Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>ClCCl.CN(C1C=CN=CC=1)C>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:8]2[CH2:7][C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]2=3)=[O:31])=[CH:33][CH:34]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CNc1ccccc1S2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Sc2ccccc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 112.6 %

Procedure:
To a solution of 1.6 g of 10,11-dihydrodibenz[b,f][1,4]thiazepine in 30 ml of dichloromethane is added 0.1 g of 4-(N,N-dimethylamino)pyridine, 4 ml of triethylamine and 1.0 g of 4-nitrobenzoyl chloride and the mixture is stirred for 16 hours. The mixture is poured into ice-water and extracted with 3×150 ml of dichloromethane. The combined organic extract is washed with water, 2N HCl, 2N Na2CO3, water and dried (MgSO4). The solvent is removed in vacuo and the product (2.6 g) purified by chromatography on silica gel with hexane-ethyl acetate (4:1) as eluent to give 2.2 g of crystals, m.p. 147°-149° C.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:25]1([C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH:15]3[C:38](=[O:39])[CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])([OH:17])[CH2:10][CH2:9]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: Cc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2C(C(=O)Cc3ccccc3)NC[C@H]21

Procedure:
By working in accordance with the operating method of Example 22 below, starting from 0.68 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methylphenyl)perhydroisoindol- 4-ol hydrochloride and 0.28 cm3 of phenylacetyl chloride, 0.4 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methylphenyl)-2-phenylacetylperhydroisoindol-4-ol is obtained in the form of white crystals which melt at 208° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25]C4CCNCC4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][C:36]([OH:38])=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH:25]4[CH2:5][CH2:9][N:8]([C:36](=[O:38])[CH2:35][CH2:34][O:33][CH3:32])[CH2:7][CH2:6]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COCCC(=O)O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Product: COCCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 279.2 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 382 mg; 0.87 mmol) and 3-methoxypropanoic acid (180 mg; 1.73 mmol), 620 mg of the title compound was obtained as a yellow oil after purification by a silica gel chromatography (EtOAc).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][CH:6]=[N:5]2)[CH2:3][CH2:2]1.[Br:9]Br>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>[Br:9][C:7]1[CH:6]=[N:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:8]=1
Reactant: c1cnn(C2CC2)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1cnn(C2CC2)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-cyclopropyl-1H-pyrazole (108 mg, 1.00 mmol) in CHCl3 (4 mL) at room temperature was added Br2 (51 uL, 1.0 mmol) via syringe. The orange solution was stirred for 1 h. The reaction was diluted with saturated aqueous Na2S2O3 (3 mL) and saturated aqueous NaHCO3 (3 mL). The mixture was extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated on a rotary evaporator without heating the sample to give 4-bromo-1-cyclopropyl-1H-pyrazole as a volatile, light yellow liquid that was used without further purification, m/z 187.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[C:7]2=[O:13].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[Cl:12][C:11]1[C:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:31])([F:19])[F:32])=[CH:26][CH:25]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:13])[N:6]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:5]=[CH:4]2
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)cc3)c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of (S)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propanamide (100.0 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylfonnamide (2 mL, 0.02 mol) was stirred at 60° C. for 3 days. The reaction was only about 40% complete. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the product as light yellow solid. MS m/z=452.1 (M+H). 1H NMR (400 MHz; DMSO-d6) δ10.21 (s, 1H), 8.15 (d, J=8.68 Hz, 1H), 7.74 (d, J=7.76 Hz, 2H), 7.66-7.58 (m, 4H), 7.49 (d, J=7.95 Hz, 1H), 7.25 (s, 1H), 6.43 (d, J=7.50 Hz, 1H), 5.47-5.42 (q, J=7.07 Hz, 1H), 3.90 (s, 2H), 1.53 (d, J=7.39 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([CH:23]=O)[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1)(=[O:31])[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21](/[CH:23]=[CH:30]/[C:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[O:31])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 8 %

Procedure:
The title compound was prepared by condensing 2-(5-formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester (Ex-36A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 8% yield, mp 182–183° C. 1H-NMR (CDCl3) δ 8.21 (d, J=8 Hz, 2H), 8.19 (d, J=13 Hz, 1H), 8.16 (d, J=7 Hz, 1H), 8.07 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.54 (d, J=7 Hz, 1H), 7.52 (d, J=13 Hz, 1H), 7.29–7.35 (m, 1H), 7.23 (d, J=7 Hz, 1H), 6.55 (s, 1H), 6.50 (s, 1H), 4.00 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H). MS m/z=528 ([M+H]+, 100%). Anal. calc. for C31H29NO7H2O: C, 68.25; H, 5.73; N, 2.56; found: C, 68.63; H, 5.62; N, 2.45.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[C:25]5[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=5[N:27]=[CH:28][N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][NH2:14])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[C:25]5[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=5[N:27]=[CH:28][N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:13][NH:14][CH:2]([CH3:4])[CH3:1])=[CH:8][CH:7]=1
Reactant: CC(C)=O
Reactant: C[C@@H]1CCc2ncnc(-c3ccc4c(C(CN)c5ccc(Cl)cc5)c[nH]c4c3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC[C@H](c1ccc(Cl)cc1)c1c[nH]c2cc(-c3ncnc4c3[C@H](C)CC4)ccc12
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
Acetone (0.0195 mL, 0.266 mmol) was added to a solution of 2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethanamine (107 mg, 0.266 mmol) and N,N-diisopropylethylamine (0.139 mL, 0.797 mmol) in methylene chloride (2.0 mL). The reaction mixture was stirred for 10 minutes, and then sodium triacetoxyborohydride (0.0188 g, 0.0885 mmol) was added. After stirring for 2.5 hours, saturated NaHCO3 was added, and the mixture was stirred vigorously 10 minutes. The mixture was extracted with DCM (3×10 mL). The combined organic were dried (Na2SO4), filtered and concentrated. The crude product was purified by SFC chiral chromatography (Chiral OJH (21.2×250 mm) 25% methanol+0.1% TEA) to give N-((R)-2-(4-chlorophenyl)-2-(6-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indol-3-yl)ethyl)propan-2-amine (19.8 mg, 16.8%) as the first peak. LCMS: M+1 445.3. 1H NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 8.93 (s, 1H), 7.93 (s, 1H), 7.49-7.46 (m, 3H), 7.38 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 4.36 (t, 1H), 3.89 (m, 1H), 3.23 (m, 1H), 3.14-2.99 (m, 2H), 2.94-2.86 (m, 1H), 2.77 (m, 1H), 2.34 (m, 1H), 1.68 (m, 1H), 0.96 (d, 6H), 0.92 (d, 3H).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH2:40])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:42](Cl)(=[O:44])[CH3:43].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH:40][C:42](=[O:44])[CH3:43])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](N)C(=O)OC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NC(C)=O)C(=O)OC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To (S)-2-Amino-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinolin-7-yloxy]-butyric acid cyclopentyl ester (120 mg, 0.216 mmol) in DCM (2 ml) were added acetyl chloride (15 μL, 0.216 mmol) and triethylamine (33 μL, 0.238 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. then at room temperature for 1 hour. The crude mixture was concentrated under vacuum and purified by preparative HPLC to provide the title compound as a mono-TFA salt (67 mg, 52% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([O:15]C(C)(C)C)[CH2:12][N:11]1[S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][CH2:9][C@H:10]1[N:11]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:12][C@H:13]([OH:15])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc2ccccc2c1)N1C[C@H](O)C[C@H]1COCc1ccccc1
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Trifluoroacetic acid (100 ml) was cooled to 0° C., then (2S,4R)-2-benzyloxymethyl-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine (7.0 g) was added in one portion. The reaction mixture was stirred for 3 h at the same temperature and then concentrated without heating under vacuum. The residue crystallized from Et2O/hexane to obtain (3R,5S)-5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-ol (5.07 g) as a colorless solid, mp 124–126° C., MS: 398 (MH+).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[Na].Cl[CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl>C(O)C.O>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][CH2:8][S:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:12][CH:13]=1
Reactant: Oc1ccc(SCCCl)cc1
Reactant: O=C(O)CS
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)CSCCSc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Mercaptoacetic acid (3.5 g, 0.039 mole) was added to ethyl alcohol (100 ml) containing sodium (1.8 g, 0.078 mole). The compound of Example 36 (7.3 g, 0.039 mole) in ethyl alcohol (20 ml) was added dropwise and the mixture refluxed 1 hour. The reaction mixture was cooled to room temperature, poured into water (250 ml) and acidified with 2N hydrochloric acid. The product was extracted into ethyl ether (2×150 ml) and the ethyl ether extracted with 1M sodium bicarbonate (3×80 ml). The combined basic washes were acidified with 2N hydrochloric acid and extracted with ethyl ether (3×150 ml). The combined ethyl ether extracts were washed with water (3×75 ml) and saturated sodium chloride (50 ml), dried over magnesium sulfate, filtered and concentrated to give yellow solid. Recrystallization from ethyl ether/pentane gave the title compound, m.p. ca. 105° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH2:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=[S:34])[NH2:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(N)=O)c(OCc1ccccc1)c2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCCn2c1nc(C(N)=S)c(OCc1ccccc1)c2=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.54 g, 1.64 mmol, 1.0 equiv) in THF (33 mL) under a nitrogen atmosphere, was added Lawesson's reagent (0.40 g, 0.98 mmol, 0.6 equiv). The yellow solution was then heated to 70° C. (oil bath). After stirring for 1 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica gel chromatography (30-100% ethyl acetate/hexane) to provide the title compound (0.28 g, 49% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (s, 1H), 7.63 (s, 1H), 7.50-7.57 (m, 2H), 7.27-7.41 (m, 3H), 5.30 (s, 2H), 3.96-4.08 (m, 4H), 1.62 (s, 6H); LCMS (ES+, (M+H)+) m/z 346.17.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:14][OH:15])[C:10]([F:13])([F:12])[F:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.O>C1COCC1>[F:13][C:10]([F:11])([F:12])[C:9]1[C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[O:15][N:14]=1
Reactant: ON=C(c1ccc(O)cc1O)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2c(C(F)(F)F)noc2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of 1-(2,4-dihydroxyphenyl)-2,2,2-trifluoroethanone oxime (Example 70, 0.25 g, 1.13 mmol) in THF (15 mL) was added triphenylphosphine (0.63 g, 2.4 mmol) and the mixture was cooled to 0° C. A solution of DEAD (0.48 mL, 2.3 mmol) in THF (10 mL) was slowly added while the temperature was kept at 0° C., after which the reaction mixture was stirred at 0-5° C. for 4 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3×). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/hexane (v/v) 1:10 to 3:2 gradient) gave 0.23 g of the title compound with minor impurities. The material was used without further purification. GC-MS [M+H]+:204.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[C:11]1([C:9]2[O:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1oc(-c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A solution of the above-prepared 2,4-diphenyl-oxazole-5-carboxylic acid ethyl ester (500 mg, 1.70 mmole, 1.0 eq) in dioxane (6 ml) was treated with 2N NaOH(1.7 ml, 3.4 mmole, 2.0 eq) and the mixture stirred at room temperature overnight under nitrogen. The mixture was then partitioned between ethyl acetate and 2.0N HCl. The organic phase washed with 0.5N HCl and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 426 mg of the title compound as a crude yellow solid. The product was used directly in the next step, without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]2.[CH3:18][N:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])[C:20](=[O:23])[CH:21]=[CH2:22]>C(O)C>[CH3:18][N:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])[C:20](=[O:23])[CH2:21][CH2:22][NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[CH:9]2
Reactant: C=CC(=O)N(C)c1ccccc1C
Reactant: Cn1c(=O)ccc2cc(OCCCN)ccc21
Solvent: CCO
Product: Cc1ccccc1N(C)C(=O)CCNCCCOc1ccc2c(ccc(=O)n2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
6-(3-Amino-propoxy)-1-methyl-1H-quinolin-2-one (194 mg) was added to an ethanol solution (5 ml) of N-methyl-N-o-tolyl-acrylamide (146 mg). The mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound (172.6 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][N:13]([C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>>[CH3:12][N:13]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:23][CH:22]=1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cnc2ccccc2c1
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cnc3ccccc3c2)cc1

Procedure:
3-Bromoquinoline (42 mg, 0.2 mmol) and tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66 mg, 0.2 mmol) were reacted using General Procedure (A) to afford tert-butyl methyl(4-(quinolin-3-yl)phenyl)carbamate a clear wax (44 mg, 66%). 1H NMR (400 MHz, CDCl3): δ 9.18 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.15 (m, 1H), 7.89 (m, 1H), 7.73 (m, 1H), 7.68 (m, 2H), 7.59 (m, 1H), 7.42 (m, 2H), 3.3 (s, 3H), 1.50 (s, 9H); MS (ESI): 335 (M+H+). tert-Butyl methyl(4-(quinolin-3-yl)phenyl)carbamate (44 mg, 0.13 mmol) was then treated with TFA by using the general procedure P. The crude product was purified by HPLC to afford T477 as an orange-colored wax (13 mg, 29%). 1H NMR (400 MHz, CDCl3): δ 9.46 (d, J=2.0 Hz, 1H), 8.79 (d, J=1.6 Hz, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.95 (m, 1H), 7.83 (m, 1H), 7.62 (m, 2H), 6.82 (m, 2H), 2.94 (s, 3H); MS (ESI): 235 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[O:12][CH2:11][CH2:10][N:9]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCC(=O)Cl
Reactant: c1ccc(C2CNCCO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.6 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and hexanoyl chloride (336.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(2-phenylmorpholin-4-yl)hexan-1-one are collected and the solvent is removed in vacuo to give 437 mg of colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].Br[CH2:10][C:11]([O:13]CC)=[O:12]>>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:10][C:11]([OH:13])=[O:12])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc[nH]n1
Reactant: CCOC(=O)CBr
Product: CC(C)c1ccn(CC(=O)O)n1

Procedure:
Prepared according to the analogous method described for Preparation 75, using 3-isopropyl-1H-pyrazole and ethyl bromoacetate isolating the higher running peak as the desired isomer, followed by the hydrolysis method of Preparation 74.
Reaction SMILES: Cl.[CH3:2][NH2:3].[F:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9]>>[F:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([NH:3][CH3:2])=[O:9]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(F)c(F)c1
Yield: 75 %

Procedure:
Using methylamine hydrochloride and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids (Scheme C), the title compound was obtained (75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (d, J=4.55 Hz, 3 H) 7.55 (dt, J=10.61, 8.34 Hz, 1 H) 7.72 (dddd, J=8.59, 4.55, 2.15, 1.39 Hz, 1 H) 7.86 (ddd, J=11.68, 7.89, 2.15 Hz, 1 H) 8.48-8.59 (m, 1 H). ESI-MS: m/z 172.1 (M+H)+. mp=142.7-145.0° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([NH2:11])=[O:10])=[CH:4][N:3]=1.Cl.[C:13]12([NH2:18])[CH2:17][CH:15]([CH2:16]1)[CH2:14]2.C(=O)(O)[O-].[Na+].CN1C(=O)CCC1>O>[C:13]12([NH:18][C:6]3[C:5]([C:9]([NH2:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:17][CH:15]([CH2:16]1)[CH2:14]2
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Reactant: NC12CC(C1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(Cl)nc1NC12CC(C1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
A mixture of 2,4-dichloro-pyrimidine-5-carboxamide (2 g), bicyclo[1.1.1]pentan-1-amine hydrochloride (1.18 g), sodium bicarbonate (1.75 g), and NMP (10 mL) was stirred at 25° C. for 24 h. Water (10 mL) was charged maintaining the reaction temperature less than 30° C., and the mixture was stirred at 25° C. for 2 h. The suspension was filtered, and washed with NMP:water (1:1 10 mL), then water (2×10 mL), and dried in a vacuum oven at 40° C. with nitrogen sweep to give 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-chloropyrimidine-5-carboxamide as a white solid (1.97 g, 83% yield). 1H NMR (DMSO-d6) δ 2.14 (s, 6H), 2.51-2.53 (m, 1H), 7.76 (br. s., 1H), 8.23 (br. s., 1H), 8.60 (s, 1H), 9.57 (s, 1H).