Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13](Br)[C:8]=2[O:7][C:6]1([CH3:16])[CH3:15])(=O)C.C([Li])CCC.[B:22](OC)([O:25]C)[O:23]C>O1CCCC1>[OH:4][CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([B:22]([OH:25])[OH:23])[C:8]=2[O:7][C:6]1([CH3:16])[CH3:15]
Reactant: CC(=O)OC1c2cccc(Br)c2OC1(C)C
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2c(B(O)O)cccc2C1O
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
A stirring solution of 5.7 grams (0.020 mole) of 3-acetoxy-7-bromo-2,3-dihydro-2,2-dimethylbenzofuran in 150 mL of tetrahydrofuran is cooled to -80° C., and 18.2 mL of n-butyllithium in hexanes (2.5 Molar--0.046 mole) is added dropwise during a 15 minute period, while maintaining the reaction mixture temperature at about -80° C. Upon completion of the addition, the reaction mixture is stirred at -80° C. for 15 minutes. After this time, 6.9 mL (0.061 mole) of trimethyl borate is added during a 1 minute period. The reaction mixture is then allowed to warm slowly to ambient temperature during a 3 hour period, where it is stirred for an additional 1 hour. After this time, the reaction mixture is concentrated under reduced pressure to a volume of about 50 mL. The concentrate is then poured into 500 mL of ice-water. The mixture is then made acidic with about 26 mL of aqueous 2N hydrochloric acid. The mixture is filtered, yielding 2,3-dihydro-3-hydroxy2,2-dimethylbenzofuran-7-ylboronic acid.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([F:28])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([F:28])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1F
Agent: [Pd]
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1F

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-fluorobenzoate obtained in Example (176a) (32 mg, 0.08 mmol) and a 10% palladium-carbon catalyst (50 mg), to obtain the title compound as an oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: CO.O.Cl.CS[C:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19](OC)([O:25]C)[C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]>C(Cl)Cl>[S:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:14][CH:15]=1)=[O:25]
Reactant: COC(=O)C(C)(SC)c1ccc(C(OC)(OC)c2cccs2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Yield: 105.6 %

Procedure:
Methanol (4 ml), 1 ml of water, and 0.2 ml of conc. hydrochloric acid were added to 405 mg of methyl α-methylthio-α-[p-[dimethoxy(2-thienyl)methyl]phenyl]propionate, and the resulting mixture was heated under reflux for 30 minutes. After the mixture was cooled and shaken with 50 ml of methylene chloride, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 320 mg of methyl α-[p-(2-thienylcarbonyl)phenyl]propionate as a colorless oil in a yield of 90%.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([CH:9]1[NH:13][CH2:12][CH:11]([CH3:14])[O:10]1)[CH3:8].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C>[CH2:7]([CH:9]1[N:13]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:12][CH:11]([CH3:14])[O:10]1)[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1NCC(C)O1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC1OC(C)CN1S(C)(=O)=O

Procedure:
A solution was formed containing 25 ml. of benzene and 6 g. of 2-ethyl-5-methyl oxazolidine suspended in 24 ml. of benzene. Then, 5.5 g. of triethylamine was added. The solution was cooled in an ice bath, wherein 5.8 g. of methane sulfonyl chloride was added dropwise with stirring to yield 6.4 g. of product, nD30 = 1.4778.
Reaction SMILES: [C:1]([O-:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[K+].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:26])[C:22]([O:24][CH3:25])=[O:23].[I-].[K+]>CN1CCCC1=O>[C:1]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:26])[C:22]([O:24][CH3:25])=[O:23])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])/C=C/c1ccccc1
Reactant: COC(=O)C(=O)c1ccccc1CBr
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C(=O)c1ccccc1CC(=O)C=Cc1ccccc1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
10.4 g (56 millimoles) of potassium transcinnamate and 12.0 g (47 millimoles) of methyl orthobromomethylphenylglyoxalate are dissolved in 250 ml of N-methylpyrrolidone, a pinch of potassium iodide is added and the mixture is stirred for 15 hours at room temperature (23° C.). Thereafter, the mixture is poured onto 500 ml of ice water and extracted with 3×200 ml of methyl tert-butyl ether and the organic phase is washed with water, dried over sodium sulfate and evaporated down in a rotary evaporator. The yield of ketoester is 15.0 g (99%). Thin layer chromatographic analysis shows that it is virtually pure.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[S:17][C:18]([CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([Cl:31])[CH:29]=3)[NH:24][CH:23]=2)=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[C:30]2[C:22]([CH2:21][C:18]3[S:17][C:16]([NH:7][CH2:8][C:9]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)=[N:20][CH:19]=3)=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1ncc(Cc2c[nH]c3ncc(Cl)cc23)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(CNc2ncc(Cc3c[nH]c4ncc(Cl)cc34)s2)cc1
Reaction time: 8 h
Yield: 28.8 %

Procedure:
To the solution of crude [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (628, 0.186 mmol theory) in dichloromethane (5 mL) at room temperature was added trifluoroacetic acid (1 mL) and the reaction was allowed to stir overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate and then washed with saturated aqueous potassium carbonate making sure basicity was reached. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified by silica gel chromatography (0-10% methanol/ethyl acetate). The solvent was removed in vacuo and the material was triturated with dichloromethane to give the desired compound as an off-white solid (20 mg, 29% over 2 steps) consistent with compound structure by 1H-NMR and MS (ESI): [M+H+]+=372.9.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=2)[C:7]([C:13](=[O:36])[CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])(=[O:4])[CH3:3].[OH-].[Na+].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52]>C(O)(C)C.[O-2].[O-2].[Mn+4]>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[C:2]([C:5]1[C:6]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-:45])=[O:44])[CH:38]=2)=[C:7]([C:13](=[O:36])[CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[C:8]([CH3:12])=[N:9][C:10]=1[CH3:11])(=[O:4])[CH3:3]
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Agent: [Mn+4]
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Product: CC(=O)c1c(C)nc(C)c(C(=O)CCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)c1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.2 g (1.9 mmol) 5-acetyl-1,4-dihydro-2,6-dimethyl-3-[5-(4,4-diphenyl-1-piperidinyl)pentanoyl)-4-(3-nitrophenyl)-pyridine hydrochloride are converted into the free base by shaking with excess 1N NaOH, and the base is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is dried in vacuo and is then taken up in 30 ml anhydrous methylene chloride. 2.5 g(29 mmol) manganese dioxide are added. The mixture is stirred vigorously at room temperature for 12 h. Another 2 g (23 mmol) manganese dioxide are added in portions of 0.5 g each in the course of a further 8 h. The mixture is then centrifuged and the sediment is decanted off. The supernatant is concentrated and the residue is chromatographed over silica gel with toluene/acetone=8/2. The product thus obtained is taken up in 30 ml isopropanol, and 0.22 g (1.9 mmol) fumaric acid in 20 ml isopropanol is added. The title compound crystallized overnight. Yield: 0.7 g (52%). M.p.: 181°-190° C. decomp. (acetonitrile).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C)C(O)=[N+](C)C.[NH2:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:7][C@@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9]([NH:37][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1nccs1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step A, 144 mg; 0.5 mmol), O-benzotriazol-1-yl-N,N,N′,N′, -tetramethyluronium hexafluorophosphate (BOP, 268 mg; 0.55 mmol) and 2-aminothiazole (50 mg; 0.5 mmol) in dry methylene chloride (3 mL) at room temperature was added N,N-diisopropylethylamine (0.20 mL; 1.15 mmol) dropwise. The mixture was allowed to stir for 1 h. The mixture was then diluted with methylene chloride and washed with water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue. Flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 30% ethyl acetate/hexanes) provided 150 mg (81%) of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as an off white foam: EI-HRMS m/e calcd for C20H23N3O2S (M+) 369.1511, found 369.1511.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:20])[C:15](=[CH:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.O>[N+](C)([O-])=O>[O:20]=[C:14]1[C:11]2[C:10](=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([Cl:1])[C:12]=2[Cl:13])[CH:18]([CH3:19])[CH:15]1[CH2:16][CH3:17]
Reactant: CC=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1C
Temperature: 60 °C
Yield: 65 %

Procedure:
[2,3-Dichloro-4-(2-ethylidenebutyryl)phenoxy]acetic acid (22.5 g.) is added with stirring to concentrated sulfuric acid (88 ml.) and heated at 60° C. for six hours. The reaction mixture is then cooled and poured into a mixture of ice and water (1 liter). The crude product which separates is ground in a mortar with water (100 ml.), filtered, washed with water and dried. There is thus obtained 14.5 g. (65% yield) of (1-oxo-2-ethyl-3-methyl-6,7-dichloro-5-indanyloxy)acetic acid, which after recrystallization from nitromethane (75 ml.) melts at 167°-168° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: ClCCCBr
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a suspension of sodium hydride (60%, 1.7 g, 43 mmol) in dimethylformamide (200 mL) was added 4'-chloro-4-hydroxybenzophenone (5 g, 22 mmol) portionwise. The mixture was stirred at room temperature for 2 hours, then 1-bromo-3-chloropropane (4.4 mL, 43 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (10 mL) and filtered through Celite®. The filtrate was taken up in ether (300 mL), washed thrice with water (150 mL) and dried over sodium sulfate. The solution was concentrated to give 6.1 g (90%) of 4'-chloro-4-chloropropoxybenzophenone as an amber oil. 1H NMR (CDCl3): δ7.98-6.89(m,8H), 4.19(t,2H), 3.85(t,2H), 2.29(m,2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]3[C@H:15]([CH3:20])[CH2:16][NH:17][C:18](=[O:19])[C:10]3=[CH:9][C:8]=2[CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH3:20][C@H:15]1[N:11]2[C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:7][C:8]=3[CH:9]=[C:10]2[C:18](=[O:19])[NH:17][CH2:16]1
Reactant: C[C@@H]1CNC(=O)c2cc3cc(OCCCCl)ccc3n21
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: C[C@@H]1CNC(=O)c2cc3cc(OCCCN4CCCCC4)ccc3n21
Yield: 71 %

Procedure:
The title compound was synthesized in analogy to example 2, from (R)-8-(3-chloro-propoxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, piperidine (commercially available), potassium carbonate and potassium iodide, to give the desired product as a light yellow solid (71%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C@H:8]2[CH2:20][OH:21])[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[CH2:20][OH:21])[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCNC[C@H]1CO

Procedure:
Racemic trans-4-(2,5-Dimethylbenzimidazol-1-yl)-3-hydroxymethyl-N-Boc piperidine (250 mg; 0.70 mmol) was dissolved in 4M HCl in dioxane for 60 min. All volatiles were then removed under reduced pressure and the resulting sticky solid was triturated with diethyl ether to yield racemic trans-4-(2,5-dimethylbenzimidazol-1-yl)-3-hydroxymethylpiperidine dihydrochloride as a white solid (231 mg; quant.).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[C:20](OC(=O)C)(=[O:22])[CH3:21].C(OCC)(=O)C.O>N1C=CC=CC=1>[C:20]([O:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCC[C@@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC[C@@H](OC(C)=O)C(=O)O
Reaction time: 12 h

Procedure:
To (R)-(+)-2-hydroxyhexadecanoic acid (0.5 g; prepared according to the method described in Agric. Biol. Chem., 54(12), 3337-3338, 1990) dissolved in pyridine (15 ml) was added acetic anhydride (0.23 ml) at 0° C., and the mixture was stirred 12 hours. The reaction mixture was distributed into ethyl acetate and water, and the ethyl acetate layer was dried and concentrated to give (R)-(-)-2-acetoxyhexadecanoic acid (0.52 g). The acetoxy derivative was dissolved in DMF (20 ml), and N-hydroxysuccinimide (191 mg) and N,N'-dicyclohexylcarbodiimide (342 mg) were added to the solution at 0° C. The mixture was stirred at room temperature for 12 hours. The reaction mixture was then filtered, and 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (0.65 g) and triethylamine (1.1 ml) were added to the filtrate. The mixture was stirred for 12 hours. After the reaction mixture was concentrated, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK198 in the yield of 119 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[NH:25][CH2:24][C:23]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[C:2]([CH3:1])[CH:7]=3)=[O:10])[CH2:24][C:23]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
The 2-methyl-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step B (0.50 g, 2.06 mmol) was suspended in thionyl chloride (3 mL) and the mixture heated at reflux for 30 minutes. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a brown oil. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.57 g, 3.10 mmol) and N,N-diisopropylethyl amine (0.79 mL, 4.53 mmol) in dichloromethane (15 mL). After stirring for 1 hour, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent gradient of 15 to 25% ethyl acetate in hexane yielded a white foam which crystallized upon sonication with ethanol/hexane to give 0.42 g of the desired title product as a white solid, m.p. 133-135° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:26])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:9])(C)(C)C.[ClH:28]>>[ClH:28].[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[N:21]=[CH:22][CH:23]=[CH:24][N:25]=1)=[O:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ncccn1
Agent: Cl
Product: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ncccn1
Reaction time: 1 h
Yield: 99 %

Procedure:
{(S)-1-[4-Fluoro-2-(pyrimidin-2-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (350 mg, 0.93 mmol) was dissolved in hydrochloric acid (4.0M in 1,4-dioxane) and stirred for 1 h. The reaction was concentrated in vacuo to yield the title compound (289 mg, 0.93 mmol, 99%). 1H NMR (MeOD, 400 MHz): δ 8.69 (2H, d, J=5.3 Hz), 7.62 (1H, d, J=9.3 Hz), 7.60 (1H, dd, J 8.7, 2.7 Hz), 7.19 (1H, 9.0, 7.9, 2.9 Hz), 7.19 (1H, t, J=5.3 Hz), 4.21 (1H, q, J=7.2 Hz), 1.58 (3H, d, J=7.2 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19](=[O:21])[CH3:20])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)Oc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-isopropoxy-phenol (800 mg, 5.26 mmol, 1.0 eq.) and triethylamine (1.47 mL, 10.5 mmol, 2.0 eq.) in DCM (22 mL), acetyl chloride (0.45 mL, 6.36 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred at r.t. for 4 days. Sat. aq. NaHCO3 soln. was added and the layers were separated. The org. phase was dried over MgSO4, filtered, and concentrated in vacuo to give acetic acid 4-isopropoxy-phenyl ester as a yellow oil. The product was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=O)[CH2:11][C:12](O)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13](OCC)=[O:14])[CH:7]=[CH:6][N:5]=1)[CH3:2].Cl.[NH2:26][NH2:27]>C(O)C>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13](=[O:14])[NH:26][N:27]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1nccc(C(=O)CC(O)(C(=O)OCC)C(=O)OCC)n1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCNc1nccc(-c2cc(C(=O)OCC)c(=O)[nH]n2)n1
Temperature: 130 °C

Procedure:
A mixture of 2 g of diethyl 2-[2-(2-ethylaminopyrimidin-4-yl)-2-oxo-ethyl]-2-hydroxymalonate, 485 mg of hydrazine hydrochloride and 20 ml of ethanol is stirred under reflux for 24 hours. After cooling while stirring, the precipitate is filtered off with suction, heated in 4 ml of N-methylpyrrolidinone (NMP) at 130° C. for 3 hours and, after cooling, mixed with 15 ml of n-heptane and stirred. The precipitate is then filtered off with suction and stirred with methylene chloride, again filtered off with suction and dried.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([O:22][C:23]([C:25]1([C:56](Cl)=[O:57])[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:42]=[C:41]([C:43]4[CH:48]=[CH:47][C:46]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[C:45]([F:55])[CH:44]=4)[O:40][N:39]=3)=[CH:34][CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>ClCCl>[CH2:15]([O:22][C:23]([C:25]1([C:56](=[O:57])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:42]=[C:41]([C:43]4[CH:48]=[CH:47][C:46]([C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)=[C:45]([F:55])[CH:44]=4)[O:40][N:39]=3)=[CH:34][CH:33]=2)[CH2:29][CH2:30]1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccn1)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of triethyl amine (0.34 g, 0.0034 mol) in dichloromethane (20 mL), 2-amino pyridine (0.152 g, 0.0016 mol) is added. A solution of 4-chlorocarbonyl-1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}-piperidine-4-carboxylic acid benzyl ester in dichloromethane (10 mL) is added slowly into the reaction mixture at 0-50 C. It is then stirred at room temperature for 1 hr. Demineralized water (15 mL) is added to the reaction mixture, organic layer is separated and the aqueous layer is extracted with (1×20 mL) dichloromethane. Combined organic layer is dried over sodium sulphate and concentrated under reduced pressure to get the crude material, which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate 60:40) to furnish 1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}-4-(pyridin-2-ylcarbamoyl)piperidine-4-carboxylic acid benzyl ester (138) (BS6.555).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>C(C(C)=O)C.O>[CH2:22]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCn1cc(C#N)c2ccc(O)cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOc1ccc2c(C#N)cn(CC)c2c1
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodoethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are dried and concentrated. Flash chromatography (CH2Cl2) gives 94 mg (100%) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.