Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][NH2:15])[CH2:11][C@H:10]2[C:16]([NH:18][CH2:19][CH:20]([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])=[O:8])=[CH:3][CH:2]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([NH:15][N:14]=[C:12]1[CH2:13][N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:6][CH:5]=2)=[O:8])[C@H:10]([C:16]([NH:18][CH2:19][CH:20]([OH:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:17])[CH2:11]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: NN=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Solvent: c1ccncc1
Product: CC(=O)NN=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 8 h

Procedure:
A hydrazono pyrrolidine derivative obtained by the general method outlined in Example 17, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide (51 mg, 0.111 mmol) was dissolved in pyridine (1 mL). Acetic anhydride (3 eq, 32 μl, 0.35 mmol) was added, and the mixture was stirred overnight. The solvent was evaporated and the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (20:1) to collect the desired product, e.g. (2S,4EZ)-4-(acetylhydrazono)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two isomers as a colorless solid in 73% yield (98.4% purity by HPLC).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]([OH:47])[CH3:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO.[Pd]>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH:45]([OH:47])[CH3:46])[CH:27]=2
Reactant: CC(O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)c1ccc2cc(N)c(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl [2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(1-hydroxyethyl)quinolin-3-yl]carbamate (0.020 g, 0.031 mmol) and 10% Pd on carbon (0.100 g, 0.0940 mmol) in MeOH (20 mL) was hydrogenated under 20 psi of H2 for 2 h. The catalyst was removed by vacuum filtration, and the clear filtrate was concentrated under reduced pressure. To the residue, a mixture of DCM (1.0 mL) and TFA (1.0 mL, 13 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure and the residue was diluted with MeOH and neutralized with small amount of NH4OH. The mixture was filtered and purified by prep LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound as white powder. LCMS calc. for C22H27N6O2 (M+H)+: m/z=407.3. Found: 407.2. 1H NMR (500 MHz, DMSO) δ 9.40 (s, 1H), 8.26 (d, J=5.3 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.54 (s, 1H), 7.51 (dd, J=8.7, 1.5 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 6.84 (s, 2H), 5.29 (d, J=3.8 Hz, 1H), 4.89-4.79 (m, 1H), 3.20 (d, J=10.9 Hz, 1H), 3.16 (d, J=4.2 Hz, 1H), 3.15-3.06 (m, 1H), 2.71-2.63 (m, 1H), 2.47-2.41 (m, 1H), 1.95 (d, J=12.9 Hz, 1H), 1.92-1.82 (m, 2H), 1.41 (d, 3H), 1.27-1.16 (m, 1H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[NH:28][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cn2)nc(Cl)c1Cl
Product: COc1cccc(Nc2nc(-c3ccc(C(F)(F)F)cn3)nc(C)c2Cl)c1

Procedure:
The title compound was prepared from 4,5-dichloro-6-methyl-2-[5-(trifluoromethyl)-2-pyridinyl]pyrimidine (100 mg, 0.325 mmol) and m-anisidine (37 μl, 0.325 mmol) similar to Example 11 as a pale white solid (26 mg, 20%). 1H NMR (CDCl3): 9.05 (dd, J=0.8, 1.4 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.06 (dd, J=2.3, 8.3 Hz, 1H), 7.57 (t, J=2.3 Hz, 1H), 7.36 (s, 1H), 7.31 (t, J=8.1 Hz, 1H), 7.18–7.14 (m, 1H), 6.75–6.72 (m, 1H), 3.88 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [NH2:1][NH2:2].[NH2:3]/[C:4](/C(Cl)(Cl)Cl)=[C:5](/[C:11]#[N:12])\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>CN(C=O)C>[NH2:3][C:4]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([NH2:12])[NH:2][N:1]=1
Reactant: NN
Reactant: CCOC(=O)/C(C#N)=C(\N)C(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)n[nH]c1N
Temperature: 100 °C
Yield: 58 %

Procedure:
Hydrazine (2.19 mL, 70 mmol) was added to (Z)-ethyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate (15.0 g, 58 mmol) in DMF (50 mL). The reaction mixture was heated to 100° C. for 1 hr, then cooled to room temperature. The DMF was removed in vacuo, then the residue was slurried in a 95:5 mixture of DCM:2M methanolic ammonia solution. The resulting precipitate was filtered off, washed with a 95:5 mixture of DCM:MeOH, and dried under vacuum to afford 5.72 g (58%) of ethyl 3,5-diamino-1H-pyrazole-4-carboxylate as a white solid. 1H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 5.28 (br, 4H), 4.14 (q, J=7.1, 2H), 1.33-1.15 (t, J=7.1, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@@H:7]([OH:8])[C@H:6]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[C:5]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:4]=2[O:3]1>C(O)C.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:4]2[O:3][C:2]([CH3:22])([CH3:1])[C@@H:7]([OH:8])[C@H:6]([N:9]3[CH2:13][CH2:12][CH2:11][C:10]3=[O:14])[C:5]=2[CH:15]=1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N2CCCC2=O)[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2ccc(N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Reaction time: 18 h

Procedure:
To a solution of 8.0 g (0.025 mol) of trans-3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-oxopyrrolidin-1-yl)-2H-1-benzopyran-3-ol (U.S. Pat. No. 4,647,670) in 800 mL of ethanol is added 2.8 g of 10% Pd/C, and the reaction mixture is stirred under a hydrogen atmosphere for 18 h. The reaction mixture is filtered, evaporated, and the resulting oil subjected to chromatography on silica gel utilizing 4% methanol in dichloromethane as eluent. The eluates are analyzed by thin layer chromatography, and the appropriate fractions are combined and evaporated to afford the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[C:14]2[N:13]=[C:12]([CH3:28])[CH:11]=1>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]3[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[C:14]2[N:13]=[C:12]([CH3:28])[CH:11]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(-c2cnn3c(Cl)cc(C)nc23)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc2c(-c3c(C)cc(C)cc3C)cnn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
A solution of 3-pentanol (140 mg, 1.5 mmol) in 1 ml of dry THF was treated with 60% sodium hydride in oil (28 mg, 0.7 mmol) and stirred at room temperature for 10 min. A solution of 7-chloro-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (75 mg, 0.262 mmol) in 1 ml of dry THF was added and the resulting mixture was heated at reflux for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give the crude material. The residue was purified through silica gel column chromatography using 3:7 chcloroform:hexane as eluent to give 75 mg (88%) of the title compound. 1H NMR (CDCl3) ä 7.97(s, 1H), 6.97(s, 2H), 6.03(s, 1H), 4.56(m, 1H), 2.53(s, 3H), 2.32(s, 3H), 2.13(s, 6H), 2.10(m, 4H), 1.09(t, 6H) ppm.
Reaction SMILES: C([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[NH2:33]>ClCCl>[NH2:8][C@H:9]([CH3:10])[C:11]([NH:33][C:32]1[CH:34]=[C:35]([CH3:37])[CH:36]=[C:30]([CH3:29])[CH:31]=1)=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cc(C)cc(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(C)cc(NC(=O)[C@@H](C)N)c1
Yield: 138.9 %

Procedure:
This compound is an intermediate for the synthesis of the compound of example 6. To the solution of N-Boc-L-alanine (1.000 g, 5.28 mmol) in dichloromethane (10 ml) is added dicyclohexylcarbodiimide (DCC, 1,094 g, 5.28 mmol) in dichloromethane (10 ml). To this mixture is added 3,5-dimethylaniline (0.640 g, 5.28 mmol) in dichloromethane (10 ml). After 16 h of mixing at room temperature, the dicyclohexylurea is recovered on a filter, the filtrate is dry evaporated. 1.41 g (91%) of white powder are obtained, mp 134°–136° C. The material is dissolved in trifluoroacetic acid (5 ml) and the solution is mixed for 30 min. at room temperature. The solution is dry evaporated. The product is dissolved in methanol (10 ml). To this solution dichloromethane (30 ml) is added and the solution is washed with a solution of 1 M (30 ml) sodium carbonate and water (2×30 ml). The organic phase is dry evaporated. 0.64 g (63%) of product are obtained in the form of a brown oil.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])[C:3](Cl)=[O:4].[CH2:16]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1)[CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)C(C)C)(C)C>>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])[C:3]([N:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1)=[O:4]
Reactant: CN(C(=O)Cl)c1ccccc1C(F)(F)F
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)N(C)c1ccccc1C(F)(F)F
Yield: 26 %

Procedure:
Following the procedure of Example 7, Step B, N-methyl-N-[2-(trifluoromethyl)phenyl]carbamoyl chloride (from Example 7, Step A) was reacted with 1.2 equivalents of N-pentyl-N-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]amine (from Step D) in the presence of N,N-diisopropylethylamine. Flash chromatography of the crude product on silica gel (elution with 4:1 and then 3:1 hexane-EtOAc) gave two major products. Concentration of fractions containing the pure second product afforded a 26% yield of the title compound as a stiff foam, homogeneous by TLC in 3:1 EtOAc); FAB-MS m/e 772 (M+Li)+. The 1H NMR spectrum indicated the presence of two isomeric forms.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[S:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.Cl.[SH:15][CH2:16][CH2:17][NH2:18].[OH-].[K+]>O>[NH2:18][CH2:17][CH2:16][S:15][CH2:2][CH2:3][NH:4][C:5](=[S:13])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1
Reactant: S=C(CC1CCCCO1)NCCCl
Reactant: NCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NCCSCCNC(=S)CC1CCCCO1
Yield: 190.5 %

Procedure:
N-(2-Chloroethyl)-tetrahydropyran-2-ylthioacetamide (0.48 g, 2 mmol), 2-mercaptoethylamine hydrochloride (0.34 g, 3 mmol), potassium hydroxide (0.34 g, 6 mmol) methanol (5 cm3) and water (1 cm3) were mixed and heated at 75 C for 2 h. After cooling, 111acetone (50 cm3) was added and the resulting mixture filtered. Volatile components were removed from the filtrate under reduced pressure to give a pale yellow residue. This material was purified firstly by chromatography on silica using a mixture of ethyl acetate, methanol, and aqueous ammonia (90:9:1) as the eluant and then by reverse phase h.p.l.c. using aqueous acetonitrile as the eluant. The purified N-[2-(2-aminoethylthio)ethyl]-tetrahydropyran-2-ylthioacetamid e (1 g, 32%) was obtained as a pale yellow oil.
Reaction SMILES: C1(C[O:5][C:6](=[O:32])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)=[C:14]([Cl:31])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[CH3:10][CH:9]([CH3:11])[CH2:8][CH:7]([C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[C:14]([Cl:31])[CH:13]=1)[C:6]([OH:32])=[O:5]
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc(Cl)c(Cl)c2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc(Cl)c(Cl)c2)c(OCC2CC2)c1
Yield: 90.5 %

Procedure:
4-Methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid cyclopropylmethyl ester (0.37 g, 0.75 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure to give 4-methyl-2-(2,3′,4′-trichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-pentanoic acid as a white solid (0.30 g, 90%). M.p.=118-119° C. 1H NMR (300 MHz, CDCl3/TMS): δ 9.70 (br s, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.53 (dd, J=8.2, 1.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.78 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 2.02-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.47 (m, 2H), 0.24-0.16 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.4, 157.0, 140.3, 134.8, 133.9, 132.5, 131.6, 131.3, 129.9, 129.6, 127.0, 121.5, 111.1, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=1)[CH3:15])=O)(C)(C)C.[O:32]=[C:33]1[O:37][CH:36]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43]C=2)[CH:35]([NH:47][C:48](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:49])[CH2:34]1>>[CH2:39]([O:38][CH:36]1[CH:35]([NH:47][C:48]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=2)[CH3:15])=[O:49])[CH2:34][C:33](=[O:32])[O:37]1)[C:40]1[CH:41]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(=O)Nc1c(Cl)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1Cl
Yield: 72 %

Procedure:
Prepared from 1-[2-(4-acetylamino-3,5-dichloro-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and syn-(2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 230 mg of title compound (72% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.36 (d, 0.6H), 1.47 (d, 2.4H), 1.68-2.47 (m, 4H), 2.23 (s, 3H), 2.60-3.15 (m, 2H), 3.40-3.90 (m, 2H), 4.15-4.95 (m, 5H), 5.68 (d, 0.8H), 5.84 (d, 0.2H), 7.20-7.98 (m, 7H). Analytical HPLC: 13.07 min. LC-MS (ES+): m/e=605.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2([C:43](O)=[O:44])[CH2:42][CH2:41][CH2:40]2)=[O:38])=[CH:32][CH:31]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:43]([C:39]4([C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=5)=[O:38])[CH2:42][CH2:41][CH2:40]4)=[O:44])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CCC1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CCC4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 10.7 %

Procedure:
4-(Dimethylaminomethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (114 mg) was dissolved in N,N-dimethylformamide (4.0 ml). 1-(4-Fluorophenylcarbamoyl)cyclobutanecarboxylic acid (279 mg), triethylamine (0.164 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (520 mg) were added under a nitrogen atmosphere at room temperature and stirred overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with 0.5N hydrochloric acid (4 times), water, a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of a mixture of diethyl ether and heptane (1:3) to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (19.1 mg, 11%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10][C:11]1[C:16](Cl)=[N:15][CH:14]=[CH:13][N:12]=1)[CH2:5][OH:6].Cl.N>CO>[N:15]1[C:16]2[NH:1][C:2]3[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][CH:14]=1
Reactant: Nc1cc(CO)ccc1Sc1nccnc1Cl
Agent: Cl
Agent: N
Solvent: CO
Product: OCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 0 °C
Yield: 96.9 %

Procedure:
To 1.47 g of 3-amino-4-[(3-chloropyrazin-2-yl)thio]benzyl alcohol were added 20 ml of methanol and 0.45 ml of conc. hydrochloric acid and the resulting mixture was heated under reflux for 30 minutes. Then the reaction mixture was made alkaline by adding ice-water and aqueous ammonia. The precipitate was collected by filtration and dried to thereby give 1.23 g of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:28]=[O:29])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[CH:20]=[N:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:20]=[N:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=4[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([OH:29])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: COc1cc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)cn1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(OC)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.23 mL, 0.69 mmol) was added to a stirred solution of 9-chloro-1-(6-methoxy-4-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (207 mg, 0.580 mmol) in tetrahydrofuran (5.0 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (141 mg, 0.364 mmol, 63%).
Reaction SMILES: O([C:8]([NH:10][C:11]1[N:16]=[C:15]([O:17][CH:18]([F:20])[F:19])[CH:14]=[C:13]([CH3:21])[N:12]=1)=[O:9])C1C=CC=CC=1.[CH2:22]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35])[CH3:23].N12CCCCC1C=NCCC2.Cl>C(#N)C.O.C(OCC)(=O)C>[CH2:22]([O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:37][C:8]([NH:10][C:11]1[N:16]=[C:15]([O:17][CH:18]([F:19])[F:20])[CH:14]=[C:13]([CH3:21])[N:12]=1)=[O:9])(=[O:35])=[O:36])[CH3:23]
Reactant: CCOCCOc1ccccc1S(N)(=O)=O
Reactant: Cc1cc(OC(F)F)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOCCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC(F)F)n1
Reaction time: 1 h

Procedure:
A solution of 3.5 g of 2-phenoxycarbonylamino-4-difluoromethoxy-6-methyl-pyrimidine (crude product) and 2.9 g of 2-(ethoxy-ethoxy)-benzenesulfonamide in 100 ml of absolute acetonitrile is decomposed with 1.8 g of 1,5-diazabicyclo[5.4.0]undec-5-ene; it is then stirred for 1 hour at 20° to 25° C., diluted with 500 ml of water and acidified with hydrochloric acid. The precipitated oil is taken up with 200 ml of ethyl acetate, dried over sodium sulfate and concentrated by evaporation. Crystallisation of the oily residue from diethyl ether and acetone yields, as colourless crystals, N-[2-(2-ethoxy-ethoxy)-phenyl-sulfonyl]-N'-(4-difluoromethoxy-6-methyl-pyrimidin-2-yl)-urea, m.p. 90° to 95° C. (decomposition); yield 2.7 g.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:22][CH:21]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>ClCCl.CO.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:3]=2)[CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:22][CH:21]=1
Reactant: O=C(Cn1ccnc1)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(N)cc1-c1ccc(F)cc1
Agent: [Ti+4]
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(NC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Titanium chloride (2.86 ml; 26 mmol) was added portionwise to a solution of methyl 4-amino-2-(4-fluorophenyl)benzoate (5 g; 20 mmol), 1-(4-fluorophenyl)-2-(imidazol-1-yl) ethanone (4.08 g; 20 mmol) and triethylamine (8.4 ml; 60 mmol) in dichloromethane (120 ml) at 0° C. under argon atmosphere. After stirring overnight at ambient temperature, sodium cyanoborohydride (1.4 g; 0.22 mmol) in solution in methanol (10 ml) was added at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature, treated with 5% aqueous sodium hydrogen carbonate solution, filtered and extracted with dichloromethane. After evaporation to dryness of the organic phase, the residue was purified by flash chromatography eluting with dichloromethane/ethanol 95/5 to give methyl 4-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylamino]-2-(4-fluorophenyl)benzoate. Yield 52%.