Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:15])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:15][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cc(NC(C)=O)ccc1C(=O)OC
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 10 g (47.8 mmol) of methyl 4-acetylaminosalicylate in 30 ml of DMF is added 19.8 g (143.4 mmol) of finely ground potassium carbonate in a single portion at room temperature, followed by 8.3 ml (95.6 mmol) of allyl bromide in a similar fashion. The reaction mixture is heated to 60° C. and stirred at that temperature for 4 hours. After cooling to room temperature the reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered and concentrated. Flash chromatography (10% ethyl acetate/hexane) provides methyl 2-allyloxy-4-acetylaminobenzoate which can be used directly in the next step.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[C:21]1([S:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)(=[O:19])=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Pd/C 10 wt. % (0.10 g, 0.094 mmol) was added to a solution of 5-(benzyloxy)-1-(phenylsulfonyl)-1H-indole (Intermediate 7, 6.00 g, 16.5 mmol) and ammonium formate (15.6 g, 248 mmol) in THF/MeOH 1:1 (300 mL). The reaction mixture was stirred overnight at room temperature and filtered through a short plug of silica gel. The filtrate was evaporated and dissolved in DCM and filtered through a plug of silica gel eluating with 2.5% MeOH in DCM. The purest fractions (monitored by TLC) were evaporated to give the title compound (4.2 g) as a white powder. MS m/z 273 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][C:8]=2[C:17]([F:20])([F:19])[F:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[OH-].[Na+]>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:17]([F:20])([F:18])[F:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cnc(-c2ccccc2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cnc(-c2ccccc2)c(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
To a solution of N-(6-phenyl-5-(trifluoromethyl)pyridin-3-yl)acetamide (1.68 mmol, 0.280 g) in ethanol (6 ml), 2N aqueous NaOH (5 ml) was added. The mixture was heated at 110° C. for 3 hours. The solvent was removed, the pH was set at 8 and extracted with CHCl3. The solvent was removed to afford 0.394 g (98% of yield) of the expected product.
Reaction SMILES: [OH:1][CH:2]([CH2:5][OH:6])[CH2:3][SH:4].[H-].[Na+].CN(C)C=[N:12][S:13]([C:16]1[S:17][C:18](Br)=[CH:19][CH:20]=1)(=[O:15])=[O:14]>CN(C=O)C.O>[OH:1][CH:2]([CH2:5][OH:6])[CH2:3][S:4][C:18]1[S:17][C:16]([S:13]([NH2:12])(=[O:15])=[O:14])=[CH:20][CH:19]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccc(Br)s1
Reactant: OCC(O)CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(SCC(O)CO)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2,3-dihydroxypropanethiol (8.11 g, 0.075 mol) in DMF (10 ml) was added dropwise to a stirred mixture of NaH (3.45 g, 50% oil, 0.075 mol) and DMF (40 ml) under nitrogen. When gas evolution was complete, a solution of N,N-dimethyl-N'-(5-bromothiophene-2-sulfonyl)formamidine (14.85 g, 0.05 mol) in DMF (50 ml) was added rapidly and the resulting mixture was heated on the steam bath for one hour. After an additional 16 hours at ambient temperature, the reaction mixture was diluted with water (500 ml) and extracted with ethyl acetate (250 ml). Sodium hydroxide (100 g) was added to the aqueous layer and this solution warmed on the steam bath for two hours. After cooling to ambient temperature, the mixture was filtered and the clear filtrate was acidified with concentrated HCl. The solution was extracted with ethyl acetate (3×300 ml), the extracts were washed with saturated NaCl and dried (Na2SO4) Filtration and evaporation of the solvent left the product as a light amber oil, 13.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][N:3]=1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)C(F)(F)F

Procedure:
2.11 g (0.01 mol) of 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 30 ml of methylene chloride at room temperature. 7.3 ml (0.012 mol) of an approximately 10% strength sodium hypochlorite solution are metered in within 5 minutes with vigorous stirring and the mixture is stirred for a further 2 hours during which the reaction temperature rises to 30° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.5 mbar, 100°-120° C. bath temperature), 1.13 g (54% of theory) of 2-chloro-5-trifluoroacetylpyridine are obtained, which, according to GC, is 99.8% pure. nD20 : 1.4887.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:18][C:19]1[N:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[N:22]=[N:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([N:23]4[C:19]([CH3:18])=[N:20][N:21]=[N:22]4)=[CH:25][CH:26]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.02 min; Mass spectrum (ESI+): m/z=439 [M+H]+.
Reaction SMILES: CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:30]([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]([NH:50][C:51]([NH:53][C@@H:54]([C:62](O)=[O:63])[CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:52])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:36])([CH3:33])([CH3:32])[CH3:31].[F:65][C:66]1[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:67]=1[CH2:68][NH2:69]>C(Cl)Cl.CN(C=O)C>[C:30]([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]([NH:50][C:51]([NH:53][C@@H:54]([C:62](=[O:63])[NH:69][CH2:68][C:67]1[CH:70]=[CH:71][C:72]([F:74])=[CH:73][C:66]=1[F:65])[CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:52])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:36])([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)N[C@H](CC1CCCCC1)C(=O)O)C(=O)OC(C)(C)C
Reactant: NCc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)N[C@H](CC1CCCCC1)C(=O)NCc1ccc(F)cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N-Methylmorpholine (53 μl, 0.48 mmol), 1-hydroxybenzotriazole (28 mg, 0.208 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.8 mg, 0.192 mmol) were added in the stated sequence to a solution of tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((R)-1-carboxy-2-cyclohexyl-ethyl)-ureido]-hexanoate (80 mg, 0.16 mmol) and 2,4-difluorobenzylamine (22.9 mg, 0.16 mmol) in 3 ml of CH2Cl2 and 1 ml of DMF, and the mixture was stirred at RT for about 14 h. Extraction with CH2Cl2/H2O, drying of the organic phase with MgSO4 and evaporation afforded tert-butyl (S)-6-tert-butoxycarbonylamino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluorobenzylcarbamoyl)-ethyl]-ureido}-hexanoate as crude product. The entire crude product was dissolved in 4 ml of CH2Cl2, 1 ml of TFA was added and, after 4 h, a further 0.5 ml of TFA was added, and deprotection was carried out at RT for about 10 h. Purification of the deprotected crude product by preparative HPLC afforded 25 mg (27%) of (S)-6-amino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluorobenzylcarbamoyl)-ethyl]-ureido}-hexanoic acid trifluoroacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]([F:19])([F:18])[F:17].[CH:21]1([CH:24]=O)[CH2:23][CH2:22]1>[N+](C1C=CC=CC=1)([O-])=O>[CH:21]1([C:24]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:17])[F:18])[C:7]3=[N:6][C:5]([OH:20])=[CH:4][CH:3]=[C:2]3[N:1]=2)[CH2:23][CH2:22]1
Reactant: Nc1ccc(O)nc1Nc1ccccc1OC(F)(F)F
Reactant: O=CC1CC1
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1ccc2nc(C3CC3)n(-c3ccccc3OC(F)(F)F)c2n1
Temperature: 120 °C
Yield: 10.3 %

Procedure:
5-Amino-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-ol (0.10 g, 0.32 mmol) was dissolved in nitrobenzene (0.5 mL). Cyclopropanecarbaldehyde (0.044 g, 0.64 mmol) was added. The reaction mixture was heated to 120° C. overnight. After cooling, hexanes was added to the reaction mixture to form a precipitate. The precipitate was collected, washed with hexanes, and purified via HPLC to give the title compound (11 mg). LCMS m/z=336.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 1.35 (m, 4H), 2.03 (m, 1H), 6.86 (d, J=8.8 Hz, 1H), 7.71 (m, 2H), 7.83 (m, 2H), 7.83 (d, J=8.8 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[O:15]=[C:9]([CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=O)Cl
Reactant: O=C1CCOCC1
Product: CCOC(=O)C(=O)C1COCCC1=O
Yield: 18.8 %

Procedure:
Ethyl 2-oxo-2-(4-oxotetrahydro-2H-pyran-3-yl)acetate (272 mg, 19%) was synthesised from tetrahydro-4H-pyran-4-one (1 ml, 10.83 mmol) and ethyl 2-chloro-2-oxoacetate (0.808 ml, 7.22 mmol) by the general procedure for the preparation of diketones. MS (ES−) m/z 199.1 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[N:10](C(OC(C)(C)C)=O)[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(-c3ccc(F)cc3)cn(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.3 %

Procedure:
To a solution of compound 53c (705 mg, 1.91 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated to give compound 53d (603.3 mg) as a white solid. MS m/z (M+H+) 270.1.
Reaction SMILES: CN(C)CCCN=C=NCC.[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][NH:19][CH2:20]2)[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])([OH:23])[CH2:15]1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([CH3:44])[C:41](O)=[O:42]>ClCCl.O.OC1C2N=NNC=2C=CC=1>[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:41](=[O:42])[C@H:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[CH3:44])[CH2:20]2)[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])([OH:23])[CH2:15]1
Reactant: COc1ccccc1C1(O)CC(CO)CC2CNCC21
Reactant: COc1ccccc1[C@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
2.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide are added to a solution of 2.77 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol, 1.80 g of (S)-2-(2-methoxyphenyl)propionic acid and 30 mg of hydroxybenzotriazole hydrate in 80 cm3 of dichloromethane. After stirring at 20° C. for 20 hours, the reaction mixture is washed with 40 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, height 40 cm) in a mixture of cyclohexane and ethyl acetate (30:70 by volume) and then in a mixture of ethyl acetate and methanol (90:10 by volume). Evaporation of the eluent and drying. I under reduced pressure (2.7 kPa) give 3.6 g of 6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol (mixture of the 2 diastereoisomers, 3aR,4R,6S,7aS,S and 3aS,4S,6R,7aR, S) in the form of a white solid. M.p.K =178° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2>CO.O.[Pt](=O)=O>[OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1
Reactant: OCc1cnc2ccccc2c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: OCC1CNc2ccccc2C1
Reaction time: 6 h
Yield: 83.2 %

Procedure:
3-Hydroxymethylquinoline (0.45 g, 2.83 mmoles) (prepared as described in: B. R. Brown, D. Ll. Hammick and B. H. Thewlis, J. Chem. Soc., 1951,1145-1149.) was dissolved in methanol (100 mL) and placed in a Parr bomb. Platinum (IV) oxide monohydrate (0.225 g. 0.918 mmoles) was added and the mixture was hydrogenated at 50 psi at 25° C. for 6 h. The catalyst was removed by decantation and washed with methanol. The methanol was evaporated to dryness and the product was chromatographed on silica gel using 3% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (0.3843 g, 83%): CIMS: m/z 164.35 (MH+); δH (CDCl3) 6.50 (1H, d, Ar—H8), 6.64 (1H, t, Ar—H6), 6.98 (1H, d, Ar—H5) and 6.99 ppm(1H, m, Ar—H7); δC (CDCl3) CH2: 29.5, 44.0, 65.2; CH: 34.9, 114.2, 117.4, 126.9, 129.8; C: 120.2, 144.5.
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][NH:7][CH2:6]2.C(O[C:17](=[O:19])[CH3:18])(=O)C>N1C=CC=CC=1>[C:3]([O:12][C:11]1[CH:10]=[C:9]2[C:8](=[CH:4][C:3]=1[O:2][C:11](=[O:12])[CH3:10])[NH:7][CH:6]([C:17](=[O:19])[CH3:18])[CH2:5]2)(=[O:2])[CH3:4]
Reactant: Oc1cc2c(cc1O)CNC2
Reactant: CC(=O)OC(C)=O
Agent: Br
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(cc1OC(C)=O)NC(C(C)=O)C2
Reaction time: 0.5 h
Yield: 89 %

Procedure:
500 mg (2.15 mmol) of 5,6-dihydroxyisoindoline hydrobromide was dissolved in 2.5 ml of pyridine, and 2.5 ml of acetic anhydride was added thereto at room temperature. The mixture was stirred at the same temperature for 30 minutes, and then excess pyridine and acetic anhydride were distilled off under reduced pressure. Ethyl acetate was added to the residue, and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure, and the crystalline residue was washed with ethyl ether to obtain 532 mg (yield: 89.0%) of the above identified compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[O:12].[CH:18]1([CH2:24]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>CN(C=O)C>[CH:18]1([CH2:24][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:11]=[O:12])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCC1CCCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCC1CCCCC1

Procedure:
In 175 ml of DMF containing 138 g of anhydrous potassium carbonate (1.0 m) was added 100 g of 3-hydroxy-4-methoxybenzaldehyde and 127 g of cyclohexylmethybromide. The mixture was heated at reflux temperature overnight and then poured into cold water and extracted with ethyl acetate. The extracts were dried and evaporated in vacuo to render the desired subtitled intermediate, b.p. 130°-135 ° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([N:12]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[N:15][N:14]=[N:13]2)[CH:3]=1.Cl.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:37][C@H:36]3[N:32]([CH2:33][CH2:34][CH2:35]3)[C:31]([CH3:39])([CH3:38])[CH2:30]2)[C:25]([F:40])=[CH:24][N:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[CH:17]1([C:16]2[N:12]([C:4]3[CH:3]=[C:2]([NH:1][C:22]4[N:27]=[C:26]([NH:28][C@@H:29]5[CH2:37][C@H:36]6[N:32]([CH2:33][CH2:34][CH2:35]6)[C:31]([CH3:38])([CH3:39])[CH2:30]5)[C:25]([F:40])=[CH:24][N:23]=4)[CH:11]=[CH:10][C:5]=3[O:6][CH2:7][CH2:8][OH:9])[N:13]=[N:14][N:15]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: Nc1ccc(OCCO)c(-n2nnnc2C2CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OCCO)c(-n4nnnc4C4CC4)c3)ncc2F)C[C@@H]2CCCN21
Yield: 64.6 %

Procedure:
Similarly, 2-(4-amino-2-(5-cyclopropyl-1H-tetrazol-1-yl)phenoxy)ethan-1-ol (67 mg, 0.26 mmol) was used in a similar displacement reaction using (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (95 mg, 0.28 mmol) and pTsOH.H2O (98 mg, 0.51 mmol) in IPA (5 mL) at reflux to give the product (88 mg, 66% yield) after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 9:1).
Reaction SMILES: O.[OH-].[Li+].[N:4]1([C:8]([C:10]2[CH:11]=[C:12]([Cl:32])[C:13]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:31])[CH2:29][OH:30])[CH:26]=3)[C:20]([O:22]C)=[O:21])=[N:14][CH:15]=2)=[O:9])[CH2:7][CH2:6][CH2:5]1>O.C1COCC1>[N:4]1([C:8]([C:10]2[CH:11]=[C:12]([Cl:32])[C:13]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:31])[CH2:29][OH:30])[CH:26]=3)[C:20]([OH:22])=[O:21])=[N:14][CH:15]=2)=[O:9])[CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@@H](C)CO)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
Lithium hydroxide monohydrate (529 mg, 12.59 mmol) in water (25 mL) was added to a solution of methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoate (5.3 g, 12.6 mmol) in THF (50 mL) and stirred at RT for 3 hours. The THF was removed in vacuo and the aqueous layer was washed with ethyl acetate (50 mL) to remove any impurities. The aqueous layer was acidified and extracted into ethyl acetate (2×50 mL), and the organics washed with brine, dried (MgSO4), and concentrated in vacuo to give the desired compound as a white foam (3.74 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CN(C=O)C.Br[CH2:26][C:27]1[S:31][C:30]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:29]=2[CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:19]([CH2:26][C:27]2[S:31][C:30]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:29]=3[CH:28]=2)[C:9]2=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: Clc1ccc2cc(CBr)sc2c1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCOC)ncc2n1Cc1cc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 660 mg (2.497 mmol) 5-(2-Methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester in 15 mL absolute DMF 24 mg (2.497 mmol) NaH (96%) were added in an argon atmosphere. The mixture was stirred for 30 min. at room temperature. 623 mg (2.497 mmol) 2-Bromomethyl-6-chloro-benzo[b]thiophene [prepared by adopting a procedure described by Ewing, William R. et al. in; PCT Int. Appl. (1999), 300 pp. WO 9937304 A1; and Ewing, William R. et al. PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture stirred for 1 h at room temperature. The solvent was removed in vacuo and the residue purified by preparative HPLC (eluent: CH3CN/H2O/0.1% CF3COOH). The fractions containing the product were combined, concentrated in vacuo and lyophilized. Yield: 900 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13]Br>C1(C)C=CC=CC=1.[OH-].[Na+].[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
To a solution of 2-(3-chlorophenyl)acetonitrile (3.2 g, 21 mmol) and 1,2-dibromoethane (3 mL, 35 mmol) in toluene (20 ml), 35% sodium hydroxide and tetrabutylammonium iodide (400 mg, 1.3 mmol) were added. The mixture was vigorously stirred at room temperature for 4 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic solution was concentrated to afford brown oil. Chromatography on silica gel (hexane/ethyl acetate=5/1) afforded 1-(3-chlorophenyl)cyclopropanecarbonitrile (2.1 g, 56% yield) as light yellow oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][C:8](O)=[O:9])[CH2:2]1>C1COCC1>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][OH:9])[CH2:2]1
Reactant: O=C(O)CCC1CCOC1
Solvent: C1CCOC1
Product: OCCCC1CCOC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(tetrahydro-3-furanyl)propanoic acid (1 g, 6.94 mmol) in dry THF (20 ml) at 0° C. was added a 1M solution of Boron THF complex (21.16 ml, 21.16 mmol) in THF dropwise over 2 mins. The mixture was stirred at 0° C. for 1 hour then allowed to warm to room temperature and stirred for 18 h. The reaction mixture was cautiously quenched with methanol (˜20 ml) and the solvent removed in vacuo. The residue was re-dissolved in methanol and concentrated in vacuo four times to give the title compound a colourless oil (3.37 g)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH2:6][O:7][CH3:8].[I-].[CH3:23][N:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:34][N+](C)(C)C)=[CH:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:19])([CH3:20])[CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:34][CH:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[N:24]([CH3:23])[CH2:25]2)[C:10]1=[O:18])[CH2:6][O:7][CH3:8]
Reactant: COCC(n1c(=O)[nH]c2ccccc21)C(C)(C)C(=O)OC
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC(n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21)C(C)(C)C(=O)OC
Temperature: 100 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
To a mixture of 4-methoxy-2,2-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyric acid methyl ester (137 mg, 0.47 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (225 mg, 0.65 mmol) in DMF (2.5 mL) was added K2CO3 (200 mg, 1.45 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 50% EtOAc in Hexane as the eluent to afford the desired 3-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-2,2-dimethyl-butyric acid methyl ester (50 mg, 24%).