Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].C[Si]([N:25]=[N+:26]=[N-:27])(C)C.C([Sn](=O)CCCC)CCC.O1CCCC1>C(OCC)(=O)C>[N:2]1[NH:25][N:26]=[N:27][C:1]=1[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:15]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccc2cc(-c3nn[nH]n3)[nH]c12)c1cccs1
Yield: 23 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.40 g), trimethylsilylazide (0.35 mL), dibutyltin oxide (33 mg) and tetrahydrofuran (15 mL) was heated under reflux overnight. To the reaction mixture was added ethyl acetate, the mixture was ice-cooled, and the resulting crystals were filtrated, washed with cold ethyl acetate, and dried to give the title compound (0.09 g, yield 23%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 274-275° C. (decomposition).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C1CCC(=O)O1
Reactant: C=C(C)C(=O)OCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCOC(=O)CCC(=O)O
Yield: 77.7 %

Procedure:
2-Hydroxyethyl methacrylate (25 g, 0.195 mol) and succinic anhydride (19.5 g, 0.195 mol) were added to dichloromethane (200 mL) under nitrogen. Triethylamine (28.5 ml, 20.72 g, 1.05 equiv.) was then added dropwise over 20 minutes and the reaction mixture was refluxed for 1.5 hours. The reaction mixture was then diluted with dichloromethane (200 mL), washed with 2 M HCl (150 mL) and then finally with brine (100 mL). The organic phase was separated from the aqueous phase, dried (MgSO4 and Na2SO4) and evaporated to dryness, yielding a viscous, colourless liquid (34.9 g, 77.8% yield). 1H NMR δ 1.89 (s, 3H, CH3), 2.59-2.67 (m, 4H, 2×CH2CO), 4.31 (br. s, 4H, 2×CH2OCO), 5.55 (s, 1H, vinyl CH), 6.08 (s, 1H, vinyl CH). 13C NMR δ 17.96, 28.64, 28.73, 62.15, 62.29, 126.12, 135.79, 167.11, 171.90, 177.73.
Reaction SMILES: [CH3:1][C:2]1[C:15](=[O:16])[N:14]=[C:13]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:7]([O:12]2)[CH2:6]3)[CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Li+]>CN(C)C(=O)C>[N:17]([C@@H:7]1[C@@H:8]([CH2:10][OH:11])[O:9][C@@H:5]([N:4]2[CH:3]=[C:2]([CH3:1])[C:15](=[O:16])[NH:14][C:13]2=[O:12])[CH2:6]1)=[N+:18]=[N-:19]
Reactant: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 130 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
2,3'-Anhydrothymidine (0.673 g, 3.0 mmol), lithium azide (0.4 g, 9.0 mmol) and N,N-dimethylacetamide (7.5 ml) were heated together with stirring at 130° C. for 16 hr. The products were then worked-up and chromatographed on silica gel to give 3'-azido-3'-deoxythymidine (0.64 g, 80%). identical to authentic material.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@H:20]([CH:25]([CH3:27])[CH3:26])[CH2:21][C:22]([NH2:24])=[O:23]>>[C:22]([CH2:21][C@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH:25]([CH3:27])[CH3:26])(=[O:23])[NH2:24]
Reactant: CC(C)[C@@H](N)CC(N)=O
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)[C@H](CC(N)=O)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6 using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and (3S)-3-amino-4-methyl-pentanamide monohydrochloride (CAN 173336-51-1, 39 mg, 0.24 mmol) as starting materials and isolated (55 mg, 74%) as light yellow solid; LC-MS (UV peak area, ESI) 98%, 347.2082 (M+H)+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=2[N:15]=[N:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[CH:19]=[CH:18][C:17]4[S:13][N:14]=[N:15][C:16]=4[CH:21]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2snnc2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2snnc2c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzo[d][1,2,3]thiadiazole-5-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.36 (d, J=8.5 Hz, 1H), 9.19 (s, 1H). MS (DCI/NH3) m/z 315. Anal. Calculated for C16H18N4OS.HCl: C, 54.77; H, 5.46; N, 15.97. Found: C, 53.27; H, 4.94; N, 15.47.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Product: COc1cc2ncc(NC3CCCCC3)nc2cc1OC
Temperature: 135 °C
Yield: 69 %

Procedure:
To 0.3 g (1.34 mmol) of 2-chloro-6,7-dimethoxyquinoxaline is added approx. 1 mL of cyclohexylamine. The mixture is heated overnight at 105° C. and a further 10 hours at 135° C. The mix is partitioned between CH2Cl2 and saturated NaHCO3. The organic layer is dried (MgSO4) and concentrated. The resulting syrup is chromatographed (1:1 EtOAc:CH2Cl2) to provide 0.265 g of the product as a It. brown solid in 69% yield (m.p. 188-189.5). Anal. calcd for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.82; H, 7.28; N, 14.45.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:33][O:34][CH2:35][CH2:36][NH:37][CH3:38]>>[C:23]([O:22][C:20]([C:6]1[C:7]([N:37]([CH2:36][CH2:35][O:34][CH3:33])[CH3:38])=[N:8][C:9]2[C:4]([C:5]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[O:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CNCCOC
Product: COCCN(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 92 step A from tert-butyl 6-chloro-4-phenyl-2-(trifluoromethylsulfonyloxy)quinoline-3-carboxylate (prepared in analogy to example 91 step A to C, 100 mg, 0.21 mmol) and 2-methoxy-N-methylethanamine (183 mg, 2.05 mmol). Pale yellow solid (75 mg, 86%). MS (ESI): 427 (M+H)+.
Reaction SMILES: C([O:5][C:6](=O)[C:7]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1)([F:9])[F:8])(C)(C)C.[NH3:18]>CO>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]([F:9])([F:8])[C:6]([NH2:18])=[O:5])=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)C(F)(F)c1ccc(Br)cn1
Reactant: N
Solvent: CO
Product: NC(=O)C(F)(F)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl-2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (300 mg, 0.974 mmol) is dissolved in 7M ammonia in methanol (5 mL) and the mixture is stirred at ambient temperature for 3 days. The mixture is evaporated to dryness to give the title (240 mg). 1H-NMR (400 MHz, DMSO-d6) 7.70 (d, 1H), 8.05 (bs, 1H), 8.3 (d, 1H), 8.40 (bs, 1H), 8.85 (s, 1H). m/z (Cl) 251+253 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CC#N
Product: O=C1Cc2cc(F)cc(Br)c2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A suspension of 5-fluoro-1,3-dihydro-indol-2-one (1.5 g, 10 mmol) in 15 ml of acetonitrile and N-bromosuccinimide (1.8 g, 10 mmol) was stirred at room temperature overnight until the precipitate was formed. The solid was filtered, washed with ethanol (5 ml) and dried in vacuo to give 7-bromo-5-fluoro-1,3-dihydro-indol-2-one (1.6 g, 69.6%) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][C:45]=1[CH3:46].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:41]=[N:42][CH:43]=[CH:44][C:45]=5[CH3:46])=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1Br
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccncc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-4-methylpyridine (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (380 mg, 71%) as a brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30]Cl)[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:26]
Reactant: CCOC(=O)CCCl
Reactant: c1cnc2nc(CCCc3ccc4[nH]ccc4c3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a solution of 2-[3-(1H-indol-5-yl)-propyl]-[1,8]naphthyridine (0.180 g, 0.627 mmol) in DMF (2 mL) was added sodium hydride (24.0 mg. 1.00 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. After cooling to 0° C., 3-chloro-propionic acid ethyl ester (85.0 mg, 0.63 mmol) was added and stirred overnight at room temperature. Ice water was added and the resulting mixture was extracted with methylene chloride. The combined organic layers were washed with water and brine, and dried over Na2SO4. Chromatography of the crude product on silica gel (methylene chloride/methanol, 95:5) gave the title product (0.11 g, 45% yield). 1H NMR (CDCl3) δ 9.08 (d, 1H), 8.13 (d, 1H), 8.08 (d, 1H), 7.30-7.50 (m, 4H), 7.10 (m, 2M), 6.40 (dd, 1H), 4.40 (t, 2H), 4.10 (m, 2H), 3.10 (t, 2H), 2.80 (m, 4H), 2.25 (m, 2H), 1.20 (q, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:23])=[N:18][N:17]=[CH:16]2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:23])=[N:18][N:17]=[CH:16]2
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(C)nncc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(C)nncc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 4-methyl-3-(1-methylphthalazin-6-yl)benzoate (51.7 mg, 169 μmol) in tetrahydrofuran (800 μl) and methanol (400 μl) was added 1N aqueous sodium hydroxide solution (338 μl, 338 μmol) and stirred at RT for 18 h. The reaction was concentrated in vacuo and the residue was taken up in water and the pH was adjusted with 10% aqueous HCl solution to ˜7. The aqueous mixture was extracted with 15% MeOH/CHCl3 (3×) and the organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to give 4-methyl-3-(1-methylphthalazin-6-yl)benzoic acid as a maize solid. MS (ES+): 279.1 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O)#[N:23].O[NH:38][C:39](=[NH:58])[C:40]1[CH:48]=[C:47]2[C:43]([C:44]([CH2:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[CH:45][NH:46]2)=[CH:42][CH:41]=1>CN(C=O)C>[C:22]([C:24]1[CH:25]=[C:26]([C:27]2[O:29][N:38]=[C:39]([C:40]3[CH:48]=[C:47]4[C:43]([C:44]([CH2:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[CH:45][NH:46]4)=[CH:42][CH:41]=3)[N:58]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])#[N:23]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CC(C)(C)OC(=O)CCc1c[nH]c2cc(C(=N)NO)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)c[nH]c4c3)no2)cc1C#N
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 33.9 %

Procedure:
EDCI (151 mg) and HOBT (121 mg) were added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848, 135 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 45 min. 1,1-dimethylethyl 3-{6-[(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D16) (199 mg) was added and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was heated to 80° C. and stirred at that temperature for 5 hours. DMF was evaporated. EtOAc (100 mL) was added and the organic solution was washed with saturated aqueous sodium bicarbonate solution (75 mL) and water (75 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was purified by Biotage (25→33% EtOAc in hexane) to afford 1,1-dimethylethyl 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D19) (105 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (9H, s), 1.39 (6H, d), 2.60 (2H, t), 2.96 (2H, t), 4.98 (1H, m), 7.35 (1H, d), 7.55 (1H, d), 7.72 (2H, m), 8.12 (1H, d), 8.42 (1H, dd), 8.51 (1H, d), 11.21 (1H, s). MS (ES): C27H28N4O4 requires 472; found 473.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CCOC(C)=O>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[N:3]=[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:10]=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Nc2nc(N3CCCCC3)ccc2C(N)=O)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 6-chloro-2-(4-(methylsulfonyl)phenylamino)nicotinamide (19.4 mg, 0.060 mmol) and piperidine (2 mL) in a sealed tube was stirred in a 90° C. oil bath for 5 h. The mixture was diluted with EtOAc (25 mL), washed with saturated NH4Cl(2×5 mL), brine (5 mL), dried (MgSO4), and concentrated. After addition of CH2Cl2 (2 mL), white solid precipitated from the solution upon sitting. The solid was collected by filtration (14.1 mg, 60%). LCMS: (M+H)+=375.1. 1H NMR (400 MHz, acetone-d6) δ ppm 12.20 (1H, s), 7.90-8.09 (3H, m), 7.78-7.89 (2H, m), 6.33 (1H, d, J=8.78 Hz), 3.58-3.89 (4H, m), 3.07 (3H, s), 1.52-1.85 (6H, m).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@@H:6]1[CH2:11][O:10][CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[N:24]1[N:25]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](O)=[O:32])[N:26]=[CH:27][CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C@@H:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:31]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[N:25]1[N:26]=[CH:27][CH:28]=[N:24]1)=[O:32]
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Ic1cccc(C[C@@H]2COCCN2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccccc1-n1nccn1)N1CCOC[C@H]1Cc1cccc(I)c1
Reaction time: 22 h

Procedure:
A solution of (R)-3-(3-iodo-benzyl)-morpholine B-5 (100 mg, 0.33 mmol) and DIPEA (57 μL, 0.33 mmol) in DMF (1.5 mL) was added to a RT solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid E-2 (62 mg, 0.33 mmol), TBTU (111 mg, 0.35 mmol) and DIPEA (57 μL, 0.33 mmol) in DMF (1.5 ml) under argon and the resulting mixture was stirred for 22 h. The reaction mixture was quenched with sat. aq. NaHCO3 and stirred for 10 min before being diluted with water and extracted with DCM (3×). The combined organic extracts were washed with 2M aq. NaOH (1×), 2M aq. HCl (1×) and brine (1×), dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method F) to give the title compound as a white solid. LC-MS D: tR=0.93 min; [M+H]+=474.91.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:17])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:9]=3[CH2:10][NH:11][C:12]4=[O:17])=[CH:6][CH:7]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3cccc4c3CNC4=O)cc2)c1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
An 0° C. suspension of Example 1D (1.94 g, 8.68 mmol) in THF (44 mL) was sequentially treated dropwise with N-methylmorpholine (0.95 mL, 8.68 mmol) and 3-methylphenyl isocyanate (1.12 mL, 8.68 mmol). The mixture was stirred for 1 hour, diluted with THF (20 mL), stirred at room temperature for 3 hours, and quenched with water (20 mL). The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was suspended in 5% methanol/dichloromethane and filtered. The filter cake was washed with dichloromethane and dried to provide 2.94 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.52 (s, 2H), 6.80 (d, J=7.5 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.23–7.27 (m, 1H), 7.31 (s, 1H), 7.53–7.60 (m, 5H), 7.64–7.67 (m, 2H), 8.63 (s, 1H), 8.65 (s, 1H), 8.80 (s, 1H); MS (ESI(+)) m/e 358.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:13]([C:12]3[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:19][C:11]=3[F:10])=[N:1][C:2]=2[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Reactant: Nc1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3o2)c(F)c1
Temperature: 195 °C
Yield: 80.5 %

Procedure:
2-Amino-4-bromophenol (1.77 g, 9.4 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.4 mmol) were dissolved in polyposphoric acid (60 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by evaporation of EtOAc afforded the crude. Crude was purified on combiflash with a gradient mixture of EtOAc and Petether (33:67) to obtain the titled compound (2.8 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][NH:23][CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:24]([N:23]([CH3:22])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH3:26])[CH3:25]
Reactant: CNC(C)C
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (170 mg, 0.50 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), N-methylpropan-2-amine (73 mg, 1.00 mmol, 2.00 equiv), and potassium carbonate (207 mg, 1.50 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water. The resulting solids were collected by filtration. This resulted in 109.8 mg (59%) of methyl 3-(isopropyl(methyl)amino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[CH2:3]1.[CH3:13]C1C=C(C)C=C2C=1CCC(=O)C2>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[CH2:3]1
Reactant: Cc1cc(C)c2c(c1)CC(=O)CC2
Reactant: CC1CC(=O)Cc2ccccc21
Product: CC1(C)CC(=O)Cc2ccccc21

Procedure:
Using method A, 4-methyl-2-tetralone and 5,7-dimethyl-2-tetralone were also prepared.
Reaction SMILES: [Li][CH2:2]CCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CI.[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][C:31]2=O>C1COCC1>[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][C:31]2=[CH2:2]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Reactant: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CI
Solvent: C1CCOC1
Product: C=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of n-BuLi (2.5 M, 3.80 mL) was added to a mixture of PPh3.MeI. (4.092 g, 10.13 mmol) in THF at −10. The mixture was stirred for 1 h at the same temperature, and then 6-bromo-2-phenylchroman-4-one (2 g, 6.62 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. The resulting mixture was concentrated and purified by column chromatography to give 6-bromo-4-methylene-2-phenylchroman (400 mg, 20%). 1H-NMR (CDCl3): 2.76 (m, 2H), 4.90 (d, 1H), 5.01 (m, 1H), 5.48 (d, 1H), 6.76 (d, 1H), 7.31 (m, 6H), 7.62 (d, 1H).