Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[Cl:14][C:15]1[S:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=1>O1CCOCC1>[Cl:14][C:15]1[S:16][C:17]([CH2:20][N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:18][CH:19]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: ClCc1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1C(=O)N(Cc2ccc(Cl)s2)c2ccccc21
Reaction time: 0.08 h
Yield: 22.4 %

Procedure:
A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0° C. under argon. The mixture was allowed to stir for 5 minutes and then 2-chloro-5-(chloromethyl)thiophene (0.12 mL, 1.02 mmol) in dioxane (10 mL) was added dropwise to the resulting mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22%). 1H NMR (400 MHz): δ 7.62 (d, J=7.4, 1H), 7.56 (t, J=7.8, 1H), 7.14 (t, J=7.7, 1H), 6.94 (d, J=8.0, 1H), 6.90 (d, J=3.2, 1H), 6.78 (d, J=3.7, 1H), 4.90 (s, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C@H:8]([NH:48][C:49](=[O:65])[C@H:50]([CH:62]([CH3:64])[CH3:63])[NH:51][C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:53])[CH:9]=[CH:10][S:11]([CH:14]=[CH:15][C@@H:16]([NH:30][C:31](=[O:47])[C@H:32]([CH:44]([CH3:46])[CH3:45])[NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(OO)(C)(C)C.C1(C(C2C=CC=CC=2)[C@H](NC(=O)[C@H](CC(C)C)NC(OCC2C=CC=CC=2)=O)C=CS(C=C[C@@H](NC(=O)[C@H](CC(C)C)NC(OCC2C=CC=CC=2)=O)C(C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[C:18]1([CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:16]([NH:30][C:31](=[O:47])[C@H:32]([CH:44]([CH3:45])[CH3:46])[NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[CH:15][CH2:14][S:11]([CH2:10][CH:9]=[C:8]([NH:48][C:49](=[O:65])[C@H:50]([CH:62]([CH3:64])[CH3:63])[NH:51][C:52]([O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:53])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)(=[O:12])=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OO
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(=CCS(=O)(=O)CC=C(NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 21 %

Procedure:
Cbz-Val-Phe-VS-Ph was treated with butyllithium and tert-butylhydroperoxide in freshly distilled THF as described with Cbz-Leu-Phe-VS-Ph above to give Cbz-Val-Phe-AS-Ph as a white powder, yield 21%. 1H-NMR (CDCl3) δ 0.70-0.85 (2d, 6H, Val-CH3), 2.1 (m, 1H, Val-CH), 3.80 (d, 2H, CH2-Phe), 3.95 (m, 3H, CH2—SO2 and α-H), 4.90 (t, 1H, CH═), 5.12 (m, 3H, NH and Cbz), 7.1-7.4 (m, 10H, 2×Ph), 7.55 (t, 2H, SO2-Ph), 7.65 (t, 1H, SO2-Ph), 7.91 (d, 2H, SO2-Ph), 8.42 (b, 1H, NH). 13C NMR (300 MHz, CDCl3) δ 172.1, 156.3, 144.4, 140.8, 135.7, 134.2, 133.6, 131.2, 129.5, 129.4×2, 129.3, 128.8×2, 128.7, 128.6, 128.4, 128.3, 127.8, 127.3, 126.9, 106.3, 67.6, 56.0, 55.6, 41.7, 22.0, 21.0, 18.4. MS (FAB+) m/z 521 (M+1, 100%). Anal. calcd. for C29H32N2O5S.1/10 H2O: C, 66.67; H, 6.21; N, 5.36. Found: C, 66.31; H, 6.23; N, 5.26.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C@H:3]2[CH2:7][CH:8]=[CH:9][CH2:10][C@@H:2]12.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].S(=O)(=O)(O)O>C(OCC)C.O.C1COCC1>[OH:5][CH2:4][CH:3]1[CH:2]([CH2:1][OH:6])[CH2:10][CH:9]=[CH:8][CH2:7]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCC1CC=CCC1CO
Temperature: 25 °C

Procedure:
30 g cis-1,2,3,6-tetrahydrophtalic acid anhydride in 150 ml abs. THF are added through a separating funnel to a solution of 45 g lithium aluminum hydride in 900 ml abs. THF and heated for 48 hours under reflux. Then the mixture is first cooled to room temperature and then in an ice-brine bath to about 15° C. and the unused portion of the hydride is carefully broken down with water. Through the addition of diluted sulphuric acid the salts are dissolved and through the addition of diethylether the organic phase is separated from the aqueous phase.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([O:34]COC)[CH2:33][CH2:32][CH2:31]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][C:12]=3[F:24])[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([OH:34])[CH2:31][CH2:32][CH2:33]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][C:12]=3[F:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)cc5F)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: CN(C)CC(=O)Nc1ccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)c(F)c1

Procedure:
The title compound was prepared as described in Example 22E, substituting N-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-fluorophenyl)-2-(dimethylamino)acetamide (Example 60C) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (400 MHz, DMSO-D6) ppm 12.49 (s, 1H) 10.12 (s, 1H) 8.37 (s, 1H) 8.22 (s, 1H) 7.95 (m, 1H) 7.84 (dd, 1H) 7.59 (dd, 1H) 6.90 (d, 1H) 6.69 (s, 1H) 3.12 (s, 2H) 2.63 (m, 2H) 2.41 (m, 2H) 2.29 (s, 6H) 1.99 (m, 2H); MS ESI(+) m/z 500.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([NH:17][C:18]2([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:8][CH2:7]1.[OH-].[K+:36]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([NH:17][C:18]2([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O-:27])=[O:26])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:8][CH2:7]1.[K+:36]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cccc4c3N(Cc3ccc(Cl)c(Cl)c3)CC4)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccc(C2(NC(=O)c3cccc4c3N(Cc3ccc(Cl)c(Cl)c3)CC4)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Methyl 4-[1-({[1-(3,4-dichlorobenzyl)-2,3-dihydro-1H-indol-7-yl]carbonyl}amino)cyclopropyl]benzoate (57 mg, 0.12 mmol) was dissolved in EtOH (0.54 ml). 2M KOH (0.075 ml, 0.13 mmol) was added and the mixture stirred at 80° C. for 2 h. The mixture was cooled and the solvents removed. 1H NMR (500 MHz, DMSO-d6): δ 9.05 (s, 1H), 7.65 (d, 2H), 7.55 (m, 2H), 7.25 (d, 1H), 7.15 (t, 2H), 7.00 (d, 2H), 6.65 (t, 1H), 4.30 (s, 2H), 3.25 (2H), 2.95 (t, 2H), 1.10 (2H), 0.95 (m, 2H). MS+ESI (480.8).
Reaction SMILES: [C:1]([O:6]CC)(=O)[C:2]([CH3:4])=O.[F:9][C:10]([F:26])([F:25])[C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:15][CH:16]=1>>[F:9][C:10]([F:25])([F:26])[C:11]1[CH:12]=[C:13]([N:17]2[C:18]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:24]=[C:2]([CH3:4])[C:1]2=[O:6])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)=O
Product: Cc1nc2ccccc2n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
Preparation as in Example 1 but using ethyl pyruvate and N-(3-trifluoromethylphenyl)benzene-1,2-diamine gave the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccccc2)c1OCC1CC1
Yield: 15.1 %

Procedure:
The title compound was prepared from Intermediate 2 (100 mg, 0.231 mmol) and phenylboronic acid (33 mg, 0.276 mmol) using Pd[(C6H5)3P]4 (26 mg, 0.023 mmol) and sodium carbonate (48 mg, 0.461 mmol) in toluene (5 ml) and ethanol (2 ml) and water (2 ml) according to the procedure outlined in Example 1 to yield crude product which was purified by column chromatography to afford 15 mg of the desired product; 1H NMR (300 MHz, CDCl3) δ 0.32 (d, J=4.2 Hz, 2H), 0.57 (d, J=7.2 Hz, 2H), 0.99-1.70 (m, 1H), 3.76-3.82 (m, 5H), 6.78-6.82 (m, 3H), 6.91-6.98 (m, 3H), 7.36-7.43 (m, 4H), 7.93 (d, J=6.5 Hz, 1H), 8.27 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 431.33 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.CCN(CC)CC.[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30](Cl)=[O:31])=[CH:24][CH:23]=1.O>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:30]([O:29][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[O:31])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of (S)-tert-butyl piperidin-3-ylcarbamate (5 g, 24.9 mmol) and Et3N (3.8 mL, 27.4 mmol) in CH2Cl2 (75 mL) was added Cbz-Cl (3.92 mL, 27.4 mmol) at 0° C., after the addition was complete the reaction was warmed to rt and stirred for 4 h. The reaction was diluted with ice cooled water (30 mL) and the CH2Cl2 layer was separated and dried over Na2SO4 and concentrated in vacuo to give (7.5 g, 89%) of the tilted compound. 1H NMR (400 MHz, CDCl3): δ 7.40-7.24 (m, 5H), 5.18 (s, 2H), 4.58 (bs, 1H), 3.80-3.62 (m, 2H), 3.55-3.41 (m, 1H), 3.37-3.21 (m, 2H), 1.82-1.78 (m, 1H), 1.75-1.69 (m, 1H), 1.61-1.53 (m, 2H), 1.42 (s, 9H). ES-MS: m/z [M+1]=335.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:9][NH2:10].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH3:9])=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(Br)cn1
Yield: 24 %

Procedure:
A solution of 5-bromo-2-fluoropyridine (2.5 g, 14 mmol) in THF (50 mL) was stirred with a solution of methylamine in THF (c=2 mol/L) (35 mL, 70 mmol) at 23° C. for 16 h. Water was added and the mixture was extracted with ether, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a residue which was purified by silica gel column chromatography with heptane/ether, followed by trituration with heptane to give the title compound as a white solid (630 mg, 24%). MS (ISP) 187.1 [(M+H)+], 189.2 [(M+2+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:63]=[CH:62][C:27]([C:28]([N:30]([CH2:54][C:55]([O:57]C(C)(C)C)=[O:56])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:42]=[C:41]([NH:43][S:44]([C:47]4[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=4)(=[O:46])=[O:45])[O:40][N:39]=3)=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:23][C:24]2[CH:63]=[CH:62][C:27]([C:28]([N:30]([CH2:54][C:55]([OH:57])=[O:56])[CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[N:42]=[C:41]([NH:43][S:44]([C:47]5[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=5)(=[O:46])=[O:45])[O:40][N:39]=4)=[CH:36][CH:37]=3)=[O:29])=[CH:26][CH:25]=2)=[O:12])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc(N)cc4)cc3)no2)cc1
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(NS(=O)(=O)c5ccc(C)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Yield: 18 %

Procedure:
Prepared using General Procedures 7 and 8: To a stirring suspension of 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (26.4 mg, 0.113 mmol) in DCM (1 mL) and DMF (10 μL) was added oxalyl chloride (9.85 μL, 0.113 mmol) at room temperature. After 1 h the reaction mixture was added to a solution of tert-butyl 2-(4-amino-N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-69 (13 mg, 0.023 mmol) in DCM (0.5 mL) and TEA (6.27 μL, 0.045 mmol). After stirring at room temperature for 2 h TFA (0.5 mL) was added. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford 3.2 mg (18%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 480 as an off-white solid. LCMS-ESI (m/z) calculated for C35H30F3N5O8S: 737; found 738 [M+H]+, tR=5.74 min (Method 9).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[O:7])=[CH:4][CH:3]=1>C(OC(=O)CC)(=O)CC>[C:6]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[O:7])=[CH:14][CH:15]=1)(=[O:7])[CH2:5][CH3:4]
Reactant: Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Agent: CCC(=O)OC(=O)CC
Product: CCC(=O)Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
5.0 g (24.4 millimoles) of cis-2-(p-aminobenzoyl)-cyclopropanecarboxylic acid (see Example 9a) and 50 ml of propionic anhydride are kept at 80° C. for 30 minutes. The solution is then poured into ice water. The oil which hereupon separates out is left to stand overnight at room temperature in the aqueous phase, during which time it solidifies. It is then filtered off, washed with water and recrystallized from ethyl acetate/petroleum ether. 1.9 g (30% of theory) of cis-2-(p-propionylaminobenzoyl)-cyclopropanecarboxylic acid are isolated as colorless crystals of melting point 182°-183° C.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>O=S(Cl)Cl.C(Cl)Cl.CN(C=O)C.CC(O)C>[F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:18][C:17]3[CH:19]=[CH:20][C:14]([F:13])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Fc1cc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc2cn1
Temperature: 84 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A suspension of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (93) (4.90 g, 29.68 mmol) in SOCl2 (250 mL), CH2Cl2 (50 mL) and DMF (8 drops) was heated under reflux for 3 h. The solvents were then removed by vacuum distillation and the residue was evaporated to dryness. The resulting crude 4-chloro-6-fluoropyrido[3,4-d]pyrimidine was dissolved in CH2Cl2 (50 mL) and iPrOH (120 mL), to which 4-fluoro-3-(trifluoromethyl)aniline (5.85 g, 32.66 mmol) was added before the solution was heated under reflux at 84° C. for 30 min using an air condenser. During reflux the CH2Cl2 was evaporated and the crude product precipitated from the remaining iPrOH as a pale yellow solid. The mixture was cooled to the room temperature, poured into an ice-cold beaker of 5% aqueous Na2CO3 and stirred for 15 min at 0° C. The solid was collected by filtration, washed several times with water and then hexane before being dried in a vacuum oven (45° C.) overnight to give 6-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine (163) (9.68 g, 100%) as a yellow solid, m.p. 247-249° C. 1H NMR [(CD3)2SO] δ 10.25 (s, 1H), 8.99 (s, 1H), 8.75 (s, 1H), 8.34 (dd, J=6.5, 2.7 Hz, 1H), 8.26-8.30 (m, 1H), 8.24 (s, 1H), 7.60 (t, J=9.7 Hz, 1H). Anal. Calcd for C14H7F5N4: C, 51.54; H, 2.16; N, 17.17%. found: C, 51.37; H, 2.30; N, 16.93%.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][NH:24]1>>[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][N:24]1[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: c1ccc2c(c1)CNC2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4ccccc4C3)cn2)c1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and isoindoline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.10 (2H, t, J=6.0 Hz), 3.99 (4H, s), 4.21 (2H, t, J=6.0 Hz), 7.17-7.24 (4H, m), 7.56 (1H, d, J=3.8 Hz), 7.82 (1H, s), 7.88 (1H, s), 8.27 (1H, s), 8.59 (1H, d, J=5.0 Hz). [M+H] Calc'd for C19H18N4O2, 335. Found, 335.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[F:12].[CH3:13][C:14]1[C:15]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:19][C:16]=2[S:17][CH:18]=1>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:18]1[S:17][C:16]2[CH:19]=[C:20]([O:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:21]=[CH:22][C:15]=2[C:14]=1[CH3:13]
Reactant: Cc1csc2cc(Oc3ncccn3)ccc12
Reactant: O=[N+]([O-])c1cccc(CBr)c1F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1c(Cc2cccc([N+](=O)[O-])c2F)sc2cc(Oc3ncccn3)ccc12
Yield: 36.3 %

Procedure:
1-Bromomethyl-2-fluoro-3-nitrobenzene (120 mg, 0.513 mmol) and zinc chloride (71 mg, 0.520 mmol) were added to a solution of 2-(3-methyl-benzo[b]thiophen-6-yloxy)pyrimidine (114 mg, 0.470 mmol) in dichloromethane (1.0 mL), and the mixture was heated under reflux for 17.5 hours. After returning to room temperature, 1-bromomethyl-2-fluoro-3-nitrobenzene (120 mg, 0.513 mmol) and zinc chloride (71 mg, 0.520 mmol) were added thereto, and the mixture was heated under reflux for 23 hours. The reaction mixture was then concentrated under reduced pressure, and purified by column chromatography to yield the title compound (67.5 mg, 36%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[CH:27]=[CH:26][C:25]=1[O:33][C:34]([F:37])([F:36])[F:35]>>[Cl:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])[CH:27]=[CH:26][C:25]=1[O:33][C:34]([F:37])([F:36])[F:35]
Reactant: O=C=Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(OC(F)(F)F)c(Cl)c1
Yield: 68 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 2-chloro-4-isocyanato-1-trifluoromethoxy-benzene (intermediate 17) gave the titled compound in 68% yield as light brown foam. MS: 547.19 (MH+, 1Cl).
Reaction SMILES: O[CH2:2][CH:3]1[CH:8]2[O:9][C:10]([CH3:13])([CH3:12])[O:11][CH:7]2[CH:6]([O:14][CH2:15][O:16][CH3:17])[CH2:5][C:4]1=[O:18].CS(Cl)(=O)=O.Cl>N1C=CC=CC=1>[CH2:2]=[C:3]1[CH:8]2[O:9][C:10]([CH3:13])([CH3:12])[O:11][CH:7]2[CH:6]([O:14][CH2:15][O:16][CH3:17])[CH2:5][C:4]1=[O:18]
Reactant: COCOC1CC(=O)C(CO)C2OC(C)(C)OC12
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C=C1C(=O)CC(OCOC)C2OC(C)(C)OC12
Reaction time: 2 h
Yield: 8.8 %

Procedure:
Pyridine (0.5 ml) was added to 22 mg of 2-hydroxymethyl-3,4-(dimethylmethylenedioxy)-5-(methoxymethoxy)cyclohexanone, and 0.1 ml of methanesulfonyl chloride was then added at 0° C., followed by stirring the mixture for 2 hours. The reaction mixture was poured into cold dilute hydrochloric acid, and extracted with diethyl ether. The extract was washed with a saturated sodium hydrogen carbonate aqueous solution and then with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to provide 1.8 mg of 2-methylene-3,4-(dimethylmethylenedioxy)-5-(methoxymethoxy)cyclohexanone having the following properties (yield 8.8%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[N:12]([O-])=[O:13].[Na+].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[N:12]([N:7]1[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:10])[F:11])[CH2:9][CH2:8]1)=[O:13]
Reactant: O=N[O-]
Reactant: FC(F)(F)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=NN1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,2,2-trifluoroethyl)piperazine (4.88 g, 29.0 mmol) in water (4.9 mL) that cooled with ice bath, a solution of sodium nitrite (4.04 g, 58.6 mmol) in water (20 mL) and acetic acid (5.0 mL, 87.0 mmol) were added dropwise slowly, then the mixture was stirred for 1 h. The reaction mixture was all owed to warm to ambient temperature, stirred for further 2 h. The reaction mixture was adjusted to pH9 using sodium carbonate, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated to afford 1-nitroso-4-(2,2,2-trifluoroethyl)piperazine as oil (5.57 g, y. 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([NH:18][N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)(=[O:17])=[O:16])=[O:13])[N:4]=1.[K+].[Br-:25]>O1CCCC1>[Br:25][C:20]1[N:19]([NH:18][S:15]([NH:14][C:12]([NH:11][C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)=[O:13])(=[O:16])=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nn2cccc2)n1
Reactant: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nn2cccc2Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(4,6-dimethoxypyrimidin-2-yl)-N'-{[(1H-pyrrol-1-yl)amino]sulfonyl}urea (I-53; 0.164 g; 0.48 mM) synthesized according to synthesis Example 1 at room temperature was dissolved in 10 ml of tetrahydrofuran. To the solution was added under cooling with ice-water N-bromosuccinimide (0.085 g; 0.48mM). After cooled for a short period of time, the mixture was stirred at room temperature for 3 hours. The solvent in the reaction mixture was then distilled away and the resultant residue was purified with column chromatography on silica gel to obtain the target product. White solid; m.p. 157° C.; Yield 0.095 g (47.5%) IR (KBr cm-1): 3320 3132 1716 1614 1582 1454 1364 1170 NMR(CDCl3, δ): 3.7(6H,s:pyrimidine ring OCH3 ×2) 5.6(1H,s:pyrimidine ring H) 6.0(2H,m:pyrrole ring C3 and C4) 6.7~6.9(1H,m:pyrrole ring C5) 8.5(1H,bs:NH) 12.5(1H,bs:NH)