Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:11])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH:21]([C:26](O)=O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>O1CCOCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH:21]([C:26]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=3)[N:11]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: N=C(NO)c1ccc(F)cc1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Yield: 17.5 %

Procedure:
A mixture of N-hydroxy-4-fluoro-benzamidine (0.758 g, 4.92 mmol), 4-methyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (4.92 mmol), prepared as described in 62(B), EDCI.HCl (1.41 g, 7.38 mmol), HOBT (0.665 g, 4.92 mmol) and anhydrous triethylamine (1.38 mL, 9.84 mmol) in dioxane (80 mL) was stirred at room temperature for a week-end, under nitrogen atmosphere. Then, the reaction mixture was refluxed for 7 h and the solvent was evaporated under reduced pressure. The residue was diluted with water (50 mL) and ethyl acetate (50 mL), the phases were separated and the organic layer was washed sequentially with water (50 mL×2 times) and with NaOH 1N (50 mL×2 times). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil. Purification of the crude by flash chromatography (silica gel, eluent gradient: from hexane/ethyl acetate 8/2 to hexane/ethyl acetate 7/3) afforded 0.312 g of 3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [Si](OC[C@@H:10]([N:16](C)[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[Cl:28])=[O:18])C[C@@H](O)CO)(C(C)(C)C)(C)C.COC(OC)(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:28][C:22]1[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:17](=[O:18])[NH:16][CH3:10]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Product: CNC(=O)NCc1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the 1-((2S,4R)-1-(tert-butyldimethylsilyloxy)-4,5-dihydroxypentan-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea 1(4.5 g, 10.0 mmol) in DMF (170 mL) were added 2,2-dimethoxypropane (12.45 mL, 100.0 mmol) and PPTS (0.050 g, 0.02 mmol) at 0° C. After 1 h the reaction was warmed up to RT and stirred for an additional 2.5 h. The crude reaction mixture was then added into a saturated aqueous solution of NaHCO3 (350 mL) and extracted with EtOAc (3×300 mL). Combined organic layers were washed with Brine (2×400 mL) and dried over MgSO4. The solution was then concentrated to give 1-((S)-1-(tert-butyldimethylsilyloxy)-3-(R)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea, which was used without further purification. LRMS (M+H+) m/z 490.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=2[CH2:25][N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=2[CH2:25][N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: CC(=O)N(C)Cc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CC(=O)N(C)Cc1ccccc1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-benzyl]-N-methyl-acetamide was converted to N-{2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-benzyl}-N-methyl-acetamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.10 (s, 1H), 7.5 (m, 4H), 7.28 (d, 1H), 7.1 (m, 2H), 4.56 (s, 2H), 4.34 (t, 2H), 3.3 (s, 3H), 2.89 (s, 3H), 2.71 (t, 2H), 2.05 (s, 3H); MS (m/e) 481 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccc(Cl)cc2)nc(Cl)n1
Temperature: 90 °C
Yield: 9.6 %

Procedure:
2,4-Dichloro-6-methylpyrimidine (10 g, 61.3 mmol) and 4-chloroaniline (7.83 g, 61.3 mmol) were dissolved in acetonitrile (100 mL). Diisopropylethylamine (21.37 mL, 122.7 mmol) was added and heated to 90° C. for 4 days. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography with ethyl acetate-hexane as eluent to give (2-chloro-6-methyl-pyrimidin-4-yl)-(4-chloro-phenyl)-amine (1.5 g, 10%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6]C[CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[S:31])=[CH:25][C:24]=3[F:43])[CH:14]=2)=[N:11][CH:12]=1.O1CCOC1C1C=CC(C2SC3C(=NC=CC=3OC3C=CC(N)=CC=3F)C=2)=NC=1>>[O:1]1[CH2:6][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[S:31])=[CH:25][C:24]=3[F:43])[CH:14]=2)=[N:11][CH:12]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Agent: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Yield: 60 %

Procedure:
Following the procedure described above for the synthesis of compound 32 (Scheme 9) but substituting compound 31 for compound 38, title compound 39 was obtained in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.49 (s, 1H), 12.48 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 8.33 (dd, J=8.2, 0.8 Hz, 1H), 8.07-8.03 (m, 1H), 7.99 (dd, J=8.2, 2.2 Hz, 1H), 7.56-7.55 (m, 2H), 7.38 (dd, J=8.7, 5.6 Hz, 2H), 7.19 (t, J=9.0 Hz, 2H), 6.70 (d, J=5.5 Hz, 1H), 5.90 (s, 1H), 4.12-4.06 (m, 2H), 4.04-3.98 (m, 2H), 3.84 (s, 2H). MS (m/z): 605.1 (M+H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:9][O:10][C:11]2[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.[F:22][C:23]([F:34])([F:33])[C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26][CH2:25]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[CH3:3][C:4]1([CH2:9][O:10][C:11]2[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][N:6]([C:30]([C@H:27]2[CH2:26][CH2:25][C@H:24]([C:23]([F:22])([F:33])[F:34])[CH2:29][CH2:28]2)=[O:31])[CH2:5]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCOC(=O)c1ncccc1OCC1(C)CCNC1
Agent: Cl
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1ncccc1OCC1(C)CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using ethyl 3-((3-methylpyrrolidin-3-yl)methoxy)picolinate dihydrochloride (EXAMPLE 86, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:9](=S)[NH:10][N:11]=1)[CH2:4][CH2:5][CH3:6]>C(Cl)Cl>[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:9]([Cl:1])=[N:10][N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc([N+](=O)[O-])cc1
Reactant: ClCl
Solvent: ClCCl
Product: CCCCc1nnc(Cl)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
Chlorine gas was bubbled through a stirred solution of 5.00 g (17.1 mmole) of 5-n-butyl-2,4-dihydro-4-(4-nitrobenzyl)-3H-1,2,4-triazole-3-thione in 260 ml of dry CH2Cl2 for 1.5 hours. A precipitate formed after 10 minutes. (This material, which is not the desired final product, is not isolated). The reaction mixture was poured into 400 ml of ethyl acetate and washed with 3×500 ml of saturated NaHCO3 solution, 400 ml of H2O, and finally 400 ml of saturated NaCl solution. The ethyl acetate phase was dried over MgSO4, filtered, and concentrated. The residue was pre-absorbed onto silica gel by evaporation from methanol. This was added as a slurry to the top of a silica gel column, which was eluted with a gradient of 0-1% methanol in CH2Cl2. Concentration of pooled product fractions yielded 1.90 g (37%) of a yellow oil, which showed satisfactory purity by TLC in 19:1CH 2 Cl2 --MeOH and gave a positive Bellstein test for chlorine; mass spectrum (EI) m/e 294 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][OH:8])[C:5]([F:10])=[N:4][CH:3]=1
Reactant: O=Cc1cc(Br)cnc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Br)cnc1F
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a suspension of 5-bromo-2-fluoronicotinaldehyde (5.00 g, 24.51 mmol) in ethanol (125 mL) immersed in a room temperature bath to moderate any potential exotherm was added sodium borohydride (0.464 g, 12.26 mmol) in one portion. After 30 minutes at room temperature, LC/MS indicated clean, complete conversion to the product. The reaction was cooled to 0 C and quenched by the cautious addition of saturated ammonium chloride solution (effervescence). The reaction was concentrated and partitioned between water and ether. The etheral was washed with water (2×), then brine, dried over anhydrous magnesium sulfate and concentrated to give a yellow oil which solidified upon standing to give 4.66 g (92% yield) of title compound as yellow crystalline solid. 1H-NMR (CDCl3, 500 MHz) δ: 8.21 (s, 1H), 8.08 (ddd, J=8.3, 1.6, 0.8 Hz, 1H), 4.70-4.88 (m, 2H). Mass spec.: 206.0 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1(O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([C:14]([O:16][CH:19]1[CH2:18][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCc2ccccc21
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)OC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-2-methylalanine (2.00 g, 8.4 mmol) in DCM (10 ml) at 0° C. was added indanol (2.26 g, 16.9 mmol), EDCI (1.78 g, 9.3 mmol) and finally DMAP (103 mg, 0.8 mmol). The reaction mixture was warmed to RT and stirred for 18 hours. The reaction mixture was washed with 1M HCl (10 ml), sat. Na2CO3 (20 ml), dried (MgSO4) filtered and concentrated in vacuo to leave a brown oil. The crude product was purified by column chromatography (20% EtOAc in heptane) to yield the desired product as a white solid (2.26 g, 76%). LC/MS: m/z 354 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(O)C>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(NC(=O)CCC(=O)O)ccc21
Reaction time: 0.25 h

Procedure:
A mixture of 3.08 g (0.015 mol) of compound obtained in Example 4 and 1.5 g of succinic anhydride is heated until melted and kept for 15 minutes. After 4 hours at room temperature the reaction mixture is dissolved in hot ethanol; the title compound is obtained as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18]([OH:20])[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:10]=23)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18]([O:20][CH3:32])[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:10]=23)=[CH:4][CH:3]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)O)cc(F)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)OC)cc(F)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
To a solution of the alcohol of Step 1 (105 mg, 0.25 mmol) in DMF (5 mL) at 0° C. was added NaH (11 mg, 0.3 mmol). The reaction mixture was stirred at 0° C. for 20 minutes and MeI (51 mg, 0.4 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 30% EtOAc in Hexanes to provide 90 mg of the title compound as a white solid.
Reaction SMILES: [OH:1]N1C(=O)C2=CC=CC=C2C1=O.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.N1C=CC=C(C)C=1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:13]([OH:1])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=Cc1cccnc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: Cc1cccnc1
Solvent: CC(=O)O
Product: O=C(O)c1cccnc1

Procedure:
In the presence of an oxidation catalyst (N-hydroxyphthalimide (NHPI)) and a metal catalyst (cobalt acetate and manganese acetate) with nicotinaldehyde as a co-oxidizing agent, β-picoline was oxidized in acetic acid solvent at 140° C. and 2 MPa with air to produce nicotinic acid. From the reaction mixture, acetic acid was removed, to the condensate was added 2-ethylhexanol. The mixture was cooling-crystallized to 25° C. at atmospheric pressure and filtrated, and the residue washed with methanol and filtrated to separate nicotinic acid. The components in the mixture obtained by combining the filtrate and washing liquid were analyzed, and as a result, 9.4 g of nicotinic acid, 160 g of 2-ethylhexanol, 32 g of acetic acid, 63 g of β-picoline, 150 g of methanol, 0.5 g of N-hydroxyphthalimide (NHPI), 10 g of phthalic acid (PA), 8 g of phthalimide (PI), 2.5 g of phthalic anhydride (APA), 1.1 g of total cobalt, 1.1 g of total manganese were contained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]2[N:9]([CH2:27][CH3:28])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>>[CH2:27]([N:9]1[C:8]2[CH:29]=[CH:30][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH3:28]
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 62 %

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2.1 g) was prepared by following General Procedure E starting from 1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (3.5 g) and sodium hydroxide (2.0 N solution, 8.0 mL). LCMS: m/z 424; and 1H NMR (DMSO-d6, 400 MHz): δ 8.17 (1H, m), 7.96 (1H, m), 7.75 (1H, m), 7.88-7.85 (1H, m), 7.65-7.63 (1H, m), 7.59-7.57 (1H, m), 7.40-7.37 (1H, m), 4.26-4.25 (2H, q), 1.35-1.32 (3H, t) —COOH proton signal was not observed.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@H:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:18][C@H:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: CC(C)C[C@@H](N)CO
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)C[C@H](CO)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2R)-2-amino-4-methyl-1-pentanol (CAN 53448-09-2) as starting materials, LC-MS (UV peak area/ESI) 100%, 333.2165 (M+H)+.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:12][C@:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][C@H:14]1[CH:16]=[CH2:17].[CH:23]1[N:27]=[CH:26][N:25]([C:28](N2C=NC=C2)=[O:29])[CH:24]=1>C1COCC1>[N:25]1([C:28]([NH:12][C@:13]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][C@H:14]2[CH:16]=[CH2:17])=[O:29])[CH:24]=[CH:23][N:27]=[CH:26]1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)n1ccnc1)C(=O)OCC
Yield: 70 %

Procedure:
Under nitrogen, (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate tosylate salt (5 g, 1 eq.) and CDI (2.7 g, 1.1 eq.) were dissolved in THF (50 mL) containing TEA (2.3 mL, 1.1 eq.). The reaction mixture was then refluxed overnight. The solvent was removed under reduced pressure. The residue was dissolved in DCM, and washed twice with water. The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by chromatography on silica gel to yield compound 33 as pale yellow oil in 70% yield.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[C:11]1([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)=[CH:16][CH:15]=1)[CH2:3]2
Reactant: O=C1CN2CCC1CC2
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: Nc1ccc(-c2ccc(NC3CN4CCC3CC4)cc2)cc1
Reaction time: 0.33 h

Procedure:
3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) in acetic acid (25 mL) was treated with biphenyl-4,4′-diamine (Aldrich, 0.92 g, 5.0 mmol), Na2SO4 (anhydrous, Aldrich, 7.40 g, 50 mmol) and NaBH(OAc)3 (Aldrich, 3.16 g, 15 mmol) at ambient temperature for 15 hours. The reaction mixture was slowly poured into a flask containing 75 mL of saturated NaHCO3, stirred for 20 minutes, and extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with brine (2×20 mL). The organic phase was concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 80:20:4, Rf. 0.10) as a solid (0.98 g, yield, 67%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40-1.52 (m, 1H), 1.64-1.84 (m, 2H), 1.89-2.04 (m, 2H), 2.57 (ddd, J=13.9, 5.2, 2.1 Hz, 1H) 2.75-3.00 (m, 4H), 3.27-3.35 (m, 1H), 3.50-3.60 (m, 1H), 6.61-6.69 (m, 2H), 6.80-6.86 (m, 2H), 6.92-6.97 (m, 2H), 7.06-7.13 (m, 2H) ppm. MS (DCl/NH3) m/z 294 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]3)=[CH:37][CH:38]=2)[N:25]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 89 %

Procedure:
To a nitrogen de-gassed solution of methyl 2-(2-ethynylphenyl)acetate (I4: prepared according to the procedure of Peng, C. et al; Adv. Synth. Catal. 2008, 350, 2359-2364 or as detailed below) (0.114 g, 0.653 mmol) in dry DMF (6 mL) were added triethylamine (0.280 mL, 2.01 mmol) followed by tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.230 g, 0.502 mmol), triphenylphosphine (0.020 g, 0.075 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.035 g, 0.050 mmol) and CuI (0.014 g, 0.075 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-80% EtOAc in cyclohexane) to give the title compound (I5) (0.267 g, 89% yield) as an orange glassy solid; 1H NMR (400 MHz, d5-DMSO) δ 10.27 (br s, 1H), 8.76 (s, 1H), 7.65-7.49 (m, 4H), 7.49-7.38 (m, 2H), 6.95 (d, J=9.1 Hz, 2H), 3.94 (s, 2H), 3.61 (s, 3H), 3.51-3.42 (m, 4H), 3.09-3.00 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.67 min; m/z 596.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:17]=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.[I:18]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:11])[CH3:12])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)c[nH]c2n1
Yield: 80.6 %

Procedure:
A solution of N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide (101 g, 0.40 mol) in anhydrous THF (2 L) was treated with N-iodosuccinimide (98.9 g, 0.44 mol, 1.1 eq.) under N2 atmosphere at rt for 40 min. The solvent was evaporated, and the residue was taken up in CH2Cl2 (1.5 L), and washed with Na2SO3 (500 mL×3) and brine (300 mL×3). Evaporated and recrystallizion from MeOH gave the title product as a white powder (122 g, 81% yield, HPLC purity: 98.2%). tR: 6.19 min. 1H-NMR (DMSO-d6) δ 12.65 (br.s, 1H), 10.11 (br. s, 1H), 7.76 (d, 1H), 1.24 (s, 9H).