Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:22]3[CH:23]=[N:24][C:25]4[N:26]([C:32](=[O:34])[NH2:33])[CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=3)[C:19]=2[C:20]#[N:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:22]3[CH:23]=[N:24][C:25]4[N:26]([C:32](=[O:34])[NH2:33])[CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=3)[C:19]=2[C:20]#[N:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2C#N)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2C#N)CC1
Temperature: 60 °C

Procedure:
5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-4-cyano-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (100 mg, 0.22 mmol), 10% Pd on carbon (88 mg, 0.083 mmol) and ammonium formate (210 mg, 3.3 mmol) are mixed in MeOH (2.0 mL). The reaction mixture is heated at 60° C. for 24 hrs. Then the solid is filtered and the filtrate is concentrated to give the crude 5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-4-cyano-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester which is used in the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH:11]([NH:15][C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:32][CH3:33])[C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:10][C@H:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@@H](C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of methyl 3-{[(2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoate (223 mg, 0.513 mmol) in chloroform (4 mL) and acetic acid (500 uL) was added acetaldehyde (1.0 ml) and stirred for 30 min at 0° C. Then sodium triacetoxyborohydride (343 mg, 1.54 mmol) was added to the reaction mixture at 0° C. The reaction mixture was stirred at 23° C. for 4 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The content was extracted with ethylacetate. The organic layer was washed with brine. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethylacetate=4/1 to 1/2) to give the titled compound as a colorless oil. (105.5 mg, 44% yield). MS (ES) [M+H] 463.3.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[C:6]([O:15][CH2:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])[C:7]2[O:11][C:10]([CH3:12])=[N:9][C:8]=2[C:13]=1[CH3:14])(=[O:3])[CH3:2].[OH:36]O>C(O)(=O)C>[C:1]([C:4]1[C:5]([O:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=2[O-:36])=[C:6]([O:15][CH2:16][CH2:17][CH:18]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH3:19])[C:7]2[O:11][C:10]([CH3:12])=[N:9][C:8]=2[C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)c1c(OCCc2ccccn2)c(OCCC(C)c2ccc(F)cc2)c2oc(C)nc2c1C
Solvent: CC(=O)O
Product: CC(=O)c1c(OCCc2cccc[n+]2[O-])c(OCCC(C)c2ccc(F)cc2)c2oc(C)nc2c1C
Temperature: 100 °C

Procedure:
To a stirred solution of Example 8) (24 mg, 0.05 mmol) in acetic acid (0.5 mL) at room temperature was added H2O2 (30% aq.) and the solution heated to 100° C. for 23 h. The acetic acid was removed in vacuo and the brown oil partitioned between NaHCO3 (20 mL) and EtOAc (20 mL). The aqueous phase (pH=10) was extracted with EtOAc (2×10 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo. The product was purified by column chromatography (silica gel, hexane/Et2O (1:4) to Et2O to MeOH/DCM (1:19)). The title compound (10 mg, 41%) eluted from the column with MeOH/DCM (1:19) as a pale yellow oil. 1H NMR (CDCl3): δ 8.26-8.24 (m, 1H), 7.41-7.38 (m, 1H), 7.21 (m, 4H), 7.00-6.94 (m, 2H), 4.44 (t, J=6 Hz, 2H), 4.22-4.15 (m, 2H), 3.32 (t, J=6 Hz, 2H), 3.05-2.95 (m, 1H), 2.57 (s, 3H), 3.37 (s, 3H), 2.34 (s, 3H), 2.10-1.90 (m, 2H), 1.30 (d, J=6.9 Hz, 3H), ESIMS m/z [M+H]+ 493.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)CCl>[C:12]1([NH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClCCCl
Product: COC(=O)C=C(Nc1ccccc1)C(=O)OC
Reaction time: 1 h

Procedure:
To a stirred solution of dimethylacetylenedicarboxylate (DMAD, 0.10 mol) in 50 mL of ethylene dichloride (EDC), is slowly added a solution of aniline (0.10 mol) in 15 mL of EDC. The temperature of the reaction mixture is maintained below 30° C. and stirring is continued for about one hour until the reaction is essentially complete. The EDC is then removed under vacuum to afford the dimethyl 3-phenylaminobut-2-ene-dioate.
Reaction SMILES: CS([C:5]1[S:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)(=O)=O.[NH3:25].CC(O)C>>[NH2:25][C:5]1[S:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2
Reactant: N
Reactant: CCOC(=O)c1cccc(-c2ccc3nc(S(C)(=O)=O)sc3n2)c1
Solvent: CC(C)O
Product: CCOC(=O)c1cccc(-c2ccc3nc(N)sc3n2)c1
Temperature: 90 °C
Reaction time: 30 h
Yield: 91 %

Procedure:
Ethyl 3-(2-(methylsulfonyl)thiazolo[5,4-b]pyridin-5-yl)benzoate (3.6 g, 9.91 mmol) was added to a 2N ammonia solution in IPA (24.8 mL, 49.57 mmol). The reaction mixture was heated at 90° C. and stirred for 30 h. The solvent was removed with in vacuo to give 2.7 g (91%, crude yield) ethyl 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoate as a yellow solid.
Reaction SMILES: [CH2:1]([C:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].C[O-].[Na+]>>[CH2:1]([CH:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH:10]1[CH:13]([C:12]([O:19][CH3:20])=[O:18])[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)CC(=O)OC
Reactant: CCCCCC1=CCCC1=O
Agent: C[O-]
Agent: [Na+]
Product: CCCCCC1C(=O)CCC1C(C(=O)OC)C(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
The reaction product was refined to obtain 95 g (0.6 mol) of 2-pentyl-2-cyclopentenone. Moreover, 95 g (0.6 mol) of 2-pentyl-2-cyclopentenone was dropped to a solution, prepared by dissolving 118 g (0.9 mol) of dimethyl malonate in 38 g of methanol anhydride in a nitrogen atmosphere, cooling the mixture to 0° C. and adding 6.5 g (0.036 mol) of sodium methoxide (30% methanol solution), at 0° C. over 2 hours. After the addition was finished, unreacted dimethyl malonate was vacuum-distilled to obtain 160 g of dimethyl 2-pentyl-3-oxo-cyclopentylmalonate.
Reaction SMILES: [CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-])=O)[C:12]=1[OH:21])(=[O:10])=[O:9])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H][H]>[Pd]>[CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=1[OH:21])(=[O:9])=[O:10])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1O
Yield: 93.6 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-((2R)-tetrahydrofurfuryl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (660 mg, 1.96 mmol) was reduced with hydrogen and Pd/C (303 mg) to form the desired product (563 mg, 94%). EI-MS mn/z 305(M-H)−.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:6]([OH:18])[N:5]=[C:4]([SH:19])[N:3]=1.[OH-].[Na+].I[CH3:23].Cl>O.CN1CCCC1=O>[OH:18][C:6]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:2]([OH:1])[N:3]=[C:4]([S:19][CH3:23])[N:5]=1
Reactant: Cc1cccc(C(=O)Nc2c(O)nc(S)nc2O)c1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1nc(O)c(NC(=O)c2cccc(C)c2)c(O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
28.6 g of N-(4,6-dihydroxy-2-mercapto-pyrimidin-5-yl)-3-methyl-benzamide in 280 ml of water were cooled to 0° C. With cooling, 10.3 g of sodium hydroxide were added, and the mixture was stirred at 0° C. for 30 min. Then a solution of 6.4 ml of iodomethane in 108 ml of N-methylpyrrolidin-2-one was added. After completion of the reaction (6 h), the mixture was acidified with 6 N hydrochloric acid, and the precipitate filtered off and dried. 21.3 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11](Br)Br)=[CH:7][N:6]=1)=[O:4].C([OH:16])C>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=[O:16])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C(Br)Br)cn1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(C=O)cn1
Temperature: 80 °C

Procedure:
A solution of 5-dibromomethyl-pyrazine-2-carboxylic acid methyl ester (1.00 g, 3.23 mmol) in a mixture of ethanol (20 mL) and THF (10 mL) was heated to 80° C. A solution of silver nitrate (2.20 g, 12.9 mmol) in H2O (4 mL) was added. The reaction mixture was heated at 80° C. for 1.25 h and was filtered while hot. The filtrate was concentrated to yield the title compound (1.36 g). This material was carried to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH3:43])[CH3:42])=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([CH3:43])[CH3:42])=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(OC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1)c1ccccc1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)c2ccccc2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-phenylpropan-2-yl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[C:8]=2[N:9]=1)[CH3:3].FC(F)(F)[C:27]([OH:29])=[O:28]>ClCCl>[C:7]([O:29][C:27](=[O:28])[NH:1][C@@H:2]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[C:8]=2[N:9]=1)[CH3:3])([CH3:13])([CH3:8])[CH3:6]
Reactant: CCOc1ccc(-n2c([C@@H](C)N)nc3c(c2=O)CCCN3C)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@@H](C)NC(=O)OC(C)(C)C)nc3c(c2=O)CCCN3C)cc1

Procedure:
(R)-2-(1-Amino-ethyl)-3-(4-ethoxy-phenyl)-8-methyl-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-4-one (G2) To a solution of 110 mg G1 (0.26 mmol, 1.00 equiv.) dissolved in 2 mL dichloromethane cooled by an ice-bath was added 4 mL trifluoroacetic acid all at once. The reaction was equilibrated to room temperature. After 40 min. the reaction was concentrated in vacuo and the concentrate was partitioned between 25 mL each dichloromethane and saturated aqueous sodium bicarbonate. The aqueous separation was extracted again with 25 mL dichloromethane. Combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford G4 as a faint yellow glassy solid, 83 mg. The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:23][CH2:24][N:25]([S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])[CH2:26][CH2:27]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCNCC4)ncc3O2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CCN(c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)CC1

Procedure:
The title compound is prepared by treatment of 4-(5-piperazin-1-yl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester with isopropylsulfonyl chloride in dichloromethane in the presence of triethylamine. LC (method 10): tR=1.48 min; Mass spectrum (ESI+): m/z=495 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[C:8]([CH3:17])=[N:9][O:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:4][CH:3]=1.[N:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[C:21]=[O:22]>ClCCl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[C:8]([CH3:17])=[N:9][O:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:21]([NH:20][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)=[O:22])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1noc([C@H]2CCCN2)c1Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1noc([C@H]2CCCN2C(=O)Nc2ccc(C(F)(F)F)cc2)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a solution of (R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)isoxazole (20 mg, 0.07 mmol) in dichloromethane (2 mL) was added 1-isocyanato-4-(trifluoromethyl)benzene (13 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. Purification of the resulting residue by semi-preparative HPLC afforded (R)-2-(4-(4-chlorobenzyl)-3-methylisoxazol-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxamide (20 mg, 62%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=[CH:10][C:2]1=2.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:10]1[C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1cccc2c1OCCO2
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(Br)c2c1OCCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
To a solution of N-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acetamide (5.5 g, 28.5 mmol) in chloroform (20 mL) cooled at −20° C. was slowly added a solution of bromine (1.6 mL, 30 mmol) in chloroform (5 mL) so that the reaction temperature was maintained below −10° C. The reaction was stirred at 0° C. for 10 minutes, and then quenched immediately with water. The mixture was extracted with dichloromethane; the combined extracts were washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (dichloromethane) to afford the product N-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acetamide (5 g, yield 64%). 1H NMR (400 MHz, CDCl3) δ ppm 9.23 (s, 1H), 7.46-7.48 (d, 1H, J=8.8 Hz), 7.04-7.06 (d, 1H, J=9.2 Hz), 4.32-4.40 (m, 4H), 2.07 (s, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH2:15])=[C:5]([C:7]([CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])=[O:8])[CH:6]=1.[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F)([O-:18])=[O:17].C([O-])(O)=O.[Na+]>C(O)C>[NH2:15][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]([CH2:9][CH:10]([NH:14][C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17])[C:11]([OH:13])=[O:12])=[O:8]
Reactant: Nc1ccccc1C(=O)C[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccccc1C(=O)CC(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Reaction time: 0.08 h
Yield: 71 %

Procedure:
L-Kynurenine (125 mg) is dissolved in 5 cc of absolute ethanol in a 50 cc flask. A solution of 2,4-dinitrofluorobenzene, 71 mg in EtOH 5 cc is then added (a clear yellow solution is formed). After five minutes, 2 cc of a 10% NaHCO3 solution are introduced drop-wise in the flask. The reaction is left at room temperature overnight. The following morning the formed light yellow precipitate is filtered, washed with water and ethanol and dried in UHV obtaining 80 mg of product (approx. yield 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Li+].[Br:13][C:14]1[C:27]2=[N:28][O:29][C:25]3=[C:26]2[C:17]([C:18](=[O:30])[C:19]2[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:16](Br)[CH:15]=1.CC(OC)(C)C>CC(N(C)C)=O>[Br:13][C:14]1[C:27]2=[N:28][O:29][C:25]3=[C:26]2[C:17]([C:18](=[O:30])[C:19]2[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:16]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: O=C1c2ccccc2-c2onc3c(Br)cc(Br)c1c23
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: COC(C)(C)C
Product: O=C(O)c1ccc(Nc2cc(Br)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Reaction time: 19 h

Procedure:
Mixing 4-amino benzoic acid and lithium hydroxide in DMAc, then adding 3,5-dibromo-6H-anthra[1,9-cd]isoxazol-6-one into the mixture and raising the temperature to about 45° C. to 55° C. Stirring the reaction mixture for 18-20 hours. Slowly adding MTBE to the reaction mixture and then cooling to 0 to 10° C. Filtering the solid and drying at room temperature to get 4-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid (Intermediate 5).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[C@@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:4][CH2:3]1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[C@@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:4][CH2:3]1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)[C@H]1CC(=O)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC(O)(c2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl (1S,2S)-5-oxo-2-[(4-phenylpiperazin-1-yl)carbonyl]-cyclohexanecarboxylate (130.0 mg, 0.0003775 mol) in anhydrous tetrahydrofuran (4.0 mL, 0.049 mol) at −78° C. was added 1.00 M of phenylmagnesium bromide in tetrahydrofuran (0.755 mL). The reaction mixture was stirred at −78° C. for 1 h, then slowly warmed to −35° C. over 3 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL), extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash with 30-80% EtOAc/Hex to give the product as a colorless solid. (123 mg, 62% in yield). MS (ESI): (M+H)+=423.1.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][CH2:18][C:19](N(OC)C)=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27].Br[C:29]1[S:30][CH:31]=[C:32]([Cl:34])[N:33]=1>C1COCC1>[Cl:34][C:32]1[N:33]=[C:29]([C:19](=[O:20])[CH2:18][CH2:17][N:9]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:6]3[C:7]([N:2]([CH3:1])[C:3](=[O:27])[N:4]([CH3:26])[C:5]3=[O:25])=[CH:8]2)[S:30][CH:31]=1
Reactant: Clc1csc(Br)n1
Reactant: CON(C)C(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Isopropylmagnesium chloride lithium chloride complex solution (1.3M, 2.93 mL, 3.81 mmol) was added dropwise to a solution of 3-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-N-methoxy-N-methylpropanamide (470 mg, 1.269 mmol) and 2-bromo-4-chlorothiazole (Intermediate Q) (252 mg, 1.269 mmol) in THF (20 mL). The mixture was stirred at room temperature for 45 mins. The reaction was quenched with saturated NH4Cl(aq) and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-70% EtOAc/hexane afforded the title compound.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[N:25]=[C:26]2[N:31]([C:32](=[O:42])[C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:30][CH2:29][O:28][C:27]2([CH3:44])[CH3:43])=[O:23])(=O)=O.[N-:45]=[N+:46]=[N-:47].[Na+].O>CN(C=O)C>[N:45]([CH2:6][C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[N:25]=[C:26]2[N:31]([C:32](=[O:42])[C:33]=1[O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:30][CH2:29][O:28][C:27]2([CH3:43])[CH3:44])=[O:23])=[N+:46]=[N-:47]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1COS(C)(=O)=O)c(OCc1ccccc1)c2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN=[N+]=[N-])c(OCc1ccccc1)c2=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
To a solution of intermediate 194, (R)-(1-(2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methyl methanesulfonate (0.150 g, 0.239 mmol) in DMF (10 mL) was added sodium azide (0.019 g, 0.287 mmol). The resulting mixture was stirred at 50° C. for 6 h. Water (50 mL) was then added and the organic material was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with H2O (50 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (0.125 g, 91% yield). LCMS (M+H)+ m/z 576.