Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O.O.[OH-].[Li+]>C1COCC1>[C:10]([O:9][C:7]([NH:6][CH2:5][CH:4]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[C:3]([OH:21])=[O:2])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
The 3-tert-butoxycarbonylamino-2-p-tolyl-propionic acid methyl ester (12.3 g, 41.9 mmol) was dissolved in 200 mL 1:1 THF:water and treated with lithium hydroxide monohydrate (2.64 g, 62.9 mmol) at room temperature. The reaction was stirred at room temperature overnight to completion and concentrated in vacuo. The oily mixture was partitioned with water and washed with EtOAc (discarded). The aqueous was treated with solid KHSO4 until pH<2, then extracted with EtOAc. The combined organic was dried over Na2SO4, filtered, and concentrated in vacuo to afford the 3-tert-butoxycarbonylamino-2-p-tolyl-propionic acid as a white solid (10.95 g, 93%). 1H NMR (ca. 1:1 mixture of rotamers) (CDCl3, 400 MHz) δ 10.40-8.40 (br s, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.80 or 4.91 (br s, 1H), 3.86 and 3.75 (m, 1H), 3.55 (m, 1H), 3.47 (m, 2H), 2.31 (s, 3H), 1.44 and 1.41 (s, 9H). LCMS (APCI−) m/z 557 [2M−H]−. HPLC R2=2.80 min.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1>>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cnccn1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 11.02 of 2,6-di-tert-butyl-1,4-benzoquinone and 4.76 g of aminopyrazine was heated with stirring at 150° C. for 6 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:4), giving 3.95 g of Compound 1a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:19])[C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 97 %

Procedure:
A solution of 2C (8.5 g, 28 mmol) in DMF (30 mL) was added with an. K2CO3 (1.5 mol eq, 5.99 g) and, after few minutes, iodomethane (1.2 mol eq, 3.21 mL) was added and the mixture heated at 50° C. for 12 h. The solvent was removed under reduced pressure, water was added to the residue (150 mL) and the aqueous phase extracted with EtOAc (3×60 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 3C as a pale yellow oil (8.6 g, 97% yield). 1HNMR (DMSO, 200 MHz) δ 2.88 (s, 3H), 3.52 (s, 3H), 3.66 (m, 2H), 4.02 (q, 1H, J=6), 4.602 (t, 1H, J=6.1), 5.11 (t, 1H), 7.64 (d, 2H), 7.76 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[NH2:11][C:12]1[NH:16][N:15]=[C:14]([S:17](Cl)(=[O:19])=[O:18])[N:13]=1>C(#N)C>[NH2:11][C:12]1[NH:16][N:15]=[C:14]([S:17]([NH:4][C:3]2[C:5]([Cl:10])=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=2[Cl:1])(=[O:19])=[O:18])[N:13]=1
Reactant: Nc1nc(S(=O)(=O)Cl)n[nH]1
Reactant: Cc1ccc(Cl)c(N)c1Cl
Solvent: CC#N
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Temperature: 65 °C
Reaction time: 120 h
Yield: 67 %

Procedure:
In a manner similar to that described in Example 3, 8.8 g (0.05 mole) of 2,6-dichloro-3-methylaniline, 9.6 g (0.05 mole) of 5-amino-3-chlorosulfonyl-1,2,4-triazole and 25 ml of dry acetonitrile were stirred at about 65° C. for a total of 5 days. The reaction product was recovered as in Example 3 to obtain 10.8 g of the title compound as white solid, m.p. 240°-241° C. (dee.). This assayed by HPLC to be about 98 percent pure. The methylene chloride washes were concentrated to obtain 2.7 g of solid which was over 80 percent purity unreacted 2,6-dichloro-3-methylaniline. The yield of the desired sulfonamide was therefore 88 percent based on unrecovered aniline.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.4 %

Procedure:
To a solution of 4-nitroimidazole (7.28, g, 64.4 mmol) in 60 mL of dry DMF at 0° C. was added triethylamine (9.87 mL, 70.8 mmol), then chlorotriphenylmethane (17.95 g, 64.4. mmol). After 5 minutes, the solution was warmed to room temperature. After 30 minutes, the reaction mixture was poured over ice, filtered, and washed with ice water. The resulting product was dried in vacuo next to P205 to provide the titled product as a white powder (22.29 g, 97% yield) which was sufficiently pure for use in the next step.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CCN(C(C)C)C(C)C.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:4][CH2:3][CH2:1][OH:2])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: NCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(CNCCO)cc1

Procedure:
A solution of ethanolamine (10.05 mL, 166.6 mmol), DIPEA (5.08 mL, 29.2 mmol) and 4-nitrobenzyl bromide (6.00 g, 27.8 mmol) in DCM (50 mL) was stirred at room temperature for 4 hours. The volatiles were removed in vacuo and the resulting residue partitioned between water and EtOAc. The aqueous phase was separated and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound A68 as a light yellow solid (3.34 g, 61%); 1H NMR (300 MHz, d6-DMSO) δ 8.18 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 4.49 (t, J=5.4 Hz, 1H), 3.84 (s, 2H), 3.47 (q, J=5.6 Hz, 2H), 2.56 (t, J=5.8 Hz, 2H), 2.28 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.Cl.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.Cl>>[CH3:15][N:16]1[CH2:21][CH2:20][C:19]2[NH:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([O:3][CH3:2])=[O:13])=[CH:10][C:9]=3[C:18]=2[CH2:17]1
Reactant: CN1CCC(=O)CC1
Reactant: COC(=O)c1ccc(NN)cc1
Agent: Cl
Product: COC(=O)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Temperature: 100 °C

Procedure:
Methyl-4-hydrazinylbenzoate hydrochloride (1 equiv.) and 1-methylpiperidin-4-one HCl (0.76-1.4 equiv.) are taken aqueous HCl and heated at 100° C. overnight (the product was detected by LCMS). The reaction mixture is concentrated and refluxed (90° C.) in methanolic HCl overnight (product was detected by LCMS and TLC). The reaction mixture is concentrated and basified with aqueous NaHCO3 solution and extracted with EtOAc. The crude product is crystallized in DCM and ether and hexane.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([N:11]2[CH2:14][CH:13]([F:15])[CH2:12]2)=[O:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.[OH:16][C:17]1[C:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=2[CH:20]=[C:19]([C:28]([O:30][CH3:31])=[O:29])[CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:16][C:17]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:28]([O:30][CH3:31])=[O:29])[CH:18]=2)[CH:5]=[N:4][C:3]=1[C:9]([N:11]1[CH2:14][CH:13]([F:15])[CH2:12]1)=[O:10]
Reactant: O=C(c1ncc(F)cc1F)N1CC(F)C1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CC(F)C3)c(F)c2)c2c(c1)OC(C)(C)C2
Temperature: 110 °C
Yield: 72 %

Procedure:
A mixture of (3,5-difluoropyridin-2-yl)(3-fluoroazetidin-1-yl)methanone (7.49 g, 34.60 mmol), methyl 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (7.69 g, 34.60 mmol) and Cs2CO3 (16.90 g, 52.0 mmol) in DMF was heated to 110° C. for 30 min, cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage eluting with 25-40% EtOAc in hexanes to give a white foam with ˜20% impurity (10.49 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.27 Hz, 1 H) 7.21-7.30 (m, 2 H) 6.98-7.06 (m, 1 H) 5.26-5.49 (m, 1 H) 4.64-4.77 (m, 1 H) 4.46-4.60 (m, 1 H) 4.28-4.42 (m, 1 H) 4.07-4.23 (m, 1 H) 3.88 (s, 3 H) 2.91 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H20F2N2O5 m/z 419.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH3:13][C:14]1([OH:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:17]2[CH2:18][CH2:19][C:14]([OH:20])([CH3:13])[CH2:15][CH2:16]2)[N:7]=1
Reactant: CC1(O)CCNCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N2CCC(C)(O)CC2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A mixture of methyl 2,4-dichloropyrimidine-6-carboxylate (1.66 g, 8.0 mmol), 4-methyl-piperidin-4-ol (1.21 g, 8 mmol) and sodium carbonate (1.74 g, 16.0 mmol) in methanol (8 mL) was stirred for 1 h at 20° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was subsequently washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give crude title compound (1.70 g, 72%) as light yellow solid. MS ISP (m/e): 286.1 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.C(O)(=O)C>[Fe].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([CH3:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(Br)cc(N)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A heterogeneous reaction mixture of 4-bromo-2-methoxy-6-nitrotoluene (500 mg, 2.032 mmol), acetic acid (20 ml), and iron (1135 mg, 20.32 mmol) was stirred at rt for 24 hr. Ethyl acetate was added, then the mixture was filtered through celite and the filtrate concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with further ethyl acetate. The combined organic phases were washed with water and brine, then dried over sodium sulfate, filtered and concentrated to afford the title compound. MS m/z: 218.0 (M+H)+.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:42][CH:41]=1>O1CCCC1>[CH2:47]([O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][CH:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][C@@H:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:45][CH:44]=1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1ccc(OCc2ccccc2)cc1)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.8 %

Procedure:
Di-tert-butyl N-trityl-L-glutamate (1.63 g, 3.25 mmol) was dissolved in tetrahydrofuran (12 ml) and the solution was cooled to −78° C. To the solution was added lithium 1,1,1,3,3,3-hexamethyldisilazide (1M in tetrahydrofuran, 7.14 ml) and, after stirring at −78° C. for 20 min, benzyl 4-(bromomethyl)phenyl ether (1.08 g, 3.90 mmol) in tetrahydrofuran (8 ml) was slowly added. The cooling bath was removed and the reaction mixture was stirred for 2 h. Then, 50 ml of 2 M aqueous hydrogen chloride solution were added and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure; the residue was purified by silica gel column chromatography to yield 813 mg (30%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](P(O)(O)=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].N12CCCN=C1CCCCC2.[CH:32]12[CH2:38][CH:35]([CH2:36][CH2:37]1)[CH2:34][CH:33]2[CH:39]=O>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]([NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[CH:39][CH:33]1[CH2:34][CH:35]2[CH2:38][CH:32]1[CH2:37][CH2:36]2
Reactant: O=CC1CC2CCC1C2
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C(=CC1CC2CCC1C2)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
In a round bottom flask was placed N-(benzyloxycarbonyl)-α-phosphonoglycine methyl ester (2.05 g, 6.18 mmol) in dichloromethane (5 mL) and cooled to 0° C. in an ice bath. To this mixture was then added slowly 1,8-diazabicyclo[5.4.0]undec-7-ene (801 μL, 5.36 mmol) and it was stirred at 0° C. for 20 min. The mixture was then treated with a solution of bicyclo[2.2.1]heptane-2-carbaldehyde (512 mg, 4.12 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was allowed to warm to 25° C. and stirred overnight. The mixture was concentrated in vacuo and then dissolved in ethyl acetate (50 mL) and washed with a saturated aqueous ammonium chloride solution (2×25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash chromatography (25 g column, 15% ethyl acetate/hexanes to 34% ethyl acetate/hexanes) afforded 2-benzyloxycarbonylamino-3-bicyclo[2.2.1]hept-2-yl-acrylic acid methyl ester (491 mg, 36%) as a clear colorless oil.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][CH:22]2[O:27][CH2:26][C:25](=[O:28])[NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[C:16]([O:15][C:14](=[O:20])[N:13]([C@@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])[CH2:21][CH:22]1[O:27][CH2:26][C:25](=[O:28])[N:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:23]1)([CH3:17])([CH3:19])[CH3:18]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNC(=O)CO1)C(=O)OC(C)(C)C
Reactant: Ic1ccccc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2ccccc2)C(=O)CO1)C(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 104.4 %

Procedure:
tert-Butyl ((R)-1-(naphthalen-1-yl)ethyl)((5-oxomorpholin-2-yl)methyl)carbamate (300 mg, 0.78 mmol) (Intermediate-9), iodobenzene (104 μL, 0.93 mmol), potassium phosphate (330 mg, 1.56 mmol), copper iodide (14.8 mg, 0.078 mmol) and N,N′-dimethylaminoethane (17 μL, 0.15 mmol) were added in 1,4-dioxane. The reaction mixture was heated to 110° C. and further stirred overnight at the same temperature. After reaction completion the reaction mixture was concentrated and the residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain the title compound (375 mg) as an oil. m/z 461.08
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25]Cl)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:27][O-:28].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:28][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Yield: 78 %

Procedure:
The mixture of 5-bromo-3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (23 mg, 0.050 mmol), 0.1 M NaOMe (1 ml) in methanol (1 mL) was refluxed overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (18.0 mg, 78%).
Reaction SMILES: ClC1C=CC(OC2C=CC(NC(=O)[NH:15][C@@H:16]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:18])=CC=2)=CC=1.Cl.O1CCOCC1.[F:46][C:47]1[CH:62]=[CH:61][C:50]([O:51][C:52]2[CH:57]=[CH:56][C:55]([N:58]=[C:59]=[S:60])=[CH:54][CH:53]=2)=[CH:49][CH:48]=1>C(Cl)Cl>[CH:26]([N:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:20][NH:19][C:17](=[O:18])[C@@H:16]([NH:15][C:59]([NH:58][C:55]1[CH:54]=[CH:53][C:52]([O:51][C:50]2[CH:61]=[CH:62][C:47]([F:46])=[CH:48][CH:49]=2)=[CH:57][CH:56]=1)=[S:60])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:27])[CH3:28]
Reactant: CC(C)N(CCNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1)C(C)C
Reactant: Fc1ccc(Oc2ccc(N=C=S)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)[C@H](Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccc(F)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of [(S)-1-(2-diisopropylamino-ethylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (Example 3, step B) (0.093 g, 0.24 mmol) in CH2Cl2 (2 mL) a 4 M solution of HCl in dioxane (0.6 mL, 2.4 mmol) was added, and the mixture was stirred for 3 h at rt. The solvents were removed, and the residue was treated with CH2Cl2. The solvents were removed again under reduced pressure. The residue was dissolved in MeOH and treated with strongly basic ion exchange resin. After 10 min of stirring, the resin was filtered off and the solvents were removed. The residue was dissolved in CH2Cl2 (2 mL), and 4-(4-fluoro-phenoxy)-phenylisothiocyanate (0.064 g, 0.26 mmol) was added. After the mixture was stirred for 4 h, a small amount of 4-(4-fluoro-phenoxy)-phenylisothiocyanate (0.02 g) was added, and the mixture was stirred for 12 h. The crude mixture was purified by flash column chromatography using 0–20% MeOH(1% NH4OH)/CH2Cl2 afforded 0.07 g (55%) of the desired product. MS (electrospray): mass calculated for C30H37FN4O2S, 536.26; m/z found, 537.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.26–6.89 (m, 13H), 5.17 (t, J=7 Hz, 1H), 3.17–2.96 (m, 6H), 2.44 (m, 2H), 1.02 (d, J=6.5 Hz, 12H).
Reaction SMILES: [C:1]([CH:4]([CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:28]/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(C/C=C/c3ccccc3)C(C)=O)c(=O)[nH]2)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cc2nn3c(C(C/C=C/c4ccccc4)C(C)=O)nc(C)c3c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 1, 540 mg (1.10 mmol) of (4E)-2-acetyl-N-{1-[3-(3,4-di-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenyl-4-pentenamide and 540 mg (3.50 mmol) of phosphorus oxychloride are reacted to give 7-[(3E)-1-acetyl-4-phenyl-3-butenyl]-2-(3,4-dimethoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[CH2:55]([N:57]1[CH2:61][CH2:60][CH2:59][CH:58]1[CH2:62][NH2:63])[CH3:56]>ClCCl>[CH2:55]([N:57]1[CH2:61][CH2:60][CH2:59][CH:58]1[CH2:62][NH:63][C:18]([C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([CH3:24])([CH3:25])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:11]2)[CH:23]=[CH:22][CH:21]=1)=[O:19])[CH3:56]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: CCN1CCCC1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Reaction time: 0.5 h
Yield: 122.7 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (100 mg, 0.29 mmol, 1.0 eq.) in dichloromethane (6.7 ml) was added N-hydroxybenzotriazole (59.7 mg, 0.44 mmol, 1.5 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (169.7 mg, 0.88 mmol, 3.0 eq.), followed by 4-methylmorpholine (89.5 mg, 0.88 mmol) and the resultant mixture was stirred at room temperature for 40 min. Then (1-ethylpyrrolidin-2-yl)methanamine (0.33 mmol, 1.1 eq.) was added to the flask and the reaction mixture was stirred for an additional 30 min, LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 160 mg of methyl 2-(3-((1-ethylpyrrolidin-2-yl)methylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow oil, which was purified by column chromatography (dichloromethane: methanol=8:1) to afford 45 mg desired product as a yellow powder, yield: 34.0%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:33])[CH3:32]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[CH2:13][CH:12]([C:26]3[O:27][N:33]=[C:31]([CH3:32])[N:30]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3cccc(C(F)(F)F)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
150 mg (0.34 mmol) of the compound from Example 150A and 39 mg (0.51 mmol) of N′-hydroxyacetamidine were reacted according to the General Method 2. Yield: 71 mg (48% of theory)