Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[CH2:29]([O:31][C:32](=[O:41])[C:33]([N:35]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]1)=[O:34])[CH3:30]>C1COCC1.CCN(C(C)C)C(C)C>[CH2:29]([O:31][C:32](=[O:41])[C:33]([N:35]1[CH2:39][CH2:38][CH:37]([NH:40][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[CH2:36]1)=[O:34])[CH3:30]
Reactant: CCOC(=O)C(=O)N1CCC(N)C1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(=O)N1CCC(NC(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
106.3 5-Chloro-thiophene-2-carboxylic acid (0.94 g) was dissolved in THF (10 ml) and CDI (0.94 g) was added. This mixture was stirred at 25° C. for 30 min. A solution of (3-amino-pyrrolidin-1-yl)-oxo-acetic acid ethyl ester trifluoroacetate (1.57 g), dissolved in THF (10 ml) and DIEA (0.89 ml), is added to the reaction mixture. The obtained reaction mixture was stirred for 18 h at 25° C. Finally, the reaction mixture was evaporated to dryness. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2 to CH2Cl2/MeOH 98:2) to give {3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidin-1-yl}-oxo-acetic acid ethyl ester (1.9 g) as an orange oil. MS 331.3 ([M+H]+, Cl-isotopes).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10]1)[CH2:4][C:5]([OH:7])=[O:6].CCN(C(C)C)C(C)C.CN(C=O)C.Br[CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)=[O:44]>C(OCC)(=O)C>[F:26][C:2]([F:1])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)[CH2:10]1)[CH2:4][C:5]([O:7][CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)=[O:44])=[O:6]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=C(O)CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)OCC(=O)c1ccc(Cl)cc1
Yield: 77.5 %

Procedure:
In a 10 mL pear-shaped flask, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanoic acid (50 mg, 130 μmol) and DIEA (50.6 mg, 68.3 μl, 391 μmol) were combined with DMF (2 ml) to give a colorless solution. 2-Bromo-1-(4-chlorophenyl)ethanone (60.9 mg, 261 μmol) was added and the resultant mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed with brine and H2O, dried with MgSO4, filtered and concentrated. The crude residue was purified on a silica column (100% hexane to 30% ethyl acetate/hexane eluent) to afford 54 mg (77%) of 2-(4-chlorophenyl)-2-oxoethyl 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)-phenyl)piperidin-1-yl)methyl)butanoate as an oil. MH+=536.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(CO)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(C=O)c1
Reaction time: 1.25 h
Yield: 42.8 %

Procedure:
To a stirring mixture of 3.6 g (17.9 mmol) of methyl 2-chloro-6-(hydroxymethyl)isonicotinate, 8.9 g of 4A powdered molecular sieves, 3.1 g (26.5 mmol) of NMO in 55 mL of CH2Cl2 was added (after about 10 min.) 659 mg (1.87 mmol) of TPAP. The mixture began to gently reflux, and the mixture was stirred for 75 min., filtered through Celite, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 1.53 g of methyl 2-chloro-6-formylisonicotinate in 43% yield as an off-white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@@H:10]([NH:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1)[CH2:11][CH2:12][CH3:13].O>C(Cl)(Cl)Cl>[Br:1][C:20]1[N:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:22]2[C:18]([N:19]=1)=[C:17]([NH2:30])[N:16]=[C:15]([NH:14][C@H:10]([CH3:9])[CH2:11][CH2:12][CH3:13])[N:23]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC[C@@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC[C@@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Yield: 29.6 %

Procedure:
N-Bromosuccinimide (2.08 g, 11.69 mmol) was added portionwise to a stirred solution of N2-[(1R)-1-methylbutyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (2.27 g, 7.46 mmol) in chloroform (30 ml) at 0° C. under at atmosphere of nitrogen. The reaction mixture was allowed to stir for 1.5 hours when chloroform (20 ml) and water (50 ml) were added. After mixing the layers were separated using a hydrophobic frit, the aqueous layer was washed with an additional portion of chloroform and the combined organic extracts were evaporated. The residue was dissolved in dichloromethane and purified on a 110 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white foam (0.846 g).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[C:18]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1)#[N:19]>CCOC(C)=O>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH:26][C:15](=[O:17])[CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(ncn2CC(=O)NCCc2ccc(C#N)cc2)n(C)c1=O
Yield: 21.2 %

Procedure:
Compound 409 (93 mg, 21%) was prepared from 101 (300 mg, 1.3 mmol) and 115 (175 mg, 1.2 mmol) according to General Procedure B. MS (APCI): m/z 367 [M+H]+. Anal. Calcd. for C18H18N6O3.0.04 EtOAc.0.1H2O: C, 58.68; H, 5.02; N, 22.61. Found: C, 58.75; H, 5.01; N, 22.46.
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][NH:5][NH:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[C:12]1([CH2:11][O:9][C:8](=[O:10])[CH2:7][NH:6][NH:5][CH:4]=[N:3][NH2:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN=CNNCC(=O)O
Reactant: OCc1ccccc1
Agent: Cl
Product: NN=CNNCC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
HCl (g) was bubbled through a suspension of [2-(aminoiminomethyl)hydrazino]-acetic acid (2.00 g, 15.2 mmol) in benzyl alcohol (30 mL). The reaction was stirred for about an hour until everything was in solution. The crude product was precipitated out by adding Et2O. This material was recrystallized from MeOH/EtOAc to yield [2-(aminoiminomethyl)hydrazino]acetic acid phenylmethyl ester monohydrochloride (3.20 g, 82%) as a white crystalline solid.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[C:30]#[CH:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.ClCCl.CO.N>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[C:30]#[C:31][C:2]3[CH:14]=[CH:13][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Ic1ccc(CN2CCCCC2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(CN2CCCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)piperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 6 mg (4% of theory); melting point: 179.5° C.; C27H25ClN2O (M=428.96); calc.: molecular ion peak (H+ H)+: 429/431; found: molecular ion peak (M+H)+: 429/431; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](Br)[CH:14]=[C:15]([CH3:21])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:24]1[CH:25]=[C:26](/[CH:27]=[CH:28]/[C:13]2[CH:14]=[C:15]([CH3:21])[CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:19]=[C:18]3[OH:20])[CH:29]=[CH:30][CH:31]=1
Reactant: C=Cc1cccc(Cl)c1
Reactant: Cc1cc(Br)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/c2cccc(Cl)c2)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Temperature: 120 °C

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-8-bromo-6-methylquinazolin-4-ol (29 mg) in DMF (2 mL) was added 3-chlorostyrene (0.020 mL), followed by palladium acetate (4.0 mg), tri-o-tolylphosphine (9.0 mg) and N,N-diisopropylethylamine (0.20 mL). The resulting mixture was heated at 120° C. for 24 h, then was cooled to room temperature. The supernatant was concentrated in vacuo to a dark semi-solid which was triturated with 50% (v/v) methanol/dichloromethane (4 mL) and diethyl ether (ca. 0.1 mL) to afford the title compound as a tan solid (20 mg). 1H NMR (300 MHz, DMSO-d6): δ11.0 (s, 1H), 9.06 (s, 1H), 8.55 (d, J=2.6 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.98 (d, J=16.7 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.69 (dd, J=1,8, 1.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.59 (dd, J=8.0, 1.8 Hz, 1H), 7.43 (dd, J=8.9, 8.0 Hz, 1H), 7.39 (dd, J=8.6, 2.6 Hz, 1H), 7.37 (d, J=16.7 Hz, 1H), 7.35 (m, 1H), 2.43 (s, 3H). HPLC (Method B) 11.7 min. MS (APCI+): m/z 456, 458.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH3:38])(=[O:37])=[O:36])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=1[O:27]C)(=[O:18])=[O:17])[CH3:2].[Cl-].[Li+].C(OCC)(=O)C.Cl>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH3:38])(=[O:36])=[O:37])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=1[OH:27])(=[O:18])=[O:17])[CH3:2]
Reactant: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Temperature: 140 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 4.62 g of ethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetate in 40 mL of N,N-dimethylformamide was added 1.03 g of lithium chloride, and the mixture was stirred at 140° C. for 2 hours. After being cooled to room temperature, the reaction mixture was poured into a mixture of 60 mL of ethyl acetate, 6 mL of toluene, and 32 mL of 1 mol/L hydrochloric acid. The organic layer was separated, and washed with 1 mol/L hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: acetic acid-ethyl acetate) to give 3.67 g of ethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetate as a colorless amorphous material.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:22]Br>C(O)(=O)C.C(Cl)Cl.C(=O)([O-])O>[Br:22][C:3]1[C:4]2[CH:9]=[C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sccc2c1
Reactant: BrBr
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2scc(Br)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of (1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide (30 mg, 0.1 mmol) in acetic acid (2 mL) was added bromine (5.5 μL, 0.1 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with methylene chloride (5 mL) and neutralised by careful addition of a saturated hydrogen carbonate solution. The layers were separated and the aqueous was extracted with methylene chloride (2×5 mL). The organic extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo to give (1S,2R,3S,4R)-3-(3-bromo-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide as a glass (37 mg, 97%). M/e 378/380 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C)C=O.C(O)(C)C.CCOCC>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:15][CH:14]=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(C)O
Product: C=CCOC1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of N-acetyl-4-hydroxypiperidine (100 g.) in dimethylformamide (250 ml.) was added dropwise to sodium hydride (38 g., 50% mineral oil dispersion) under an atmosphere of nitrogen. The mixture was stirred for 2 hours then allyl bromide (93 g.) was added slowly whilst maintaining the reaction temperature at 25° C. by external cooling. The mixture was then stirred at room temperature overnight, diluted with isopropanol (20 ml.) and ether (500 ml.), filtered, and evaporated in vacuo. Distillation of the residue gave N-acetyl-4-allyloxypiperidine (108.8 g.), B.P. 128° C./2 mm, identified spectroscopically.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][C:10]=1[C:11]#[N:12].CS(C)=O.[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:27]1)(=[O:25])[CH3:24]>C(OCC)(=O)C>[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:15]2[C:14]([F:18])=[CH:13][C:10]([C:11]#[N:12])=[C:9]([Cl:8])[N:16]=2)[CH:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:27]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCC(N)C(NC(=O)OC(C)(C)C)C1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)N1CCC(Nc2nc(Cl)c(C#N)cc2F)C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
Triethylamine (0.096 ml) and 2,6-dichloro-5-fluoronicotinonitrile (109 mg) were added to a DMSO (2 ml) solution containing tert-butyl (1-acetyl-4-aminopiperidin-3-yl)carbamate (147 mg) obtained in the 4th step, followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction solution. The reaction solution was washed with water and saturated saline and dried over anhydrous sodium sulfate. Next, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:3). A light yellow solid of tert-butyl (1-acetyl-4-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)piperidin-3-yl)carbamate (91 mg) was thus obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH:24]([NH:27][CH:28]([CH3:30])[CH3:29])([CH3:26])[CH3:25]>CN(C)C=O>[CH:24]([N:27]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH:28]([CH3:30])[CH3:29])([CH3:26])[CH3:25]
Reactant: CC(C)NC(C)C
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CC(C)N(Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1)C(C)C
Yield: 61.7 %

Procedure:
72 g (212 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 80° for 16 hours in 150 ml (1.06 mol) of diisopropylamine and 300 ml of N,N-dimethylformamide. After evaporating the solvent the residue was dissolved in methylene chloride and the solution was extracted twice with 100 ml of 2N hydrochloric acid. The acidic phase was made alkaline with conc. sodium hydroxide solution and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate/methanol/acetic acid 95/3/2 and recrystallization from ethanol there were obtained 51.6 g (61%) of 3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 117°-119°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CCOCC.O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1O
Temperature: 110 °C
Yield: 117.3 %

Procedure:
In a vial 2,4-dihydroxybenzonitrile (300 mg, 2.2 mmol), 2-chloro-5-nitropyridine (351.96 mg, 2.22 mmol) and K2CO3 (920 mg, 6.62 mmol) were dissolved in DMF (5 mL). The reaction was heated for 1 hour under microwave irradiations (Set Temperature: 110° C.). The reaction mixture was diluted with Et2O and water, acidified with aqueous 1N HCl until pH=2, the phases were separated and the organics were dried over Na2SO4. The solid was filtered out and the solvent was removed affording crude 2-hydroxy-4-[(5-nitro-2-pyridinyl)oxy]benzonitrile (664 mg) as a brown solid. To a solution of this crude in dry DMF (5 mL) potassium carbonate (460 mg, 3.33 mmol) and isopropyl bromide (313 μL, 3.33 mmol) were added and the reaction mixture was stirred overnight at 50° C. The reaction was diluted with brine (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 25 g) eluting from 100:0 to 75:25 cyclohexane/ethyl acetate affording the title compound (260 mg) as white solid.
Reaction SMILES: C(N(CC)CC)C.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18].CS(O[CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][N:45]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:46][C@H:47]([OH:59])[C:48]2[C:56]3[S:55][C:54](=[O:57])[NH:53][C:52]=3[C:51]([OH:58])=[CH:50][CH:49]=2)=[CH:40][CH:39]=1)(=O)=O>C(#N)C>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][N:27]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[CH:40][C:41]([CH2:44][N:45]([CH2:46][C@H:47]([OH:59])[C:48]4[C:56]5[S:55][C:54](=[O:57])[NH:53][C:52]=5[C:51]([OH:58])=[CH:50][CH:49]=4)[C:60](=[O:61])[O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[CH:42][CH:43]=3)[CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(c1nc2ccccc2s1)N1CCOC2(CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)c2nc4ccccc4s2)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C

Procedure:
Triethylamine (0.25 mL) was added to a solution of benzo[d]thiazol-2-yl(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 106, step b) (0.22 g) in acetonitrile (2.5 mL). This solution was added to a solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.5 g) in acetonitrile (2.5 mL). The resulting mixture was heated at 80° C. for 48 hours. The reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a cream foam. Yield 0.34 g.
Reaction SMILES: Br[C:2]1[C:3]([F:33])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]([OH:31])[C:20]4[N:24]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:23]=[CH:22][CH:21]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:32]=1.[CH3:34][C:35]([OH:39])([CH3:38])[C:36]#[CH:37].C(NC(C)C)(C)C>CN(C=O)C>[F:33][C:3]1[C:2]([C:37]#[C:36][C:35]([OH:39])([CH3:38])[CH3:34])=[CH:32][C:6]2[C:7]3[N:8]([C:13]([CH:19]([OH:31])[C:20]4[N:24]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:23]=[CH:22][CH:21]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:12][CH:11]([C:5]=2[CH:4]=1)[CH2:10]3
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)n1c-2nc(C(N)=O)c1C(O)c1ccnn1C1CCCCO1

Procedure:
9-Fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford the title compound which was carried forward to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6](/[CH:19]=[CH:20]/[C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[Li+].[OH-].CO>C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6](/[CH:19]=[CH:20]/[C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(/C=C/c4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 55 °C

Procedure:
To a solution of 65.0 mg (0.190 mmol) of ethyl (E)4-[2-(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)- 2-naphthalenyl)ethenyl)-benzoate (Compound 44) in 4.0 ml of THF was added 30.0 mg of LiOH (0.909 mmol, 1.0 ml of a 1.1M solution) and 1.0 ml of MeOH. The solution was heated to 55° C. for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in H2O and extracted with hexanes. The aqueous layer was acidified to pH 1 with 10% HCl, and extracted with Et2O. The combined organic layers were washed with saturated aqueous NaCl, diluted with EtOAc to give a clear solution, and dried over Na2SO4. The solvents were removed under reduced pressure to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 7.86 (2H, d, J=8.4 Hz), 7.66 (2H, d, J=8.4 Hz), 7.58 (1H, dd, J=1.7, 8.1 Hz), 7.41 (1H, d, J=8.1 Hz), 7.28 (1H, d, J=16.5 Hz), 7.23 (4H, s), 7.08 (1H, d, J=1.7 Hz), 7.07 (1H, d, J=16.5 Hz), 5.97 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.31 (2H, d, J=4.6 Hz), 1.29 (6H, s).