Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([NH2:15])=[N:12][NH:13][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OCC)(=O)[CH2:17][C:18]([CH3:20])=O>C(O)(=O)C>[C:1]1([S:7]([C:10]2[CH:14]=[N:13][N:12]3[CH:16]=[CH:17][C:18]([CH3:20])=[N:15][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1n[nH]cc1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1ccn2ncc(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of 1.0 g (4.47 mmol) of 4-benzenesulphonyl-1H-pyrazol-3-ylamine and 0.6 ml (5.37 mmol) of ethyl acetoacetate in 8 ml of acetic acid was heated at reflux for 1.5 hrs. The reaction solution was cooled to RT and evaporated. The residue was partitioned between CH2Cl2 and H2O and the aqueous phase was washed three times with 150 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 20:1) yielded 0.91 g (70%) of 3-benzenesulphonyl-5-methyl-pyrazolo[1,5-a]pyrimidine as beige crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11](N)=[CH:12][C:7]=2[N:6]=[N:5]1.N([O-])=[O:17].[Na+]>OS(O)(=O)=O.O>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:17])=[CH:12][C:7]=2[N:6]=[N:5]1
Reactant: O=N[O-]
Reactant: CC(C)(C)Cn1nnc2cc(N)ccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)Cn1nnc2cc(O)ccc21
Temperature: 25 °C

Procedure:
To a solution of 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-amine (2-4, 150 mg, 0.734 mmol, 1.0 equv.) in 20% H2SO4 (5 mL), was slowly added sodium nitrite (70.8 mg, 1.026 mmol, 1.4 equiv.). The reaction mixture was stirred at room temperature until LCMS showed complete conversion to diazonium ion. The reaction solution was transferred to a microwave vial, and then irradiated at 120° C. for 50 minutes. LCMS showed complete hydrolysis of the diazonium salt. The reaction mixture was diluted with water, then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was purified with normal phase silica gel chromatography (EtOAc/hexane gradient from 0 to 100%) to yield 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (2-5 LRMS m/z (M+H) 206.0 found, 206.1 required.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3]C(C)(C)C)=O.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1C(Cl)=O.C(N(CC)CC)C>ClCCl>[N:8]1([C:1]([C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:26])([F:25])[F:14])=[O:3])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-Boc-piperazine (1.96 g, 10.5 mmol) in dichloromethane (50 mL) was added 2-trifluoromethylbenzoyl chloride (2.09 g, 10.0 mmol) as a dichloromethane solution in the presence of triethylamine (3 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 18 hours and then quenched with water (25 mL). The organic phase was washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to afford the desired product as a pall yellow solid used for next step reaction without further purification.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][C:12](=[O:34])[C@H:13]([NH:26]C(=O)OC(C)(C)C)[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:36])([CH3:35])[O:3]1>Cl.CCOC(C)=O>[NH2:26][C@H:13]([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:36])([CH3:35])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2cc(NC(=O)[C@H](N)CCc3ccc(C(F)(F)F)cc3)ccc21
Yield: 96.7 %

Procedure:
(R)-tert-butyl 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (1.44 g, 2.844 mmol) was stirred with 4.4 M HCl/EtOAc (10 mL) at room temperature for 30 min. The solution was evaporated to dryness under vacuum to produce (R)-2-amino-N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(4-(trifluoromethyl)phenyl)butanamide (CLXIX) as a light orange solid (1.22 g, 2.75 mmol, 97% yield). 1H NMR (DMSO-d6) δ ppm 1.46 (s, 6H), 2.22-2.29 (m, 2H), 2.83-2.91 (m, 2H), 4.17-4.22 (m, 1H), 7.35 (d, 1H, J=8 Hz), 7.47 (d, 2H, J=8 Hz), 7.62 (d, 2H, J=8 Hz), 7.65-7.68 (m, 1H), 7.92 (s, 1H), 8.53 (brs, 3H), 10.76 (s, 1H); 19F NMR (DMSO-d6) δ ppm −60.17 (s, 3F); ESIMS found for C20H22BF3N2O3 m/z 407.4 (M+H), 405.3 (M−H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([C:33]4[CH:48]=[CH:47][C:36]([C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[CH:35][CH:34]=4)[N:15]3[CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[CH:11][CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].[F-].[Cs+].[OH:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=1.O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:7]([C:5]3[S:6][C:2]([C:62]4[CH:61]=[CH:60][CH:59]=[C:58]([OH:57])[CH:63]=4)=[C:3]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:4]=3)=[O:8])[CH:17]=2)[CH:13]=[C:14]1[C:33]1[CH:48]=[CH:47][C:36]([C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(O)c1
Yield: 81.6 %

Procedure:
A mixture of 5 (60 mg, 0.075 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), CsF (34 mg, 0.22 mmol), 3-hydroxyphenylboronic acid (16 mg, 0.12 mmol), and H2O (80 μL) in DME (8 mL) was degassed with N2 for 10 min and then refluxed. When the reaction was over by TLC monitoring, the mixture was poured into H2O (10 mL) and then extracted with 70 mL Et2O. The organic layer was washed with brine (2×10 mL), dried over MgSO4, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 6 as a yellow amorphous solid (50 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=8.0 Hz, 2H), 8.04 (s, 1H), 7.74-7.61 (m, 7H), 7.56 (d, J=8.0 Hz, 2H), 7.49-7.26 (m, 6H), 7.13 (s, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 5.40 (s, 2H), 4.32 (t, J=7.2 Hz, 2H), 4.16-4.06 (m, 2H), 3.72 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 1.72-1.69 (m, 2H), 1.49-1.46 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.62, 171.45, 168.65, 166.21, 157.16, 149.47, 143.69, 141.59, 138.00, 137.26, 137.23, 136.09, 134.28, 131.99, 131.82, 130.66, 130.37, 130.33, 130.12, 129.33, 128.90, 128.62, 128.53, 123.49, 121.88, 121.13, 120.87, 116.54, 116.46, 112.82, 104.20, 67.20, 61.46, 43.92, 37.36, 34.81, 27.45, 25.84, and 14.42.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6](Cl)(=[O:8])[CH3:7].[S:10]1[C:14]([NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2.O>ClCCl>[C:6]([C:13]1[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[S:10][C:14]=1[NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])(=[O:8])[CH3:7]
Reactant: CCS(=O)(=O)Nc1cc2ccccc2s1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)Nc1sc2ccccc2c1C(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Tin (IV) chloride (173 μL, 1.48 mmol) was added to a solution of acetyl chloride (124 μL, 1.75 mmol) in dichloromethane (10 mL), at 0° C., and the resulting solution was stirred for 5 min. To the resulting mixture was then added a solution of ethanesulfonic acid benzo[b]thiophen-2-ylamide (325 mg, 1.35 mmol) in dichloromethane (2 mL) at 0° C. The resulting solution was allowed to warm to ambient temperature and then stirred overnight. The resulting solution was treated with water (10 mL), the organic layer separated, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo to yield N-(3-acetyl-benzo[b]thiophen-2-yl)-ethanesulfonamide as a colorless solid. 1H-NMR (DMSO-d6): δ 1.25 (t, 3H), 2.71 (s, 3H), 3.39 (q, 2H), 7.34-7.48 (m, 2H), 7.94 (d, 1H), 8.10 (d, 1H); MS: m/z 284.1 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=1)[C:18]#[N:19])#[CH:12].N>>[F:21][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: C#Cc1ccc(F)c(C#N)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: N#Cc1cc(-c2cc(-c3cccnc3)no2)ccc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and the product of Example 68A (73 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.49 (s, 1H), 7.52-7.68 (m, 2H), 8.28 (ddd, J=8.8, 5.1, 2.4 Hz, 1H), 8.33-8.41 (m, 2H), 8.68 (dd, J=4.9, 1.5 Hz, 1H), 9.09 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=2[N:34]=1.C(N(C(C)C)CC)(C)C>CCO>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:30]2[O:31][C:32]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:33]=3[N:34]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Cc1ccc2oc(Cl)nc2c1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)c2nc3cc(C)ccc3o2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.300 g, 0.76 mmol), chloro-5-methyl-benzooxazole (0.135 g, 0.81 mmol), and diisopropylethylamine (0.5 mL, 2.87 mmol) were combined in EtOH (2 mL) in a sealed tube, and the reaction was stirred at 80° C. for 8 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16]CC)=O)[CH:10]=[CH:9]2.[CH3:19][S:20][CH2:21][S:22]([CH3:24])=[O:23]>CN(C)C=O>[O:16]=[C:14]([C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:4]([Cl:3])[CH:5]=[CH:6][CH:7]=2)[CH:12]=1)[CH:21]([S:20][CH3:19])[S:22]([CH3:24])=[O:23]
Reactant: CSCS(C)=O
Reactant: CCOC(=O)c1ccc2cccc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(C(=O)c1ccc2cccc(Cl)c2c1)S(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
A suspension of 9.2 g sodium hydride in 50 ml of N,N-dimethylformamide was added in one portion to a stirred solution of 5.6 g (24 mM) of ethyl 8-chloro-2-naphthylformate and 4.4 g (36 mM) of methyl methylthiomethyl sulfoxide in 10 ml of N,N-dimethylformamide. The reaction mixture was stirred for four hours at 25° C., and then concentrated to dryness. The product was dissolved in 250 ml of ethyl acetate and the solution was washed with 5% hydrochloric acid, saturated sodium bicarbonate and brine. The solution was dried and the solvent was removed by evaporation to give 4.73 g (63% yield) of 1-oxo-1-(8-chloro-2-naphthyl)-2-methylthio-2-methylsulfinylethane. A solution of 3.12 g (10 mM) of the product in 150 ml of formic acid and 12 ml of acetic anhydride was stirred at 65° C. for thirty minutes. To the reaction mixture were added 856 mg (4 mM) of sodium periodate and stirring was continued for an additional fifteen minutes. The reaction mixture was cooled and concentrated to dryness, and the product was dissolved in ethyl acetate, washed with sodium bicarbonate and brine, and the solvent was removed to give 1.2 g (46% yield) of methylthio α-oxo-α-(8-chloro-2-naphthyl)acetate.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([OH:38])=[C:11]2[C:16](=[C:17]([C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[N:18]=1)[N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14](=[O:31])[C:13]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:12]2)=[O:8].[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:24]([N:15]1[C:16]2[C:11](=[C:10]([OH:38])[C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:8])=[N:18][C:17]=2[C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[CH:12]=[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:14]1=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CCNC(=O)c1nc(-c2cscn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1nc(-c2cscn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
A mixture of 3-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-thiazol-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-propionic acid methyl ester (24 mg, 0.044 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 3-4, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound. MS: (+) m/z 527.33 (M+1).
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[C:22]([OH:29])=[C:23]([CH:25]=[CH:26][C:27]=2[Cl:28])[NH2:24])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]=[C:39]=[O:40]>>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[C:22]([OH:29])=[C:23]([NH:24][C:39]([NH:38][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=3[Cl:30])=[O:40])[CH:25]=[CH:26][C:27]=2[Cl:28])(=[O:19])=[O:20])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3cccc(Cl)c3Cl)c2O)CC1
Yield: 20.9 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-[4-(tert- butoxycarbonyl)piperazin-1-yl]sulfonyl4-chloro-2-hydroxyaniline (110 mg, 0.28 mmol) and 2,3-dichlorophenylisocyanate (64 mg, 0.34 mmol) were coupled to form the desired urea (34 mg, 25%). EI-MS (m/z) 576.65, 578.65, 580.67 (M−).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:20])=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.[C:21]([O:25][C:26]([C@@H:28]1[CH2:32][C@@H:31](O)[CH2:30][C@H:29]1[C:34](=[O:46])[NH:35][C@:36]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([CH:28]1[CH2:32][CH:31]([O:20][C:7]2[C:6]3[C:11](=[C:12]([CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:30][CH:29]1[C:34](=[O:46])[NH:35][C:36]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:38][CH:37]1[CH:39]=[CH2:40])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: COc1ccc2c(O)nc(-c3ccccc3)nc2c1C
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccccc3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 75.8 %

Procedure:
Quinazolinol derivative (83) (480 mg, 1.8 mmol) was coupled to compound 15 (0.55 mg, 1.5 mmol) as described in example 16, which gave the title compound (700 mg, 75%)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[S:22][C:21]([CH2:23][CH2:24][NH:25][C:26]([NH:28][NH:29]C(OC(C)(C)C)=O)=[O:27])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O1CCOCC1.Cl>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[S:22][C:21]([CH2:23][CH2:24][NH:25][C:26]([NH:28][NH2:29])=[O:27])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCNC(=O)NNC(=O)OC(C)(C)C)s3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCNC(=O)NN)s3)nc2)CC1
Yield: 42.5 %

Procedure:
By a method similar to Production Example 115, step 5, tert-butyl 2-{[2-(5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)ethyl]carbamoyl}hydrazinecarboxylate (498.0 mg, 0.964 mmol) was deprotected with 4M hydrogen chloride dioxane solution. The crude product was purified by aminopropylated silica gel and recrystallized from dichloromethane-methanol to give the title compound (170.8 mg, yield 42.5%) as a slightly yellow white solid.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[CH3:29][C:30]1([CH3:44])[CH2:34][C:33]2[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41](O)=[O:42])[CH:37]=[CH:38][C:32]=2[O:31]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:41](=[O:42])/[CH:40]=[CH:39]/[C:36]4[CH:37]=[CH:38][C:32]5[O:31][C:30]([CH3:29])([CH3:44])[CH2:34][C:33]=5[CH:35]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: CC1(C)Cc2cc(/C=C/C(=O)O)ccc2O1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: CC1(C)Cc2cc(/C=C/C(=O)N3CCC(C(NC4CCC(c5c[nH]c6ccccc56)CC4)C(N)=O)CC3)ccc2O1

Procedure:
The title compound was prepared from the product of Example 1, step J, and (2E)-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a yellow solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C33H40N4O3: 541 (M+H). Found: 541
Reaction SMILES: C(=O)=O.CC(C)=O.[NH3:8].C([O:11][C:12]([C:14]1[O:25][C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]([CH3:26])[C:16]=2[C:15]=1[O:27][CH3:28])=O)C>O1CCCC1>[CH3:28][O:27][C:15]1[C:16]2[N:17]([CH3:26])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]=2[O:25][C:14]=1[C:12]([NH2:8])=[O:11]
Reactant: N
Reactant: CCOC(=O)c1oc2c3ccccc3n(C)c2c1OC
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1c(C(N)=O)oc2c3ccccc3n(C)c12
Temperature: 0 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A flask fitted with a Dewar condenser containing dry ice/acetone was cooled in a dry ice/acetone bath and charged with 350 ml of anhydrous ammonia. A few crystals of hydrated ferric nitrate catalyst were added, and the cooling bath was removed. Lithium amide was then generated by the addition, over one hour, of 1.78 g (0.26 mole) of freshly cut lithium metal ribbon. After the addition of 65 ml of cold tetrahydrofuran, a solution of 16.5 g (0.060 mole) of 3-methoxy-4-methyl-4H-furo[3,2-b]indole-2-carboxylic acid ethyl ester in 75 ml of tetrahydrofuran was added over 30 minutes. The Dewar condenser was removed, and the mixture was stirred for 16 hours as the excess ammonia evaporated. The total reaction mixture was added to 600 g of ice/water, and the crude amide product was filtered and washed with water. Recrystallization from aqueous ethanol yielded 11.7 g (79% yield) of final product, mp 174°-177° C. An additional recrystallization as above yielded an analytically pure sample, mp 179°-182° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:30]3[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]3)=[CH:24][C:23]=2[CH3:31])=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].O>ClCCl>[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:30]3[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]3)=[C:24]([Br:1])[C:23]=2[CH3:31])=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C(=O)c2c(C)cc3ccccn23)ccc1N
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Reaction time: 2 h
Yield: 89.4 %

Procedure:
0.492 g (2.73 mmol) of N-bromosuccinimide is added, under an inert atmosphere at ambient temperature, to 0.812 g (2.6 mmol) of methyl 2-amino-5-[(2-methylindolizin-3-yl)carbonyl]benzoate in 17 ml of dichloromethane. The reaction medium is stirred for 2 hours and then hydrolysed with water. The aqueous phase is extracted with dichloromethane. The organic phase obtained is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with dichloromethane. 0.9 g of a yellow solid is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[C:29]([CH3:36])([CH3:35])[C:30](OCC)=[O:31].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15]([NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)=[O:27])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[C:29]([CH3:36])([CH3:35])[CH:30]=[O:31]
Reactant: CCOC(=O)C(C)(C)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C=O)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of (±)-ethyl 2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoate (100 mg, 0.18 mmol) in anhydrous toluene was added DIBAL-H (0.4 mL, 1 M) at −78° C. The mixture was stirred for 30 min and quenched with MeOH. The organic layer was separated, dried and concentrated to give crude (±)-7-bromo-N-(2-adamantyl)-3-(2-methyl-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide which was used for the next step without purification.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>O=[Pt]=O.CO>[C:1]([N:8]1[CH2:16][C@@H:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:14][C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](C2CCCCC2)CN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A mixture of N-BOC-4(R)-phenyl-(L)-proline, methyl ester from Example 61, Step B (0.165 g, 0.54 mmol), PtO2 (0.1 g, 0.44 mmol) and MeOH was shaken under 50 psi of H2 overnight. The reaction was filtered through a pad of celite and concentrated in vacuo to afford N-BOC-4(R)-cyclohexyl-(L)-proline, methyl ester which was used without further purification.