Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>C(#N)C>[OH:31][C:29]([CH3:32])([CH3:30])[CH2:28][NH:27][CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Reactant: CC(C)(O)CN
Solvent: CC#N
Product: CC(C)(O)CNCC(=O)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Yield: 88 %

Procedure:
Prepared from 2-chloro-N-{2-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (Example 38 step A) (150 mg, 0.406 mmol, HPLC 1.185 min) and 1-amino-2-methyl-propan-2-ol (723 mg, 8.1 mmol) in acetonitrile (3 ml) according to the procedure described for Example 3 step B. Obtained the title compound as an off-white solid (151 mg, 88%, HPLC 0.563 min), MS (ISP) m/e=423.3 [(M+H)+].
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])(=[O:4])[CH3:3].[CH:20](Cl)(Cl)Cl>CO>[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:20])=[O:16])=[O:12])(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CO
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Temperature: 0 °C

Procedure:
Hydrogen chloride gas was passed through a gently boiling solution of 3-(5-acetamido-2-hydroxybenzoyl) propionic acid (1.2g) in dry methanol (20 ml) until esterification was complete. The reaction mixture was then poured into ice-water and chloroform added. The chloroform extract was washed with sodium bicarbonate solution then water, and finally dried and evaporated to leave methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate as a solid (0.75g, 59%; m.p. 145°-147° C; M+, 265, M 265).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:23][NH:24][CH3:25]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:24]([CH3:25])[CH3:23])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: FC(F)(F)Oc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CNC
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(OC(F)(F)F)cc1
Yield: 97.6 %

Procedure:
A solution of 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (250 mg, 0.716 mmol) and dimethylamine (0.716 mL, 1.432 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-N,N-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (250 mg, 0.699 mmol, 98% yield). LC-MS (M+H)+=358.0.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([O-:7])=[O:6].O>CN(C=O)C>[CH:1]([NH:4][S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1)(=[O:21])=[O:22])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 18 h

Procedure:
0.22 ml (2.52 mmol) of isopropylamine is added to a solution of 150 mg (0.50 mmol) of 4′-nitrobiphenyl-4-sulfonyl chloride in 2.0 ml of DMF. After 18 h at room temperature, 2.5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction and dried under high vacuum. 126 mg (64.4% of theory) of the title compound are obtained and reacted further without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>C(Cl)Cl>[Cl:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a stirred solution of aniline (0.4 mL, 4.30 mmol) in anhydrous CH2Cl2 (10 mL) was added 3-chloromethylbenzoyl chloride (360 mg, 1.90 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was removed under reduced pressure. Purification of the residue on strong acid ion exchange resin column (elution with methanol) afforded the title compound (400 mg, 86%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([OH:19])=O)[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[O:7][CH:8]=1.[NH2:20][C@@H:21]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:22][C@H:23]([OH:42])[C@@H:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[O:41][N:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)Cl>CO>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([NH:20][C@@H:21]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:22][C@H:23]([OH:42])[C@@H:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[O:41][N:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:19])[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[O:7][CH:8]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)O)co1
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccno2)co1
Yield: 64 %

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alanine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after silica gel chromatography using 92:8 CH2Cl2 :CH3OH, the desired compound (Rf 0.48, 92:8 CH2Cl2 :CH3OH) in 64% yield. 1H NMR (DMSO-d6) δ 1.08 (d, 3H), 1.24 (d, 6H), 1.50 (m, 2H), 2.82 (s, 3H), 3.0 (m, 1H), 4.25 (s, 2H), 4.60 (d, 1H), 5.05 (s, 2H), 6.20 (br d, 1H), 6.32 (d, 1H), 7.20 (m, 11H), 7.50 (br d, 1H), 7.78 (s, 1H), 8.51 (d, 1H). Mass spectrum: (M+H)+ =661.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>C1COCC1>[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:22]=1[NH:31][C:32]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:33]
Reactant: COc1cc(Br)c(N=C=O)cc1OC
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(Br)c(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
(S)-2-(4-Fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (57 mg, 0.30 mmol) from Preparation 3 was dissolved in 10 ml of THF and cooled to −40° C. n-BuLi (1.1 eq, 0.12 ml of a 2.5 M soln) was added dropwise, forming a purple suspension. This mixture was allowed to stir for 30 minutes until the purple color changed to white. 1-Bromo-2-isocyanato-4,5-dimethoxy-benzene (1 eq, 77 mg) was added. The mixture was allowed to stir for 15 minutes at −40° C. then allowed to warm to room temperature and stir for 2 hours. The reaction was then quenched with saturated ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/ethyl acetate 7:3) to obtain (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (2-bromo-4,5-dimethoxy-phenyl)-amide (82 mg, 61%) as a brown oil. MS (ES+) m/z 449 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:18][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1cc(C)c(COc2cccnc2N)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(C)c1

Procedure:
A mixture of 2-amino-3-(2,4,6-trimethylbenzyloxy)pyridine (2.00 g, 0.0082 mol), 4chlorophenyl isothiocyanate (1.68 g, 0.0099 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.37 g (70%), m.p. 180°-182 ° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[C:8]([CH3:15])([CH3:14])[C:6]=2[N:7]=1.[CH2:23]([NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)=[O:27])[CH3:24]>>[CH2:23]([NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[C:5]3[CH:10]([CH3:11])[S:9](=[O:13])(=[O:12])[C:8]([CH3:15])([CH3:14])[C:6]=3[N:7]=2)=[CH:31][CH:30]=1)=[O:27])[CH3:24]
Reactant: CC1c2c(N3CCOC[C@@H]3C)nc(Cl)nc2C(C)(C)S1(=O)=O
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3c(n2)C(C)(C)S(=O)(=O)C3C)cc1

Procedure:
The title compound was synthesised following the procedure in Example 5 (step viii) using 2-chloro-5,7,7-trimethyl-4-((S)-3-methylmorpholino)-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide and 1-ethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea. LC-MS (Method D), (ES+) 474, RT=3.00 min.
Reaction SMILES: [ClH:1].[CH3:2][CH2:3][OH:4].[F:5][C:6]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:35][CH:34]([O:36][CH3:37])[CH2:33]4)=[N:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16]C=1CNC(NC(=O)[O-])=N.C[CH2:39][OH:40]>>[ClH:1].[ClH:1].[ClH:1].[C:29]([NH:32][C:39](=[O:40])[O:4][CH2:3][C:2]1[CH:16]=[CH:17][CH:18]=[C:19]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[N:30][C:29]([N:32]4[CH2:35][CH:34]([O:36][CH3:37])[CH2:33]4)=[N:28][CH:27]=3)[CH2:24][CH2:25]2)[C:6]=1[F:5])(=[NH:28])[NH2:30]
Reactant: CCO
Reactant: COC1CN(c2ncc(N3CCN(c4cccc(CNC(=N)NC(=O)[O-])c4F)CC3)cn2)C1
Agent: Cl
Product: COC1CN(c2ncc(N3CCN(c4cccc(COC(=O)NC(=N)N)c4F)CC3)cn2)C1
Temperature: 25 °C

Procedure:
A 4M hydrogen chloride/EtOH solution (1.5 ml) was added to a mixture of 2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzylcarbamimidoylcarbamate (285 mg) and EtOH (5 ml), followed by stirring at room temperature. The precipitated yellow solid was collected by filtration and washed with EtOH. The obtained solid was dried at 40° C. under reduced pressure to obtain 2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate trihydrochloride (330 mg).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C1CCCCC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)C1CNCCN1c1ncccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1=CCCCC1
Product: CC(C)(C)OC(=O)C1CNCCN1c1ncccc1N
Temperature: 70 °C
Yield: 86.9 %

Procedure:
3-Nitro-2-(Boc-piperazine)pyridine 6 (1.765 g, 5.72 mmol) was dissolved in methanol (15 mL) at room temperature. Then Pd(OH)2 (1.234 g) and cyclohexene (2.0 mL, 19.52 mmol) were added. The resulting mixture was heated at 70° C. for 2 h. The mixture was concentrated to remove the solvent. DCM was added and then it was filtered through a pad of silica gel, washed with DCM and 10% MeOH/DCM. The collected solution was concentrated and dried under high vacuum to afford a slight pink solid as the product (1.384 g, 87% yield). 1H-NMR (CDCl3): 7.794 (dd, J=5.0 Hz and 1.5 Hz, 1 H, Ar—H), 6.956 (dd, J=7.5 Hz and 1.5 Hz, 1 H, Ar—H), 6.854 (dd, J=7.5 Hz and 5.0 Hz, 1 H, Ar—H), 3.783 (br, 2 H, NH2), 3.571 (t, J=4.5-5.0 Hz, 4 H, 2 CH2), 3.059 (t, J=4.5-5.0 Hz, 4 H, 2 CH2), 1.482 (s, 9 H, 3 CH3). LC-MS: 279.2 (MH+). (ref. Romero D. L. et al. J. Med. Chem. 37, 999-1014, 1994.)
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OO.CC[O:52]CC.CN(C=O)C>C(O)(=O)C>[NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17]([CH3:18])=[O:52])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CCOCC
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Agent: OO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)CC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 0.17 h

Procedure:
In 5 ml of acetic acid is dissolved 900 mg of BOC-Tyr-(D)-Met-Gly-Phe-NHNHCONH2 followed by addition of 0.24 ml of 30% aqueous H2O2. The solution is stirred for 10 minutes, treated with 100 ml of ether and filtered to obtain a powder. Yield 760 mg; m.p. 114°-121° C.; [α]D21.5 -2.6° (c=0.89, DMF); Rf2 0.38.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[C:11]([C:23](O)=[O:24])[N:12]([CH2:14][CH2:15][NH:16][C@H:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]([CH2:8][C:9]1[CH:10]=[C:11]2[C:23](=[O:24])[N:16]([C@H:17]([CH3:22])[C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:15][CH2:14][N:12]2[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NCCn1nc(COc2ccccc2)cc1C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](N1CCn2nc(COc3ccccc3)cc2C1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16.9 %

Procedure:
A mixture of (R)-5-phenoxymethyl-2-[2-(1,2,2-trimethyl-propylamino)-ethyl]-2H-pyrazole-3-carboxylic acid (130 mg, 0.38 mmol) and HATU (143 mg, 0.38 mmol) in DMF (3 mL) was stirred for 5 minutes at room temperature, then DIPEA (0.16 mL, 0.945 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then washed with a saturated solution of NH4Cl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The desired product was triturated with diethyl ether to yield (R)-2-phenoxymethyl-5-(1,2,2-trimethyl-propyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (21 mg, 17% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 0.98 (s, 9H), 1.21 (d, J=7.2 Hz, 3H), 3.66-3.79 (m, 2H), 4.27-4.40 (m, 2H), 4.73 (q, J=7.2 Hz, 1H), 5.09 (s, 2H), 6.93 (s, 1H), 6.96 (t, J=7.4 Hz, 1H), 7.00 (d, J=7.8 Hz, 2H), 7.27-7.32 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][N:12]=1.[N:22]([Sn](CCCC)(CCCC)CCCC)=[N+:23]=[N-:24]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH:18]=2)[NH:13][N:12]=1
Reactant: N#Cc1ccc2[nH]nc(-c3ccc4ccccc4c3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: c1ccc2cc(-c3n[nH]c4ccc(-c5nnn[nH]5)cc34)ccc2c1
Reaction time: 4 h
Yield: 64.4 %

Procedure:
A mixture of 3-(2-naphthyl)-1H-indazole-5-carbonitrile (105 mg, 0.390 mmol), azidotributyltin (Bu3SnN3, 710 mg, 2.14 mmol, 5.49 equiv.), and 4.1 mL toluene was refluxed for 49.5 h and concentrated to an oil. The oil was stirred in 31 mL dioxane and 31 mL 6.0 N aq HCl at room temperature for 4 h. The mixture was partitioned between 6.0 N aq. NaOH and hexanes, and the layers separated. The aqueous layer was extracted with hexanes, and 2×EtOAc, and then filtered. The aqueous layer was acidified to pH ca. 4.0 with 6.0 N aq. HCl. The resulting precipitate was either collected by filtration and dried in a vacuum oven, or extracted with EtOAc, dried (Na2SO4), filtered and concentrated to afford the title compound (78.4 mg, 64.3% yield): 1H NMR (DMSO-d6) δ 13.70 (s, 1H), 8.92 (s, 1H), 8.60 (s, 1H), 8.17 (d, 1H), 8.15–8.00 (m, 3H), 7.94 (d, 1H), 7.85 (d, 1H), 7.63–7.58 (m, 2H); ES-MS (m/z) 313 [M+1]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]=[C:16]1[CH:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([CH:20]1[CH2:19][CH2:18][N:17]([CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:16]1=[O:15])=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CC(c1ccccc1)N1CCC(C(=O)O)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccc1)N1CCC(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)C1=O

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 2-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid (0.101 g; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DFM (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxamide in two fractions (two sets of diastereoisomers) A 0.041 g (less polar fraction) and B 0.047 g (more polar fraction) (50% overall) as white solids.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15])/[CH2:3]O.[Br:16]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:16][CH2:3]/[C:2](/[CH3:1])=[CH:5]/[CH2:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]=1[CH3:15]
Reactant: CC1=C(C/C=C(\C)CO)C(C)(C)CCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1=C(C/C=C(\C)CBr)C(C)(C)CCC1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of (2E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenol (Chem. Abstr., 94, 65904 h) (4.15 g) and tetrabromomethane (7.0 g) in dichloromethane (40 ml) is added over 20 min a solution of triphenylphosphine (5.51 g) in dichloromethane (30 ml). The mixture is stirred overnight under nitrogen, the solvent is removed, and the residue is triturated with hexane. The mixture is filtered, and the filtrate concentrated in vacuo to provide (2E)-1-bromo-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butene (5.25 g) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)(=[O:14])=[O:13].O>CS(C)=O>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 93.1 %

Procedure:
To a solution of 7.41 g (0.0576 mole) of 4-chlorophenol dissolved in 150 ml of DMSO was added 2.30 g (0.0576 mole) of NaOH. The mixture was heated to 60° C. and 10.0 g (0.0524 mole) of 4-chlorophenyl methyl sulfone was added. The reaction mixture was heated at 160° C. for 3 hrs and cooled. The mixture was poured into a solution of 400 ml of 2 Normal (N) aqueous NaOH and 300 ml of water. The crystalline product was collected by filtration, washed well with water, and dried, which gave 13.8 g (93.2% yield) of product, mp 109°-111° C. Recrystallization from ethanol afforded purified 4-(4-(methylsulfonyl)phenoxy)-1-chlorobenzene, mp 111°-112° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]1[CH:30]=[CH:29][C:7]2[C:8]3[NH:9][C:10](=[O:28])[N:11]([O:16]CC4C=CC(OC)=CC=4OC)[C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=1)[CH3:2].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([N:9]1[C:8]2[C:7]3[CH:29]=[CH:30][C:4]([N:3]([CH2:31][CH3:32])[CH2:1][CH3:2])=[CH:5][C:6]=3[O:14][C:13]=2[C:12](=[O:15])[N:11]([OH:16])[C:10]1=[O:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCN(CC)c1ccc2c(c1)oc1c(=O)n(OCc3ccc(OC)cc3OC)c(=O)[nH]c12
Reactant: BrCc1ccccc1
Product: CCN(CC)c1ccc2c(c1)oc1c(=O)n(O)c(=O)n(Cc3ccccc3)c12

Procedure:
Following general procedure B2 and D1, 7-Diethylamino-3-(2,4-dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with benzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) 1.09 (t, J=7 Hz, 6H); 3.34-3.47 (m, 4H); 5.48 (s, 2H); 6.69-6.83 (m, 2H); 7.24-7.37 (m, 5H); 7.48 (d, J=9 Hz, 1H); 10.75 (br s, 1H); Ret. time=2.97 min., m/z=380.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]([CH3:30])([OH:29])[CH3:28]>>[OH:29][C:27]([CH3:30])([CH3:28])[CH2:26][NH:25][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: CC(C)(O)CN
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NCC(C)(C)O)n(C)n1
Yield: 65 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 1-amino-2-methyl-propan-2-ol instead of 2-amino-2-methyl-1-propanol, to the title compound (79 mg, 65%) which was obtained as a colorless gum. MS: m/e=403.2 [M+H]+.