Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:25])=[O:23])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Reactant: C1COCCN1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
A mixture of 1-methyl-5-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 422 μmol), morpholine (368 μl, 4.22 mmol), propylphosphonic anhydride (50% in ethyl acetate, 622 μl, 1.06 mmol) and N,N-diisopropylethylamine (215 μl, 1.27 mmol) in tetrahydrofuran (6 ml) was stirred for 18 hours at 70° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate, washed with water. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid (2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (109 mg, 60.8%) as a light yellow solid. mp: 194-197° C., MS: m/z=425.3 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1.[C:25](=O)(ON1C(=O)CCC1=O)[O:26]N1C(=O)CCC1=O>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25](=[O:26])[NH:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:13][CH:12]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1cncnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cncnc2n1-c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of N4-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyrimidine-4,5-diamine (55 mg) and bis(2,5-dioxopyrrolidin-1-yl) carbonate (53 mg) in DMF (5 mL) was stirred overnight at 80° C. then at 95° C. for 3 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL), 5% aqueous lithium chloride (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 methanol/methylene chloride), solvent exchanged with acetonitrile and freeze dried from acetonitrile/water to afford 9-[4-(1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8-one (19 mg) as off-white crystals.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1>S(=O)(=O)(O)O>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[N+:1]([O-:4])=[O:2]
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Temperature: 10 °C
Yield: 94.8 %

Procedure:
A suspension of sodium nitrate (1.37 g, 16.2 mmol) in concentrated sulfuric acid(15 mL) was stirred at 10° C. until a homogeneous solution was obtained. The solution was treated with 4-bromobenzaldehyde (2.50 g, 13.5 mmol) in portionwise fashion over a 20 minute period. The mixture was poured onto ice (50 g) and the resulting pale yellow precipitate was collected by filteration. The precipitate was washed with copious amounts of water and then dried at 30° C. under reduced pressure to provide the title compound (2.95 g, 12.8 mmol, 95%) as a pale yellow solid. MS (DCI/NH3) m/e 229 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][CH3:17].[H-].[Na+].O>O1CCCC1>[CH3:15][N:16]([CH3:17])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CNC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 1-floro-4-nitro-2-trifluoromethylbenzene (2.0 g) in tetrahydrofuran (20 mL) were added dimethyamine (0.64 g) and sodium hydride (0.34 g) at room temperature, and this mixture was stirred at 50° C. for 16 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.94 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:52])[CH:10]([CH2:36][CH2:37][C:38](=[O:51])[NH:39]CC1C=CC(OC)=CC=1OC)[CH2:11][C:12]1([C:17](=[O:35])[NH:18][C@H:19]2[CH2:24][CH2:23][C@@H:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9](=[O:52])[CH:10]([CH2:36][CH2:37][C:38](=[O:51])[NH2:39])[CH2:11][C:12]1([C:17](=[O:35])[NH:18][C@H:19]2[CH2:20][CH2:21][C@@H:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:23][CH2:24]2)[CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNC(=O)CCC(CC2(C(=O)N[C@H]3CC[C@@H](C(=O)OCc4ccccc4)CC3)CCCC2)C(=O)OCc2ccccc2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC(=O)CCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.6 %

Procedure:
3-{1-[(cis-4-Benzyloxycarbonyl-cyclohexyl)carbamoyl]cyclopentyl}-2-{2-[(2,4-dimethoxyphenyl)methylcarbamoyl]ethyl}propanoic acid benzyl ester (Example 164) (0.37 g, 0.52 mmole) was dissolved in trifluoroacetic acid (10 ml). After stirring for 18 hours at room temperature the deep pink reaction mixture was poured into iced water which was basified with sodium hydrogen carbonate and extracted with dichloromethane. The combined extracts were dried (Na2SO4) and evaporated under vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane-diethyl ether and methanoldichloromethane mixtures to yield the title ester (110 mg, 38%). Rf 0.25 (silica; ethylacetate).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH2:17])[S:5][C:6]=1[CH3:7].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][S:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)(=[O:25])=[O:24])[S:5][C:6]=1[CH3:7]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1nc(-c2cc3cccc(N)c3[nH]2)sc1C
Solvent: c1ccncc1
Product: Cc1nc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)sc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
To a mixture of 2-(4,5-dimethyl-1,3-thiazol-2-yl)-1H-indole-7-amine (0.10 g) and pyridine (8 mL) was added thiophene-2-sulfonyl chloride (0.090 g) at 4° C., and the mixture was stirred at room temperature for 15 hr. The reaction solution was concentrated. The obtained residue was diluted with ethyl acetate, washed with aqueous citric acid solution and saturated brine, dried over-anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate) to give the title compound (142 mg, yield 89%) as pale-purple crystals. melting point 210-211° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[O:9][C:8]([CH2:10][CH2:11][OH:12])=[CH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:12][CH2:11][CH2:10][C:8]2[O:9][C:5]3[C:4]([Cl:14])=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: OCCc1cc2cc(Br)cc(Cl)c2o1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)cc(Cl)c3o2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
To a solution of the product of step B (3.5 g, 12.7 mmol) in dichloromethane (30 mL) was added triethylamine (3.7 mL, 25.4 mmol) followed by p-toluenesulfonyl chloride (3.6 mL, 19.05 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 12 h and concentrated in vacuo. The reaction mixture was quenched with saturated sodium bicarbonate solution, washed with 0.5 N HCl and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 4:1 hexanes/ethyl acetate) providing 2-(5-bromo-7-chlorobenzofuran-2-yl)ethyl 4-methylbenzenesulfonate (5.1 g, 95%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.66-7.62 (m, 2H), 7.49 (d, J=2.0 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.18-7.14 (m, 2H), 6.43 (s, 1H), 4.39 (t, J=6.4 Hz, 2H), 3.14 (t, J=6.0 Hz, 2H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[F:5][C:6]1[CH:7]=[C:8]([C:22]2[N:23]=[C:24]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[C:25]3[CH2:30][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[NH:12][C:13](OC1C=CC=CC=1)=[O:14]>>[CH2:34]([O:33][C:31]([N:29]1[CH2:30][C:25]2[C:24]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])=[N:23][C:22]([C:8]3[CH:9]=[CH:10][C:11]([NH:12][C:13]([NH:1][CH2:2][CH2:3][OH:4])=[O:14])=[C:6]([F:5])[CH:7]=3)=[N:27][C:26]=2[CH2:28]1)=[O:32])[CH3:35]
Reactant: NCCO
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)Oc4ccccc4)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 36 %

Procedure:
Method as described for example 51, using 2-aminoethanol and (S)-ethyl 2-(3-fluoro-4-((phenoxycarbonyl)amino)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate as starting materials. The mixture was reduced in vacuo and purified by flash SCX2 chromatography affording the title compound (10 mg, 0.020 mmol, 36%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:15])[C:9]2[N:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:27][C:26]=2[F:35])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:35][C:26]1[CH:27]=[C:28]([C:31]([OH:34])([CH3:32])[CH3:33])[CH:29]=[CH:30][C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:15])[C:9]3[N:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[N:3]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: Cn1cc(C(F)c2cccc(Br)n2)nn1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cn1cc(C(F)c2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1

Procedure:
The title compound was synthesized from 2-bromo-6-[fluoro(1-methyl-1H-1,2,3-triazol-4-yl)methyl]pyridine (111 mg, 0.41 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (120 mg, 0.41 mmol) according to the general procedure in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].[C:19](Cl)(=[O:21])[CH3:20]>>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])[C:19](=[O:21])[CH3:20]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Product: CC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Prepared from 4-(2-dimethylamino-ethyl-amino)-1,3-dinitrobenzene and acetyl chloride
Reaction SMILES: [C:1]([CH:3]1[CH2:5][CH2:4]1)#[CH:2].[N+:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-])=[O:7].C1N2CCN(CC2)C1>C(O)C>[CH:3]1([C:1]2[O:7][N:6]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=2)[CH2:5][CH2:4]1
Reactant: C#CC1CC1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)c1cc(C2CC2)on1
Yield: 92.2 %

Procedure:
A solution of ethynylcyclopropane (0.40 mL; 4.58 mmol), ethyl 2-nitroacetate (1.30 mL; 11.46 mmol), and 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.053 g; 0.458 mmol) in ethanol (3 mL) was irradiated in a microwave oven at 150° C. for 20 min and was then evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water. The organic layer was evaporated and the residue was purified by flash chromatography on silica gel (eluent: 20 to 100% of dichloromethane in heptane) to afford 0.765 g (92%) of ethyl 5-cyclopropylisoxazole-3-carboxylate as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:13]([C:16]1[C:17]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[C:14]=S>ClCCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:14]([NH:13][C:16]3[C:17]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: FC(F)(F)c1cccc(Oc2ncccc2N=C=S)c1
Solvent: ClCCCl
Product: CC(C)(C)c1ccc2nc(Nc3cccnc3Oc3cccc(C(F)(F)F)c3)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(tert-butyl)-1,2-diaminobenzene (20 mg, 0.12 mmol) in DCE (1 mL) was slowly added 3c (19 mg, 0.06 mmol). The reaction was stirred 18 h at rt and concentrated. The crude mixture containing 3d and 3d′ was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([CH3:8])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred solution of 4-bromo-3-fluorotoluene (10 g, 52.9 mmol) in H2SO4 (100 mL) was added KNO3 (5.34 g, 52.9 mmol) at 0° C. After stirring overnight at room temperature, the reaction mixture was poured into ice (200 g) and extracted with EtOAc (3×300 mL). The organic solution was washed with brine (200 mL), dried (Na2SO4), and concentrated to give 12.35 g (100%) of title compound as a pale yellow oil. 1H NMR (CDCl3): 300 MHz δ 8.29 (d, J=6.30 Hz, 1H), 7.12 (d, J=8.61 Hz, 1H), 2.60 (s, 3H).
Reaction SMILES: [NH:1]([C:29]([O:31]CC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:18]([N:20]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([NH2:24])=[O:23])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4]C(=O)N>C(O)(=O)C.[Pd]>[NH:1]1[C:29](=[O:31])[CH2:4][CH2:3][C@H:2]1[C:8]([NH:10][C@H:11]([C:18]([N:20]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([NH2:24])=[O:23])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)[C@@H]1CCCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Yield: 41 %

Procedure:
2.1 g (4 mmoles) of Z-Gln-His-HPro-NH2 are dissolved in 40 ml of acetic acid, 0.4 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is heated to 60°-70° C., maintained at this temperature for 30 minutes, and then evaporated in vacuo. The resulting crude product is subjected to ion exchange and purified as described in Step 5 of Example 15. 618 mg (56%) of Glp-His-HPro-NH2 are obtained; Rf4 =0.08, [α]D25 =-24.0° (c=1%, in methanol). Amino acid analysis: Glu: 0.97 (1.0), His: 1.00 (1.0), HPro: 0.91 (1.0).
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)=[CH:12][CH:11]=1>C(O)C.CN(C)C=O>[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)=[CH:12][CH:11]=1)=[O:2]
Reactant: BrCc1ccc(-c2noc3ccccc23)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=Cc1ccc(-c2noc3ccccc23)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
115.8 g of 2-nitropropane are introduced at about 30° C. into a solution of 23.13 g of sodium in 2,700 ml of anhydrous ethanol. The mixture is stirred for a further one hour and a solution of 288.1 g of 3-(p-bromomethyl-phenyl)-1,2-benzisoxazole in 350 ml of dimethylformamide is now added. Subsequently, the reaction mixture is warmed to 50° C., then stirred for 20 hours without external warming and finally cooled to -10° C. The product which has precipitated is filtered off with suction, washed with cold methanol and dried. This gives 107.4 g (48.1% of theory) of 3-(p-formylphenyl)-1,2-benzisoxazole in the form of a pale yellow powder with a melting point of 117° to 117.5° C. After recrystallising twice from ligroin, small, virtually colourless, glossy needles are obtained which melt at 117° to 117.5° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:14]3[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[N:16]([CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=4)[C:15]3=[O:30])[CH:12]=2)[C:7]([CH3:32])([CH3:31])[CH2:6]1)=[O:4].[CH3:33][NH:34][CH3:35]>O1CCCC1>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][N:16]2[C:17]([CH3:21])([CH3:20])[C:18](=[O:19])[N:14]([C:11]3[CH:12]=[C:13]4[C:8]([C:7]([CH3:31])([CH3:32])[CH2:6][N:5]4[C:3](=[O:4])[CH2:2][N:34]([CH3:35])[CH3:33])=[CH:9][CH:10]=3)[C:15]2=[O:30])[CH:28]=[CH:27][N:26]=1
Reactant: CC1(C)CN(C(=O)CCl)c2cc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)ccc21
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21

Procedure:
A solution of 0.951 g of 3-[1-(chloroacetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage j) of Example 3 in 80 mL of a 2M solution of dimethylamine in tetrahydrofuran is heated at 60° C. for 4 hours. The reaction mixture is then concentrated under reduced pressure and is triturated in 30 mL of water. A solid forms, which is filtered off, washed with twice 5 mL of diisopropyl ether and dried to give 3.5 g of 1-[(2-chloropyridin-4-yl)methyl]-3-[1-(N,N-dimethylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]12[C:26](=[O:27])[O:25][C:23](=O)[C:14]=1[CH2:15][CH2:16][C:17]1[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:28]([NH2:31])[CH2:29][NH2:30]>C1(C)C=CC=CC=1>[NH2:30][CH2:29][CH2:28][N:31]1[C:23](=[O:25])[C:14]2[CH2:15][CH2:16][C:17]3[C:22]([C:13]=2[C:26]1=[O:27])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: NCCN
Reactant: O=C1OC(=O)C2=C1CCc1ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: NCCN1C(=O)C2=C(C1=O)c1ccccc1CC2
Temperature: 60 °C
Yield: 97.8 %

Procedure:
27.6 g of toluene-p-sulphonic acid monohydrate are added to a solution of 27.62 g (0.138 mol) of 3,4-dihydronaphthalene-1,2-dicarboxylic acid anhydride in 300 ml of toluene, followed by 8.69 g of ethylenediamine. The mixture is heated to 60° C. for 30 minutes and then refluxed for 30 minutes, removing continuously the toluene and the water as they are formed by destillation. The residue is dried under vacuo to yield 32.7 g (90.0% of theory) of N-(2'-aminoethyl)-3,4-dihydronaphthalene-1,2-dicarboximide in the form of its toluene-p-sulphonic acid salt. This salt may be purified by recrystallisation from toluene.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:23][C:22]=3[Cl:36])=[CH:11]2)(=O)=O)C=CC=CC=1.CO.[OH-].[K+]>C(O)(=O)C>[Cl:36][C:22]1[N:23]=[C:24]([NH:26][CH2:27][C:28]2[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[S:25][C:21]=1[CH2:20][C:12]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)[NH:10][CH:11]=1
Reactant: COc1ccc(CNc2nc(Cl)c(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)s2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNc2nc(Cl)c(Cc3c[nH]c4ncc(Cl)cc34)s2)cn1
Temperature: 80 °C

Procedure:
[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine 619 was combined with methanol: potassium hydroxide (1M) (1:1, 0.5 mL). The mixture was heated at 80° C. for 2 hours. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50 mm×10 mm ID) eluting with 0.1% trifluoroacetic acid in water and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0190. MS (ESI) [M+H+]+=419.9.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O:25]1[CH2:31][CH2:30][CH2:29][O:28][C:27]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:26]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:25]1[CH2:31][CH2:30][CH2:29][O:28][C:27]2[CH:32]=[C:33]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH:34]=[CH:35][C:26]1=2
Reactant: OB(O)c1ccc2c(c1)OCCCO2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OCCCO4)n2n1
Temperature: 110 °C
Yield: 26.1 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (49 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 9.5 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-55% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (20.8 mg, 26%). ESI-MS: m/z 459.2 (M+H)+.