Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:20]([OH:21])[CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Clc1ccc(-c2ccccc2Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2-c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (29.4 mL, 47.09 mmol) was added dropwise to a solution of 2-bromo-4′-chlorobiphenyl (INTERMEDIATE 9, 12 g, 44.85 mmol) in THF (220 ml) under nitrogen, at −78° C. The resulting colored mixture was stirred at −78° C. for 30 minutes and a solution of tert-butyl 4-formylpiperidine-1-carboxylate (10.04 g, 47.09 mmol) in THF (15 ml) was added. The reaction mixture was allowed to warm to 0° C. during 3 hours and then was quenched with a solution of saturated aq. NH4Cl. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic extracts and dried over MgSO4. The mixture was filtered and evaporation of the volatiles under reduced pressure gave a residue, which was purified by column chromatography (ISCO, 330 g silica gel column, eluting with 0→40% EtOAc/hexanes) to give tert-butyl 4-[(4′-chlorobiphenyl-2-yl)(hydroxy)methyl]piperidine-1-carboxylate as a mixture of enantiomers.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([OH:11])[C:7]=1[CH:12]([CH3:14])[CH3:13].[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:11][C:8]1[C:7]([CH:12]([CH3:14])[CH3:13])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:10][N:9]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)c1c(O)noc1-c1ccco1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccco1
Yield: 83.3 %

Procedure:
5-(2-Furyl)-3-hydroxy-4-isopropylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.18 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.29 g, 83%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:34]=C)=[C:4]([CH:15]=[C:16]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:25][CH:24]=2)[C:17]=1[C:18]([F:21])([F:20])[F:19])[C:5]([NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[OH:14])=[O:6].CC(C)=[O:38].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>S([O-])([O-])(=O)=S.[Na+].[Na+].O.O.[O-][Os]([O-])(=O)=O.[K+].[K+].O>[Cl:1][C:2]1[C:17]([C:18]([F:20])([F:21])[F:19])=[C:16]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)[CH:15]=[C:4]2[C:3]=1[CH:34]([OH:38])[N:7]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[OH:14])[C:5]2=[O:6]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)N[C@@H]2CCCC[C@H]2O)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Agent: O=[Os](=O)([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1c2cc(Cc3ccc(-n4cccn4)cc3)c(C(F)(F)F)c(Cl)c2C(O)N1[C@@H]1CCCC[C@H]1O
Reaction time: 16 h

Procedure:
To a solution of rac-3-chloro-2-ethenyl-N-(trans-2-hydroxycyclohexyl)-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzamide (0.07 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00 ml) were added potassium osmate(VI) dihydrate (4.00 mg) and sodium periodate (0.08 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give rac-4-chloro-3-hydroxy-2-[trans-2-hydroxycyclohexyl]-6-[4-(1H-pyrazol-1-yl)benzyl]-5-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (0.05 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: II.Br[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]I)=[CH:12][CH:11]=1.FC1C=CC(CBr)=CC=1.[NH4+].[Cl-]>C1COCC1>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(CI)cc1
Reactant: Brc1cccs1
Agent: Fc1ccc(CBr)cc1
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of Mg (3 g, 0.123 mol) in THF (40 ml) was added a small amount of solid I2 (20 mg). The mixture was heated to reflux under nitrogen. To the mixture was then added the 2-bromothiophene solution (5 ml) (19.6 g of 2-bromothiophene in 40 ml of THF). After the iodine color disappeared, to the suspension was added the rest of 2-bromothiophene solution dropwise keeping reflux. After the addition, the mixture was heated under reflux for 2 h., then was cooled to room temperature. To this mixture was added 4-fluorobenzyl iodide (or 4-fluorobenzyl bromide) followed by Li2CuCl4 (5 ml) solution keeping the temperature under 40° C. using a cool water bath. The mixture was stirred at room temperature for 2 h. To the mixture was added sat. NH4Cl solution (100 ml), the mixture was stirred for 30 min., the organic layer was separated and washed with 10% sodium thiosulfate solution (50 ml), followed by distilled water (100 ml). The organic layer was then dried over MgSO4 and concentrated to give 19 g of 2-(4-fluorobenzyl)thiophene as an oil. Purification was achieved by vacuum distillation (110° C., 5 mm Hg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7]I.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:22]1[CH:23]=[C:24]([S:28]([OH:31])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:19])([O-:11])=[O:10]>CN(C=O)C>[CH3:7][N:21]([S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N+:9]([O-:11])=[O:10])(=[O:20])=[O:19])[C:22]1[CH:23]=[C:24]([S:28]([OH:31])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc(S(=O)(=O)O)c1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1cccc(S(=O)(=O)O)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Potassium carbonate (177 mg, 1.28 mmol), DMF (2 ml) and MeI (60 ml) were added to the compound (230 mg, 0.65 mmol) obtained in Step 1. The mixture was stirred at 40° C. for 6 hours. Potassium carbonate (44.3 mg) and MeI (40 μL) were supplemented and stirred overnight. After the solvent was removed by distillation, the purification step A was applied to give the crude product of 3-{methyl[(2-nitrophenyl)sulfonyl]amino}benzenesulfonic acid (160 mg). This crude product (144 mg, 0.39 m ml) was dissolved in DMF (3 ml), and cesium carbonate (126 mg, 0.39 mmol) and thiophenol (40 μl, 0.39 mmol) were added to the solution. The mixture was stirred at 50° C. overnight. After the solvent was removed by distillation, the purification step A was applied to give the crude product of 3-(methylamino)benzenesulfonic acid (84.1 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[N:22]1([CH2:31][C:32](O)=[O:33])[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24]>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:33])[CH2:31][N:22]3[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]3=[O:24])[CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccc(F)cc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Yield: 95.9 %

Procedure:
The title compound (900 mg, 96%) was synthesized by reaction of 1-(4-fluoro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (680 mg, 2.0 mmol) with (thymin-1-yl)-acetic acid (369 mg, 2.0 mmol) as per the procedure of example 64.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]=2[CH:6]([CH2:5][C:4]([OH:20])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(COC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.20 g, 0.67 mmol) in THF (6 mL) and H2O (2 mL) was added LiOH (0.130 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid (0.120 g, 71%). 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.42 (s, 1H), 9.10 (s, 1H), 6.99 (s, 1H), 6.82 (s, 1H), 5.46 (m, 1H), 3.28 (s, 3H), 3.03 (m, 1H), 2.02 (m, 1H). MS (ESI) m/z: 251 [M−1]−. HPLC purity: 97.87% (220 nm), 98.47% (Maxplot).
Reaction SMILES: [OH:1][C:2]([C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1)([CH3:8])[C:3](OCC)=[O:4].O.[NH2:16][NH2:17]>CCO>[OH:1][C:2]([C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1)([CH3:8])[C:3]([NH:16][NH2:17])=[O:4]
Reactant: CCOC(=O)C(C)(O)c1nc(C)cs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1csc(C(C)(O)C(=O)NN)n1
Yield: 77.5 %

Procedure:
A solution of Intermediate 106 (4.14 g, 19.23 mmol) in EtOH (60 mL) was treated with hydrazine monohydrate (FLUKA, 9.35 mL, 192 mmol). Mixture was heated at reflux for 3 h. Reaction mixture was concentrated. Residue was triturated with a mixture of DCM/Hexane and finally ether, and was filtered. Crude was purified by silica gel chromatography using a linear gradient of DCM/MeOH (0-5%) as eluents to obtain the title compound (3 g, 14.91 mmol, 78% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.05 (br s, 1H), 7.16 (s, 1H), 6.59 (s, 1H), 4.23-4.25 (m, 2H), 2.32 (s, 3H), 1.67 (s, 3H). [ES+MS] m/z 202 (MH+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[CH:20]=[CH:19][C:14]3[C:15](=[O:18])[O:16][CH2:17][C:13]=3[C:12]=2[CH3:21])[OH:10])[CH2:4]1.[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[C@@H:33]1[CH2:35][O:34]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(O)C>[OH:10][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:8][N:5]1[CH2:6][CH2:7][C@@H:3]([NH:2][CH2:35][C@H:33]([OH:34])[C:24]2[CH:25]=[CH:26][C:27]3[C:28](=[O:32])[O:29][CH2:30][C:31]=3[C:23]=2[CH3:22])[CH2:4]1
Reactant: Cc1c([C@@H](O)CN2CC[C@@H](N)C2)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cc1c([C@@H](O)CN[C@@H]2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)C2)ccc2c1COC2=O

Procedure:
A microwave vial was charged with 5-{(1R)-2-[(3R)-3-aminopyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 4] (100 mg, 0.32 mmol), 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B] (61 mg, 0.32 mmol), MP-carbonate resin (200 mg), and ethanol (1 mL). The reaction mixture was heated in a microwave reactor at 150 C for 1 hour, and then cooled, filtered and concentrated in vacuo. The resulting residue was dissolved in DMSO (1 mL) and purified by HPLC to provide 5-{(1R)-1-hydroxy-2-[(3R)-3-{[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}pyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3I)c2)CC1
Yield: 15.6 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-iodobenzoyl chloride (183 mg, 0.687 mmol), 16.0 mg (16%) of the title compound were recovered.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].ON1C(=O)CCC1=O.C(=O)(SC(C)(C)C)OC(OC(=O)C(C)C)C.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([O:53]O)=[O:52])[CH:46]=1>C(Cl)Cl.CCOCC>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:44][C:45]1[CH:46]=[C:47]([CH:48]=[CH:49][CH:50]=1)[C:51]([OH:53])=[O:52]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: CC(OC(=O)SC(C)(C)C)OC(=O)C(C)C
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In still another alternative synthesis of (10), N-hydroxysuccinimide (230 mg, 2 mmol) was added to a solution of compound (8) (248 mg, 1 mmol) in CH2Cl2 (10 mL) was added and the reaction mixture cooled to 0° C. m-Chloroperbenzoic acid (670 mg, 3 mmol, commercial grade: 77% in water) was added over a period of 10 min and the mixture allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ether (50 mL) and washed with water (2×10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (10) together with m-chlorobenzoic acid. The crude product mixture was purified by column chromatography on silica gel, eluting with 4:6 EtOAc:hexane. Residual m-chlorobenzoic acid was removed by repeated crystallizations from a mixture of tert-butyl methyl ether and hexane which resulted in analytically pure product (30 mg, 11%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:65])[CH2:59][N:60]2[CH:64]=[CH:63][CH:62]=[N:61]2)=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH:65][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:50])[CH2:59][N:60]2[CH:64]=[CH:63][CH:62]=[N:61]2)=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(Cn1cccn1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(Cn2cccn2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Reaction time: 8 h
Yield: 76.5 %

Procedure:
HATU (0.209 g, 0.55 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g, 0.50 mmol), 1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethanamine (Intermediate 92) (0.202 g, 0.5 mmol) and N,N-diisopropylethylamine (0.174 mL, 1.00 mmol) in N-methyl-2-pyrrolidinone (3.0 mL) at room temperature under argon. The resulting solution was stirred overnight. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (0.216 g, 76%) as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.N(CCO)(CCO)CCO.O.CS(C)=O.[Pd](Cl)Cl.C([O-])(=O)C.[Na+]>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCN(CCO)CCO
Solvent: Cc1ccc(C)cc1
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 84.6 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of triethanolamine and 10 ml of water were heated to 120° C. At 80° C., 19.3 mg of palladium chloride, 17.9 mg of sodium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO were added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.8 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24]CC)=O)[CH2:17]2)=[CH:12][CH:11]=1>>[C:1]1([C:22]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:24])[CH:18]2[CH2:19][CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:28][CH:27]=3)[CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCCN(CCc2ccc(OC)cc2)C1
Reactant: [Li]c1ccccc1
Product: COc1ccc(CCN2CCCC(C(O)(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
The title compound was prepared by the method of Example 11 by reacting phenyllithium with ethyl 1-(4-methoxyphenethyl)piperidine-3-carboxylate. The title compound was obtained as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.N(OCCC(C)C)=O.[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)CCON=O
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccc2)c1
Yield: 49 %

Procedure:
2-Fluoro-5-nitroaniline (30 g) was added portionwise over 45 minutes to a refluxing solution of 60 ml isoamyl nitrite in 225 ml benzene. After heating for a further 30 minutes at reflux, the mixture was cooled and the solvent removed by evaporation in vacuo. The residue was triturated many times with hot petroleum ether and the combined extracts were evaporated to give the product as a red oil (19.9 g, yield 49%). This material was used without further purification. NMR (CDCl3, 60MHz): 8.0-8.4 (m, 3H), 7.1-7.6 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:34]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:35][CH:36]=[CH:37][C:38]=1B(O)O)(=[O:30])[CH3:29].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: C[C@H]1CN(C2COC2)CCN1c1cnc(Nc2cc(Br)cn(C)c2=O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 65 °C
Yield: 30.7 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (S)-5-bromo-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl) piperazin-1-yl)pyrazin-2-ylamino)pyridin-2(1H)-one 230f (200 mg, 0.46 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]-dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (366 mg, 0.92 mmol), Pd(dppf)Cl2 (38 mg, 0.046 mmol), sodium acetate (126 mg, 0.92 mmol), K3PO4 (196 mg, 0.92 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 65° C. for 3 hrs. After cooling to room temperature the reaction was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 235a as brown solid (100 mg, 31%). MS-ESI: [M+H]+ 708.5.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4]2[N:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[H-].[Na+].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl.CCOCC>C1(C)C(C)=CC=CC=1.O>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8](=[O:9])[N:2]([CH3:1])[C:3]2[CH:17]=[CH:16][CH:15]=[N:14][C:4]1=2
Reactant: CN1C(=O)c2ccccc2Nc2ncccc21
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1C
Solvent: O
Product: CN(C)CCN1c2ccccc2C(=O)N(C)c2cccnc21
Yield: 45.6 %

Procedure:
9.0 gm of 5,11-dihydro-5-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one were dissolved in 200 ml of hot absolute xylene, 2.1 gm of 50% sodium hydride in mineral oil were added to the solution, and the mixture was refluxed for two hours. Then, 5.3 gm of 2-dimethylamino-ethyl chloride were added dropwise, and the resulting mixture was refluxed for 16 hours more. The cooled reaction mixture was taken up with a mixture of ether and water, and the organic phase was separated and extracted with dilute acetic acid. Then, the acidic aqueous extract was made alkaline with concentrated aqueous ammonia, and the precipitated oil was extracted with ether. After evaporation of the ether, the residue was distilled, yielding 5.4 gm of 11-(2-dimethylaminoethyl)-5,11-dihydro-5-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, b.p. 171°-173° C. at 0.006 mm Hg. After crystallization and recrystallization from petroleum ether, 3.2 gm of the substance, m.p. 109°-110° C., were obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Cl[CH:18]([CH3:22])[C:19](=[O:21])[CH3:20].C(N(CC)CC)C>C(OCC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH3:22])[C:19](=[O:21])[CH3:20])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(=O)C(C)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title product of Example 2 (3.0 g, 0.0126 mole) was reacted with 3-chloro-2-butanone (1.27 ml) and triethylamine (1.7 ml) in ethyl ether (20 ml) at room temperature overnight. The mixture was filtered, the crystals washed with ethyl ether and the combined filtrates evaporated in vacuo. The crude product was chromatographed on silica then recrystallized from ethyl acetate/hexane to give the title compound m.p. ca. 94°-97° C.