Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:28][CH:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[C:33]([C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[N:32]1)[CH3:30]>>[CH3:30][CH:29]([N:31]1[CH:35]=[C:34]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([C:20]2[CH:21]=[CH:22][C:23]([CH:24]=[O:25])=[CH:26][CH:27]=2)[N:6]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:33]([C:45]2[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=2)=[N:32]1)[CH3:28]
Reactant: O=Cc1ccc(-c2cc3c(Br)cccc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CC(C)n1cc(-c2cccc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure for Intermediate 100 using 4-[4-bromo-1-(phenylsulfonyl)-1H-indol-2-yl]benzaldehyde and 1-(1-methylethyl)-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 592.4.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[O:31][C:30](=[O:35])[CH:29]=[C:28]2OS(C(F)(F)F)(=O)=O>C(#N)C>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[O:31][C:30](=[O:35])[CH:29]=[C:28]2[NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Br)ccc2o1
Reactant: NC1CCN(CC=Cc2ccccc2)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Temperature: 150 °C
Yield: 34.1 %

Procedure:
To a solution of 4-amino-1-cinnamylpiperidine (1.3 g, 6 mmol) and triethylamine (1.6 mL, 7.2 mmol) in dry acetonitrile (125 mL) was added trifluoromethanesulfonic acid 6-bromo-2-oxo-2H-chromen-4-yl ester (2.23 g, 6 mmol). About 5 mL of solution was added to each of 25 dry microwave vials equipped with stir bars. The vials were capped and each was heated at 150° C. for 5 minutes in the microwave. The solutions were combined, concentrated and dissolved in chloroform. The solution was washed with water and brine and dried over Na2SO4, and concentrated. The residue was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide the desired compound (900 mg, 34%) as a yellow solid. MS (ESI(+)Q1MS m/z 440 (M+2H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.57-1.67 (m, 2H), 1.89-1.95 (m, 2H), 2.13 (m, 2H), 2.92 (m, 2H), 3.13 (m, 2H), 3.50 (m, 1H), 5.28 (sd, 1H), 6.35 (dt, 1H), 6.56 (d, 1H), 7.24-7.47 (m. 7H), 7.74 (dd, 1H), 8.45 (d, 1H).
Reaction SMILES: [CH2:1]([C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:14]([C@@H:17]([CH2:22][CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19])=[C:15]=[O:16]>C1(C)C=CC=CC=1>[CH2:1]([C:8]1([O:13][C:15]([NH:14][C@@H:17]([CH2:22][CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[C@H](N=C=O)C(=O)OC
Reactant: OC1(Cc2ccccc2)CCCC1
Solvent: Cc1ccccc1
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)OC
Temperature: 85 °C
Yield: 79 %

Procedure:
To 840.8 mg (4.77 mmol) of 1-benzylcyclopentanol in 2.4 mL of toluene was added 816.7 mg (4.77 mmol) of methyl(2S)-2-isocyanatohexanoate. The mixture was heated at 85° C. for 4 d. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:4) to give 1.31 g (79%) of methyl(2S)-2-({[(1-benzylcyclopentyl)oxy]carbonyl}amino)hexanoate. Rf=0.31 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.37 (d, J=8 Hz, 1H), 7.27-7.06 (m, 5H), 4.00 (m, 1H), 3.64 (s, 3H), 3.19 (ABq, JAB=14 Hz, ΔνAB=9 Hz, 2H), 1.96-1.78 (m, 2H), 1.76-1.38 (m, 8H), 1.36-1.14 (m, 4H), 0.86 (t, J=7 Hz, 3H); ES-LCMS m/z 370 (M+Na).
Reaction SMILES: [BH4-].[Na+].[Br:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[C:5]1=[O:14].CO.O>O1CCCC1.C(OCC)(=O)C>[Br:3][C@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[C@H:5]1[OH:14]
Reactant: O=C1c2ccc(F)cc2CC1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@@H]1c2ccc(F)cc2C[C@@H]1Br
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
Sodium borohydride (2.09 g) was added to a solution of 2-bromo-5-fluoroindan-1-one (8.43 g) in a mixture of tetrahydrofuran (120 mL) with methanol (30 mL) while cooling with ice, and the reaction solution was stirred for 20 minutes. Water and ethyl acetate were added to the reaction solution while cooling with ice and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was washed with heptane to obtain 7.54 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.Cl[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: CCOC(=O)CC(=O)Nc1nc2cccc(-c3ccoc3)n2n1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and ethyl 3-chloro-3-oxopropionate (90 mg, 0.60 mmol; 2.0 eq.) as a white powder (42 mg, 45%). HPLC, Rt: 2.72 min. (purity 90.8%). LC/MS, M+(ESI): 315.3, M−(ESI): 313.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:12][N:13]([CH2:14][CH:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH3:16])[CH3:18]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)CN(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (1.0 g, 6.58 mmol), 3-dimethylamino-1-propanol (1.01 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) at 0° C. in THF (20 mL) was added dropwise diisopropyl azodicarboxylate (1.99 g, 9.87 mmol). After stirring for 16 h at room temperature the solution was concentrated and the residue purified by column chromatography (silica gel, methanol/dichloromethane) to yield the title compound as an oily solid (1.25 g, 5.2 mmol). MS(ESI): 238.1 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:7][CH2:6][CH:5]1[OH:19])=[N+:2]=[N-:3].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]([CH:4]1[CH:5]([O:19][Si:24]([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25])[CH2:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:9]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1C=C(c2ccncc2[N+](=O)[O-])CCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccncc2[N+](=O)[O-])=CC1N=[N+]=[N-]
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of (+/−)-2-azido-4-(3-nitropyridin-4-yl)cyclohex-3-enol (1.0 equiv.) in DCM (0.15 M) was added TBSCl (2.0 equiv.), imidazole (2.0 equiv.) and DMAP (0.1 equiv.) at room temperature. After 18 h, water was added, the organics were dried with brine, then Na2SO4, and concentrated. The crude material was loaded to silica gel and purified via column chromatography (ISCO) eluting with ethyl acetate and hexanes (20%). Obtained (+/−)-4-(3-azido-4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl)-3-nitropyridine as a yellow oil in 60% yield. LCMS (m/z): 376.3 (MH+), LC Rt=5.848 min.
Reaction SMILES: [F:1][C:2]1([F:25])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=2.[CH2:26]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1)[CH2:27][CH2:28][CH3:29]>>[CH2:26]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:12]2[CH:11]=[CH:10][C:9]3[C:8]4[C:3](=[CH:4][C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=4)[C:2]([F:25])([F:1])[C:15]([F:17])([F:16])[C:14]=3[CH:13]=2)=[CH:33][N:32]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(Br)ccc1-2
Reactant: CCCCOc1ccc(B(O)O)cn1
Product: CCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(-c3ccc(OCCCC)nc3)ccc1-2

Procedure:
From 9,9,10,10-tetrafluoro-2-bromo-7-hexyl-9,10-dihydrophenanthrene and 2-butoxypyridine-5-boronic acid in analogy to Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:15][C@@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1)=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)=[O:18])=[CH:27][CH:28]=1
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)C1)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 34 mg, 0.17 mmol) in DMF (5 mL) was added 2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)propan-1-one hydrochloride (Preparation 103, 50 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIPEA (94 μL, 0.54 mmol). After 5 min, EDCI (43 mg, 0.23 mmol) was added and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (25 mL) and ethyl acetate (3×20 mL). The combined organic layer was washed with 2N sodium hydroxide solution (2×10 mL), brine (10 mL), dried (MgSO4) and concentrated in vacuo. Purification via chromatography on silica gel eluting with methanol:dichloromethane (7:93) gave the title compound. m/z (ES+)=431 [M +H]+; RT=3.49 min.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([CH2:23]O)[CH:20]=[N:21][CH:22]=2)=[CH:13][CH:12]=1>ClCCl>[Cl:3][CH2:23][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(-c2ccc(Cl)cc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cncc(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
543 mg (0.333 ml, 4.56 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 500 mg (2.28 mmol) [5-(4-Chloro-phenyl)-pyridin-3-yl]-methanol in 30 ml dichloromethane and stirred for 2 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (444 mg, 75%) used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10](OC(OCC)OCC)C.S(=O)(=O)(O)O>>[OH:9][C:8]1[C:2]2[O:1][CH:10]=[N:4][C:3]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cccc(O)c1O
Agent: O=S(=O)(O)O
Product: Oc1cccc2ncoc12

Procedure:
A mixture of 2,3-dihydroxyaniline (2.5 g.), triethylorthoformate (4.5 g.) and 0.1 g. sulfuric acid is heated at 130° C. for one hour. After cooling, the remaining material is purified by HPLC on silica gel.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([NH:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=3)[CH:6]=[CH:5][N:4]=1.[ClH:36].C(OCC)C>O1CCOCC1>[ClH:36].[CH3:20][O:19][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:18]=[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([N:2]([CH3:35])[CH3:1])[N:8]=1)[CH:10]=[C:11]2[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 4-((3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)amino)piperidine-1-carboxylate (142) (215 mg, 0.45 mmol) in dioxane (6 ml) was added 4 M hydrochloric acid in dioxane (3 ml). The mixture was stirred at room temperature for 24 hours. Diethylether (100 ml) was added and the solid isolated by centrifugation. The solid was washed with diethylether (2×50 ml) and dried under vacuum to give 4-(6-methoxy-4-(piperidin-4-ylamino)naphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (143) as a pale yellow/orange solid (196 mg). LCMS m/e 378 (M+H)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[C:10]([N+:1]([O-:4])=[O:2])[CH:11]=1
Reactant: Fc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(F)ccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At −10° C., 90% fuming nitric acid (25 mL) was added to concentrate sulfuric acid (50 mL) slowly to keep the temperature below 0° C. At −20° C., 1-fluoro-4-trifluoromethoxy-benzene (5 g, 27.7 mmol) was added portionwise to keep the temperature of the reaction mixture below 0° C. After addition, the reaction mixture was kept at 0° C. for 30 min, poured into ice-water, extracted with EtOAc. The extracts were concentrated to give a mixture (6.05 g) of 4-fluoro-2-nitro-1-trifluoromethoxy-benzene and 1-fluoro-2-nitro-4-trifluoromethoxy-benzene in a 3:1 ratio. The crude nitration product (6.05 g) was dissolved in ethanol (40 mL) and shacked with 10% Pd/C (310 mg) and concentrate HCl (2.8 mL) under H2 (50 psi) for 3.5 h. Filtration and concentration gave a mixture (8.0 g) of 5-fluoro-2-trifluoromethoxy-phenylamine and its isomer 2-fluoro-5-trifluoromethoxy-phenylamine in 3:1 ratio. Without purification, the phenylamines (7 g, 35.8 mmol) were suspended in dichloromethane (100 mL), treated with trifluoroacetic anhydride (71 mmol) and triethylamine (20 mL) for 16 h. The reaction mixture was washed with saturated NaHCO3 and brine. The organic phase was further purified by silica gel chromatography (hexane/EtOAc 9:1) to give a mixture (5.29 g) of 2,2,2-trifluoro-N-(5-fluoro-2-trifluoromethoxy-phenyl)-acetamide and its isomer in 1:4 ratio, which was nitrated in a same procedure as the first step. The nitrate (3 g) was heated under reflux with morpholine (10 mL) in 1,2-dichloroethane (30 mL) for 3 h. Evaporation to remove excess morpholine. The residue was diluted with dichloromethane, washed with HCl (0.5N, 100 mL). The organic phase was purified by FC (hexane/EtOAc 7:3 to 1:1) to give the title compound 5-morpholin-4-yl-4-nitro-2-trifluoromethoxy-phenylamine (2.48 g). LC-MS: m/e=306.1 (M−H), 308.2 (M+H). 1H-NMR (500 MHz, CDCl3): 8.04 (s, 1H), 6.35 (s, 1H), 4.54 (br. s, 1H), 3.90 (t, 4H), 3.07 (t, 4H).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:35])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:34])[CH2:22][CH2:23][C@H:24]([O:26]C(CCC(O)=O)=O)[CH2:25][C:20]4=[CH:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CCCC)CCCC)CCC.ClC(OCC(C)C)=O.[OH-].[Na+]>O1CCOCC1.O>[CH3:8][CH:6]([CH2:5][CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:35])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][CH2:14]2)[C@:21]2([CH3:34])[C:20]([CH2:25][C@H:24]([CH2:23][CH2:22]2)[OH:26])=[CH:19][CH2:18]3)[CH2:11][CH2:10]1)[CH3:1])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)CCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 6 h

Procedure:
20.25 Grams (41.8 mmoles) of cholesteryl hydrogen succinate (sold by Aldrich Chemicals) and 19.8 ml (83.4 mmoles) of tributylamine were dissolved in 540 ml of Dioxane. The solution was cooled and treated with 5.3 ml (5.7 g, 41.7 mmoles) of isobutyl chloroformate. The reaction was permitted to proceed in the cold for 30 minutes, and then the mixture was added in one portion to a stirred, cooled solution of 50.0 g (41.7 moles) of bovine serum albumin in 1100 ml of water, 750 ml of p-dioxane, and 50 ml of 1 N NaOH. Stirring and cooling was continued for 6 hours. The material was then dialyzed against water and lyophilized to yield a stable white powder useful as a cholesterol standard.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([CH:15]2[CH2:20][CH:19]=CCN2C(OCC)=O)=[CH:7]1)=[O:5])[CH3:2]>CO>[CH2:1]([O:3][C:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([CH:15]2[CH2:20][CH2:19][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC=CCC1c1cn(C(=O)OCC)c2ncccc12
Solvent: CO
Product: CCOC(=O)N1CCC(c2cn(C(=O)OCC)c3ncccc23)CC1
Reaction time: 20 h

Procedure:
1.87 g of palladium, 10% (dry basis) on activated carbon (50% in water) were added over a solution of 8-48 g (24.7 mmol) of 3-(1-ethoxycarbonyl-1,2,3,6-tetrahydro-pyridinyl) pyrrolo[2,3-b]pyridine-1-carboxylic acid ethyl ester in 250 ml methanol and this mixture was hydrogenated at 2 bar for 20 hours. After filtering through Celite and removing the solvent under reduced pressure, 7.27 g (85% of yield) of the expected product were obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([CH3:34])[CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:30]1([CH2:29][O:28][C:20]2[CH:21]=[CH:22][C:23]([CH:25]([F:27])[F:26])=[CH:24][C:19]=2[C:18]2[C:13]3[NH:12][C:11]([CH3:33])=[C:10]([C:8]([NH:7][C@@H:5]4[CH2:6][C@@H:2]([NH:1][C:35](=[O:38])[CH2:36][CH3:37])[CH2:3][C@H:4]4[CH3:34])=[O:9])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:32][CH2:31]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1C
Product: CCC(=O)N[C@H]1C[C@@H](C)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4S*)-4-amino-2-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f69) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[C:27]1([OH:31])[CH2:30][O:29][CH2:28]1>CC#N>[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12][C:33]([NH:32][C:23]2[CH:24]=[CH:25][C:26]([C:27]3([OH:31])[CH2:30][O:29][CH2:28]3)=[C:21]([F:20])[CH:22]=2)=[O:34])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: O=C(Nc1ccc(C2(O)COC2)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C3(O)COC3)c(F)c2)n(-c2cccc(Cl)c2)n1
Yield: 76.6 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (96 mg, 0.32 mmol, 1.0 eq) in MeCN (8 mL) was added TEA (0.178 mL, 1.28 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyoxetan-3-yl)phenylcarbamate (99 mg, 0.3 3 mmol, 1.02 eq) at RT and stirred at reflux for 16 h. The solvent was evaporated and the crude product was purified by CC (EtOAc/cyclohexane 1:1 as eluent) to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)urea (116 mg; 77%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[N:20]=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[C:18]([CH2:27][N:28]4[CH2:33][CH2:32][N:31](C(OCC[Si](C)(C)C)=O)[CH2:30][C:29]4=[O:43])=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].O.O.[F-].C([N+](CC)(CC)CC)C>C(C#N)(C)=O>[C:1]([C:3]1[C:4]([NH:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][C:29]4=[O:43])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C(=O)OCC[Si](C)(C)C)CC4=O)c(C(OC)OC)nc32)ncc1C#N
Agent: CC(=O)C#N
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCNCC4=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 70 °C

Procedure:
A mixture of 2-(trimethylsilyl)ethyl 4-((8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-3-oxopiperazine-1-carboxylate (intermediate 122, 4.20 g, 5.29 mmol) and tetraethylammonium fluoride dihydrate (2.53 g, 13.22 mmol) in AcCN (50 ml) was heated for 30 minutes at 70° C. The reaction mixture was partitioned between saturated aqueous NaHCO3 solution and DCM, the DCM phase washed with brine, dried over MgSO4 and evaporated. The residue was applied to a RediSep® silica column and purified by normal phase chromatography, eluting with EtOAc then a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as a yellow-white solid. (UPLC-MS 7) tR 0.68; ESI-MS 539.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[NH2:5].[CH3:18][CH:19]([C:25]([CH3:27])=O)[C:20](OCC)=[O:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C(C(=O)C2C=CC(Cl)=CC=2)=CC=C2C=1C(O)=C(C)C(C)=N2>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:20]([OH:21])=[C:19]([CH3:18])[C:25]([CH3:27])=[N:5]2)=[CH:7][C:8]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nc2ccc(C(=O)c3ccc(Cl)cc3)c(Cl)c2c(O)c1C
Solvent: Cc1ccccc1C
Product: Cc1nc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)cc2c(O)c1C
Yield: 77 %

Procedure:
A solution of 2.7 g of 3-chloro-4-(4-chlorobenzoyl)aniline, 2.4 g of ethyl 2-methylacetoacetate, and 0.3 g of p-toluenesulfonic acid dissolved in 100 mL of xylene was heated under reflux for 31 hr. This reaction solution was cooled, and the precipitated crystals were collected by filtration and were washed with n-hexane to give 2.68 g of a mixture of 5-chloro-6-(4-chlorobenzoyl)-4-hydroxy-2,3-dimethyl-quinoline with 7-chloro-6-(4-chlorobenzoyl)-4-hydroxy-2,3-dimethyl-quinoline (yield 77%). The crystals of the mixture thus obtained were stirred in 40 mL of acetic anhydride with heating at 120 to 125° C. for one hr. The reaction solution was concentrated, and the crude product was then purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 1.0 g of 4-acetoxy-5-chloro-6-(4-chlorobenzoyl)-2,3-dimethyl-quinoline (yield 32.6%) and 0.47 g of 4-acetoxy-7-chloro-6-(4-chlorobenzoyl)-2,3-dimethyl-quinoline (yield 15.6%).