Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[O:5][CH2:6][C:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:11]=2[CH3:12])=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Reactant: CCOC(=O)CCc1cc(O)ccc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2ccccc2OCc2nc(-c3ccccc3)oc2C)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.65 g), ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate (0.46 g), anhydrous potassium carbonate (0.30 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.89 g, 95%) of 3-[2-ethoxy-5-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 146-147° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=1.CN(C)C=O.[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.[Cl-].[Li+]>ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[N:32]1[C:16](=[O:18])/[CH:15]=[CH:14]/[C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of oxalyl chloride (10.82 mL, 124 mmol) in dichloromethane (50 mL) was added dropwise to a cooled solution of (2E)-3-(4-chlorophenyl)acrylic acid (11.33 g, 62.0 mmol) in dichloromethane (110 mL) and N,N-dimethylformamide (0.4 μL, 0.01 mmol). After stirring the reaction mixture for 24 hours, the solution was added dropwise to a cooled solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (9.49 g, 53.6 mmol), triethylamine (39.2 mL, 282 mmol) and lithium chloride (11.95 g, 282 mmol) in dichloromethane (110 mL). The reaction mixture was slowly warmed to room temperature, stirred for 2 hours and then water (50 mL) was added. The mixture was diluted with dichloromethane (100 mL) and 5% citric acid solution (2×150 mL) was added. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel using dichloromethane as eluent afforded the desired product as a white solid, 14.6 g (74%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])(C(C)(C)C)(C)C.[NH+]1C=CC=CC=1.O>C(O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:37][CH:38]=1)[CH3:32]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 76.6 %

Procedure:
4-[9-(t-Butyldimethylsilyloxy)nonyl]-7-methoxymet hoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (1.34 g, 2.23 mmol) was dissolved in ethanol (70 ml), and pyridinium ptoluenesulfonate (426 mg, 1.70 mmol) was added thereto. The reaction mixture was stirred at room temperature for 10 hours, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=7:3 and 1:1) to give the title compound (831 mg, yield 77%) as a colorless oil. In this reaction, 247 mg (18%) of the unreacted starting compound was recovered.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:50][C:51]1[CH:56]=[CH:55][C:54](O)=[CH:53][CH:52]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:17][C:54]2[CH:55]=[CH:56][C:51]([Br:50])=[CH:52][CH:53]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCCCCCC(O)c1ccc(C(=O)OC)cc1
Reactant: Oc1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-heptyl)-benzoic acid methyl ester (1800 mg, 7.2 mmol) in toluene (72 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2725 mg, 10.8 mmol) at 0° C., followed by the additions of tributylphosphine (2.69 mL, 10.8 mmol) and 4-bromo-phenol (1503 mg, 8.64 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid methyl ester. 1900 mg of the ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (2 mL), and extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid (1800 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:18]=2)[N:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:13]([C:11]1[CH:12]=[C:8]([NH2:7])[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:18]=2)[N:10]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C)nn1-c1cccc(N2CCOCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(N)n(-c2cccc(N3CCOCC3)c2)n1
Yield: 87.2 %

Procedure:
A solution of Intermediate 23c (290 mg, 0.725 mmol) and TFA (3 mL) in DCM (4 mL) was stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (190 mg, 86%). LCMS (Method 1): Rt 2.29 min, m/z 301 [MH+].
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]>>[Br:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([CH3:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7]
Reactant: [Li]C
Reactant: O=C(c1ccccc1)c1ccccc1Br
Product: CC(O)(c1ccccc1)c1ccccc1Br

Procedure:
Addition of methyllithium to 2-bromobenzophenone provides 2-bromophenyl methyl phenyl carbinol. Addition of methyl magnesium iodide to methyl o-bromobenzoate provides 2-bromophenyl dimethyl carbinol.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:16][CH:15]2[C:17](=[CH2:26])[C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][C:23]=3[CH:14]2[CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]2[CH:17]([CH3:26])[CH:15]3[CH2:16][NH:12][CH2:13][CH:14]3[C:23]=2[CH:22]=1
Reactant: C=C1c2ccc(OC)cc2C2CN(Cc3ccccc3)CC12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc2c(c1)C1CNCC1C2C
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
Ammonium formate (8.1 g) and palladium (10 wt. % on activated carbon, 4.0 g) were added to a solution of 2-benzyl-5-methoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (8.1 g, 27.8 mmol) in MeOH (140 mL). The reaction mixture was stirred for 4 hours at 60° C. and then filtered through celite. The celite was washed with MeOH (200 mL) and the filtrate was concentrated to afford 5.6 g (quantitative yield) of the title compound. An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C13H17NO+H: 204, observed: 204.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=1[O:38][CH2:39][CH3:40])=[O:27])[CH2:20]2.Cl[C:42]1[N:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[N:43]=1>>[CH3:51][O:50][C:44]1[CH:45]=[C:46]([O:48][CH3:49])[N:47]=[C:42]([N:24]2[CH2:25][CH:19]3[CH:23]2[CH2:22][N:21]([C:26]([C:28]2[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][C:29]=2[O:38][CH2:39][CH3:40])=[O:27])[CH2:20]3)[N:43]=1
Reactant: CCOc1ccc2ccccc2c1C(=O)N1CC2CNC2C1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: CCOc1ccc2ccccc2c1C(=O)N1CC2CN(c3nc(OC)cc(OC)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 24 and 2-chloro-4,6-dimethoxypyrimidine. MS (ESI) mass calcd. for C24H26N4O4, 434.5; m/z found, 435.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12]([OH:21])(=[O:20])[C@H:13]([C@@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]>C(O)C>[C:17]([C@H:15]([C@@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18].[NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1CCCNC1

Procedure:
Ethyl 3-piperidinecarboxylate (200 g) was combined with (-)-D-tartaric acid (191 g) in hot 95% ethanol. The resulting precipitate was filtered and recrystallized six times from 95% ethanol to give (S)-ethyl 3-piperidinecarboxylate D-tartrate salt of high optical purity as determined by chiral HPLC analysis.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][S-:13].[Na+]>CO.O>[Br:1][C:2]1[N:3]=[C:4]([S:13][CH3:12])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: C[S-]
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1nc(Br)cn2ccnc12
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a stirred suspension of 489 g (1766 mmol) 6,8-dibromo-imidazo[1,2-a]pyrazine which was prepared according to a procedure described in the Journal of Medicinal Chemistry, 1984, vol. 27, #2, p. 206-212 in 2.9 L methanol at −20° C. was dropwise added a solution of 225 g sodium methanethiolate in 800 mL water. After stirring overnight, the clear solution was poured into 30 L water, the precipitate was filtered, washed with water and dried in vaccuo to yield 301 g (70%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:19]3[N:20]=[CH:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C:19]3[N:20]=[CH:21][NH:22][CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(O)(c1ccc(-c2ccc(Cl)cc2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1ccc(-c2ccc(Cl)cc2)cc1)c1c[nH]cn1
Yield: 68.5 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 1-(4′-chloro[1,1′-biphenyl]-4-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.00 g) and pyridine hydrochloride (1.04 g), the title compound (1.18 g) was obtained as colorless plate crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28]Br)[CH:22]=3)[O:20][C@@:6]1([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:7][O:8]2)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:58]=[CH:57][C:46]([O:47][C:48]3[CH:53]=[CH:52][C:51]([C:54](=[O:56])[CH3:55])=[CH:50][CH:49]=3)=[CH:45][CH:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>[Pd].O>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:43]4[CH:44]=[CH:45][C:46]([O:47][C:48]5[CH:53]=[CH:52][C:51]([C:54](=[O:56])[CH3:55])=[CH:50][CH:49]=5)=[CH:57][CH:58]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: CC(=O)c1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(Oc5ccc(C(C)=O)cc5)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 80 °C
Yield: 36.6 %

Procedure:
To a mixture of (1R,2S,3S,4R,55)-1-(acetoxymethyl)-5-(3-(bromomethyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (1.0 g, 1.77 mmol, Intermediate 2), 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)phenyl)ethanone (899.0 mg, 2.66 mmol), Pd (dppf) Cl2 (72 mg, 0.09 mmol) and sodium carbonate (563.0 mg, 5.31 mmol) under nitrogen atmosphere, was added DMF and H2O (9 mL, 1:1). The reaction mixture was heated at 80° C. for 1 h. After the completion of the reaction, as confirmed by TLC, the solution was cooled to r.t. and filtered through celite. The solvent was evaporated in vacuo and the crude compound was diluted with ethyl acetate (200 mL). The organic layer was washed with water (3×30 mL), separated, dried over Na2SO4 and concentrated in vacuo to afford crude compound which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet ether) to afford the title compound (450 mg, 36.6%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:38]([CH:35]2[CH2:37][CH2:36]2)(=[O:40])=[O:39])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)C2CC2)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 46.5 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol) and cyclopropylsulfonyl chloride (39.7 mg, 282 μmol) were reacted with one another for 16 h. This gave the title compound as a colorless solid (57 mg, 47% of theory).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[K+]>CO.O>[O:12]1[C:13]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[CH:11]1
Reactant: COC(=O)c1cccc2ncoc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2ncoc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 0.21 g (1.18 mmol) of methyl-7-benzoxazole carboxylate in 6 mL of CH3OH at 0° C. was added 2.9 mL of a 1N solution of KOH in water and the reaction mixture was stirred at rt for 1 h. The reaction mixture was partitioned between water and CH2Cl2. The aqueous fraction was made acidic with 1N HCl solution and extracted with CH2Cl2. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give 0.17 g of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[CH3:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].CC1C=CC=CC=1C=O.CNC>>[CH3:17][N:16]([CH3:18])[CH:15]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[CH3:12]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: Cc1ccccc1C=[N+](C)C
Agent: CNC
Agent: Cc1ccccc1C=O
Agent: [Cl-]
Product: Cc1ccccc1C(c1c(C)[nH]c2ccccc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (2-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]2[C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][N:18]=[C:17]([Cl:26])[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]2[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=[C:17]([Cl:26])[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)nc1NCC1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc(Cl)ncc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylate (544 mg, 1.41 mmol) in THF (8 mL), aq. 1N NaOH (8 mL, 8.0 mmol) was added. The mixture was stirred at room temperature for 18 h. It was acidified to pH 1-2 with 6N HCl. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (503 mg).
Reaction SMILES: NCC(N(C1C(Cl)=C(C(Cl)=CC=1)CO[C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=2[CH:15]=[CH:14][CH:13]=1)C)=O.CNC(C1C=CC(C=CC(O)=O)=CC=1)=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[CH3:22][N:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:20]=2[N:19]=[C:18]1[CH3:21]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: CNC(=O)c1ccc(C=CC(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 337.1 %

Procedure:
To a mixture of 4-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole (100 mg), 4-(methylcarbamoyl)cinnamic acid (55.4 mg) and dimethylformamide (1 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61.2 mg) and 1-hydroxybenzotriazole (49.7 mg), and the mixture was stirred for 3 hours at ambient temperature. To the mixture was added water, and the mixture was extracted with dichloromethane. The separated organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane-methanol) to give 4-[2,6-dichloro-3-[N-methyl-N-[4-(methyl-carbamoyl)cinnamoylglycyl]amino]benzyloxy]]-1,2-dimethyl-1H-benzimidazole (121 mg).
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[C:55]([F:58])[CH:56]=3)[NH:51][CH:50]=2)=[CH:45][C:44]=1[NH:59][C@H:60]1[CH2:65][CH2:64][CH2:63][C@@H:62]([NH2:66])[CH2:61]1>C1COCC1>[C:1]([C:3]1([C:6]([NH:66][C@@H:62]2[CH2:63][CH2:64][CH2:65][C@H:60]([NH:59][C:44]3[CH:45]=[C:46]([C:49]4[C:57]5[C:52](=[N:53][CH:54]=[C:55]([F:58])[CH:56]=5)[NH:51][CH:50]=4)[CH:47]=[CH:48][C:43]=3[F:42])[CH2:61]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(C(=O)O)CC1
Reactant: N[C@@H]1CCC[C@H](Nc2cc(-c3c[nH]c4ncc(F)cc34)ccc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#CC1(C(=O)N[C@@H]2CCC[C@H](Nc3cc(-c4c[nH]c5ncc(F)cc45)ccc3F)C2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-cyano-1-cyclopropane-carboxylic acid (0.058 g, 0.527 mmol) in THF at room temperature was added HATU (0.200 g, 0.527 mmol) followed by N,N-diisopropylethylamine (0.334 mL, 1.91 mmol). The solution was stirred for 10 minutes. (1S,3R)—N1-(2-fluoro-5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclohexane-1,3-diamine, 44e, (0.200 g, 0.584 mmol) was then added and solution stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and purified via silica gel chromatography (30-60% Ethyl Acetate/hexanes) to give 80 mg of 871 as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:3]=1[N:4]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C([Mg]Cl)(C)C.CON(C)[C:36]([C:38]1([CH3:41])[CH2:40][CH2:39]1)=[O:37]>C1COCC1.C(OCC)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:3]2[CH:23]=[C:24]([C:36]([C:38]3([CH3:41])[CH2:40][CH2:39]3)=[O:37])[CH:25]=[CH:26][C:2]=2[Cl:1])=[CH:7][CH:8]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(I)ccc2Cl)cc1
Reactant: CON(C)C(=O)C1(C)CC1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(C(=O)C3(C)CC3)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under argon, 7.587 g (15.37 mmol) of 2-chloro-5-iodo-N,N-bis(4-methoxybenzyl)aniline were dissolved in 100 ml of THF and cooled to −78° C. 7.65 ml (15.27 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were then slowly added dropwise. The reaction solution was then slowly warmed to −40° C. and stirred at this temperature for 30 min. 2 g (13.97 mmol) of N-methoxy-N,1-dimethylcyclopropanecarboxamide [R. Shintani et al., Chem. Eur. J., 15 (35), 8692-8694 (2009)], dissolved in 20 ml of THF, were then slowly added dropwise to the reaction solution. The reaction mixture obtained was then slowly warmed to room temperature and stirred at this temperature overnight. 50 ml of an ice-cold saturated aqueous ammonium chloride solution were then added to the reaction mixture. After separation of the phases, the aqueous phase was extracted three more times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.977 g (63% of theory) of the title compound.