Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:12][CH3:13])[CH:7]=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.C([Li])(C)(C)C.[C:19](OC)(=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C1COCC1>[CH3:23][O:22][C:20](=[O:21])[C:19]([C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:24]
Reactant: COC(=O)C(=O)OC
Reactant: COc1ccc(Br)c2c1ccn2C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OC)c2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A solution of 1-methyl-4-methoxyl-7-bromoindole (1.17 g, 4.87 mmol) in THF (33 mL) was cooled to −78° C. and a solution of tert-butyl lithium in pentanes (1.7 M, 6.3 mL, 10.7 mmol) added dropwise over 30 min. After 30 min at −78° C., the mixture was treated with dimethyl oxalate (1.44 g, 12.2 mmol) in one portion. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The extract was washed with brine and dried (Na2SO4), and concentrated. Flash chromatography (EtOAc/hexanes) afforded the title compound (0.7 g, 58.1%). 1H NMR (400 MHz, CDCl3) 3.95 (s, 3H), 4.0 (s, 3 H), 4.02 (s, 3H), 6.56 (d, J=8.61 Hz, 1H), 6.67 (d, J=3.13 Hz, 1H), 6.99 (d, J=3.13 Hz, 1H), 7.61 (d, j=8.6 Hz, 1H); MS (ES, m/z): C13H13NO4: 248.16 (M++1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[C:55]1([N:61]=[C:62]=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][N:49]([C:62]([NH:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:63])[CH2:48]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 70% yield. LCMS for C31H32ClN8O2 (M+H)+: m/z=583.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1)=[O:6]
Reactant: COc1cc(Cl)c(C(=O)O)cc1-c1ccccn1
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Product: COc1cc(Cl)c(C(=O)Nc2cc(C#N)nn2-c2ccccc2)cc1-c1ccccn1

Procedure:
The title compound was prepared according to the method described for Example 99 using 2-chloro-4-methoxy-5-(pyridin-2-yl)benzoic acid (Preparation 26) and 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53). The residue was purified using reverse phase chromatography eluting with 5-60% MeCN (with 0.1% formic acid) in water (with 0.1% formic acid).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:34]=[CH:33][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:30]([NH2:32])=[O:31])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[OH:36]S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:21]3[C:13]4[CH:12]=[C:11]([NH:10][C:8]([C:7]5[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=5)=[O:9])[CH:34]=[CH:33][C:14]=4[CH2:15][CH2:16][C:17]=3[C:18]([C:30]([NH2:32])=[O:31])=[N:19]2)=[CH:23][CH:24]=1)(=[O:36])[CH3:29]
Reactant: C#Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Temperature: 100 °C

Procedure:
A mixture of 8-{[(2-chloropyridin-3-yl)carbonyl]amino}-1-(4-ethynylphenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (442 mg, 1.2 mmol), water (65 mg, 3.6 mmol), and triflic acid (270 mg, 1.8 mmol) in dioxane (10 mL) was heated to 100° C. for 18 h. The mixture was cooled to RT, aqueous NaHCO3 was added, and filtered. The product was washed with water and ether, and dried. This gave product (293 mg, 67%). 1H NMR was consistent with its structure.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[Cl:20].N([O-])=O.[Na+].CCCCCC>C(O)C>[Cl:20][C:8]1[CH:9]=[C:10]([C:16]([F:17])([F:18])[F:19])[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: O=[N+]([O-])c1cc(Cl)cc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
(see also: EP 0 516 297 A1) 56.7 ml of 96% sulfuric acid are added dropwise over a period of 30 minutes to a brown solution of 90 g (374 mmol) of 4-amino-3-chloro-5-nitro-benzotrifluoride (Maybridge; Tintagel/England) in 500 ml of ethanol (exothermic). After heating to 75° C., 64.53 g (935 mmol) of sodium nitrite are added in portions over a period of one hour (evolution of gas). The mixture is stirred for 2.5 hours at 75° C. and then cooled to room temperature. The reaction mixture is poured onto 1.5 liters of ice-water and extracted four times with ether. Washing the organic phases with 0.1 N HCl, saturated NaHCO3solution and brine, drying (Na2SO4) and concentration by evaporation yield a brown oil. Column chromatography (SiO2; hexane) yields the title compound in the form of an oil: 1H-NMR (DMSO-d6) 8.62 (m, 1H), 8.46 (m, 2H), MS 225 (M)+, 179 (M—NO2)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17])=[CH:9][C:8]=2[N+:21]([O-:23])=[O:22])[CH2:3][CH2:2]1.O.[NH2:25][NH2:26]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[NH:25][N:26]=3)=[CH:9][C:8]=2[N+:21]([O-:23])=[O:22])[CH2:3][CH2:2]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(N2CCOCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 12.2 parts of 4(4-morpholino-3-nitrophenyl)-4-oxo-3-methylbutanoic acid, 3.8 parts of hydrazine hydrate in 50 parts by volume of absolute ethanol is heated at reflux for 4 hours, cooled and filtered. The solid product is collected, washed with hexane and dried at 80° C. under vacuum to give 6-(4-morpholino-3-nitrophenyl)-4,5-dihydro-5-methyl-3(2H)pyridazinone melting at 223°-225° C. Recrystallisation from a mixture of ethanol and dimethylformamide raises the melting point to 225°-227° C.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](O)=[O:5].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:29][CH2:30][CH2:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[S:49][C:48]3[C:43](=[N:44][CH:45]=[CH:46][C:47]=3[O:50][C:51]3[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=3[F:58])[CH:42]=2)=[CH:37][CH:36]=1)[CH3:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:29][CH2:30][CH2:31][N:32]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[S:49][C:48]3[C:43](=[N:44][CH:45]=[CH:46][C:47]=3[O:50][C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:4](=[O:5])[CH2:3][C:2]([NH:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:1])=[CH:53][C:52]=3[F:58])[CH:42]=2)=[CH:39][CH:40]=1)[CH3:33]
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCl)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a solution of the acid 1 (142 mg, 2 eq, 1.58 mmol) in dry DCM (10 ml), at 0° C., was added, BOPCl (502 mg, 2 eq, 0.826 mmol) and the reaction mixture was stirred for 10 minutes. A solution of the amine 87 (348 mg, 0.79 mmol) and iPr2NEt (610 mg, 6 eq, 4.72 mmol) in dry DCM (7 ml) was then added and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness and partitioned between EtOAc and satd NaHCO3 soln, the organic phase was washed twice with saturated NaHCO3 then collected, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude was purified by column chromatography (EtOAc) to afford the desired product 88 as an off-white solid (102 mg, 21% yield). 1H NMR (DMSO-d6) δ (ppm): 10.58 (s, 1H), 10.22 (s, 1H), 8.48 (d, J=5.28 Hz, 1H), 8.03 (s, 1H), 7.85 (m, 3H), 7.59 (m, 2H), 7.43 (m, 4H), 7.32 (m, 2H), 7.05 (t, J=7.43 Hz, 1H), 6.61 (m, 1H), 3.70 (t, J=6.65 Hz, 2H), 3.59 (s, 2H), 3.50 (s, 2H), 2.69 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=3[CH2:33][N:34]3[C@@H:38]([CH3:39])[C@@H:37]([C:40]4[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=4)[O:36][C:35]3=[O:54])[C:17]([O:21][CH3:22])=[CH:18][C:19]=2[F:20])[CH2:10][CH2:9]1)=[O:7])(=O)C.C[O-].[Na+].O>CO>[F:53][C:50]([F:51])([F:52])[C:42]1[CH:41]=[C:40]([C@H:37]2[O:36][C:35](=[O:54])[N:34]([CH2:33][C:24]3[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:23]=3[C:16]3[CH:15]=[C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:13][CH2:12]4)[C:19]([F:20])=[CH:18][C:17]=3[O:21][CH3:22])[C@H:38]2[CH3:39])[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=1
Reactant: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(F)c(C2CCN(C(=O)CO)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a stirred solution of 2-{4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]piperidin-1-yl}-2-oxoethyl acetate (24 mg, 0.031 mmol) in MeOH (1 mL) under N2 was added sodium methoxide (6.66 mg, 0.031 mmol). The resultant mixture was stirred at room temperature for 15 min. Water (10 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic fractions were washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-100% EtOAC/hexanes) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-(1-glycoloylpiperidin-4-yl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one as a yellow gum. LCMS=737.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.87 (s, 1H), 7.69 (s, 2H), 7.68-7.60 (m, 2H), 7.34-7.30 (m, 1H), 6.96-6.91 (m, 1H), 6.72 (d, J=11.9 Hz, 1H), 5.44 (d, J=7.8 Hz, 1H), 4.90 (d, J=15.8 Hz, 1H), 4.78-4.70 (m, 1H), 4.18-4.13 (m, 2H), 3.78 (s, 3H), 3.62-3.54 (m, 1H), 3.15-3.05 (m, 2H), 2.82-2.73 (m, 1H), 1.96-1.84 (m, 2H), 1.70-1.52 (m, 4H), 0.43-0.39 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:21]=1)[CH:3]1[CH2:19][CH2:18][C:6]2([CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4]1.Cl>C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([CH:3]1[CH2:19][CH2:18][C:6]2([CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4]1)[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:21]=1
Reactant: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
To a suspension of tert-butyl 8-(methyl(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (0.22 g, 0.50 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 3.5 M). The mixture was stirred at room temperature for 1.5 h, then concentrated in vacuo. The residue was diluted with DCM (10 mL) and saturated Na2CO3 (10 mL) and then extracted with DCM/MeOH (v/v)=10/1 (30 mL×4). The combined organic layers was dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/2M NH3 in MeOH (v/v)=5/1) to give the title compound as a yellow solid (0.12 g, 70%).
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][CH:8]([CH:10]([OH:13])[CH2:11][CH3:12])[CH3:9].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:11]([CH:10]([O:13][C:1](=[O:5])[CH2:2][CH:3]=[CH2:4])[CH:8]([CH3:9])[CH3:7])[CH3:12]
Reactant: C/C=C/C(=O)Cl
Reactant: CCC(O)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(=O)OC(CC)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Crotonoyl chloride (21.5 g) in dichloromethane (CH2Cl2) (100 mL) was charged into a 2-L reaction flask and cooled to 0° C. 2-Methyl-pentan-3-ol (prepared as above in EXAMPLE I) (21 g) was added followed by diisopropylethylamine (31.9 g). The reaction mixture was aged at about 0-10° C. for about 30 minutes and poured into dilute hydrochloric acid (HCl) (33 g in 170 g water). Hexanes were added and the aqueous and organic layers were split. The organic layer was separated and subsequently purified via liquid chromatography to provide but-3-enoic acid 1-ethyl-2-methyl-propyl ester (28 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12]C(=O)OC(C)(C)C)[CH2:6]2)#[N:2].[ClH:20]>O1CCOCC1.CCOCC>[ClH:20].[NH2:12][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C#N)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)CC(N)C2
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl (5-cyano-2,3-dihydro-1H-inden-2-yl)carbamate (1.85 g, 7.18 mmol) in dioxane (30 mL) at room temperature was added HCl in dioxane (18 mL of a 4.0 M solution; 72 mmol). The mixture was stirred for ca. 18 hr and diluted with ether. Solids were collected by filtration and rinsed thoroughly with ether, affording the title compound as a tan solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.65 (s, 1H), 7.59 (d, 1H, J=7.9 Hz), 7.46 (d, 1H, J=7.9 Hz), 4.14 (m, 1H), 3.51-3.43 (m, 2H), 3.10-3.04 (m, 1H).
Reaction SMILES: [CH:1]12[CH2:8][CH:4]([CH2:5][CH:6]1[OH:7])[CH2:3][NH:2]2.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:2]2[CH2:3][CH:4]3[CH2:8][CH:1]2[CH:6]([OH:7])[CH2:5]3)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: OC1CC2CNC1C2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CC3CC(O)C2C3)cc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
To a round bottom flask was added 2-azabicyclo[2.2.1]heptan-6-ol (150 mg, 1.326 mmol), 1-fluoro-4-nitrobenzene (187 mg, 1.326 mmol), K2CO3 (366 mg, 2.65 mmol) and DMF (5 mL). The reaction was stirred at 65° C. for 4 hrs. The reaction was then diluted with EtOAc (35 ml). The organic solution was washed with water (3×20 ml) and saturated aqueous NaCl (20 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 2-(4-nitrophenyl)-2-azabicyclo[2.2.1]heptan-6-ol (150 mg, 0.640 mmol, 49% yield), as a yellow solid. Anal. Calcd. for C12H14N2O3 m/z 234.2, found: 235.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.10 (d, J=9.90 Hz, 2 H), 6.49 (d, J=8.25 Hz, 2 H), 4.10 (s, 1 H), 3.99 (br. s., 1 H), 3.39 (dt, J=8.80, 2.75 Hz, 1 H), 2.78 (d, J=8.80 Hz, 1 H), 2.74 (br. s., 1 H), 1.97 (d, J=9.90 Hz, 1 H), 1.92 (ddd, J=13.61, 7.01, 2.47 Hz, 1 H), 1.78-1.71 (m, 2 H), 1.59-1.53 (m, 1 H); 13C NMR (126 MHz, CDCl3) δ ppm 151.32, 136.88, 126.54, 110.27, 71.10, 61.88, 54.11, 40.73, 35.91, 34.23.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:22])[C:5]([S:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=3[N:16]=2)=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][S:34]([C:25]2[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:29][C:24]=2[Cl:23])(=[O:36])=[O:35])[CH:3]=[C:4]([Cl:22])[C:5]=1[S:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=2[N:16]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(N)cc(Cl)c1Sc1nc2cc(Cl)ccc2s1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: CC(=O)c1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)cc(Cl)c1Sc1nc2cc(Cl)ccc2s1
Temperature: 90 °C
Yield: 72 %

Procedure:
To a 1M solution of 1-[5-Amino-3-chloro-2-(5-chloro-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone, (265) (4.12 g, 11.19 mmol) in pyridine, obtained from Aldrich, was added 2-chloro-4-trifluoromethyl-benzenesulfonyl chloride (3.75 g, 13.43 mmol) and heated to 90° C. for 1.5 hours. The crude reaction mixture was concentrated under vacuum, partitioned between 2M aqueous HCl (100 mL) and EtOAc (100 mL), and extracted 3 times with EtOAc (100 mL). The combined organic layers were washed twice with saturated aqueous brine (100 mL), dried over Na2SO4, concentrated under vacuum, purified by column chromatography (0-5% Et2O in CH2Cl2), and triturated with CH2Cl2/hexane mixture with 0.5 mL of MeOH added to yield compound 277 (4.9 g, 72%) as an off white solid.
Reaction SMILES: [N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:2]1[C:3]([OH:5])=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:2]1[C:3]([NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:5]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 100 mg of Boc-Hyp(Bzl)-OH, 33 μl of t-butylamine, 48 mg of HOBt and 71 mg of EDC hydrochloride were added and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 33 (Process3) to give 88 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([N:17]([CH3:19])[CH3:18])([C:15]#N)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([Mg]Cl)[CH:25]=[CH:24]C=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([N:17]([CH3:19])[CH3:18])([C:15]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(C#N)CCC(OCc2ccccc2)CC1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.00 g of 4-benzyloxy-1-dimethylaminocyclohexanecarbonitrile were dissolved in 50 ml of tetrahydrofuran and, while cooling with an ice bath, 19.4 ml of two molar phenylmagnesium chloride solution in tetrahydrofuran were added dropwise under a nitrogen atmosphere. After stirring overnight at room temperature, cooling was again carried out in an ice bath, and 25 ml of cold ammonium chloride solution (20 percent by weight) were added. The phases were separated and extracted twice using 80 ml of diethyl ether each time, the combined organic phases were extracted three times using 60 ml of hydrochloric acid (5 percent by weight) each time, the combined acidic extracts were rendered weakly alkaline (pH 8–9) with aqueous ammonia solution (25 percent by weight), extraction was carried out three times using 80 ml of diethyl ether each time, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. The resulting yellow oil (4.15 g) was separated on silica gel with diethyl ether/hexane (V:V=1:1). 1.83 g of the non-polar and 0.38 g of the polar diastereoisomer of (4-benzyloxy-1-phenyl-cyclohexyl)dimethylamine were obtained in the form of a yellow solid and a yellow resin, respectively. 1.48 g of the non-polar diastereoisomer were dissolved in 11.8 ml of 2-butanone; 47 μl of water and 665 μl of chlorotrimethylsilane were added, and stirred overnight. The precipitated hydrochloride was filtered off, washed with diethyl ether and dried under a high vacuum. 1.55 g of the hydrochloride of the non-polar diastereoisomer of (4-benzyloxy-1-phenyl-cyclohexyl)dimethylamine (Example 1) were obtained in the form of a white solid. In an analogous manner, 300 mg of the corresponding hydrochloride (Example 2) were obtained from 379 mg of the polar diastereoisomer.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6](=[O:25])[C:5]=1O)(=O)[CH3:2].[NH:27]([C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1)[NH2:28]>CCO.C1(C)C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:28][N:27]([C:29]4[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=4)[C:5]=3[C:6](=[O:25])[N:7]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][CH:11]=1
Reactant: Cn1nccc1NN
Reactant: COc1ccc(CN2C(=O)C(O)=C(C(C)=O)C2c2ccc(Cl)cc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)c3c(c(C)nn3-c3ccnn3C)C2c2ccc(Cl)cc2)cc1
Temperature: 115 °C
Reaction time: 20 h
Yield: 85.4 %

Procedure:
To a stirred solution of 4-acetyl-5-(4-chlorophenyl)-3-hydroxy-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (Step 71.2) (3 g, 8.07 mmol) in EtOH (50 mL) and toluene (50 mL) was added 5-hydrazinyl-1-methyl-1H-pyrazole (Step 74.2) (1.941 g, 10.49 mmol) and the resulting mixture was heated up and stirred at 115° C. for 20 hr. The reaction was quenched with a saturated aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 40-50%) to afford the title product (3.15 g, 6.89 mmol, 85% yield) as yellow solid. tR: 5.60 min (HPLC 1); tR: 1.24 min (LC-MS 2); ESI-MS: 448 [M+H]+ (LC-MS 2); Rf=0.41 (hexane/EtOAc 1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:19][CH:20]2[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)[CH:13]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:25]2[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:21][CH:20]2[CH2:19][NH:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(CNc2cccnc2)C1
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2CNc2cccnc2)cc1
Reaction time: 1 h

Procedure:
4-Methoxyphenyl isocyanate (85 mg, 0.567 mmol) was added to a solution of tert-butyl 3-((pyridin-3-ylamino)methyl)piperazine-1-carboxylate (166 mg, 0.567 mmol) in CH2Cl2(4 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, and the material was purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 81.7 mg (26%) of the TFA salt of the title compound as a white solid. LC-MS: RT=5.29 min, [M+H]+=442.2.