CH2:15][C:16]3([C:20]([F:21])([F:23])[F:22])[CH2:17][CH2:18][CH2:19]3)=[CH:6][C:7]=2[F:13])(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: NS(=O)(=O)C1CC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCC2)cc1F

Procedure:
Following the procedure as described in Example 218 step 5 and making variations as required to replace trans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclobutyl)methoxy)benzoic acid and to replace azetidine-1-sulfonamide with cyclopropanesulfonamide, the title compound was obtained as colorless solid (0.09 g, 47%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 7.17-7.09 (m, 2H), 4.34 (s, 2H), 3.12-3.04 (m, 1H), 2.38-2.27 (m, 2H), 2.19-2.09 (m, 3H), 2.03-1.94 (m, 2H), 1.14-1.10 (m, 4H), 0.90-0.84 (m, 2H), 0.70-0.64 (m, 2H); MS (ES+) m/z 436.1 (M+1); MS (ES−) m/z 434.2 (M−1).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].[P:12](OCCCCCCOC(=O)C(C)=C)([OH:15])([OH:14])=[O:13]>>[P:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([OH:15])([OH:14])=[O:13]
Reactant: C=C(C)C(=O)OCCCCO
Reactant: C=C(C)C(=O)OCCCCCCOP(=O)(O)O
Product: C=C(C)C(=O)OCCCCOP(=O)(O)O

Procedure:
The same procedures as in Example 4-1 were carried out except for using 4-methacryloyloxybutan-1-ol (47.4 g, 0.30 mole) as a starting material (ester compound) for First Dropping Step of Amine of item (2) of Example 4-1, and the reactions were carried out with the same molar ratios and procedures on and after item (2) of Example 4-1, to give 4-methacryloyloxybutyl dihydrogenphosphate (Compound 1e). The light transmittance and the electric conductivity of the resulting phosphate monomer, and the number of days for gelation of the dental adhesive were evaluated in the same manner as in Example 4-1. The results are summarized in Table 11.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[I:15])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:18][CH2:19][C@@H:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][NH:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:10]=[N:11][C:12]([N:21]2[CH2:22][C@H:23]([OH:25])[CH2:24][C@H:20]2[CH2:19][OH:18])=[CH:13][C:14]=1[I:15])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Reactant: OC[C@@H]1C[C@@H](O)CN1
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1I
Temperature: 130 °C
Reaction time: 32 h
Yield: 48 %

Procedure:
A mixture of 26.5 g (71.8 mmol) (6-chloro-4-iodo-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester and 25.4 g (144 mmol) (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine in 260 ml dimethyl sulfoxide was stirred at 130° C. for 32 h. The reaction mixture was concentrated in vacuo, treated with 200 ml 2 N sodium carbonate solution and extracted with three 200-ml portions of ethyl acetate. The organic layers were washed with 200 ml 2 N sodium carbonate solution and 200 ml brine and dried over sodium sulfate. Flash chromatography gave 15.5 g (48%) of the title compound as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:17])[CH3:16])[CH:10]=2)=[CH:4][C:3]=1[N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[O:27]=[C:28]1[NH:32][C:31](=[O:33])[CH:30]([CH2:34][C:35]2[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41](O)=[O:42])=[CH:37][CH:36]=2)[S:29]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[CH3:17][N:15]([CH3:16])[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[CH2:40][O:39][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][CH:30]3[S:29][C:28](=[O:27])[NH:32][C:31]3=[O:33])=[CH:45][CH:44]=2)=[C:3]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:4]=1
Reactant: CN(C)c1cccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c1
Yield: 97.3 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-dimethylaminophenoxy)phenyl]-N-methylcarbamate (1.00 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.57 g), diethyl cyanophosphonate (0.91 g), triethylamine (0.57 g) and anhydrous tetrahydrofuran (40 ml) and the reaction mixture was purified to give the desired product (1.69 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([OH:45])=O)=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.[NH2:60][C@@H:61]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH:72]([CH3:74])[CH3:73])=[CH:67][CH:66]=1)[C:62]#[N:63]>>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:60][C@H:61]([C:62]#[N:63])[CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH:72]([CH3:74])[CH3:73])=[CH:67][CH:66]=3)=[O:45])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CC(C)Oc1ccc(C[C@H](N)C#N)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C[C@@H](C#N)NC(=O)c2ccc3c(N4CCN(C)CC4)nc(N)nc3c2)cc1
Reaction time: 0.17 h
Yield: 12.1 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (42 mg, 0.11 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) and N,N-diisopropylethylamine (24 uL, 0.14 mmol). The reaction was stirred for 10 min., and the (2S)-2-amino-3-(4-isopropoxyphenyl)propanenitrile (28 mg, 0.14 mmol) was added. The reaction was stirred for 1 h. at r.t., and was purified by RP-HPLC (pH=2) to afford the desired product (4 mg, 10%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=474.1.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([CH2:9][OH:10])[S:7][CH:8]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>C(Cl)Cl.O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[S:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)cs1
Agent: N#N
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), (4-bromo-thiophen-2-yl)-methanol (3.97 g, 20.57 mmol) was dissolved in dry CH2Cl2 (50 mL). tert-Butyldimethylsilyl chloride (3.59 g, 22.63 mmol) was added at rt followed by imidazole (1.56 g, 22.63 mmol). The reaction mixture was stirred at rt for 1 h. Water was added, the layers were separated and the org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (hept) gave the title compound as a colorless oil. TLC: rf (100:1 hept-EA)=0.44. LC-MS-conditions 02: tR=1.21 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:31]1[CH2:32][CH2:33][CH:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])[CH2:30]1)=[O:15]
Reactant: Clc1ccccc1C1CCNC1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(2-chlorophenyl)pyrrolidine oxalate (16.3 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (4.0 mg). MS (pos) m/z 387.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-:31].[Na+]>CC(C)=O>[N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([I:31])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(I)CC1

Procedure:
A mixture of 1-(p-nitrobenzyloxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine (14.78 g) in acetone (222 ml) and sodium iodide (12.71 g) was refluxed for 23 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was diluted with ethyl acetate and the extract was washed successively with aqueous 10% sodium sulfite and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to give 1-(p-nitrobenzyloxycarbonyl)-4-iodopiperidine.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23]Cl>CN(C)C(=O)C>[CH2:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH2:23][C:22]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:21]=1[Cl:20])[CH:2]=[CH2:3]
Reactant: C=CCNc1ncnc2nc[nH]c12
Reactant: Fc1cccc(Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCNc1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 58 %

Procedure:
In a procedure analogous to that of Example 9, by using 1.75 g of 6-allylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.84 g of 6-allylamino-9-(2-chloro-6-fluorobenzyl)purine as colorless needles (yield: 58%), m.p. 163°-164° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:23][CH2:22]1
Reactant: CC1CCNCC1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2)CC1
Yield: 71.7 %

Procedure:
A mixture of 0.07 mole (20.7 g) of 2,4'-dichloro-5-nitrobenzophenone, of 0.1 mole (11.4 ml) of 4-methyl-piperidine and of 10 g of K2CO3 in 100 ml of anhydrous ethanol is heated to reflux for 3 hours. After cooling of the reaction medium, the precipitate obtained is filtered, washed with water, dried then recrystallized from ethanol. 18 g (yield=71.7%) of the expected product are thus obtained. M.p.=136° C.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:33]=[CH:32][C:17]([O:18][C@H:19]3[CH2:22][C@H:21]([CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:20]3)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[N:8]1([CH2:13][C:14]2[CH:33]=[CH:32][C:17]([O:18][C@H:19]3[CH2:22][C@H:21]([CH2:23][NH2:24])[CH2:20]3)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (3.5 mL, 49 mmol) was added to a solution of example 395, tert-Butyl ({trans-3-[4-(Pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)carbamate (2.16 g, 6 mmol) in dichloromethane (20 mL). The reaction mass was stirred at room temperature for 2 h and evaporated in vacuo. The residue was diluted with water (50 mL), and the obtained solution was extracted with CH2Cl2. The organic layer was discarded. The aqueous one was alkalized with 10 N NaOH to pH 12 and extracted with CHCl3 (3×50 mL). The combined extracts were dried and evaporated to afford compound 10 (aap327) (1.4 g, 91%) as a yellow oil. LCMS-data: M+H 261.2, 262.2 (calc 260.38). 1H NMR-data (DMSO-d6): 7.17 (d, 2H, Ph, J=8.6 Hz); 6.72 (d, 2H, Ph, J=8.6 Hz); 4.65-4.76 (m, 1H); 3.47 (s, 3H, CH2); 2.63 (d, 2H, CH2, J=6.6 Hz); 2.32-2.42 (m, 4H); 2.18-2.28 (m, 3H); 2.00-2.13 (m, 2H); 1.60-1.72 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14].[C:15](O)(=[O:17])[CH3:16]>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][C:8]=2[O:7][C:6]1=[O:14]
Reactant: O=c1oc2ccccc2n1CCCCl
Reactant: CC(=O)O
Product: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Temperature: 100 °C

Procedure:
A mixture of N-(3-chloropropyl)-2-benzoxazolinone (8.5 g, 40 mmol), polyphosphoric acid (100 g), and acetic acid (2.4 g, 2.3 ml, 40 mmol), was stirred and heated at 100° C. for 2 hours. The hot solution was poured into ice-water to deposit a yellow gum. The mixture was extracted with dichloromethane, and insolubles were filtered. The dichloromethane extract was washed with water, dried (K2CO3), and concentrated to afford 6.4 g of a slightly green solid. This was recrystallized from ethanol (95%) to yield N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone as a brown solid, 3.5 g, m.p.=100°-103° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11](OC)=[C:10](OC)[CH:9]=1)=[O:7].[C:23]1(OC)[C:24](=CC=[CH:29][CH:30]=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C1C2C(=CC=CC=2)C=CC=1C(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]2[C:10](=[CH:24][CH:23]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7]
Reactant: COc1ccccc1OC
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(Cl)c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc3ccccc3c2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (2.6 mL, 20 mmol), aluminum chloride (2.9 g, 22 mmol) and 2-naphthoyl chloride (3.9 g, 20 mmol) with a reaction time of 4 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 4.52 g (77%) of the product as a white solid: mp 120-121.5° C.; 1H NMR (CDCl3) δ8.24 (s, 1 H), 8.03-7.84 (m, 4 H), 7.68-7.40 (m, 4 H), 7.00-6.87 (m, 1 H), 3.97 (s, 3 H), 3.95 (s, 3 H); 13C NMR (CDCl3) δ195.5, 153.0, 135.5, 134.9, 132.2, 131.0, 130.4, 129.2, 128.1, 128.0, 127.8, 126.7, 125.9, 125.4, 112.2, 109.8, 56.1, 56.0; Anal. Calcd for C19H16O3. Theoretical: C, 78.06; H, 5.52. Found: C, 77.73; H, 5.69.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.[CH:46]([C:49]1[CH:50]=[C:51]([NH2:57])[CH:52]=[N:53][C:54]=1[O:55][CH3:56])([CH3:48])[CH3:47].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:46]([C:49]1[CH:50]=[C:51]([NH:57][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[N:9]=3)=[CH:6][C:5]([C@H:34]([N:36]3[CH2:37][CH2:38][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:40][CH2:41]3)[CH3:35])=[CH:4][N:3]=2)[CH:52]=[N:53][C:54]=1[O:55][CH3:56])([CH3:48])[CH3:47]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(C(C)C)c3)n2)cc1
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a solution of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Examples 145 and 146) 0.380 g, 0.598 mmol) and 5-isopropyl-6-methoxypyridin-3-amine (0.149 g, 0.897 mmol) in 3 mL THF at 0° C. was added lithium bis(trimethylsilyl)amide 1.0 M in THF (2.69 mL, 2.69 mmol) dropwise via syringe over 1 min. The dark red reaction was allowed to stir 30 min and was quenched by addition of saturated aq. NH4Cl. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 20-100% EtOAc/hexane followed by 10% MeOH/EtOAc to elute the desired product. The product-containing fractions were concentrated to afford (R)-4-(2-(5-isopropyl-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.097 g, 0.124 mmol, 21% yield) as a red oil. m/z (ESI, +ve ion) 782 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H), 8.70 (d, J=2.2 Hz, 1H), 8.15-8.29 (m, 2H), 7.77 (d, J=2.5 Hz, 1H), 7.15-7.25 (m, 4H), 6.77-6.96 (m, 4H), 4.71-4.97 (m, 4H), 3.95 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.53 (q, J=6.8 Hz, 1H), 3.11-3.20 (m, 5H), 2.69 (s, 3H), 2.47-2.63 (m, 7H), 1.38 (d, J=6.7 Hz, 3H), 1.21 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1>>[F:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:13][CH:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(F)c2)C1
Yield: 83.9 %

Procedure:
The title compound (D37) (1.26 g) was prepared according to the experimental procedure described in Description 34 starting from 1-Boc-3-pyrrolidinol (1 g, 5.34 mmol) and 3-Fluorophenol (0.478 ml, 5.34 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14]Br)=[CH:9][CH:10]=1)=[O:4].[OH:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14][O:26][N:27]2[C:31](=[O:32])[C:30]3[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]2=[O:37])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(OCCCBr)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCCCON2C(=O)c3ccccc3C2=O)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 68.6 %

Procedure:
This compound was produced using similar methods as those used in Step 1, example 4, starting with 6-(3-bromo-propoxy)-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.60 g, 1.46 mmol), N-hydroxyphthalimide (0.30 g, 1.86 mmol) and N,N-diisopropylethylamine (0.36 g, 2.88 mmol). The crude material was purified by flash chromatography through silica gel using methylene chloride to give 6-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-propoxy]-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.50 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6); δ 8.01 (dd, 1H), 7.88 (d, 1H), 7.84 (s, 4H), 7.74 (s, 4H), 7.31 (d, 1H), 4.31 (t, 2H), 4.22 (t, 2H), 3.82 (s, 3H), 2.09 (m, 2H).
Reaction SMILES: O.[CH3:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[S:5][CH:4]=1.[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[I:14][C:4]1[S:5][C:6]2[NH:7][C:8](=[O:13])[C:9](=[O:12])[NH:10][C:11]=2[C:3]=1[CH3:2]
Reactant: O=I(=O)Cl
Reactant: Cc1csc2[nH]c(=O)c(=O)[nH]c12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(I)sc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 24.7 %

Procedure:
7-Methylthieno[2,3-b)pyrazine-2,3(1H,4H)-dione hydrate (1.0 g, 5.0 mmol) was suspended in 60 ml of acetic acid and benzyltrimethylammonium dichloroiodate 95% (2.1 g, 5.75 mmol) and zinc chloride (1.64 g, 12.0 mmol) was added. The mixture was stirred for 4.5 h at room temperature, the precipitate was filtered off, washed with acetic acid, water and dried. The crude compound (1.13 g) was recrystallized from acetic acid/water and twice from ethanol to give 0.38 g (24%) of the title compound. Decomp. above 240° C. 1H-NMR (DMSO-D6, δ): 2.12 (s, 3H), 11.98 (s, 1H), 12.22 (s, 1H).