Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([F:18])=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[C:9]([F:18])=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: COC(=O)c1cccc(N2CC[C@H](N)[C@H](OC)C2)c1F
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC)c3F)C[C@H]2OC)nc1Cl
Yield: 36.5 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-2-fluorobenzoate obtained in Example (263b) (about 0.06 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (9 mg, 0.05 mmol), WSC hydrochloride (34 mg, 0.18 mmol), HOBT (12 mg, 0.09 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 8 mg of the title compound as a colorless oily substance (33%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:23]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2c(C)noc2cc1-c1cnc(N)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(C)noc2cc1-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 5-(3,5-dimethylbenz[d]isoxazol-6-yl)pyrazine-2-ylamine (109) (7.5 mg, 0.03 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (11 μl, 0.09 mmol) followed by addition of DIEA (47 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (90 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 7.3 mg (yield: 63.8%, purity>95%) (2,6-difluorophenyl)-N-[5-(3,5-dimethylbenzo[d]isoxazol-6-yl)pyrazin-2-yl]carboxamide (110) as white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:5]([CH2:7][NH:8][CH3:9])[N:6]=1.[CH2:20]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:13]([NH:12][C:10]([C:4]1[S:3][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:35][CH:34]=2)=[N:6][C:5]=1[CH2:7][NH:8][CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: CNCc1nc(N)sc1C(=O)NCc1ccccc1
Product: CNCc1nc(NC(=O)c2ccc(Cc3ccccc3)cc2)sc1C(=O)NCc1ccccc1

Procedure:
Following the procedure as described in Example 22, making variation only as required to use 2-amino-N-benzyl-4-((methylamino)methyl)thiazole-5-carboxamide in place of 2-amino-N-benzyl-4-((diethylamino)methyl)thiazole-5-carboxamide to react with 4-benzylbenzoic acid, the title compound was obtained; 1H NMR (CD3OD, 400 MHz) δ 7.93 (d, J=8.6 Hz, 2H), 7.35-7.15 (m, 12H), 4.49 (s, 2H), 4.06 (s, 2H), 4.02 (s, 2H), 3.09 (s, 2H), 2.37 (s, 3H); MS (ES+) m/z 471 (M+1).
Reaction SMILES: [C:1]1([S:7]([C:10]([C:25]#[N:26])=[C:11](SC)[NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]2[NH:21][CH:20]=[N:19][C:18]=2[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([NH2:30])[C:28]#[CH:29]>>[C:1]1([S:7]([C:10]([C:25]#[N:26])=[C:11]([NH:30][CH2:27][C:28]#[CH:29])[NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]2[NH:21][CH:20]=[N:19][C:18]=2[CH3:22])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCN
Reactant: CSC(NCCSCc1[nH]cnc1C)=C(C#N)S(=O)(=O)c1ccccc1
Product: C#CCNC(NCCSCc1[nH]cnc1C)=C(C#N)S(=O)(=O)c1ccccc1

Procedure:
The product of Step A is reacted with a four-fold excess of propargylamine according to the general procedure of Example 2, and the title product is produced.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:23][C:9]1[N:8]([CH2:7][C:5]2[S:6][C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)=[CH:3][CH:4]=2)[C:16]2[C:11]([CH:10]=1)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(Br)s1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(-c2cccc(C(F)(F)F)c2)s1

Procedure:
Synthesized as described in Example 310D using 1-[(5-bromo-2-thienyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 314B) and [3-(trifluoromethyl)phenyl]boronic acid: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.47, (m, 4H), 7.17 (m, 1H), 6.81 (d, J=3.6 Hz, 1H), 6.65 (s, 1H), 5.49 (s, 2H), 2.56 (s, 3H); MS (ES) m/z 463 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C>CO>[CH2:31]([O:30][C:28]([C:27]1[C:26](=[O:25])[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:22])[CH:9]([CH3:11])[CH3:10])=[N:21][CH:33]=1)=[O:29])[CH3:32]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Solvent: CO
Product: CCOC(=O)c1cnc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 100 °C

Procedure:
Following the procedure of Veale, J. Org. Chem., 58,4490 (1993), to [1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (10.86 g, 35.6 mmol) in methanol (160 mL) was added diethyl ethoxymethylenemalonate (7.7 g, 35.6 mmol). The reaction is equipped with a Dean-Stark trap. The reaction was heated at 100° C. until all solvent was removed. The residue was dissolved in methylene chloride, washed with 1 N HCl and water, dried (Na2SO4), and concentrated. The resulting pale yellow syrup was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:14][S:15]([O:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1

Procedure:
Thus, for example, when 1-benzyl-3-pyrrolidinol is reacted with methanesulfonyl chloride in the presence of sodium hydroxide using a mixed solvent composed of toluene and water as the reaction solvent and the reaction mixture is obtained in the form of a two-phase system composed of a toluene phase and an aqueous phase, it is possible to obtain 1-benzyl-3-pyrrolidinol methanesulfonate as a concentrate by removing the solvent by concentrating, under reduced pressure, from the toluene solution obtained by phase separation of the reaction mixture, after or without washing the toluene phase with water.
Reaction SMILES: CO[C:3]1[C:4](=O)[C:5](=[O:9])[C:6]=1[O:7]C.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:3]2[C:6](=[O:7])[C:5](=[O:9])[C:4]=2[N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CCO
Product: CN1CCN(c2c(N3CCN(C)CC3)c(=O)c2=O)CC1

Procedure:
A solution of 1.0 gram of 3,4-dimethoxy-3-cyclobutene-1,2-dione dissolved in 30 ml. of absolute ethanol is mixed with a solution of 1.4 grams of 1-methylpiperazine in 30 ml. of absolute ethanol. The resulting mixture is stirred and heated to reflux for 5 hours under an atmosphere of dry nitrogen. After concentration to approximately one-sixth the volume under reduced pressure, the reaction mixture is cooled and crystallization is induced by scratching. The resultant precipitate is filtered, washed with 0.5 ml. of absolute ethanol, and dried in a steam cabinet. The resulting, product, 3,4-bis(4-methyl-1-piperazinyl)-3-cyclobutene-1,2-dione is obtained as white crystals melting at about 189°-191° C.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][C:15](=[CH:18][CH2:19]O)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42]N1C(=O)CCC1=O>O1CCCC1>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][C:15](=[CH:18][CH2:19][Br:42])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(=CCO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(=CCBr)CC1
Reaction time: 2 h

Procedure:
To a mixture of 2-(1-p-nitrobenzyloxycarbonyl-4-piperidinylidene)ethyl alcohol (1.13 g) and triphenyl phosphine (1.94 g) in tetrahydrofuran (65 ml) was added N-bromosuccinimide (1.31 g) at room temperature and stirred for 2 hours. The reaction mixture was filtered to remove any insoluble materials and the filtrate was concentrated in vacuo to give an oily residue which was purified by silica gel chromatography to give 2-(1-p-nitrobenzyloxycarbonyl-4-piperidinylidene)ethylbromide.
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].[CH3:5][O:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:10][C:9]=1[OH:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:5][O:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:10][C:9]=1[O:18][CH:1]([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC(C)=O)cc1O
Reactant: CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OC(C)=O)cc1OC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.6 %

Procedure:
Isopropanol (0.63 mL, 8.2 mmol) was added to a mixture of 4-Acetoxy-2-methoxy-benzoic acid methyl ester (Step 1, Example 299, 1.18 g, 5.6 mmol), Ph3P (1.84 g, 7.0 mmol), and dichloromethane (15 mL). Then DEAD (1.12 mL, 7.1 mmol) was added to the reaction. Reaction was stirred at room temperature for two days. Reaction solution was concentrated by rotary evaporation and the resulting residue was purified with silica gel prep plates and 1:5 EtOAc/Hexane as eluent. Obtained 1.11 g of 4-Acetoxy-2-isopropoxy-benzoic acid methyl ester in 79% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:5][C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][S:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:32]([N+:46]([O-:48])=[O:47])[CH:31]=2)(=[O:29])=[O:28])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH3:56][N:57]([CH3:61])[C:58](Cl)=[O:59]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:58]([N:57]([CH3:61])[CH3:56])=[O:59])[CH2:16][CH2:17]2)[CH:6]=[CH:5][C:4]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][S:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[C:32]([N+:46]([O-:48])=[O:47])[CH:31]=2)(=[O:28])=[O:29])=[O:25])=[CH:22][CH:23]=1
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(CCCN2CCNCC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCCSc3ccccc3)c([N+](=O)[O-])c2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CCCN2CCN(C(=O)N(C)C)CC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCCSc3ccccc3)c([N+](=O)[O-])c2)cc1
Reaction time: 0.5 h

Procedure:
A solution of Example 183D (108 mg, 0.157 mmol) and triethylamine (45 μL, 0.32 mmol) in THF (2 mL) at room temperature was treated with dimethylcarbamic chloride (14 uL, 0.157 mmol), and stirred for 30 minutes. The mixture was purified by flash column chromatography on silica gel with 10:10:80 methanol/acetonitrile/ethyl acetate to provide the desired product. MS (ESI(−)) m/e 759 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ1.93 (m, 2H), 2.65 (t, 2H), 2.74 (s, 6H), 2.89 (m, 2H), 3.08 (m, 4H), 3.34 (m, 6H), 3.61 (m, 2H), 3.75 (s, 3H), 6.88 (d, 1H), 6.96 (s, 1H), 7.01 (d, 1H), 7.21 (m, 2H), 7.30 (t, 2H), 7.41 (m, 3H), 7.88 (d, 1H), 7.89 (d, 2H), 8.51 (d, 1H), 8.54 (t, 1H).
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[NH:13][C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([C:2]2[C:14](=[O:15])[NH:13][C:5]3[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CSc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(C)nc(SC)nc3[nH]c2=O)cn1
Temperature: 100 °C

Procedure:
To a solution of 6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (50 mg, 0.17 mmol), 6-methoxypyridin-3-ylboronic acid (40.1 mg, 1.1 equiv), dichlorobis(triphenylphosphine) palladium(II) (6.13 mg, 0.008 mmol), DMF (2 mL) in a 5 mL microwave vial was added potassium carbonate (3 M, 1.1 equiv). The solution was degassed with N2 for 10 min before being capped and heated in the microwave reactor for 1 h. at 100° C. The reaction was poured into 20 ml brine and the precipitate was collected by filtration. It was further purified by chromatography (80% thylacetate/hexane). The title compound was obtained as a solid (30 mg, 55% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-])=O)[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl-].[NH4+]>CO.O.[Zn]>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([NH2:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(N)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 108.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methyl ester (prepared as in Example 14, 1.50 g, 4.22 mmol) in methanol (30 mL) was treated with a solution of ammonium chloride (474 mg, 8.86 mmol) in water (3 mL). The reaction mixture was stirred at 25° C. for 5 min and then treated with zinc dust (2.70 g, 41.36 mmol). The reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The filtrate was concentrated in vacuo. The resulting orange oil was dissolved in ethyl acetate, dried over magnesium sulfate, filtrated, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.49 g, 98%) as a white solid: mp 98-100° C.; EI-HRMS m/e calcd for C16H23NO4S (M+) 325.1348, found 325.1358.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10]C)[CH:5]=[N:6][C:7]=1[Cl:8].CCN(CC)CC.CC(O[C:23]([CH3:25])=[O:24])=O>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:23](=[O:24])[CH3:25])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(=O)OC(C)=O
Reactant: CNCc1cnc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of the amine from step (c) above (1.77 g, 10 mmol) and Et3N (2.78 mL, 20 mmol, Aldrich) was added Ac2O dropwise with stirring at room temperature. The mixture was stirred for 30 min at room temperature, diluted with EtOAc (30 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 80% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 219 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([NH2:27])([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:27][CH:24]([CH3:26])[CH3:25])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 5 h

Procedure:
A solution of (3S,4S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7.7 g, 22.41 mmol) and isopropylamine (5.78 mL, 67.24 mmol) in 1,2-dichloroethane (200 mL) is stirred 25 min before the addition of NaBH(OAc)3 (11.88 g, 56.03 mmol). The solution is stirred for 5 h, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The aqueous layer is back extracted twice with CH2Cl2 and the combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is used in the next step without further purification. TLC, Rf (CH2Cl2/MeOH 9:1)=0.39. MS (LC-MS): 387.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([O:25][C:26]([NH:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[NH:30])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:30][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[N:28][C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)NC(=N)NC(=O)OCc1ccccc1
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=NC(=O)OCc1ccccc1)N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 31.8 %

Procedure:
To the solution of the crude dione 15 (0.10 g, 0.346 mmol) in 25 ml of dry CHCl3 was added N-(benzyloxycarbonyl)-N′-isopropylguanidine (16) (0.122 g, 0.519 mmol) at room temperature. The reaction mixture was heated at 50° C. for 18 hours and then quenched with water. The mixture was extracted with chloroform and dried over Na2SO4. The CHCl3 was removed in vacuo and the crude product was recrystallized from hexanes/CHCl3 to yield compound 4d as light yellow crystals (51 mg, 0.11 mmol, 31%), mp 211° C. 1H NMR (300 MHz, CDCl3): δ 7.54–7.51(m, 2H), 7.41 (s, 5H), 7.25 (dd, J=8.6 and 2.4 Hz, 1H), 5.25 (s, 2H), 4.12 (m, 1H), 2.46 (d, J=6.6 Hz, 6H). 13C NMR: δ 170.83, 155.86, 153.87, 133.89, 132.56, 132.19, 131.22, 130.42, 129.21, 128.93, 128.65, 128.61, 125.60, 69.24, 45.25, 22.28. MS (m/z): 476 (M+), 370, 316, 314, 236. Anal. (C21H19Cl2N5O4) C, H, Cl, N.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH:18]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH:18]([O:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
tert-Butyl 2-(cholestan-3-yloxy)acetate 129 (634 mg, 1.26 mmol) was taken up in DCM (4 mL) before TFA (1 mL) was added. The solution was stirred at room temperature for 90 mins. The solvent was evaporated and the residue purified using a short silica plug (SiO2: DCM to 100:5 DCM:MeOH) before being recrystallized from hexane to yield 439 mg of the white solid product (78%). 1H nmr (400 MHz, CDCl3) δ: 4.25 (s, 2H, CH2O), 3.37 (m, 1H, CHO), 1.99-0.58 (m, 31H), 0.89 (d, 3H, J=6.6, CH3), 0.85 (d, 3H, J=2.0, CH3), 0.84 (d, 3H, J=1.4, CH3), 0.80 (s, 3H, CH3), 0.64 (s, 3H, CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](O)([CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:20]S(O)(=O)=O>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([CH3:18])[CH2:10][C:9]1=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(O)c2ccccc21
Reactant: O=S(=O)(O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CC(=O)N(C(=O)OC(C)(C)C)c2ccccc21
Yield: 92 %

Procedure:
A solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4hydroxy-4-methylquinoline (109 mg, 0.41 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (10 mg) and a trace of conc. H2SO4 at rt for 7 h. Filtration over Celite™ afforded 93 mg (92%) of 1-tert-Butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinolinone. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.62(d, J=8.1, 1H), 7.16 (d, J=7.8, 1H), 7.11 (ddd, J=7.8, 7.8, 1.6, 1H), 7.01 (ddd, J=7.7, 7.5, 1.0, 1H), 3.71 (m, 2H), 2.87 (ddq, J=6.8, 6.8, 6.8, 1H), 2.04 (dddd, J=7.4, 7.4, 7.4, 6.1, 1H), 1.61 (m, 1H), 1.51 (s, 9H), 1.3 (d, J=6.8, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][C:28]1=[O:37])[C:25]#[CH:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:28]3=[O:37])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Reactant: C#CCN1C(=O)CCc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CCc4ccccc43)cc1C(c1ccccc1F)=NC2
Reaction time: 0.17 h

Procedure:
A mixture of 0.84 g (2 mmol) of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, 0.48 g (2.6 mmol) of 3,4-dihydro-1-(2-propynyl)-2(1H)quinolinone, 80 mg of triphenylphosphine, 20 mg of cuprous iodide, 1.5 ml of triethylamine and 50 ml of dimethylformamide was deqassed with argon for 10 minutes. Palladium acetate, 25 mg, was then added and stirring was continued for 18 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated. dried and evaporated and the residue was chromatographed over 50 g of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. Crystallization of the combined clean fractions from ethyl acetate gave colorless crystals of 1-{3-[6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][ 1,4]benzodiazepin 8-yl]-2-propynyl}3,4 dihydro-2(1H)-quinolinone with m.p. 236°-239°.