Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>FC(F)(F)C(O)=O>[F:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[F:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=c1[nH]c2cc(F)c(F)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 55 °C
Reaction time: 20 h
Yield: 68.1 %

Procedure:
To a suspension of 6,7-difluoro-1,4-dihydro-2,3-quinoxalinedione (837 mg, 4.23 mmol) in trifluoracetic acid (30 mL) was added KNO3 (512 mg, 5.07 mmol). The mixture was stirred at 55° C. for 20 h at the end of this time, 256 mg (2.50 mmol) of KNO3 was added and the reaction mixture was stirred at 55° C. for 20 h, then another 256 mg (2.50 mmol) of KNO3 was added and the mixture was stirred at 55° C. for 20 h. The reaction mixture was then rota-evaporated to dryness. To the residual solid was added ice-cold water (about 15 mL), the solid was collected by vacuum filtration, washed with ice-cold water (5×5 mL), and dried at 40° C. under 1 mm Hg for 14 h, giving 700 mg (68%) of the title compound as a yellow powder. Mp 288°-90° C. (dec.). IR (KBr) 3424, 3226, 1752, 1717, 1554, 1356, 1304 cm-1. 1H NMR (DMSO-d6): 12.249 (s, 1H), 11.864 (bs, 1H), 7.330 (dd, 1H, J=10.5, 7.8 Hz). Analysis for C8H3F2N3O4, calcd: C, 39.50, H, 1.24, N, 17.29; found: C, 39.42, H, 1.26, N, 17.08.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[I:11]([O-])(=O)=O.[K+].[I-].[K+]>O.OS(O)(=O)=O>[OH:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cnc(O)c(I)c1
Temperature: 60 °C

Procedure:
6-Hydroxynicotinic acid (20 g) in water (200 ml) and H2SO4 (80 ml) was heated to 90° C. for 1 hour. Potassium iodate (0.42 equivalent) and potassium iodide (0.96 equivalent) were both added portionwise over 2 hours. After a further hour at 90° C. the mixture was cooled to 60° C. and added to 1 kg of ice. The brown solid was filtered off, dried and taken up in DMF (30 ml)/EtOH(1 litre). Sodium metabisulfite was added until the brown colour disappeared and the mixture was poured onto ice (2 kg), a further 1.5 litre water added and the white solid filtered to give title compound (16.5 g). NMR δ(DMSO) 12.95 (1H, broad), 12.35 (1H, broad), 8.36 (1H, d), 8.03 (1H, d)
Reaction SMILES: [CH2:1]([NH:8][S:9](Cl)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([NH:17][C:18](=[NH:21])[O:19][CH3:20])([O:15][CH3:16])=[O:14].C(N(CC)CC)C>C1COCC1>[C:13]([NH:17][C:18](=[N:21][S:9](=[O:11])(=[O:10])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:19][CH3:20])([O:15][CH3:16])=[O:14]
Reactant: COC(=N)NC(=O)OC
Reactant: O=S(=O)(Cl)NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NC(=NS(=O)(=O)NCc1ccccc1)OC
Temperature: 25 °C

Procedure:
A solution of benzylsulfamoyl chloride (168 g) in anhydrous THF (300 ml) is added dropwise to a stirred solution of N-carbomethoxy-O-methylisourea (107 g) and triethylamine (90 g) in anhydrous THF (800 ml) under nitrogen at -70° C. The resulting suspension is warmed to RT, filtered and the filtrate evaporated in vacuo. The residue is partitioned between methylene chloride and 0.5N aq. HCl. The organic layer is dried, filtered, and concentrated in vacuo affording the desired product as an oil.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([OH:32])=O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1.[CH2:33]([O:35][C:36](=[O:48])[CH2:37][CH:38]1[NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=2[O:40][CH2:39]1)[CH3:34]>CCOC(C)=O>[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([N:43]3[C:42]4[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH:38]3[CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:48])=[O:32])[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: CCOC(=O)CC1COc2ccccc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1COc2ccccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 75 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
T3P (50% solution in EtOAc, 132.4 g, 0.208 mol) was added to 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (22.1 g, 0.114 mol), ethyl-2-(3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate (23.0 g, 0.104 mol) and TEA (57.9 mL, 0.416 mol) in EtOAc (139 mL) at rt. The resulting mixture was stirred at 75° C. for 16 h. The resulting solution was diluted with 800 mL of EtOAc and washed with aq. sat. NaHCO3 solution (300 mL), 0.5 M HCl solution (300 mL) and brine (300 mL). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by re-crystallization from MeOH to afford the title compound (14.5 g, 35%) as a white solid.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][N:8]([CH3:29])[C:9]1[N:20]2[C:12]([CH:13]=[N:14][C:15]3[N:16](COCC[Si](C)(C)C)[CH:17]=[CH:18][C:19]=32)=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([S:3]([CH2:6][CH2:7][N:8]([CH3:29])[C:9]1[N:20]2[C:12]([CH:13]=[N:14][C:15]3[NH:16][CH:17]=[CH:18][C:19]=32)=[CH:11][CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCN(C)c1ccc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)CCN(C)c1ccc2cnc3[nH]ccc3n12
Reaction time: 2 h
Yield: 100 %

Procedure:
(2-Ethanesulfonyl-ethyl)-methyl-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-3,4,8a-triaza-as-indacen-8-yl]-amine (68 mg, 0.16 mmol) was taken up in methylene chloride (3 mL) and TFA (2 mL) and lightly capped and stirred for 2 hours. The volatiles were removed on the rotovap and the remainder was taken up in CH2C12 (25 mL). The volatiles were stripped and the remainder placed on a drying pump for 30 minutes. The material was taken up methylene chloride (2 mL) and ethylene diamine (2 mL) and stirred for 1.5 hours. Ethyl acetate (40 ml) and brine (40 mL) was added and the material shaken in a separatory funnel. The ethyl acetate phase was collected and washed with an equal volume of brine solution. The aqueous phases were back extracted with ethyl acetate (2×30 ml), the organics combined, dried (MgSO4), filtered and stripped. The crude was purified via preparative TLC using 7% MeOH in CH2Cl2 as eluant to provide 49 mg of (2-ethanesulfonyl-ethyl)-methyl-(3H-3,4,8a-triaza-as-indacen-8-yl)-amine as a green-black crystalline solid. MS (M+H)+=291.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C4CCCCO4)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[O:22]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=2)[O:13][C:11]2([CH2:12][NH:9][CH2:10]2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CNC1)O2)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4 M HCl in dioxane (1.90 ml) was added dropwise to a solution of (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (360 mg, 0.78 mmol) in DCM (14 ml). The mixture was stirred at RT overnight. The formed precipitate was filtered off, washed with DCM, dried under vacuum to give (E)-3-[4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (154 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][O:17][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COC(c1ccc(N)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), 2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g), PPh3 (1.56 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (0.93 mL) slowly. The reaction was stirred at RT for 5 h and at reflux for overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken into ether. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a crude product as a very viscous brown oil which was chromatographed through silica gel (400 g, 2:1:7 to 3:1:6 EtOAc/Et3N/hexanes) to afford 2-[1-(4-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[C:11]([CH:13]=2)[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[C:11]([NH:12][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(-c2ccccc2)cc(-c2cccnc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccc2)cc(-c2cccnc2)c1)Oc1ccccc1
Yield: 99.8 %

Procedure:
The title compound (0.289 g, 100%) was prepared by methodology of description 67 using 5-phenyl-3-(pyrid-3-yl) aniline (0.194 mg, 0.79 mmol), phenyl chloroformate (0.12 ml, 0.87 mmol) and triethylamine (0.12 ml, 0.81 mmol) in DCM (10 ml)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])[C:5]([F:21])=[CH:4][C:3]=1[C:22]#[N:23].[CH2:24]([NH2:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[F-].[K+]>CS(C)=O>[C:22]([C:3]1[CH:4]=[C:5]([F:21])[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])=[N:7][C:2]=1[NH:29][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])#[N:23]
Reactant: CC(C)(C)CN
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(Cl)c(C#N)cc2F)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CONC(=O)c1ccc(C)c(Nc2nc(NCC(C)(C)C)c(C#N)cc2F)c1
Temperature: 150 °C
Yield: 1.8 %

Procedure:
A mixture of 3-(6-chloro-5-cyano-3-fluoro-pyridin-2-ylamino)-N-methoxy-4-methyl-benzamide (52 mg, 0.15 mmol), neopentylamine (0.12 mL) and potassium fluoride (12 mg) in DMSO (1 mL) was heated to 150° C. overnight. The product (1.1 mg, 1.8%) was isolated after purification by HPLC. C20H24FN5O2 MS m/e=386 (M+H).
Reaction SMILES: Cl.[CH2:2]1[O:16][C:15]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][NH2:13])[O:8][C:7]=3[CH:14]=2)[O:3]1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28](=[O:32])[O:29]2)=[CH:24][CH:23]=1.[I-].[Na+]>CN(C=O)C>[CH2:2]1[O:16][C:15]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][NH:13][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]5[CH:26]=[CH:27][C:28](=[O:32])[O:29][C:30]=5[CH:31]=4)[O:8][C:7]=3[CH:14]=2)[O:3]1
Reactant: NC[C@H]1COc2cc3c(cc2O1)OCO3
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNC[C@H]3COc4cc5c(cc4O3)OCO5)cc2o1
Temperature: 80 °C
Yield: 16.3 %

Procedure:
(S)-2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-methanamine hydrochloride (5.50 g, 22.4 mmole), 7-(3-chloropropoxy)coumarin (5.49 g, 23.0 mmole) diisopropylethylamine (39.0 ml, 224 mmole) and sodium iodide (3.45 g, 23.0 mmole) were combined in 200 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with chloroform. The mixture was treated with an equal volume of saturated aqueous sodium bicarbonate and the aqueous phase was then back-extracted with 3:1 chloroform-isopropanol. The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on a silica gel column using dichloromethane as eluant. The product-containing fractions (Rf=0.59 on silica gel tlc with 1:5:95 ammonium hydroxide-methanol-chloroform) were combined and concentrated in vacuum, and the residue redissolved in methanol and acidified with 4N HCl/isopropanol to pH<3 in an ice bath to precipitate a white solid. This was recrystallized from methanol and triturated with a small amount of isopropanol to give 1.50 g of the title compound as an off-white crystalline, solid, monohydrochloride, m.p. 244°-245° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([O:36][CH3:37])[CH:6](O)[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][CH:8]=1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:38])[CH:5]([O:36][CH3:37])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(OC)C(O)c1ccc(OCCCc2nc(-c3ccc(OC)cc3)oc2C)c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1ccc(OCCCc2nc(-c3ccc(OC)cc3)oc2C)c2ccccc12)OC
Reaction time: 4 h
Yield: 64.5 %

Procedure:
0.228 g of the above prepared 3-hydroxy-2-methoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-propionic acid ethyl ester (0.44 mmol) was dissolved in 2.3 ml of trifluoroacetic acid, treated at 0° with 0.697 ml of triethylsilane (10 eq.) and then kept for 4 h at 0°. The reaction mixture was then poured onto crashed ice/AcOEt/NaHCO3, the organic layer washed twice with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) yielded 0.143 g of the title compound as colorless oil.
Reaction SMILES: FC1C=CC(C2(CCC3O[N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)CCCCC2)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][CH2:42][CH:41]([C:44]([O:46]C)=O)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:38]2[CH2:39][CH2:40][CH:41]([C:44]3[O:46][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)[CH2:42][CH2:43]2)=[CH:36][CH:37]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1CCC1(c2ccc(F)cc2)CCCCC1
Reactant: COC(=O)C1CCC(c2ccc(Cl)cc2)CC1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1

Procedure:
This compound was prepared according to the general procedure described for Preparation 26A, employing methyl 4-(4-chlorophenyl)cyclohexanecarboxylate as the starting material. LC/MS M+1=390.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J31) (256 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (282 mg, 67%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:29]I>O1CCCC1>[CH:1]1([N:6]([CH3:29])[C:7]2[C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CCCC3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)C3CCCC3)nc2c1
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(cyclopentylamino)-2-phenylquinoxaline-6-carboxylate (214.1 mg, 0.62 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). This was followed by the addition of sodium hydride (246.8 mg, 6.17 mmol, 10.00 equiv, 60%) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at room temperature. To this was added a solution of CH3I (1.75 g, 12.32 mmol, 20.00 equiv) in tetrahydrofuran (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (crude) of methyl 3-(cyclopentyl(methyl)amino)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[NH:9][C:10]([C:12]1[CH:16]=[CH:15][NH:14][N:13]=1)=[O:11])(=[O:3])[NH2:2].CC(O)=O.C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl>[Br:28][C:7]1[S:6][C:5]([NH:9][C:10]([C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)=[O:11])=[C:4]([C:1](=[O:3])[NH2:2])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)c1ccsc1NC(=O)c1cc[nH]n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1cc(Br)sc1NC(=O)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1H-Pyrazole-3-carboxylic acid (3-carbamoyl-thiophen-2-yl)-amide (355 mg, 1.5 mmol) is mixed with AcOH (5 mL). NBS (280 mg, 1.58 mmol) is then added and the mixture is stirred at room temperature overnight. Evaporation gives a residue that is subsequently dissolved in DCM, the resulting organic phase is washed with aqueous NaHCO3, dried over MgSO4, filtered and evaporated to give a residue that is used as such.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[NH2:56][CH2:57][C:58]([OH:60])=[O:59]>>[CH2:22]([O:21][N:16]1[C:17]([CH3:19])([CH3:20])[CH2:18][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]3[CH2:38][C:39]([CH3:55])([CH3:54])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:41]([CH3:44])([CH3:43])[CH2:42]3)[N:3]=[C:2]([NH:56][CH2:57][C:58]([OH:60])=[O:59])[N:7]=2)[CH2:14][C:15]1([CH3:30])[CH3:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: NCC(=O)O
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(NCC(=O)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and glycine according to the procedure of Example 15.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12]([CH:14]1[CH2:26][CH2:25][N:17]2[C:18]3[C:23]([CH:24]=[C:16]2[CH2:15]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH3:10].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][N:17]2[C:18]3[C:23]([CH:24]=[C:16]2[CH2:15]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1CCn2c(cc3ccccc32)C1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(cc3ccccc32)C1
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a -78° C. THF (12 mL) solution of lithium diisopropylamide (generated in situ from diisopropylamine (3.8 mL) and 15% n-butyl lithium in hexane (17 mL) at 0° C.) was added dropwise a THF solution of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylic acid ethyl ester. After 30 minutes, the temperature was brought to 0° C. After 1 hour, ethyl chloroformate (2.6 mL) was added over one hour. The reaction was allowed to come to room temperature overnight. The reaction was quenched with saturated NH4Cl and extracted t-butyl methyl ether (3×). The extract was washed with water, dried, filtered, and concentrated to give a residue. The residue was purified by flash chromatography eluting with 15% ethyl acetate/hexane to give the title compound 1.29 g (33% yield) as off white crystals (M. Pt. 69° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][N:8]=1)[CH3:2].O=P(Cl)(Cl)[Cl:23]>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([Cl:23])=[N:9][N:8]=1)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCc1n[nH]c(=O)c2cc(OC)ccc12
Solvent: CC#N
Product: CCOC(=O)CCc1nnc(Cl)c2cc(OC)ccc12
Yield: 84.8 %

Procedure:
Operating analogously to example 114 starting from 3-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)-propionic acid ethyl ester (552 mg, 2 mmoles), prepared as described in example 119, and POCl3 (1.12 ml, 12 mmoles) in acetonitrile (5 ml), 0.5 g of the title compound were obtained (yield: 84.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[S:5][C:4](=[O:13])[CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:9][CH:10]=2)[S:5][C:4](=[O:13])[CH2:3]1
Reactant: CC1(C)CC(=O)Sc2cc(Br)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)Sc2cc(C#C[Si](C)(C)C)ccc21
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A solution of 1.0 g (3.7 mmol) of 4,4-dimethyl-7-bromo-2-oxo-thiochroman in 1 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 2.0 g (2.75 ml, 20.0 mmol) of trimethylsilylacetylene and a powdered mixture of 0.038 g of cuprous iodide and 0.084 g of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 55 degrees C. for 24 hours, and thereafter allowed to cool to room temperature. Solvent was removed in-vacuo to give the title compound as a yellow oil.