Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[C:17]2[O:16][CH2:15][CH2:14][C:13]([C:18]([O:20]C)=O)=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)([OH:6])=[O:5].Cl.[NH2:23][C:24]([NH2:26])=[NH:25].Cl>CO.CN(C)C=O.O>[C:4]([C:7]1[C:17]2[O:16][CH2:15][CH2:14][C:13]([C:18]([NH:25][C:24]([NH2:26])=[NH:23])=[O:20])=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)([OH:6])=[O:5]
Reactant: N=C(N)N
Reactant: COC(=O)C1=Cc2cccc(C(=O)O)c2OCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: N=C(N)NC(=O)C1=Cc2cccc(C(=O)O)c2OCC1
Reaction time: 18 h
Yield: 66.7 %

Procedure:
Under nitrogen atmosphere, 28% sodium methoxide in methanol (5.5 ml) was added to a solution of methyl 2,3-dihydro-9-carboxy-1-benzoxepin-4-carboxylate (1.5 g) and guanidine hydrochloride (2.9 g) in N,N-dimethylformamide (15 ml) at ambient temperature. The mixture was stirred at the same temperature for 18 hours. The reaction mixture was poured into water and the mixture was adjusted to pH 6.5 with 6N hydrochloric acid. The isolated precipitate was collected by filtration to give (2,3-dihydro-9-carboxy-1-benzoxepin-4-carbonyl)guanidine (1.11 g).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].C[C:16]1[CH:25]=[C:24](C)[CH:23]=[C:22]2[C:17]=1[CH2:18][C:19](=[O:57])[CH:20]([C:27]1[CH:32]=[C:31](OCC3C=CC=CC=3)[C:30](OCC3C=CC=CC=3)=[C:29](OCC3C=CC=CC=3)[CH:28]=1)[O:21]2.O1C2C(=CC=CC=2)CC(O)C1C1C=CC=CC=1>>[O:21]1[C:22]2[C:17](=[CH:16][CH:25]=[CH:24][CH:23]=2)[CH2:18][C@H:19]([OH:57])[C@@H:20]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(C)c2c(c1)OC(c1cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c1)C(=O)C2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OC1Cc2ccccc2OC1c1ccccc1
Agent: [Li+]
Product: O[C@H]1Cc2ccccc2O[C@H]1c1ccccc1

Procedure:
Preparation of (2,3-Cis)-5,7-dimethyl-2-(3,4,5-tribenzyloxyphenyl)chroman-3-ol (30): The cis 3-flavanol 30 was synthesized by the stereoselective L-selectride reduction of the 3-flavanone 29 in the same manner as given for 3-flavanol 23 (Scheme 3). The final product was obtained as a colorless oil (62% yield), after flash chromatography on silica gel using 20% of ethyl acetate in hexanes. 1H NMR (300 MHz, CDCl3): δ 1.73 (s, 1H, OH), 2.20 (s, 3H, CH3, 2.27 (s, 3H, CH3), 2.83 (d, J=17.1 Hz, 1H, 4-H), 2.95 (dd, J=4.2, 17.1 Hz, 1H, 4-H), 4.23–4.28 (m, 1H, 3-H), 4.87 (s, 1H, 2-H), 5.06 (s, 2H, OCH2Ph), 5.13 (s, 4H, OCH2Ph), 6.66 (s, 1H, 8-H), 6.68 (s, 1H, 6-H), 6.81 (s, 2H, 2′,6′-H), 7.25–7.43 (m, 15H, Ar—H). MS (ESI, positive ion) 595 (M+Na), 1167 (2M+Na).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC[C@H]1CN>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][C@H:23]2[CH2:32][NH2:33])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: NC[C@@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@H]2CN)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidin-2-ylmethanamine. MS(m/e): 400.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:21]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:25]([CH:21]3[CH2:24][CH2:23][CH2:22]3)=[O:26])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCC2)CC1
Reaction time: 2 h
Yield: 22 %

Procedure:
1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.063 g, 0.22 mmol, from Example 47, Step 1) was combined with cyclobutanecarboxylic acid chloride (0.037 mL, 0.32 mmol) and triethylamine (0.090 mL, 0.64 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and then concentrated. The resulted residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (18 mg, 22%). LCMS calculated for C20H23ClN3O2 (M+H)+: m/z=372.1; Found: 372.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][CH3:14].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
Dissolve 4-bromo-benzenethiol (2.0 g, 10.6 mmol) in dry dimethylformamide (50 mL) and cool to 0° C. under nitrogen. Add sodium hydride (305 mg, 12.7 mmol) in portions. After the vigorous gas evolution stops, add 1-bromo-propane (1.4 mL, 15.9 mmol) and stir the reaction mixture overnight at room temperature. Slowly pour the reaction into water (400 mL) and extract with diethyl ether (2×150 mL). Wash the combined organic layers with water (100 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo to yield 2.7 g of 1-bromo-4-propylsulfanyl-benzene (quantitative yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C)nc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C)nc3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M218) (260 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (137 mg, 66%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[C:2]=[O:3].[CH3:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]1[N:31]=[CH:32][N:33]=[CH:34][C:25]2=1.CCN(C(C)C)C(C)C>C1COCC1.CO>[CH3:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)=[O:3])=[CH:17][C:16]=1[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]1[N:31]=[CH:32][N:33]=[CH:34][C:25]2=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-c1ccc2[nH]c3ncncc3c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc2[nH]c3ncncc3c2c1
Temperature: 25 °C

Procedure:
To 1-isocyanato-3-(trifluoromethyl)benzene (9.8 μl, 0.070 mmol) was added a solution of 4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)aniline (17.5 mg, 0.064 mmol) and DIPEA (16 μL, 0.089 mmol) in THF (0.4 mL). The reaction was stirred at ambient temperature until LCMS indicated complete reaction, typically 16 hours. The reaction mixture was diluted to a total of 2 mL with THF and MeOH and purified by preparative LCMS to recover the product as a TFA salt (17.1 mg, 46.6%). 1H NMR (300 MHz, DMSO): δ 13.1 (bs, 1H), 9.66 (s, 1H), 9.15 (s, 2H), 8.92 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.72 (d, 1H), 7.62 (dd, 1H), 7.4-7.6 (m, 3H), 7.2-7.4 (m, 3H), 2.21 (s, 3H). MS (EI) m/z=462 (M+H).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.Cl[C:15]1[N:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>O1CCCC1.CO>[Cl:25][C:22]1[CH:23]=[N:24][C:15]([N:5]2[CH2:6][CH:3]([OH:2])[CH2:4]2)=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: OC1CNC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)cnc1N1CC(O)C1
Temperature: 75 °C
Yield: 76.6 %

Procedure:
To a mixture of 3-Hydroxyazetidine hydrochloride (37.17 g, 0.339 mol) and triethylamine (70.93 ml, 0.508 mol) in tetrahydrofuran/methanol (840/280 ml) Methyl 2,5-dichloronicotinate (70 g, 0.339 mol) was added and the resulting mixture was heated at 75° C. for 4 hours then at 62° C. overnight. 3-Hydroxyazetidine hydrochloride (3.7 g, 0.03 mol) and triethylamine (23.60 ml, 0.16 mol) were added and the reaction mixture was further heated at 80° C. for 28 h. Solvents were evaporated in vacuo. The residue was taken in dichloromethane (400 ml) and water (500 ml). The formed solid was filtered, washed with water (500 ml) and dried in vacuum to afford a first batch of the title compound (D62) (63 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([NH2:15])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]=2[NH2:15]
Reactant: BrCc1cccc(Br)c1
Reactant: COCCOc1nc(N)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2ncn(Cc3cccc(Br)c3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2-methoxyethoxy)-9H-purin-6-amine (15) (1.0 g, 4.78 mmol), 3-bromobenzyl bromide (1.5 g, 6.00 mmol) and anhydrous potassium carbonate (0.85 g, 6.15 mmol) were combined in DMF (15 mL) and stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried with sodium sulfate and the solvent was removed under vacuum. The resulting residue was triturated with a mixture of diethylether and ethyl acetate (4:1) and filtered. 9-(3-bromobenzyl)-2-(2-methoxyethoxy)-9H-purin-6-amine, Compound (39) (0.77 g, 43%) was obtained as a yellowish solid. 1H-NMR (DMSO) δ: 8.07 (s, 1H), 7.57 (s, 1H), 7.52-7.46 (m, 1H), 7.34-7.22 (m, 4H), 5.26 (s, 2H), 4.32 (t, J=4.5 Hz, 2H), 3.60 (t, J=4.5 Hz, 2H), 3.27 (s, 3H). MS: 378/380 (MH+)
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[Cl:25][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(Cl)c(Cl)c1
Reactant: CCNCC
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(Cl)c(Cl)c1

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(3,4-dichlorophenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diethylamine to give ethyl 4-(3,4-dichlorophenyl)-2-(N,N-diethylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 157°-158° C.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].N1C=CC=CC=1.[C:34]([CH2:38][C:39](Cl)=[O:40])([CH3:37])([CH3:36])[CH3:35]>ClCCl>[CH3:35][C:34]([CH3:37])([CH3:36])[CH2:38][C:39]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:4]2[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=3)(=[O:20])=[O:19])=[CH:26][CH:25]=1)=[O:40]
Reactant: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC(=O)CC(C)(C)C)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A stirred solution of 4-[(6-ethyl-8-fluorophenanthridin-5(6H)-yl)sulfonyl]phenol (Example 40, Step d, 0.05 g, 0.13 mmol) in dichloromethane (2 mL) was treated sequentially with pyridine (0.04 mL, 0.52 mmol) and t-butylacetyl chloride (0.04 mL, 0.26 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, sodium bicarbonate solution (50 mL). The separated aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient) to yield the title compound as a white solid (0.05 g, 71%), m.p. 128° C.;
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C@H:14]([NH2:18])([CH2:16][CH3:17])[CH3:15].CCOC(C)=O.CCCCCC>O1CCOCC1>[C@H:14]([NH:18][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=2[N:6]=1)([CH2:16][CH3:17])[CH3:15]
Reactant: N#CCc1ccc2nc(Br)sc2c1
Reactant: CC[C@@H](C)N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@@H](C)Nc1nc2ccc(CC#N)cc2s1
Temperature: 135 °C
Yield: 69.7 %

Procedure:
A mixture of 2-(2-bromobenzo[d]thiazol-6-yl)acetonitrile (2.00 g, 7.90 mmol) and (R)-sec-butylamine (4.0 mL, 39.4 mmol) in 1,4-dioxane (30 mL) was heated at 135° C. in a sealed bottle for 3.5 hr. The excess (R)-sec-butylamine and 1,4-Dioxane were removed under vacuum. The residue was diluted with AcOEt (150 mL), washed successively with saturated NaHCO3 solution (twice) and brine, and dried over anhydrous MgSO4. The title compound (1.35 g, 70% yield) was isolated as a light orange oil by ISCO (40% AcOEt/hexane).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[OH:8])[CH2:2][CH2:3][CH3:4].[C:11]([CH2:13][C:14](O)=[O:15])#[N:12].CN(C=O)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:5][C:6]([CH:7]([O:8][C:14](=[O:15])[CH2:13][C:11]#[N:12])[CH3:9])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(C)O
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)C(C)OC(=O)CC#N

Procedure:
A mixture of 292.32 g of butyllactate, 204.14 g of cyanoacetic acid, and 14.66 g of 4-dimethylaminopyridine (DMAP) in 2000 ml of CH2Cl2 was stirred in a 3 L three-neck round bottom flask equipped with a mechanical stirrer. About 50 ml of N-N′-dimethylformide (DMF) was added to make a clear solution. The above clear solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (495.19 g in 500 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as light yellow solid.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[CH:8]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:21])=[CH:18][C:19]=2[F:20])=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[C:10]([OH:25])[CH:9]=1>CO>[CH3:2][O:23][C:22]([C:11]1[CH:12]=[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:21])=[CH:18][C:19]=2[F:20])[CH:8]=[CH:9][C:10]=1[OH:25])=[O:24]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
Compounds 32 and 33 were prepared according to Scheme 6. TMS-diazomethane (5.87 mL, 11.75 mmol, 2 M solution in hexane) was added to a solution of diflunisal (1.03 g, 4.11 mmol) in MeOH (10 mL) and stirred at rt for 5 h. Upon completion, the reaction was concentrated in vacuo and the residue was purified by flash chromatography (10:1 hexane:ethyl acetate) to afford 32 (774 mg, 71%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.97 (dd, 1H, J=2.2, 1.3 Hz), 7.59 (dt, 1H, J=8.8, 2.1 Hz), 7.36 (dq, 1H, J=7.7, 1.5 Hz), 7.48 (td, 1H, J=7.8, 1.7 Hz), 7.38 (dddd, 1H, J=8.8, 6.4 Hz), 7.05 (d, 1H, J=8.7 Hz), 6.93 (m, 1H), 6.90 (ddd, 1H, J=10.6, 8.9, 2.5 Hz), 3.96 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 170.6, 163.6, 161.3, 158.5, 136.4, 131.2, 130.3, 126.2, 124.2, 118.0, 112.6, 111.8, 104.6, 52.6, 124.2. HRFABMS calculated for C14H10F2O3 (M+) 264.0596, found 264.0598. Normal phase HPLC retention time: 6.9 min. Reverse phase HPLC retention time: 14.7 min. >99% pure.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:15]1[N:19]=[CH:18][N:17]2[CH2:20][CH2:21][C:22](=[O:23])[C:16]=12.Cl.ClCCl>O1CCCC1>[OH:23][C:22]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[C:16]2[N:17]([CH:18]=[N:19][CH:15]=2)[CH2:20][CH2:21]1
Reactant: O=C1CCn2cncc21
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCn3cncc32)cc1
Reaction time: 0.25 h

Procedure:
A solution of 8.18 mmol of 4-iodobenzonitrile [3058-39-7] in 20 ml of tetrahydrofuran at −20° C. is admixed dropwise with 8.18 mmol of isopropylmagnesium chloride (2M in tetrahydrofuran) and the reaction mixture is subsequently stirred for 15 minutes. A mixture of 4.09 mmol of 5,6-dihydropyrrolo[1,2-c]imidazol-7-one [426219-43-4] in 5 ml of tetrahydrofuran is added. After 1 hour the reaction mixture is poured into 1:1 1N HCl/dichloromethane and the phases are separated. The aqueous phase is rendered basic with saturated sodium hydrogen carbonate solution, stirred thoroughly, extracted with tert-butyl methyl ether (in order to separate unreacted ketone) and then extracted with dichloromethane (3×). The combined dichloromethane phases are dried with sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as a white foam. Rf=0.20 (dichloromethane/ammonia (2M in EtOH) 95:5), Rt=3.81 (Gradient I).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.Cl[Si](CC)(CC)CC.C([Li])(CC)C.[F:25][C:26]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>C1COCC1>[F:25][C:26]1[CH:33]=[C:32]([CH:34]([OH:35])[C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: Cn1ccnc1
Reactant: N#Cc1ccc(C=O)cc1F
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1-Methylimidazole (15.88 mL, 0.199 mol), dissolved in anhydrous THF (500 mL) in flame-dried glassware under Ar, was cooled to −78° C. and treated with n-butyl lithium (1.6M in hexane)(124 mL, 0.199 mol) via syringe. After stirring for 1 hr chlorotriethylsilane (33.4 mL, 0.199 mol) was added and the reaction mixture was left to warm to ambient temperature overnight. The THF was removed in vacuo with gentle warming, and the residue was redissolved in dry THF (500 mL), cooled to −78° C., and treated with sec-butyl lithium (1.3M in cyclohexane) (153 mL, 0.199 mol) dropwise. After 1 hr this solution was cannulated into a solution of 2-fluoro-4-formylbenzonitrile (27 g, 0.181 mol) in THF (200 mL). After 15 min the cooling bath was removed, the mixture was stirred for 2 hr at ambient temperature, then was quenched with saturated NH4Cl solution. After 15 min 10% HCl was added to pH 3. After 0.5 hr the THF was removed in vacuo, the mixture was made basic with solid Na2CO3 and extracted with EtOAc (3×200 mL). The organics were combined, washed with 10% HCl (3×), the aqueous acidic layers combined, made basic with solid Na2CO3, extracted with EtOAc (3×), the organics combined, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[S:10][C:11]([C:17]3[C:22]([F:23])=[CH:21][C:20]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:19][C:18]=3[F:28])=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][C:31](B(O)O)=[N:30]1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:28][C:18]1[CH:19]=[C:20]([C:24]([OH:27])([CH3:26])[CH3:25])[CH:21]=[C:22]([F:23])[C:17]=1[C:11]1[S:10][C:9]([NH:8][C:5]2[N:6]=[N:7][C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)=[CH:3][CH:4]=2)=[C:13]([C:14]([NH2:16])=[O:15])[CH:12]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(Cl)nn3)s2)c(F)c1
Reactant: OB(O)c1cc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(-c4ccn[nH]4)nn3)s2)c(F)c1

Procedure:
To a solution of 2-[(6-chloropyridazin-3-yl)amino]-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (64 mg, 0.15 mmol) in THF (3 ml), was added 1H-pyrazol-3-yl boronic acid (34 mg, 0.30 mmol), and sodium bicarbonate (0.38 ml, 0.75 mmol, 2 M). Palladium tetrakis triphenylphosphine (35 mg, 0.03 mmol) was added last and the vial was purged with nitrogen for 5 minutes. The crude product was washed with 3:1 chloroform:isopropanol and water. The resulting organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Purification by column chromatography yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[C:5]([NH2:7])=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[CH2:5][NH2:7]
Reactant: NC(=O)c1cc(Cl)cc(CO)c1
Solvent: C1CCOC1
Product: NCc1cc(Cl)cc(CO)c1

Procedure:
Step N5. To 3-chloro-5-(hydroxymethyl)benzamide (0.7 g, 3.77 mmol) in THF (20 mL) was added borane-dimethylsulfide complex (0.9 g, 11.8 mmol) slowly. The mixture was refluxed for 20 hours. Excess borane reagent was quenched with methanol and solvent was removed by rotovap. The resulting residue was purified by column with dichloromethane/methanol (1:1) as the eluant. 3-chloro-5-(hydroxymethyl)benzylamine was obtained in white solid (240 mg, 37%). 1H NMR (300 MHz, CD3OD): δ 3.81 (s, 2H), 4.61 (s, 2H), 7.25 (s, 1H), 7.28 (s, 1H), 7.59, 7.30 (s, 1H). MH+=172.08.