Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[C:3]1([C:9]2[CH:13]=[CH:12][N:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a slurry of 8g (0.2 mol) of sodium hydride in 100 mL of DMF at room temperature was added 23g (0.16 mol) of 3-phenylpyrazole. The mixture was stirred 1 hr and 17.8 mL (0.16 mol) of ethyl bromoacetate was added. The reaction was heated at about 100° C. for 2 hr, cooled, poured into water, extracted into methylene chloride, dried over magnesium sulfate and stripped. The resulting oil was chromatographed on silica gel HPLC using 25% ethyl acetate in hexane. The first, and major, component to elute was the 3-isomer. It was recrystallized from ether-hexane to yield 6.0g of ethyl 3-phenyl-1H-pyrazole-1-acetate having an Rf of 0.66 on silica gel in 1:1 ethylacetate-hexane. The third component to elute from the HPLC separation was a minor fraction containing the 5-isomer. Upon stripping the solvent one obtained 1.0g of ethyl 5-phenyl-1H-pyrazole-1-acetate as an oil having an Rf of 0.51 on silica gel in 1:1 ethyl acetate-hexane.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[CH:24]([C:29]([OH:31])=[O:30])[CH:25](O)[CH2:26][S:27][C@H:22]12)=[O:19]>O1CCCC1>[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH2:26][S:27][C@H:22]12)=[O:19]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Yield: 67.9 %

Procedure:
Trifluoroacetic anhydride (1 ml.) was added to a solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 1 g.) in tetrahydrofuran (3 ml.) and the mixture was treated in a similar manner to that of Example 18 to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 0.65 g.).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][C:20](OC)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][CH2:19][C:20]1[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)CCNC(=O)OC(C)(C)C
Reactant: CC(C)C(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
2.20 g (21.54 mmol) N-hydroxy-isobutyramidine are placed in 10 ml dimethylformamide and molecular sieve. 0.948 g (23.69 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 6.20 g (30.51 mmol) methyl 3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added, the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[CH:5]=[CH:6][CH:7]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:31]#[N:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCC#N)c(-c3ccccc3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (63.0 mg) and triethylamine (22.8 mg) in dichloromethane (3 mL) was added methanesulfonyl chloride (18.9 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was added to sodium cyanide (14.7 mg) in dimethylformamide (2 mL) and the mixture was stirred at 60° C. for 5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]hexanenitrile as an yellow oil (58.5 mg).
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([CH3:35])[C:26]3[C:31]([C:32]=2O)=[CH:30][C:29]([CH3:34])=[CH:28][CH:27]=3)=O)CCCCC1>C1(C)C=CC=CC=1>[CH2:35]([N:25]1[C:26]2[C:31](=[CH:30][C:29]([CH3:34])=[CH:28][CH:27]=2)[C:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[CH2:2][CH2:3]2)=[C:23]([C:21]#[N:20])[C:24]1=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2C
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 110 °C
Yield: 154.5 %

Procedure:
piperazine-1-yl-thiophen-2-yl-methanone (490 mg, 2.5 mmol) was added to a solution of Compound 20 (309 mg, 1 mmol) in toluene (20 mL) and heated overnight at 110° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0-2% methanol in dichloromethane gradient to yield 362 mg (77%) of white solids. M.P. 183° C. 1H NMR (DMSO-d6): δ 2.36 (s, 3H), 3.69 (m, 4H), 3.94 (m, 4H), 5.47 (s, 2H), 7.16-7.20 (m, 4H), 7.23-7.33 (m, 3H), 7.44 (d, J=8.8 Hz, 1H), 7.50 (d, J=3.8 Hz, 1H), 7.70 (s, 1H), 7.81 (d, J=4.8 Hz, 1H). EIMS m/z 491 (M+23). Anal. (C27H24N4O2S) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CN(C)C1C=CC=CC=1.[C:20]([C:23]1[CH:31]=[C:27](C(Cl)=O)[C:26]([OH:32])=[C:25](C(=O)C)[C:24]=1[OH:36])(=[O:22])C.Cl.[OH-].[Na+]>CC(C)=O>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([Cl:10])[C:5]=1[OH:9])[NH:1][C:20](=[O:22])[C:23]1[CH:31]=[CH:27][C:26]([OH:32])=[CH:25][C:24]=1[OH:36]
Reactant: CC(=O)c1cc(C(=O)Cl)c(O)c(C(C)=O)c1O
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccc(O)cc1O
Yield: 84.8 %

Procedure:
4-Amino-2,6-dichlorophenol (10 g.) and N,N-dimethylaniline (10 ml.) were dissolved in acetone (100 ml.) to which, with stirring and under cooling at 0°-4° C., the acetone solution of diacetyl-β-resorcyloyl chloride was added dropwise. After several hours, the reaction mixture was made acidic with hydrochloric acid, and was subjected to evaporation under reduced pressure until the volume was halved. The resultant solution was added to 1 liter of 4 N hydrochloric acid and allowed to stand in the cold. Precipitates were obtained and dissolved in acetone. The acetone solution was made alkaline with 2 N sodium hydroxide and stirred for several hours at room temperature. Acidifying the solution to pH 1-2 with dilute hydrochloric acid gave precipitate which was recrystallized in aqueous acetone to give light yellow prism-like crystals of 3',5'-dichloro-2,4,4'- trihydroxybenzanilide (13.2 g.). Yield: 84.8%. The melting point is 235°- 237° C.
Reaction SMILES: [C:1](=O)([O:32]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[CH:43]([NH2:46])([CH3:45])[CH3:44]>C(Cl)Cl>[CH:43]([NH:46][C:1](=[O:32])[O:2][CH2:3][C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)([CH3:45])[CH3:44]
Reactant: O=C(OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 45 mg (0.073 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)ethyl 4-nitrophenyl carbonate in 3 mL of methylene chloride was added 0.3 mL of isopropylamine and stirred for 4 h at rt. The reaction mixture was then concentrated and the residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound as a white solid. 1NMR (CDCl3) δ 1.15 (d, 6H, J=5.7 Hz), 3.90 (br s, 1H), 3.99 (s, 2H), 4.06 (s, 2H), 4.54 (s, 1H), 4.74 (s, 2H), 6.68-6.74 (m, 3H), 7.29-7.39 (m, 8H); Mass Spectrum: m/e=531 (M+1 35Cl, 35Cl) and 533 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][O:8][CH3:9].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([C:21](=[O:23])[CH3:22])[C:5](=[O:10])[CH2:6][CH2:7][O:8][CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: COCCC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCC(=O)C(C(C)=O)C(=O)OC
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To an ice cooled solution of 5.28 g (32.96 mmol) 5-methoxy-3-oxo-pentanoic acid methyl ester and 3.14 g (32.96 mmol) anhydrous magnesium chloride in 50 ml dichloromethane was dropped within 3 min 5.3 ml (65.92 mmol) pyridine. 3.27 ml (34.61 mmol) of acetic anhydride was then added within 3 min. The reaction mixture was stirred over night at RT and after concentration under reduced pressure it was partitioned between ether, 1N HCl and water. The ether solution was concentrated under reduced pressure to give 5.87 g pure 2-acetyl-5-methoxy-3-oxo-pentanoic acid methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[Cl:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([NH:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[O:16]
Reactant: NCc1ccncc1
Reactant: O=C(Cl)CCOCCCl
Product: O=C(CCOCCCl)NCc1ccncc1

Procedure:
Title compound was prepared starting from (4-pyridyl)methanamine and 3-(2-chloroethoxy)propanoyl chloride following the procedure outlined for Example 27A. 1H NMR (CDCl3): δ 2.38-2.41 (m, 2H), 2.60-2.63 (m, 2H), 3.54-3.60 (m, 2H), 3.66-3.69 (m, 2H), 4.45 (d, 2H, J=6.1 Hz), 6.12 (br t, 1H, D2O exchanged), 7.09-7.11 (m, 2H), 8.40-8.42 (m, 2H).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2.[CH2:15]([NH:17][CH2:18][CH2:19][OH:20])[CH3:16].O>C(OCC)(=O)C>[CH2:15]([N:17]([CH2:18][CH2:19][OH:20])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2)[CH3:16]
Reactant: CCNCCO
Reactant: CC(=O)c1ccc2cc(O)ccc2c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CCO)c1ccc2cc(C(C)=O)ccc2c1
Yield: 12 %

Procedure:
A mixture of 1-(6-hydroxy-2-naphthyl)ethanone (744 mg, 3.92 mmol), sodium hydrogen sulfate(IV) (1.66 g, 16 mmol), 2-ethylaminoethanol (2 mL) and water (5 mL) was heated in a steel bomb at 130-140° C. for 3 days. After cooling, the mixture was distributed between water and ethyl acetate, and the organic layer was washed with brine, dried and evaporated. The residue was dissolved in acetone and loaded onto a 4 mm dry silica plate for radial chromatography. The plate was eluted with a 1:1 mixture of petroleum ether and ethyl acetate. Appropriate fractions were collected and evaporated to give 125 mg (12%) of 1-{6-[ethyl-(2-hydroxylethyl)-amino]-2-naphthyl}ethanone.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH3:34][NH:35][S:36]([CH:39]=[CH2:40])(=[O:38])=[O:37]>>[CH3:34][NH:35][S:36]([CH2:39][CH2:40][N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)(=[O:38])=[O:37]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: C=CS(=O)(=O)NC
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)CCN1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure for 320, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and N-methyl ethene sulfonamide were reacted to give 465. LCMS: RT=7.25 min, [M+H]+=489. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, t, J=8.17 Hz), 7.89 (1H, s), 7.06 (1H, dd, J=8.21, 1.88 Hz), 6.97 (1H, d, J=1.83 Hz), 5.93-5.83 (1H, m), 4.91 (1H, s), 4.38 (2H, t, J=5.03 Hz), 3.76 (2H, t, J=7.01 Hz), 3.72-3.62 (1H, m), 3.41-3.34 (2H, m), 3.25 (2H, t, J=6.71 Hz), 3.08-3.02 (2H, m), 2.99-2.91 (2H, m), 2.80 (3H, s), 1.60 (6H, d, J=6.78 Hz)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:4][CH:3]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)NS(C)(=O)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(CCCc4ccccc4)NS(C)(=O)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using N-{1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butyl}-methanesulfonamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:7]=[C:8]([CH2:12][S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C1C=CC=CC=1>[N+:3]([C:6]1[CH:7]=[C:8]([CH2:12][S:13]([NH:2][CH3:1])(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CN
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Solvent: c1ccccc1
Product: CNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
40% aqueous methylamine (10 mL, 0.1 mol) was added to a vigorously stirred solution of (3-Nitrophenyl)methanesulfonyl chloride (2.36 g, 10 mmol) in benzene (30 mL) and allowed to stir for 2 h at room temperature. To this end, the benzene layer was separated, and the aqueous layer extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), water (30 mL), filtered over anhydrous Na2SO4, filtered and the solvent removed under reduced pressure to give 2.07 g (90%) of (3-nitrophenyl)-N-methylmethanesulfonamide as crystals.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.Cl.[CH2:16](O)[CH3:17]>O1CCOCC1>[CH2:16]([O:9][C:8]([CH2:7][C:3]1[CH:2]=[C:1]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=1)=[O:10])[CH3:17]
Reactant: CCO
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(CC(=O)O)c1

Procedure:
A solution of preparation 1 (44.3 g, 177 mmol) and 2,2′-(1,3-phenylene)diacetic acid (59.2 g, 308 mmol) in ethanol (24 mL) and dioxan (290 mL) was treated dropwise with hydrochloric acid (12 M, 4.9 mL, 58.8 mmol). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated to low volume. The reaction mixture was diluted with toluene (125 mL) and the resulting slurry filtered. The filtrate was concentrated in vacuo and the residue taken up in water and basified with sodium bicarbonate until pH neutral. The mixture was diluted with ethyl acetate (200 mL) and the organic layer was separated and washed with sodium bicarbonate solution (5×30 ml) and brine (50 mL). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with diethylether (3×30 mL). The organics were combined, dried (MgSO4) and concentrated in vacuo. The residue was triturated with pentane to yield a colourless solid (10.8 g). 1HNMR (CD3OD, 400 MHz) δ: 1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15 (2H, q), 7.18–7.32 (4H, m); LRMS ESI m/z 245 [M+Na]+
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:13]([N:15]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=2[N:38]([CH2:41][C@H:42]2[CH2:47][CH2:46][C@H:45]([CH2:48][C:49]([OH:51])=[O:50])[CH2:44][CH2:43]2)[CH2:39][CH3:40])[C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:18][N:17]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:54](O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CCN=C=NCCCN(C)C.Cl.O>ClC(Cl)C.CN(C1C=CN=CC=1)C>[CH2:54]([O:50][C:49](=[O:51])[CH2:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([CH2:41][N:38]([C:29]2[CH:30]=[CH:31][C:32]([C:34]([F:36])([F:37])[F:35])=[CH:33][C:28]=2[CH2:27][N:15]([CH:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:53])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH3:14])[C:16]2[N:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:20][N:21]=2)[CH2:39][CH3:40])[CH2:43][CH2:44]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: OCc1ccccc1
Reactant: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCN(C[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, a solution of the (S)-isomer-dominant semi-chiral compound (4) of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (744.1 g, 0.95 mol) obtained in Step 2 in anhydrous dichloroethane (11.6 L) was added with benzyl alcohol (113.1 g, 1.05 mol), WSC.HCl (200.5 g, 1.05 mol) and DMAP (11.9 g, 98 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was added with water (10 L), and the mixture was extracted with chloroform (19 L, 14 L). The organic layer was washed with saturated brine (12 L), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 28 g, developing solvent: heptane/ethyl acetate=6/1) to obtain a semi-chiral compound (5) of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid benzyl ester (yellow oil, 745.8 g, yield: 90%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[CH:18]2[Si:23]([CH:26]1[C:34]2[C:29](=[C:30](Br)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[CH3:36])([CH3:25])[CH3:24]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH3:37])[CH:18]3[Si:23]([CH:26]2[C:34]3[C:29](=[C:30]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:8]=4)[CH:31]=[CH:32][CH:33]=3)[CH:28]=[C:27]2[CH3:36])([CH3:25])[CH3:24])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3cccc(C(F)(F)F)c3)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3cccc(C(F)(F)F)c3)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 28.0 ml of 15 mL of THF with 0.5 M ZnCl2 (14.0 mmol) in THF, 12.3 ml of 1.02 M 3-trifluoromethylphenylmagnesium bromide (12.6 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 9.66 ml of 0.02 M Pd(PtBu3)2 (0.19 mmol, 4 mol. %) in THF and 2.42 g (4.83 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.86 g (98%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [CH2:1]([S:13][C:14]1[S:18][C:17]([SH:19])=[N:16][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Cl[C:23]1[C:24]([C:29]#[N:30])=[N:25][CH:26]=[CH:27][N:28]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:13][C:14]1[S:18][C:17]([S:19][C:23]2[C:24]([C:29]#[N:30])=[N:25][CH:26]=[CH:27][N:28]=2)=[N:16][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N#Cc1nccnc1Cl
Reactant: CCCCCCCCCCCCSc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to Example 1 by using 5-(dodecylthio)-1,3,4-thiadiazole-2-thiol (319 mg, 1.00 mmol), NaH (60% dispersion in mineral oil, 44 mg, 1.10 mmol), and 3-chloropyrazine-2-carbonitrile (140 mg, 1.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere overnight.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH:47]1([C:50](O)=[O:51])[CH2:49][CH2:48]1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH:47]1([C:50]([O:27][CH:24]([C:5]2[C:6]3[N:7]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]5[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=5)[C:8]4=[N:9][C:10]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:25][CH3:26])=[O:51])[CH2:49][CH2:48]1
Reactant: O=C(O)C1CC1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(OC(=O)C1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.1 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (122.3 mg, 0.316 mmol) in tetrahydrofuran (0.5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (121.2 mg, 0.632 mmol), triethylamine (88 μL, 0.632 mmol), cyclopropanecarboxylic acid (37.8 μL, 0.474 mmol) and 4-dimethylaminopyridine (57.9 mg, 0.474 mmol). The reaction mixture was stirred at room temperature for 3.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (105.2 mg, 0.231 mmol, 73%).