Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[CH2:26][O:25]4)=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]([OH:25])[CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1OC
Reactant: C1COCCN1
Solvent: CCO
Product: COc1ccc(-c2coc3cc(OCC(O)CN4CCOCC4)ccc3c2=O)cc1OC
Yield: 52.1 %

Procedure:
A mixture of compound 4 (obtained from example 2) (0.35 g, 1 mmol), morpholine (0.43 g, 5 mmol), and ethanol (30 mL) was refluxed for 6 hrs (TLC monitoring). After removal of solvent in vacuo, the residue was treated with H2O (50 mL). The resulting precipitate was collected and purified by column chromatography (MeOH/CH2Cl2=1:25) to give the title compound 6a (0.23 g, 51% yield). M.p.: 135-136° C.
Reaction SMILES: C([C@@:4]1([OH:28])[C@:8](C(=O)C)([OH:9])[C@@H:7]([CH2:13][O:14]C(=O)C)[O:6][C@H:5]1[N:18]1[C:27]2[N:26]=[CH:25][N:24]=[C:22](O)[C:21]=2[N:20]=[CH:19]1)(=O)C.S(Cl)([Cl:31])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:31][C:22]1[N:24]=[CH:25][N:26]=[C:27]2[C:21]=1[N:20]=[CH:19][N:18]2[C@@H:5]1[O:6][C@H:7]([CH2:13][OH:14])[C@@H:8]([OH:9])[C@H:4]1[OH:28]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 60 %

Procedure:
50 g of 2′,3′,5′-O-triacetylinosine was dissolved in 400 ml of chloroform. 30 ml of thionyl chloride and 7.2 ml of dimethylformamide were added, and the solution was refluxed with heating for 2 to 4 hours. The reaction mixture was poured into ice cold water, and the separated chloroform layer was washed with saturated aqueous solution of sodium hydrogencarbonate and brine. After drying over sodium sulfate anhydride, the solvent was distilled off. The residue was dissolved in 20% ammonia methanol solution and the container was sealed. After stirring for 3 to 5 hours, the solution was concentrated under reduced pressure. The precipitated crystalline was separated by filtration and dried to give 6-chloro-9-β-D-ribofuranosyl-9H-purine (yield: 60%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:14]=[C:13]([F:15])[C:9]([C:10]([OH:12])=[O:11])=[C:8]([F:16])[CH:7]=1.[ClH:17]>S(=O)(=O)(O)O.C(O)(=O)C.O.[Cu]Cl>[Cl:17][C:6]1[CH:14]=[C:13]([F:15])[C:9]([C:10]([OH:12])=[O:11])=[C:8]([F:16])[CH:7]=1
Reactant: Cl
Reactant: Nc1cc(F)c(C(=O)O)c(F)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1c(F)cc(Cl)cc1F
Temperature: 15 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of sodium nitrite (220 mg, 3.18 mmol) in concentrated sulphuric acid (2 ml) was added over 15 minutes to a suspension of 4-amino-2,6-difluorobenzoic acid (550 mg, 3.18 mmol) in acetic acid (6 ml) at 15° C. The mixture was stirred at 15° C. for 1 hour then heated to 90° C. and poured into a solution of copper(I)chloride (800 mg) in concentrated hydrochloric acid (11 ml) at 95° C. The mixture was heated at 95° C. for 45 minutes and then allowed to cool. The mixture was diluted with water, extracted with ethyl acetate, the organic extracts dried (MgSO4) and the solvent removed by evaporation to give 4-chloro-2,6-difluorobenzoic acid (600 mg, 98%)
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([SiH2][O:24][C:25](C1C=CC=CC=1)(C1C=CC=CC=1)[C:26]1[CH:31]=[CH:30][N:29]2[N:32]=[C:33]([CH3:52])[C:34]([C:35]3[C:36](=[O:51])[NH:37][C:38](=[O:50])[C:39]=3[C:40]3[C:48]4[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=4)[NH:42][CH:41]=3)=[C:28]2[CH:27]=1)(C)(C)C>C1COCC1>[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]2[N:32]=[C:33]([CH3:52])[C:34]([C:35]3[C:36](=[O:51])[NH:37][C:38](=[O:50])[C:39]=3[C:40]3[C:48]4[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=4)[NH:42][CH:41]=3)=[C:28]2[CH:27]=1
Reactant: Cc1nn2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nn2ccc(CO)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
TBAF (1.0 M in THF, 1.4 ml, 1.4 mmol, 1.1 equiv) is added to a solution of 3-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-2-methyl-pyrazolo[1,5-a]pyridin-3-yl]-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione in THF (10 ml). The reaction mixture is stirred for 1 hour at room temperature. The solvent is removed in vacuo, and the residue is purified by flash chromatography (gradient of hexane/EtOAc 100:0 to 20:80) to afford the title compound (400 mg, 84%). 1H NMR (400 MHz, d6-DMSO): δ=11.85 (br s, 1H), 10.99 (br s, 1H), 8.53 (d, J=7.8 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.35-7.34 (m, 1H), 6.82-6.79 (m, 2 H), 6.51 (t, J=8.1 Hz, 1H), 6.22 (d, J=8.1 Hz, 1H), 5.38 (t, J=5.7 Hz, 1H), 4.45 (d, J=4.9 Hz, 1H), 2.45 (s, 3H), 1.79 (s, 3H). MS (ES+): 387 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:5]=1.BrC1C([F:35])=C(C=C(Br)C=1)C(OC)=O>>[F:35][C:5]1[C:6]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])=[CH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:22]
Reactant: COC(=O)c1cc(Br)cc(Br)c1F
Reactant: COC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Product: COC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F

Procedure:
Prepared in an analogous manner to D7 from methyl 3,5-dibromo-2-fluorobenzoate (D38).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH:20]1([CH2:19][O:18][C@@H:15]2[CH2:16][CH2:17][N:13]([C:11]([C:9]3[S:10][C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[NH:33][C:29]4[CH:30]=[C:31]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:23])=[CH:32]5)[CH:8]=3)=[O:12])[CH2:14]2)[CH2:22][CH2:21]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](OCC2CC2)C1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC[C@@H](OCC6CC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 447.2 (MH+); HPLC Rf: 5.341 min.; HPLC purity: 100%.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=4)[N:15]=3)[NH:10][C:9]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CN2C3C(=N[CH:39]=[C:40]([C:43]4C=CC(C(OC)=O)=CC=4)[N:41]=3)NC2=O)CCCCC1>[OH-].[Li+].O1CCCC1>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]([NH:41][CH:40]([CH3:43])[CH3:39])=[O:22])=[CH:24][CH:25]=4)[N:15]=3)[NH:10][C:9]2=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 90 %

Procedure:
4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoic acid. A solution of methyl 4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate (See Example 56.A) (350 mg, 0.95 mmol) in 1N lithium hydroxide (4.5 mL) and tetrahydrofuran (4.5 mL) was allowed to stir at rt for 19 h. Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was treated with 1N hydrochloric acid and sonicated. The resulting precipitate was collected by vacuum filtration, and dried under high vacuum to afford the title compound (300 mg, 90% yield) as a tan solid. MS (ESI) m/z 353.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][CH2:15][C:14]3=[O:25])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:35][CH2:36][OH:37]>CC(C)=O>[OH:37][CH2:36][CH2:35][O:24][C:20]1[CH:19]=[C:18]([C@@H:17]2[N:13]([C:10]3[CH:9]=[N:8][C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=4)=[CH:12][N:11]=3)[C:14](=[O:25])[CH2:15][CH2:16]2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CC[C@H](c2cccc(O)c2)N1c1cnc(Oc2ccc(Cl)cc2)cn1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CC[C@H](c2cccc(OCCO)c2)N1c1cnc(Oc2ccc(Cl)cc2)cn1
Temperature: 70 °C
Reaction time: 65 h
Yield: 70.1 %

Procedure:
A mixture of (R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-hydroxyphenyl)pyrrolidin-2-one (276 mg, 0.72 mmol), acetone (9 mL), K2CO3 (996 mg, 7.2 mmol) and 2-iodoethanol (1.86 g, 10.8 mmol) is stirred at 70° C. for 65 h. Then, acetone is removed by evaporation and the residue is dissolved in ethyl acetate (120 mL), washed with brine (20 mL) and dried over Na2SO4. After concentration, the residue is purified on silica gel (0-50% ethyl acetate in hexane) to give the title compound (215 mg, 70%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 9.12 (s, 1H), 7.99 (s, 1H), 7.37-7.32 (m, 2H), 7.22 (t, J=7.6 Hz, 1H), 7.08-7.03 (m, 2H), 6.84-6.74 (m, 3H), 5.68 (dd, J=8.0, 3.2 Hz, 1H), 4.09-3.99 (m, 2H), 3.98-3.92 (m, 2H), 2.89-2.75 (m, 1H), 2.72-2.58 (m, 2H), 2.09-1.98 (m, 1H). HPLC-MS calculated for C22H20ClN3O4 (M+H+) 426.12, found 426.10.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.S([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=1)(O)(=O)=O>>[CH3:26][N:25]([C:22]1[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=1)[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1
Reactant: Clc1cnc2cc(Cl)c(Cl)cc2n1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Product: CN(c1ccc(O)cc1)c1cnc2cc(Cl)c(Cl)cc2n1

Procedure:
2,6,7-Trichloroquinoxaline was reacted with 4-(N-methylamino)phenol sulfate, following essentially the same procedure as that described in Example 1 Part (a), to give 4-[N-methyl-N-(6,7-dichloro-2-quinoxalinyl)amino]phenol. Proton magnetic resonance spectrum (d6 -acetone; δ in ppm): 8.25 (1H, s, quinoxaline hetero-ring proton); 8.0 (1H, s, quinoxaline benzo-ring proton); 7.9 (1H, s, quinoxaline benzo-ring proton); 7.15 (4H, m, phenoxy protons; 3.55 (3H, s, N-CH3).
Reaction SMILES: BrC1C=C[C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4C(C)=NN(C)C=4)[C:5]=3[C:4]=2C=1.[Br:24]C1C=C([N+]([O-])=O)C(OC)=NC=1>>[Br:24][C:4]1[CH:5]=[C:6]2[N:12]([CH3:23])[C:13](=[O:22])[N:14]([CH3:15])[C:7]2=[N:8][CH:9]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cn1c(=O)n(C)c2ncc(Br)cc21

Procedure:
The title compound was synthesized in a similar manner as described for Intermediate A using 5-bromo-2-methoxy-3-nitro-pyridine (Stage 67.1.3) to give the title compound as a violet solid. (HPLC: tR 2.63 min (Method A); M+H=242, 244 MS-ES).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:16][CH:15]=1>>[CH2:1]([N:5]([CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: ClCCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Product: CCCCN(CCCC)CCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Yield: 36 %

Procedure:
Reaction of this product (2.0 g, 6.3 mmol) with dibutylamine produced 1.1 g (36% yield) of the named compound as the HCl salt, mp 172°-173° C. IR(KBr): 3400, 1600 cm-1. MS: 409(MH+). 1H NMR (CDCl3): δ 8.37-6.79 (m, 10H), 4.67 (t, J=5.4 Hz, 2H), 3.55 (t, J=5.4 Hz, 2H), 3.12 (m, 4H), 1.99-0.79 (m, 14H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[C:7]([O:23][CH3:24])[CH:8]=2)[N:3]=1.NC(N)=[S:29]>C(O)C>[CH2:16]([O:15][C:13]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[C:7]([O:23][CH3:24])[CH:8]=2)[N:3]=[C:2]([SH:29])[N:11]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C(C(=O)OCC)c1nc(Cl)nc2cc(OC)c(OC)cc12
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1nc(S)nc2cc(OC)c(OC)cc12

Procedure:
The resultant product (600 mg) of (166-1) and thiourea (250 mg) were dissolved in ethanol (100 mL), and the mixture was heated under reflux for 48 hrs. The yellow solid precipitated in the reaction mixture was collected by filtration and washed with water and ethyl acetate to give the title compound (500 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[OH-].[K+:25]>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[K+:25]
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound [97] (118 mg) in ethanol (5 mL) was added an aqueous solution of 1N-potassium hydroxide (0.34 mL) at room temperature, and then the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the titled compound (128 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[CH2:17]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=O)[CH:28]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=1)[CH3:18].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=[C:20]3[O:19][CH2:17][CH3:18])[C:9](=[O:11])[N:10]=1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Reactant: O=C1CSC(NCc2ccc(F)cc2Cl)=N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one (example 17a, 41.4 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-thiazol-4-one as a light brown solid: 46.6 mg (61.7%), MS: m/e 472 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)=[CH:6][C:5]([F:27])=[CH:4][N:3]=1.[CH2:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]#[CH:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C>CN(C=O)C.[Cu]I>[C:34]([O:33][C:32]([NH:31][CH2:28][C:29]#[C:30][C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)=[CH:6][C:5]([F:27])=[CH:4][N:3]=1)=[O:38])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3C#CCNC(=O)OC(C)(C)C)nc12
Temperature: 95 °C

Procedure:
(R)-ethyl 5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 12, Step C; 153 mg, 0.392 mmol) in DMF (2 mL) was added tert-butyl prop-2-ynylcarbamate (122 mg, 0.785 mmol), copper(I) iodide (11 mg, 0.0578 mmol), triphenylphosphine (82.4 mg, 0.314 mmol), di-triphenylphosphine palladium(II) chloride (116 mg, 0.165 mmol), and diisopropylamine (99.3 mg, 0.981 mmol). The reaction mixture was sealed and heated to 95° C. for 8 hours, then cooled to ambient temperature and concentrated under reduced pressure The residue was purified by silica column chromatography, eluting with 33% EtOAc/Hexanes to afford the final product mixed with Ph3P (160 mg, 80.2% yield). MS (apci) m/z=508.9 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.Br>[CH3:12][O:11][C:9](=[O:10])[CH:8]([Br:13])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccccc1F
Agent: Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccccc1F
Yield: 100 %

Procedure:
To a solution of methyl 2-(2-fluorophenyl)acetate (1.0 g, 5.95 mmol) in CCl4 (15 mL), are added N-bromo succinimide (1.06 g, 5.95 mmol) and 48% hydrogen bromide (33 uL, 0.30 mmol) and the reaction is refluxed for 15 hours. Reaction is diluted with DCM and washed with Na2CO3 and water. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum to afford intermediate I261 as a dark brown oil (1.47 g, quantitative yield).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[N:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[N:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ncccc3C2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ncccc3C2)no1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[7,8-dihydro[1,6]naphthyridin-6(5H)-ylcarbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 29) (281 mg, 0.58 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (245 mg).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)[C:10]([N:12]([C@H:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:23](O)=[O:24])[C@@H:13](C(OC)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[P].[F:52][C:53]([F:57])([F:56])[CH2:54][NH2:55]>CN(C)C=O>[CH2:41]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[C@H:9]1[NH:8][C:6](=[O:7])[C@@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:12]([C@H:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:23]([NH:55][CH2:54][C:53]([F:57])([F:56])[F:52])=[O:24])[C:10]1=[O:11]
Reactant: COC(=O)[C@@H](CC(C)C)N(C(=O)[C@H](NC(=O)OC(C)(C)C)C1Cc2ccccc2C1)[C@@H](C(=O)O)c1ccc(F)cc1
Reactant: NCC(F)(F)F
Agent: [P]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NCC(F)(F)F)c1ccc(F)cc1
Reaction time: 0.03 h

Procedure:
A solution of (2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid (73 mg) in N,N-dimethylformamide (2 ml) was sequentially treated with diisopropylethylamine (51 μL), phosphorus, (1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-(T-4)-hexafluorophosphate (80 mg) and then after 2 minutes, 2,2,2-trifluoroethylamine (25 μl). This reaction mixture was stirred for 2 hours before being partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before being dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in 4M hydrogen chloride in dioxane and stirred for 7 hours at room temperature. The reagent was removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic fraction was washed with brine before being dried over magnesium sulphate and evaporated in vacuo. The crude material was purified by column chromatography (silica) eluting with methanol: dichloromethane (1% to 3%) to furnish ((2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide (10 mg)
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=[N:11]O)[CH2:6]2.C([O-])(=O)C.[NH4+]>C(O)C.[Ni]>[NH2:11][CH:5]1[CH2:4][CH:3]2[N:2]([CH3:1])[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6]1
Reactant: CN1C2CCCC1CC(=NO)C2
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1C2CCCC1CC(N)C2
Reaction time: 24 h
Yield: 86.5 %

Procedure:
N-methyl-9-azabicyclo-[3.3.1]-nonan-3-one oxime (3.25 g., 0.02 mole) was dissolved in ethanol and hydrogenated over Raney nickel in the presence of ammonium acetate at 300 p.s.i. at 50° C. for 24 hours. The mixture was filtered, evaporated in vacuo, dissolved in dilute hydrochloric acid, basified and extracted into ethyl acetate. The combined organic layers were dried (K2CO3), filtered and evaporated in vacuo to yield 3 -amino-9-methyl-9azabicyclo-[3.3.1]-nonane (2.67 g., 90%), used without further purification.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:12]=[CH:13][C:14]2[NH:20][C:19]3[N:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=3[CH2:17][N:16]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:15]=2[CH:43]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>CCO.O>[OH:1][C:2]([C:11]1[CH:12]=[CH:13][C:14]2[NH:20][C:19]3[N:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=[CH:24][C:18]=3[CH2:17][N:16]([S:29]([C:32]3[CH:33]=[CH:34][C:35]([O:38][C:39]([F:40])([F:42])[F:41])=[CH:36][CH:37]=3)(=[O:31])=[O:30])[C:15]=2[CH:43]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)(c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(O)(C(=O)O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 2-hydroxy-3-methyl-2-[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]butanoate (153 mg, 0.242 mmol, Example 509) in 4 mL of EtOH was added a solution of 1N LiOH (2.5 ml) in water, and the solution was stirred for 48 h at rt. LC-MS showed the reaction complete. The reaction pH was adjusted to 6-7 with 1N HCl, and the mixture was concentrated. The resulting residue was dissolved in CH2Cl2 and filtered to remove the salt. The filtrate was concentrated and the residue was purified by chromatography to give the title compound as a white solid; Mass Spectrum: m/e=606 (M+1).