Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:14]([C:22]([OH:24])=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:32]1[CH2:37][CH2:36][CH:35]([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]2)[CH2:34][CH2:33]1.[OH-].[Na+]>O1CCCC1>[C:28]([O:27][C:25](=[O:26])[NH:13][C@@H:14]([C:22](=[O:24])[NH:46][CH2:45][CH:42]1[CH2:41][CH2:40][N:39]([CH2:38][CH:35]2[CH2:34][CH2:33][O:32][CH2:37][CH2:36]2)[CH2:44][CH2:43]1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: NCC1CCN(CC2CCOCC2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
6.7 g of carbonyldiimidazole is added to a solution of 10 g of Boc-D-Phe-OH in 80 ml of tetrahydrofuran, cooled to 0° C. The resulting solution is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of tetrahydrofuran is dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 1 hour. 100 ml of 1M NaOH is added to the mixture, and the tetrahydrofuran is evaporated at low pressure. Dichloromethane and water are added to the residue; the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate, compound (12) is crystallised from ethyl acetate to obtain 14.73 g of white solid. Yield 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:38][C:39]1[N:44]=[C:43](Cl)[C:42]([Cl:46])=[CH:41][N:40]=1.O>CN(C=O)C>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:41]2[C:42]([Cl:46])=[CH:43][N:44]=[C:39]([Cl:38])[N:40]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
A solution of tert-butyl [3-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)phenyl]carbamate (8.15 g, 19.1 mmol) in DMF (19 mL) was treated with potassium carbonate (3.42 g, 24.8 mol) and stirred at 25° C. for 5 minutes. The reaction mixture was treated with 2,4,5-trichloropyrimidine (2.40 mL, 21.0 mmol) dropwise and stirred at 20° C. overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated and washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give a crude orange oil. The residue was purified with silica gel chromatography to give the desired product (10.9 g, 99.5%). LCMS calculated for C28H33Cl2N5O4Na (M+Na)+: m/z=596.0, 598.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].CCN(CC)CC.Cl[C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)C(=O)Cl
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M−H]−); IR (thin film) 1740, 1701, 1114, 808 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH2:14])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH:14][C:16](=[O:18])[CH3:17])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCC[C@@H](C)[C@@H](C)/C(N)=C/C(=O)OCC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NC(C)=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a 1 L 3-necked round bottom flask equipped with an overhead stirrer, thermocouple, addition funnel, and nitrogen inlet, was charged 150 g (0.70 mol) of (4R,5R)-3-amino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester and 50 mL of dry CH2Cl2. The reaction mixture was cooled to −20° C. To the mixture was added, successively, acetyl chloride (60 mL, 0.84 mol) and pyridine (66.8 g, 0.84 mol) over 0.5-hour time intervals. After the additions, the mixture was stirred at −20° C. to 0° C. for 2 hours and then filtered to remove the pyridine.HCl salt. The filtrate was diluted with 200 mL of CH2Cl2 and washed 2× with aliquots of aq NH4Cl. The organic solution was treated with silica gel (50 g), MgSO4 (20 g) and charcoal (20 g), and stirred at room temperature for 0.5 hours. The solids were filtered off and the filtrate was concentrated under reduced pressure to give 166.5 g (93% yield) of the titled compound as an oil: 1H NMR (400 MHz, CHLOROFORM-D) 0.85 (t, J=7.4 Hz, 3 H), 0.95 (d, J=6.8 Hz, 3 H), 1.00 (d, J=7.0 Hz, 3 H), 1.11 (m, 1 H) 1.29 (t, J=5.8 Hz, 3 H), 1.40–1.25 (m, 2 H), 1.65 (m, 1 H) 2.13 (s, 3 H), 3.80 (m, 1 H) 4.2–4.14 (m, 3 H), 5.01(s, 1 H), 11.28(s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:13]=2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36]([C:2]3[CH:3]=[C:4]([C:12]4[CH:17]=[CH:16][N:15]=[C:14]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH:13]=4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCN(c2cc(-c3cc(Br)c4c(N)ncnn34)ccn2)CC1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1CCN(c2cc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)ccn2)CC1
Temperature: 80 °C
Yield: 20.6 %

Procedure:
To a stirred solution of 5-bromo-7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (60 mg, 0.16 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (103 mg, 0.31 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II) complex with dichloromethane (5.6 mg, 0.008 mmol) in degassed DME (1.2 mL) was added aqueous sodium carbonate solution (2 M, 232 □L). The reaction was heated (80° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL) and the layers were separated. The organic phase was washed with brine (25 mL), dried (Na2SO4), and concentrated. The crude material was purified by preparative HPLC using a gradient elution from 5% to 35% acetonitrile in water to obtain 17 mg (21%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.81-8.79 (m, 1 H), 8.58 (s, 1 H), 8.28-8.21 (s, 1 H), 7.98-7.94 (m, 1 H), 7.87-7.81 (m, 1 H), 7.68 (s, 1H), 7.41-7.29 (m, 5 H), 7.24-7.19 (m, 1H), 7.12-7.08 (m, 1 H), 6.97-6.91 (m, 1 H), 5.67 (s, 2 H), 3.58-3.52 (m, 4 H), 2.44-2.37 (m, 4 H), 2.22 (s, 3 H); ES-MS m/z 516.24 [M+H]+, HPLC RT (min) 2.28.
Reaction SMILES: [NH2:1][NH2:2].C([O:5][C:6](=O)[CH:7]([C:21](=O)[C:22]([F:25])([F:24])[F:23])[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)C.CO>C1(C)C=CC=CC=1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:6]([OH:5])=[N:1][NH:2][C:21]=2[C:22]([F:25])([F:24])[F:23])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C(C(=O)C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2c(O)n[nH]c2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Anhydrous hydrazine (0.040 mL, 41 mg, 1.27 mmol) was added to a stirred solution of 1-(tert-butoxycarbonyl)-α-(trifluoroacetyl)-4-piperidineacetic acid ethyl ester (275 mg, 0.75 mmol, from Step B) in toluene (2.0 mL) at RT. The mixture was warmed to 60° C. for 4 h, followed by 16 h at 80° C. The mixture was allowed to cool to RT, transferred to another flask with CH3OH, and evaporated to give the title compound as a white solid. For the title compound: 1H NMR (500 MHz, CD3OD) δ 4.15 (bd, J=13, 2H), 2.86–2.70 (m, 3H), 1.88 (bq, J=12, 2H), 1.62 (bd, J=13, 2H), 1.47 (s, 9H); ESI-MS 280.3 (M+H−56) and 236.3 (M+H−100); HPLC A: 3.0 min.
Reaction SMILES: [Cl:1][C:2](=[CH2:18])[CH2:3][C:4]1([CH3:17])[CH2:12][C:11]2[C:6](=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([OH:13])[CH:10]=2)[C:5]1=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28]>CN(C=O)C>[O:16]=[C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:13][CH2:26][C:27]([OH:29])=[O:28])=[C:8]([Cl:14])[C:7]=2[Cl:15])[CH2:12][C:4]1([CH2:3][C:2]([Cl:1])=[CH2:18])[CH3:17]
Reactant: C=C(Cl)CC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cl)CC1(C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
[1-Oxo-2-(2-chloroallyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid is prepared following substantially the same procedure described in Example 4, Step D, using the following reagents: 2-(2-chloroallyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (4.8 g., 0.0157 mole), potassium carbonate (6.0 g.), ethyl bromoacetate (4.5 ml.) and DMF (55 ml.). The above procedure gives 2.7 g. (48%) of [1-oxo-2-(2-chloroallyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which after recrystallization from butyl chloride melts at 160°-162° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:33]2([CH3:34])[C@H:18]([C@H:19]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:22]([CH2:23][C@H:24]([CH2:26][CH2:27]2)[OH:25])=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)[CH3:14])[CH3:9].C(N(CC)CC)C>ClCCl>[CH3:14][C@@H:13]([C@@H:15]1[C@@:33]2([CH3:34])[CH2:32][CH2:31][C@@H:30]3[C@@:28]4([CH3:29])[CH2:27][CH2:26][C@H:24]([O:25][C:1]([C:2]([CH3:4])=[CH2:3])=[O:5])[CH2:23][C:22]4=[CH:21][CH2:20][C@H:19]3[C@@H:18]2[CH2:17][CH2:16]1)[CH2:12][CH2:11][CH2:10][CH:8]([CH3:7])[CH3:9]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6 ml of methacryloyl chloride in 30 ml of dichloromethane is added dropwise to 20 g (51.72 mmol) of cholesterol and 8 ml of triethylamine in 170 ml of dichloromethane (abs.). The mixture is stirred overnight at room temperature. The solvent is distilled off under reduced pressure, and the residue is recrystallized three times from the ca. 400 ml of ethanol (95%). Drying is carried out at a pressure of 10−2 mbar for 24 h
Reaction SMILES: C=O.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7]1.[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23].CO>C(O)C>[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23].[CH:15]1[C:13]2[C:14]3[N:6]4[CH2:5][CH2:4][NH:3][CH2:19][C:7]4=[CH:8][C:9]=3[CH2:10][CH2:11][C:12]=2[CH:18]=[CH:17][CH:16]=1
Reactant: NCCn1ccc2c1-c1ccccc1CC2
Agent: C=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: c1ccc2c(c1)CCc1cc3n(c1-2)CCNC3
Yield: 53 %

Procedure:
36% aqueous formaldehyde solution (1.4 ml) was added under argon to a solution of 3.7 g of 1-(2-aminoethyl)-4,5-dihydro-1H-benzo[g]indole in 70 ml of ethanol. The reaction solution was stirred under reflux for 2 hours, subsequently cooled and freed from solvent. The residue was chromatographed on 250 g of silica gel with methylene chloride/methanol (49:1) as the eluent. 1.3 g of a total of 2.8 g of product were dissolved in a 20-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. The precipitated solid was boiled in a 150-fold amount of methanol, filtered while hot and concentrated to a 60-fold amount of solvent. There were obtained 1.2 g (53%) of 5,6,8,9,10,11-hexahydrobenzo[g]pyrazino[1,2-a]indole fumarate (2:1); m.pt.: 183°-184° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27](OC)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:32][NH2:33]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:32][NH2:33])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O

Procedure:
To a solution of 120 mg (0.27 mmol) of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate (Example 47) in EtOH was added hydrazine, monohydrate (135 μl, 2688 μmol). After being refluxed for 14 h, the reaction was concentrated, diluted (H2O) and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (5% MeOH/CH2Cl2, gradient elution) provided the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][N:5]([C:7](=[O:38])[C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[C:22]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]3[CH2:36][CH2:35]3)[CH2:26][CH2:25]2)=[O:23])=[CH:10][C:9]=1[Cl:37])[CH3:6].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:37][C:9]1[CH:10]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[C:22]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]3[CH2:35][CH2:36]3)[CH2:26][CH2:25]2)=[O:23])[C:12]([Cl:14])=[CH:13][C:8]=1[C:7]([N:5]([CH2:4][C:3]([OH:39])=[O:2])[CH3:6])=[O:38]
Reactant: COC(=O)CN(C)C(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(CC(=O)O)C(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 0.057 g (0.10 mmol) ({2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoyl}-methyl-amino)-acetic acid methyl ester (Example 31) in 1 mL dioxane and 1 mL water was added 0.005 g (0.12 mmol) lithium hydroxide monohydrate. After stirring at room temperature for 2 hours, dioxane was removed by evaporation. The pH of the formed yellow solution was adjusted to 1 with 1M aqueous hydrochloric acid. The aqueous solution was saturated with solid sodium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give 0.053 g (95%) of the title compound as a yellow solid. MS (ESI): m/z=555.12 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: Cc1ccccc1S
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccccc2C)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 2-methylbenzenethiol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.94 (s, 3H) 2.32 (s, 3H) 6.79 (s, 1H) 7.58-7.68 (m, 3H) 7.76-7.88 (m, 3H) 7.92 (d, J=8.14 Hz, 1H) 8.18 (d, J=8.24 Hz, 1H) 10.38 (s, 1H) 13.10 (bs, 1H); ESI-MS: m/z calc'd for C20H17N3OS 347.11. found 348.3 (M+H)+.
Reaction SMILES: O(C(C)(C)C)[K].Cl[C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:12][CH:11]=[CH:10][N:9]=1.[CH2:27]([OH:30])[CH2:28][OH:29]>N1C=CC=CC=1>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:13]2[C:8]([O:29][CH2:28][CH2:27][OH:30])=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OCCO
Agent: CC(C)(C)O[K]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 85.8 %

Procedure:
KO-t-Bu (9.92 g, 103 mmol) was added to a mixture of the product obtained in Step 1 (1 8.14 g, 60.7 mmol) and ethylene glycol (25 mL, 448 mmol) in pyridine (125 mL) at 85° C. The reaction mixture was stirred for 15 h and then poured into ice-water and extracted with toluene. The organic phase was dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 16.9 g (85%) of the title product. HRMS m/z calcd for C15H24N4O4 (M)+ 324.1798, found 324.1784.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.O.N>O1CCCC1>[NH2:26][C:11](=[O:12])[C@H:10]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C[C@H](CNC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C[C@H](CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
(Step 3) To (2R)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoic acid (15 g) in tetrahydrofuran (75 ml) solution, 1,1′-carbonyldiimidazole (7.8 g) was added under ice cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., 28% ammonia water (15 ml) was added, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, distilled water, ethyl acetate, and tetrahydrofuran were added, the aqueous layer and the organic layer were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was successively washed with saturated potassium hydrogensulfate aqueous solution and saturated saline, dried over with anhydrous sodium sulfate, and concentrated until a small amount of ethyl acetate remained. Hexane was added to the concentrated solution, and the precipitated solid was collected by filtration to obtain the title compound (13.5 g).
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].C[O-].[Na+]>>[Cl:1][C:2]([Cl:7])([CH2:12][CH2:11][C:10]([O:9][CH3:8])=[O:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: COC(=O)C(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CCC(Cl)(Cl)C(=O)OC

Procedure:
reacting methyl dichloroacetate and acrylic acid methyl ester with sodium methoxide to obtain Dimethyl 2,2-dichloroglutarate;
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH3:49][O:50][C:51]1[CH:56]=[C:55]([CH:57]2[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]2)[CH:54]=[CH:53][C:52]=1[NH2:64]>CN(C=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:64][C:52]4[CH:53]=[CH:54][C:55]([CH:57]5[CH2:58][CH2:59][N:60]([CH3:63])[CH2:61][CH2:62]5)=[CH:56][C:51]=4[O:50][CH3:49])=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc(C2CCN(C)CC2)ccc1N
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
In a 10 mL sealed tube, to N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (100 mg, 0.289 mmol) and N,N-Diisopropylethylamine (0.202 mL, 1.16 mmol) in 3.0 mL of anhydrous DMF was added N-Phenylbis(trifluoromethane-sulfonimide (113 mg, 0.318 mmol). After stirring at room temperature for 30 minutes, 2-Methoxy-4-(1-methyl-piperidin-4-yl)-phenylamine (84 mg, 0.36 mmol) was added. The reaction mixture was heated at 65° C. overnight. The reaction was conc. in vacuo. The reaction mixture was purified via silica gel column chromatography using 500:12:8 DCM:MeOH:7N NH3/MeOH as the eluant. The collected fractions afforded N-tert-Butyl-3-{2-[2-methoxy-4-(1-methyl-piperidin-4-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzenesulfonamide as a yellow solid (19.66 mg, 11%). MP 189-198° C. LCMS (E/I+) 549.21 (M+H). 1H NMR (DMSO-d6)-9.01 (s, 1H), 8.56 (s, 1H), 8.35 (d, 1H, J=7.88 Hz), 7.99 (d, 1H, J=8.56 Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.69 (t, 1H, J=7.82 Hz), 7.62 (s, 1H), 7.23 (d, 1H, J=4.72 Hz), 7.01 (d, 1H, J=4.76 Hz), 6.94 (s, 1H), 6.92 (s, 1H), 3.87 (s, 3H), 2.96-2.83 (m, 2H), 2.28-2.17 (s, 3H), 2.10-1.94 (m, 2H), 1.80-1.58 (m, 3H), 1.32-1.21 (m, 1H), 1.12 (s, 9H).