Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@@H:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]3)O1.Br[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([F:40])[C:34]=1[C:41]1[N:45]=[C:44]([CH3:46])[O:43][N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O.[Pd](Cl)Cl>[Cl:39][C:37]1[CH:36]=[C:35]([F:40])[C:34]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[C:33]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@@H:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]3)[CH:38]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)C(F)(F)F)CC2)OC1(C)C
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2Br)no1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)C(F)(F)F)CC2)no1
Temperature: 80 °C
Yield: 54.3 %

Procedure:
1-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid[(S)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yl]-amide (intermediate A-2) (0.145 g, 331 μmol) and 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) (106 mg, 364 μmol) were dissolved in DMSO (5.00 ml), then sodium carbonate (87.7 mg, 827 μmol), dissolved in water (0.63 ml) was added, followed by (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) (12.1 mg, 16.5 μmol, eq: 0.05). This mixture was heated up to 80° C. for 2 hours, then poured into H2O (50 ml) and extracted with CH2Cl2 (2×25 mL). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (0.213 g) which was purified by flash chromatography (silica gel, 20 g, 10% to 50% EtOAc in heptane) to yield the title compound (0.094 g, 54%) as light yellow solid. MS: 523.1 (MH+, 1Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][F:28])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1.CCOC(C)=O>CCO.[Pt]>[F:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][C:7]([NH2:9])=[C:6]([O:12][CH3:13])[CH:5]=3)[CH2:15][CH2:16]2)[CH2:21][CH2:22]1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCN(CCF)CC2)CC1
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(OC)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[2,5-Bis(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(2-fluoroethyl)piperazine (1.36 g, 3.43 mmol) was taken up in EtOH (50 mL) and EtOAc was added to help with solubility. The catalyst, 5% sulfided platinum on carbon (140 mg) was added. The reaction was placed on a Fischer-Porter Hydrogenator under 50 psi of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound of step F without further purification (1.2 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.42 (s, 1H), 6.28 (s, 1H), 4.53 (t, J=4.9 Hz, 1H), 4.41 (t, J=4.9 Hz, 1H), 4.31 (s, 2H), 3.63 (s, 3H), 3.61 (s, 3H), 3.15 (s, 2H), 2.57 (t, J=4.8 Hz, 1H), 2.49-2.51 (m, 1H), 2.45-2.48 (m, 6H), 2.42 (d, J=13.4 Hz, 4H), 2.17 (t, J=11.3 Hz, 1H), 1.73 (d, J=11.0 Hz, 2H), 1.46 (qd, J=11.7, 3.5 Hz, 2H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([C:18]3[CH:19]=[C:20]([NH:24][CH:25]=[O:26])[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[N:14][C:13]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29](I)[CH3:30]>CN(C)C=O>[C:1]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([C:18]3[CH:19]=[C:20]([N:24]([CH2:29][CH3:30])[CH:25]=[O:26])[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[N:14][C:13]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CNc1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C=O)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1
Reaction time: 8 h

Procedure:
As described for Example 59, 0.01 mole of N-[3-(3-benzoylpyrazolo[1,5-a]pyrimidin-7-yl]phenyl]formamide in 30 ml of dimethylformamide is reacted with 0.384 g of 60% sodium hydride in oil. To the mixture is added 0.85 ml of ethyl iodide and the mixture stirred overnight. Work up as for Example 59 gives the desired product.
Reaction SMILES: [Li+].[OH-].[CH:3]1[C:15]2[CH:14]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[NH:31][C:30](=[O:32])[C:29]5[N:33]([CH2:36][C:37]([O:39]CC)=[O:38])[CH:34]=[N:35][C:28]=5[CH:27]=4)[CH2:22][CH2:21]3)=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.O1CCCC1>O1CCCC1.O>[CH:12]1[C:13]2[CH:14]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[NH:31][C:30](=[O:32])[C:29]5[N:33]([CH2:36][C:37]([OH:39])=[O:38])[CH:34]=[N:35][C:28]=5[CH:27]=4)[CH2:22][CH2:21]3)=[O:19])[C:15]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cn1cnc2cc(N3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)[nH]c(=O)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1cnc2cc(N3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Aqueous 1N LiOH (5 equiv.) was added to a solution of 4-(3-ethoxycarbonylmethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-6-yl)-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, 6 dissolved in tetrahydrofuran/water (7:1) at room temperature Then the mixture was stirred at room temperature for 10 min. The solution was acidified (pH=3˜4) with 1 N HCl. Tetrahydrofuran was then added. Purification by silica gel chromatography gave 7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH3:13])[NH2:5].N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: COCCOc1ccc(N)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COCCOc1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirred solution of 3-fluoro-4-(2-methoxyethoxy)aniline (2.0 g, 10.8 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (2.5 mL, 32.4 mol, 3.0 eq.) and phenyl chloroformate (1.36 mL, 10.8 mmol, 1.0 eq.) at 0° C. and stirred at RT for 1 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and evaporated again. The resulting residue was purified by column chromatography using EtOAc/PE (1:4) as eluent to yield phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (2.7 g, 76.8%) as a white solid (TLC system: EtOAc/PE (3:7), Rf: 0.5).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[C:16]2[C:11]3=[C:12]([C:17](=[O:21])N[C:19](=[O:20])[C:10]3=[CH:9][CH:8]=1)[CH:13]=[CH:14][CH:15]=2>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:17](=[O:21])[C:12]2=[C:11]3[C:16](=[CH:15][CH:14]=[CH:13]2)[C:7]([Cl:6])=[CH:8][CH:9]=[C:10]3[C:19]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: O=C1NC(=O)c2ccc(Cl)c3cccc1c23
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Yield: 76.2 %

Procedure:
This compound has been reported previously. This preparation is similar to previously reports (see e.g. Daffy et al. Chem-Eur J 1998, 4, 1810-1815; de Silva et al., Chem Rev 1997, 97, 1515-1566). A portion of n-butylamine (5.00 mL, 50.6 mmol) was added to a suspension of 4-chloronaphthalene-1,8-dicarboximide (11.7 g, 50.5 mol) in 160 mL of toluene. This mixture was brought to reflux for 17 hours to give a dark black-brown solution. Crystallization from hexanes/toluene at −10° C. gave 1ax as a pure brownish-yellow powder (11.1 g, 76%). 1H NMR: δ=8.65 (d, 1H, J=7.4 Hz), 8.58 (d, 1H, J=8.6 Hz), 8.49 (d, 1H, J=7.9 Hz), 7.85 (t, 1H, J=7.9 Hz), 7.81 (d, 1H, J=7.9 Hz), 4.18 (t, 2H, J=7.6 Hz), 1.72 (m, 2H), 1.45 (m, 2H), 0.98 (t, 2H, J=7.4 Hz). 13C{1H} NMR: δ=163.8, 163.5, 139.0, 132.0, 131.2, 130.6, 129.3, 129.1, 127.9, 127.5, 123.2, 121.7, 40.5, 30.3, 20.5, 14.0. ESI/MS m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].Cl.[NH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7](=[O:8])[NH:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]1)=[O:5]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1cc(F)ccc1N1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(F)ccc1N1CCC(C(=O)O)CC1

Procedure:
The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile was added dropwise to the solution of 53 mg of 1-(2-amino-4-fluorophenyl)piperidine-4-carboxylic acid hydrochloride in 3 ml of acetonitrile with stirring. The mixture was stirred at RT for 6 h and the precipitate was filtered off with suction and dried at RT under reduced pressure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:19])[NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[H-].[Na+].O>CN(C)C=O>[O:19]=[C:6]1[NH:5][CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(NC(=O)NCCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCNC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.9 %

Procedure:
A mixture of ethyl 4-aminobenzoate (496 mg) and pyridine (60 μL) was dissolved in dichloromethane (3 mL), 1-chloro-3-isocyanatopropane (323 μL) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give ethyl 4-[3-(3-chloropropyl)ureido]benzoate (810 mg). The obtained ethyl 4-[3-(3-chloropropyl)ureido]benzoate (810 mg) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (250 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated from the organic layer. To the obtained residue was added diisopropyl ether, and the precipitate was collected by filtration to give the title compound (84 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][N:33]1[CH:38]=[CH:37][C:36]([Sn](C)(C)C)=[CH:35][C:34]1=[O:43]>[Pd].C1(C)C=CC=CC=1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([S:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([C:36]5[CH:37]=[CH:38][N:33]([CH3:32])[C:34](=[O:43])[CH:35]=5)=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[CH:21][CH:22]=[N:23]2)=[N:28][CH:27]=1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: Cn1ccc([Sn](C)(C)C)cc1=O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COc1cnc2c(Sc3ccc(Nc4nnc(-c5ccn(C)c(=O)c5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C

Procedure:
4-Chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (148 mg, 331 μmol), 1-methyl-4-(trimethylstannyl)pyridin-2(1H)-one (90 mg, 331 μmol), and the Pd catalyst were added to toluene and heated to 100° C. for 2 h. The mixture was concentrated and purified by silica gel chromatography using 0 to 30% MeOH in ethyl acetate. MS: M+H+=519.
Reaction SMILES: [C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[C:1](=[O:19])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(OCc2ccccc2)c1
Temperature: 65 °C
Yield: 96.2 %

Procedure:
To an acetone (100 mL) solution of tert-butyl 4-tert-butyl-3-hydroxyphenyl carbonate (J. Org. Chem. 2001, 66, 3435) (5.5 g, 20.7 mmol) were added potassium carbonate (8.6 g, 63 mmol) and benzyl bromide (3.0 ml, 25.0 mmol). The stirred mixture was refluxed at 65° C. for 4 hours. The precipitate was filtered off and washed with acetone. The filtrate was concentrated under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane= 1/30 to furnish 7.1 g (96% yield) of the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:27])=[O:26])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3ccccn3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(-c4ccccn4)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4- carboxylic acid ethyl ester (1.83 g, 3.7 mmol) dissolved in THF:methanol (3:1 150 ml) and 10N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.38 g (80%); off white solid; mp 217° C.; MS: 466.9 (M+H)+
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13]1=[O:38])=O)C1C=CC=CC=1>C(Cl)Cl>[NH2:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:13]1=[O:38]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O)OCc1ccccc1
Solvent: ClCCl
Product: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (3.7 g, 7.36 mmol) in 100 mL of anhydrous methylene chloride was cooled to 0° C. under nitrogen. A stream of anhydrous HBr gas was then bubbled through this solution for 1 h. The bubbler was removed and the reaction was warmed to room temperature under nitrogen. After stirring 1 h the reaction was concentrated under vacuum and the residue was redissolved in 20 mL of methylene chloride. The crude HBr salt of the product was precipitated from solution using 300 mL of anhydrous ether and collected by filtration as a light yellow solid. After washing with ether , the solid was dissolved in methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer was extracted with saturated sodium bicarbonate. The combined aqueous layers were then back extracted twice with methylene chloride. The combined organic layers were extracted once with water and dried over sodium sulfate. After concentration under vacuum, 2.27 g of the product was obtained as an orange foam which was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12]([CH2:15][C:16]3C=[CH:20][CH:19]=[C:18](F)[C:17]=3F)(=O)=O)=[N:9]2)=[N:4][CH:3]=1.CC1[O:34]C(CS)=CC=1.CC(C)([O-])C.[K+]>CS(C)=O.C1COCC1>[NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12][CH2:15][C:16]3[O:34][C:19]([CH3:20])=[CH:18][CH:17]=3)=[N:9]2)=[N:4][CH:3]=1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2nc(N)cnc12
Reactant: Cc1ccc(CS)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc(CSc2nc(N[C@H](C)CO)c3ncc(N)nc3n2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from example 10, step (a) (0.18 g) and 5-methyl-2-furanmethanethiol (75 mg) in anhydrous DMSO (3 ml) was treated with potassium t-butoxide solution in THF (1.0 M, 0.44 ml) and stirred at room temperature for 1 hour. The solution was purified directly by preparative reversed phase HPLC on a Waters 19×50 mm Symmetry C8 silica column eluted with 0.1% aqueous ammonium acetate:acetonitrile (70:30) to give an off-white solid that was dried under reduced pressure at 40° C. (8 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:4][O:5][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:32][C:33]([F:56])([F:55])[CH2:34][CH2:35][C@@H:36](OS(C(F)(F)F)(=O)=O)[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C1COCC1>[CH3:1][C:2]1[C:3]([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:36]([CH2:35][CH2:34][C:33]([F:32])([F:55])[F:56])[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=[N:4][O:5][CH:6]=1
Reactant: Cc1conc1CC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1conc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl 2-(4-methylisoxazol-3-yl)acetate (25 mg, 0.127 mmol) (S7C) in a 10 mL round bottomed flask at room temperature was added THF (Ratio: 4.00, Volume: 0.8 mL). The solution was colorless. The solution was stirred at −78° C. 10 min. Next, 0.5 M KHMDS in toluene (0.317 mL, 0.158 mmol) was added slowly. The color of the solution turned to light orange. The mixture was stirred at −78° C. for 10 min and then placed in a room temperature water bath. After 10 minutes, the reaction mixture was put into a −78° C. bath for 20 min. (R)-Benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate, Intermediate S5D (65.0 mg, 0.165 mmol) in THF (Ratio: 1.000, Volume: 0.2 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 4 h. The reaction was quenched with saturated aqueous NH4Cl at −78° C. The mixture was placed in a room temperature water bath and diluted with brine. After 5 minutes, the mixture was extracted with EtOAc. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated to give a crude material as Intermediate S7D.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:12]=[C:13](/[N:15]=[C:16](\Cl)/[C:17]([F:20])([F:19])[F:18])[CH:14]=1)=[O:8]>C(#N)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:12]=[C:13]([N:15]2[C:16]([C:17]([F:20])([F:19])[F:18])=[N:3][N:2]=[N:1]2)[CH:14]=1)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(/N=C(\Cl)C(F)(F)F)cc(-c2ccc(C)cc2)c1
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of NaN3 (481 mg, 7.4 mmol) and 5-[1-chloro-2,2,2-trifluoro-eth-(Z)-ylideneamino]-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.3 g, 3.7 mmol) in 10 ml of dry ACN was stirred at room temperature for 16 hours. The reaction mixture were poured into ice-cold aqueous Na2CO3 solution, extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting crude 4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methyl ester (1.34 g, 99% yield) was used directly in the next step.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:27])[C:25]=1[F:26]>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:22]4[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: N#Cc1cc(-c2cc(F)c(F)c(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (72 mg, 81%), MS (ISP) m/z=356.4 [(M+H)+], mp 248.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[N:40]=[C:39]3[CH2:41][O:42][C:43](=O)[C:38]3=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:43]1[C:38]2[C:39](=[N:40][C:35]([CH2:34][N:31]3[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][O:25][CH2:24][CH2:23][OH:22])[CH2:29][CH2:30]3)=[CH:36][CH:37]=2)[CH2:41][O:42]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2nc(CN3CCN(CCOCCO)CC3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CN3CCN(CCOCCO)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.2 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (72 mg, 0.47 mmol) in THF (2 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1M solution in THF, 1.2 mmol) dropwise. The resulting solution is stirred for 10 min at room temperature. A solution 2-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-ylmethyl}-7H-furo[3,4-b]pyridin-5-one (77 mg, 0.24 mmol) in THF (1.5 mL) and added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and is then treated with HCl (4M in dioxane, 5 mL) at 0° C. The reaction mixture is stirred at room temperature for 48 h. The reaction mixture is concentrated and the residue is treated with saturated aqueous NaHCO3. The aqueous solution is extracted with EtOAc (2×). The combined organic extracts are dried (MgSO4) and concentrated. The residue is purified by chromatography (silica gel, gradient elution 20:1 chloroform:MeOH to 10:1 chloroform:MeOH). The product containing fractions are concentrated and the residue is triturated from EtOAc-hexane and collected by filtration to give the title compound as a yellow solid (22 mg, 20%),