Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>C(O)C>[OH:7][C:8]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=1[C:10]([O-:12])=[O:11].[NH2+:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(O)cc1O
Solvent: CCO
Product: C1CC[NH2+]CC1
Product: O=C([O-])c1ccc(O)cc1O
Reaction time: 8 h

Procedure:
Piperidine (0.85 g; 10 mmol) was added dropwise to a solution of 2,4-dihydroxybenzoic acid (1.54 g; 10 mmol) in ethanol (10 cm3). This mixture was then left at 5° C. overnight, which resulted in the precipitation of a white solid. The product was collected by filtration and recrystallized from water to produce needle-like crystals. Found: C, 61.3%; H, 7.3%; N, 5.9%. Calculated for C12H17NO4 ; C, 60.25%; H, 7.11%; N, 5.85%. M.pt. 210°-211° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[O:29][C:30]=3[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:28]2[O:29][C:30]([C:31]([F:33])([F:32])[F:34])=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([C@H:10]4[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:43])=[O:4])[CH2:12][CH2:11]4)=[CH:14][CH:15]=3)=[O:42])=[O:25])[N:27]=2)=[CH:36][CH:37]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(F)cc4)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(F)cc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
NaOH (30.9 mg, 0.8 mmol) was added to trans-{4-[4-(3-{[2-(4-fluorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester solution (89 mg, 0.16 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 15 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2, stirred for 30 minutes, and filtered. The filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by column chromatography and purified to obtain the desired compound (75 mg, 86%) as a white solid.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([C:9](=O)[CH2:10]Br)=[C:6]([CH3:8])[N:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1>CC(N(C)C)=O>[NH2:2][C:3]1[S:4][C:5]([C:9]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:10]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cccnc1N
Reactant: Cc1nc(N)sc1C(=O)CBr
Agent: Br
Solvent: CC(=O)N(C)C
Product: Cc1nc(N)sc1-c1cn2cccc(C)c2n1
Yield: 21.8 %

Procedure:
A solution of 2-amino-4-methyl-5-(2-bromoacetyl)thiazole hydrobromide (9.5 g) and 2-amino-3-methylpyridine (9.7 g) in dimethylacetamide (100 ml) was heated at 85° C. to 88° C. for 5 hours and the reaction mixture was evaporated in vacuo. To the residue was added water and the resulting mixture was acidified to pH 0.8 with 10% hydrochloric acid. The acidified solution was treated with charcoal and filtered. The filtrate was washed with ethyl acetate. The aqueous solution was adjusted to pH 9.0 with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 2-(2-amino-4-methyl-5-thiazolyl)-8-methylimidazo[1,2-a]pyridine (1.6 g). mp 226° C. (dec.)
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:29][CH2:28]3)[CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:30][C:31]1[CH:48]=[CH:47][C:34]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:48][CH:47]=3)=[CH:43][CH:42]=2)[C:3]=1[N:22]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 49.2 %

Procedure:
The Pd(Ph3P)4 (61.8 mg, 0.053 mmol) was added to a nitrogen purged and degassed solution of (2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (125 mg, 0.27 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (77 mg, 0.29 mmol), and potassium phosphate tribasic (397 mg, 1.9 mmol) in 1,4-dioxane (3.5 mL) and water (0.9 mL). The reaction mixture was stirred in a screw-capped pressure vessel for 4 h at 90° C., cooled, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2CO3). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (2S)-isopropyl 2-(tert-butoxy)-2-(4-(3-cyclopropylpyrrolidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 80 mg (49.6%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.36 (m, 2H), 7.21-7.20 (m, 1H), 7.15-7.12 (m, 2H), 7.03-6.94 (m, 3H), 5.77/5.75 (s, 1H), 4.96-4.91 (m, 1H), 4.21 (t, J=6.6 Hz, 2H) 3.17-3.13/3.01-2.97 (m, 1H), 3.05 (t, J=6.6 Hz, 2H), 2.84-2.74 (m, 2H), 2.70-2.67/2.63-2.60 (m, 1H), 2.42/2.41 (s, 3H), 2.07/2.05 (s, 3H), 1.71-1.64 (m, 1H), 1.42-1.22/1.03-0.097 (m, 2H), 1.19-1.17 (m, 3H), 1.14-1.10 (m, 12H), 0.52-0.47 (m, 1H), 0.32-0.23 (m, 2H), −0.30-0.15 (m, 2H). UPLC (M+H)=603.5.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])[CH:19]=1>>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:15][CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[C:4]([OH:3])=[O:16])=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]([F:38])=[CH:33][CH:34]=[CH:35][C:36]=2[F:37])(=[O:30])=[O:29])[CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1c(F)cccc1F
Agent: Cl
Product: O=C(NC(Cc1ccc(Cl)cc1Cl)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
2-[4-Bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoylamino]-3-(2,4-dichloro-phenyl)-propionic acid. (S)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 4-bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford title compound. HPLC: RT=10.26 min. MS (ESI−): mass calcd. for C22H15BrCl2F2N2O5S, 608.2; m/z found, 607 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.36 (s, 1H), 7.87 (d, J=1.8, 1H), 7.52-7.44 (m, 1H), 7.39 (d, J=1.6, 1H), 7.27-7.25 (m, 1H), 7.25-7.22 (m, 1H), 7.18-7.15 (m, 1H), 6.97 (t, J=8.7, 2H), 6.79 (d, J=7.7, 1H), 5.05-5.00 (m, 1H), 3.50 (dd, J=14.2, 5.5, 1H), 3.29 (dd, J=14.2, 8.1, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH2:7]=[CH:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1.[C:10]1([NH:16][C:17]([NH2:1])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccc(N)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=Cc1ccccc1
Product: NC(=O)Nc1ccccc1

Procedure:
5.00 g (42.0 mmol) of p-aminostyrene (99% Tokyo Kasei) was added to a 250 ml round bottom flask. After ten minutes of mixing, 5.00 g (42.0 mmol) of phenyl isocyanate (99% Aldrich) was added dropwise. Within seconds, a yellow precipitate formed. Chloroform (20 ml) was added to aid stirring. The precipitate was filtered to remove the reaction liquid, then washed with 20 ml of chloroform resulting in a pale yellow powder (8.60 g, 86.0 % crude yield, mp=213° C.).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[C:12](=[O:21])[C:13]([C:16]([O:18]CC)=O)=[CH:14][N:15]=[C:4]12)[CH3:2].[CH3:22][NH2:23]>>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[C:12](=[O:21])[C:13]([C:16]([NH:23][CH3:22])=[O:18])=[CH:14][N:15]=[C:4]12)[CH3:2]
Reactant: CCOC(=O)c1cnc2n(CC)c3ccccc3n2c1=O
Reactant: CN
Product: CCn1c2ccccc2n2c(=O)c(C(=O)NC)cnc12
Yield: 63 %

Procedure:
10 g. of 90% pure 10-ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]-benzimidazole-3-carboxylic acid, ethyl ester produced in Example 1b are dissolved in 50 ml. of alcohol. After addition of 10 ml. of methylamine, the solution is heated in an autoclave at 100° for 12 hours. After this time, the solvent is distilled off and the crystalline residue is heated with hot acetone. The small amount of isomeric 1-ethyl-1,4-dihydro-N-methyl-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamide is insoluble and is filtered off. After addition of water to the mother liquor, the 10-ethyl-4,10-dihydro-N-methyl-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxamide crystallizes, yield 63%; m.p. 178°-180° (acetone).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-ethoxy-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M36) (133 mg, 0.27 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (28 mg).
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)=[O:3].[O:16]1CCOC[CH2:17]1.Cl>[Cl-].[Na+].O>[OH:16][CH2:17][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1
Reactant: C1COCCO1
Reactant: O=C(Cl)CCCCCCC1=CCCC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(CO)CCCCCCC1=CCCC1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 6.3 g of 2-[6-(chloroformyl)hexyl]cyclopent-2-en-1-one (Example 268) and 16 g of tris-trimethylsilyloxyethylene (Example 267) are stirred at 90° to 100° C. under argon for one hour. To this mixture is added 25 ml of dioxane and 10 ml of 0.6 N hydrochloric acid. The mixture is heated at 80° C. for 30 minutes. The mixture is poured into brine and extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ether containing 2% acetic acid to give 1.7 g of the title compound (Rf =0.45).
Reaction SMILES: [F:1][C@@H:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.O[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:29][N:28]=2)=[CH:23][CH:22]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:10][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][C:5]([O:4][CH2:3][C@@H:2]([F:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][CH:7]=3)=[CH:22][CH:23]=2)=[N:32][CH:31]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCC[C@H](F)COc1ccc(C(=O)O)cc1
Product: CCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(OC[C@@H](F)CCCCCC)cc3)cc2)nc1

Procedure:
(S)-4-(2-Fluorooctyloxy)benzoic acid and 2-(4-hydroxyphenyl)-5-n-nonylpyrimidine are reacted analogously to give (S)-[4-(5-n-nonylpyrimidin-2-yl)phenyl]4-(2-fluorooctyloxy)benzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=2C(O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:27]([CH2:30]C)CC)C.P(N=[N+]=[N-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=[O:33]>C1(C)C=CC=CC=1>[F:24][C:20]1[C:16]2[NH:27][C:30](=[O:33])[N:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[C:15]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2C(=O)O)CC1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c(F)cccc32)CC1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 97 %

Procedure:
2-(1-(tert-Butoxycarbonyl)piperidin-4-ylamino)-6-fluorobenzoic acid (1.081 g, 3.19 mmol) and triethylamine (0.534 ml, 3.83 mmol) were combined and suspended in toluene (20 mL). Diphenyl azidophosphate (0.826 ml, 3.83 mmol) was added to the mixture. Reaction stirred at room temperature for 35 minutes. The reaction was heated to 80° C. for 1 hour. Solvent was removed in vacuo. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as white solid in 97% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 9.64 (s, 1 H) 6.94-7.02 (m, 1 H) 6.91 (d, J=8.24 Hz, 1 H) 6.82 (t, J=9.15 Hz, 1 H) 4.42-4.54 (m, 1 H) 4.31 (d, J=10.07 Hz, 2 H) 2.86 (t, J=12.67 Hz, 2 H) 2.21-2.35 (m, 2 H) 1.78-1.87 (m, 2 H) 1.49 (s, 9 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[N:17]=3)=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2].CCN(CC)CC>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc2cc(Oc3ccncn3)ccc12

Procedure:
300 mg (0.938 mMol) 6-(2-chloro-pyrimidin-4-yloxy)-benzo[d]isoxazole-3-carboxylic acid ethyl ester in 3 ml DMF and 262 μl (1.88 mMol) Et3N are hydrogenated in presence of 120 mg Pd/C (10%; Engelhard 4505). The catalyst is filtered off, the filtrate concentrated, the residue re-dissolved in EtOAc and water, the aq. layer separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 9:1→4:1) gives the title compound: MS: [M+1]+=286; TLC(hexane/EtOAc 1:1): Rf=0.30.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:27][C:17]1[C:18]2[C:19](=[O:25])[NH:20][CH2:21][CH2:22][C:23]=2[NH:24][C:16]=1[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[N:15]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([CH3:26])=[N:8]2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2cccc(-c3[nH]c4c(c3Br)C(=O)NCC4)c2nc1NC(C)(C)C
Yield: 61.6 %

Procedure:
A solution of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.30 g, 0.86 mmol) and 1-bromopyrrolidine-2,5-dione (0.23 g, 1.28 mmol) in CHCl3 (8.6 mL) was stirred at RT for 3 h. The reaction mixture was diluted with DCM (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (3×150 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was directly injected onto the column and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give 3-bromo-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (349) (228 mg, 0.53 mmol, 62% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.60 (s, 9H) 2.55 (s, 3H) 2.97 (t, J=6.85 Hz, 2H) 3.61 (td, J=6.85, 2.74 Hz, 2H) 4.85 (s, 1H) 5.51 (br. s., 1H) 7.44 (t, J=7.92 Hz, 1H) 7.74 (dd, J=8.02, 1.37 Hz, 1H) 8.71 (dd, J=7.63, 1.37 Hz, 1H) 12.28 (br. s., 1H). MS (ESI, pos. ion) m/z: 428.0/430.1 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:26]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc2nc[nH]c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc2nc[nH]c2c1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) suspension of 5-(hydroxymethyl)-benzimidazole (920 mg, 6.2 mmol) in THF (12 mL) was added sequentially DPPA (1.46 mL, 6.8 mmol) and DBU (1.11 mL, 7.4 mmol). The resulting solution was heated to reflux for 5 h, cooled to RT, and concentrated in vacuo. The residue was partitioned between sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Silica gel chromatography (15% MeOH—CHCl3), afforded the title compound as a brown solid: Rf (8:1:1 EtOAc-MeOH—NH4H)=0.31; m.p. 110-114° C.; 1H NMR (400 MHz, DMSO-d6): δ8.25 (s, 1H), 7.27 (d, J=8.4, 1H), 7.62-7.60 (m, 2H), 7.20 (d, J=8.2 Hz, 1H), 8.24 (s, 1H); HRMS (FAB) C8H8N5 calcd. 174.1847 (M+1). Found 174.1222.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[Br:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[F:1][C:2]1[C:3]([Br:9])=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Fc1cccc(F)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1F
Reaction time: 0.25 h
Yield: 97 %

Procedure:
A solution of 1,3-difluoro-2-bromobenzene (23.5 g, 112 mmol) in concentrated sulfuric acid (48 ml) was stirred vigorously at ambient temperature. Concentrated nitric acid (70%, 8 ml) was added dropwise such that the internal temperature of the reaction mixture did not exceed 55° C. The reaction mixture was then stirred from 15 minutes and poured onto ice (300 ml). The aqueous mixture was extracted three times with methylene chloride. The combined organic layers were washed three times with a saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give a yellow solid. Recrystallization from isopropyl ether afforded a white solid (28.2 g, 97% yield): m.p. 50°-51.5° C. NMR (CDCl3, 60 MHz): 8.4-7.9 (m, 1H), 7.4-7.0 (m, 1H). Anal.: Calcd. for C6H2BrF2NO2: C, 30.28, H, 0.85, N, 5.89, Br, 33.57, F, 15.96. Found: C, 30.34, H, 0.98, N, 5.81, Br, 33.81, F, 16.04.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.[SH-:11].[Na+].O>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([SH:11])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(C)S
Temperature: 25 °C
Yield: 36 %

Procedure:
Ethyl 2-bromoisobutyrate (48.8 g, 0.250 mole), sodium hydrosulfide hydrate (84 g, 1.5 mole), water (100 mL), ethyl alcohol (200 mL). Let reaction mix stir at room temperature. Next day, no starting material observed. Crude yield: 74.3%; distillation yield: 36.0%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:32]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CCn1c(C)c(-c2ccc(C[C@H](N)C(=O)OC)cc2)c(=O)n(CC)c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c(=O)n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a suspension of 4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.76 mmol, 0.3 g) and 2,6-dichlorobenzoyl chloride (0.84 mmol, 0.175 g) in dichloromethane (2 mL) was added diisopropylethylamine (3.03 mmol, 0.53 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting brown solution was diluted with dichloromethane (25 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×25 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to afford 0.40 g (99% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C26H27Cl2N3O5 (M+Na) 554.1221, found 554.1229.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:38]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:39])[CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N1CCCC1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.20 mmol) (from Example 25a supra) in tetrahydrofuran (3 mL) was added triethylamine (32 mg, 0.3 mmol) (Aldrich), followed by the addition of 1-pyrrolidinecarbonyl chloride (34 mg, 0.24 mmol) (Aldrich). The mixture was stirred at 50° C. for 1 hour, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue were triturated with dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-[1-(pyrrolidine-1-carbonyl)-piperidin-3-yl]-1,3-dihydro-indol-2-one as a white solid. (Yield 50 mg, 50%).