Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][O:22][CH3:23])[C:4]([NH:6][C@@H:7]([CH2:18][O:19][CH3:20])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5].[C:24](=[O:27])([O-:26])[O-:25].[K+].[K+]>CN(C=O)C.O>[CH3:20][O:19][CH2:18][C@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([NH:2][CH2:11][C:12]1[O:27][C:24](=[O:26])[O:25][C:13]=1[CH3:14])[CH2:21][O:22][CH3:23])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C([O-])[O-]
Reactant: COC[C@H](NC(=O)[C@@H](N)COC)C(=O)OCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](NCc1oc(=O)oc1C)C(=O)N[C@@H](COC)C(=O)OCc1ccccc1
Reaction time: 2.5 h

Procedure:
Referring to FIG. 38, 4-(bromomethyl)-5-methyl-1,3-dioxo-2-one (278 mg. 1.44 mmol) was added to (S)-benzyl 2-((S)-2-amino-3-methoxypropanamido)-3-methoxypropanoate hydrochloride salt (1.0 g, 2.88 mmol) and potassium carbonate (400 mg, 2.88 mmol) in DMF (15 mL) at 0° C. The reaction was stirred at 0° for 2.5 hours and then diluted with water and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by Biotage flash column chromatography to give product as a yellow oil. MS for C20H26N2O8 m/z: 423 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]2[CH:26]=[CH:27][S:28][C:24]=2[CH:23]=1>ClCCCl>[Br:1][C:27]1[S:28][C:24]2[CH:23]=[C:22]([O:21][CH3:20])[CH:30]=[CH:29][C:25]=2[CH:26]=1
Reactant: COc1ccc2ccsc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: COc1ccc2cc(Br)sc2c1
Temperature: 70 °C
Yield: 82.2 %

Procedure:
N-bromosuccinimide (14.70 g, 82.59 mmol) and p-toluenesulfonic acid (2.70 g, 15.68 mmol) were added to a solution of benzothiophene (3) (15.10 g, 92.07 mmol) in 1,2-dichloroethane (300 ml). The mixture was maintained at 70° C. for 35 min, cooled in an ice bath, and the succinimide was removed by filtration. The solution was extracted with saturated sodium bicarbonate solution, dried over Na2SO4, filtered, and concentrated under vacuum to give 22.00 g as an oil. Crystallisation from pentane afforded a white solid (16.50 g, 74%), mp 62° C.
Reaction SMILES: [CH2:1]([C:4]1([CH3:19])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:18])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].[O:22]1[CH2:24][CH:23]1[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:1]([C:4]1([CH3:19])[C:9]2[N:10]([CH2:24][CH:23]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[OH:22])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:18])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C)CN(C)Cc2c1[nH]c1ccc(C)cc21
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C)CN(C)Cc2c1n(CC(O)c1ccncc1)c1ccc(C)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.2 %

Procedure:
4-Allyl-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.5 g, 9.8 mmol) was dissolved in 18 mL of DMF and stirred for 10 min at RT. Sodium hydride (1.17 g, 29.2 mmol) was added portionwise and stiffing was continued for additional 10 min. This was followed by dropwise addition of 4-oxiranyl-pyridine (2.38 g, 19.6 mmol) as a solution in DMF. The reaction mixture was stirred at RT for 16 h, quenched with ice water and extracted with EtOAc (3×120 mL). The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized in ether to obtain 1 g of 2-(4-allyl-2,4,8-trimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:52]=1[C@H:58]([NH2:63])[C:59]([F:62])([F:61])[F:60]>>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:63][C@@H:58]([C:52]2[CH:53]=[CH:54][C:55]([F:57])=[CH:56][C:51]=2[F:50])[C:59]([F:60])([F:62])[F:61])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: N[C@@H](c1ccc(F)cc1F)C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(N[C@@H](c1ccc(F)cc1F)C(F)(F)F)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(S)-4-Chloro-N-[1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl-1]-2-(quinoxaline-5-sulfonylamino)-benzamide. The title compound was prepared from the HATU-mediated coupling of 4-chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 3, Step B) and (S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethylamine hydrochloride and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H14ClF5N4O3S, 556.0; m/z found, 555/557 [M−H]−. HPLC (reverse phase): RT=9.98 min. 1H NMR (400 MHz, CDCl3): 11.07 (s, 1H), 8.84-8.83 (m, 2H), 8.56 (dd, J=7.4, 1.4 Hz, 1H), 8.31 (dd, J=7.4, 1.4 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.43-7.37 (m, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.03-6.93 (m, 3H), 6.81-6.79 (m, 1H), 6.08-6.00 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]#[N:11])[NH2:6].[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>C(O)(=O)C>[O:18]=[C:17]1[CH:16]=[CH:15][C:14](=[O:19])[N:6]1[C:5]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CC(=O)O
Product: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Temperature: 115 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 3-trifluoromethyl-4-cyano-aniline (24.0 g, 129 mmol) and maleic anhydride (14.0 g, 143 mmol) in 50 mL of acetic acid was heated at 115° C. overnight. A precipitate was obtained during the heating period. The reaction was allowed to stand at rt for an additional overnight period. The solid was removed by filtration, the filter cake was washed with diethyl ether and dried to give 21 g (79 mmol, 61%) of compound 471A as an off white solid. HPLC: 100% at 2.11 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[N+:23]([O-])([OH:25])=[O:24].O.[OH-].[Na+]>C(O)(=O)C>[N+:23]([C:5]1[CH:4]=[CH:3][C:2]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[C:1]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)([O-:25])=[O:24]
Reactant: c1ccc(-c2ccccc2OCCCN2CCOCC2)cc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCCN2CCOCC2)c(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-[3-(Biphenyl-2-yloxy)-propyl]-morpholine (t, 500 mg, 1.46 mmol) was dissolved in 3 mL acetic acid and the reaction mixture was cooled in an ice bath. Concentrated nitric acid (3 mL) was added dropwise and the mixture was stirred for 15 minutes at 0° C., then at room temperature for one hour. The reaction was subsequently poured into 100 mL water and the pH of the reaction mixture was raised to >7 with 2N NaOH. The aqueous solution was extracted with ethyl acetate and dried. The solvent was then removed to afford 500 mg 4-[3-(5-nitro-biphenyl-2-yloxy)-propyl]-morpholine (u) which was used without further purification: m/e: 342.15, MS (ES+): 343.1; 1H NMR (500 MHz, CDCl3): 8.2-6.8 (m, 9H), 4.1(m, 2H), 3.7 (m, 4H), 2.5 (m, 6H) and 1.8 (m, 2H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18](\[CH3:24])/[C:19](OCC)=[O:20]>C(Cl)Cl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18](\[CH3:24])/[C:19]([N:3]([O:4][CH3:5])[CH3:2])=[O:20]
Reactant: CNOC
Reactant: CCOC(=O)/C(C)=C/c1ccccc1F
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)/C(C)=C/c1ccccc1F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (7 g, 72 mmol) was slurried in CH2Cl2 (250 mL) and cooled to 0-5° C. A solution of trimethylaluminum (2M in toluene, 36 mL, 72 mmol) was added dropwise. The mixture was warmed to ambient temperature and stirred for 1 hr. A solution of Example 3A (5 g, 24.0 mmol) in CH2Cl2 (100 ml) was added and the solution was heated to reflux overnight. The reaction mixture was cooled in an ice bath and quenched carefully with ice cold 0.5 M HCl. The mixture was filtered through celite filter aid and extracted with CH2Cl2. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was chromatographed (SiO2, 100% hexanes to 20% ethyl acetate/hexanes) to afford the title compound (1.88 g, 35% yield) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.27-7.38 (m, 2H), 7.04-7.17 (m, 2H), 6.79 (s, 1H), 3.72 (s, 3H), 3.30 (s, 3H), 2.04 (s, 3H). MS (ESI+) 224 (M+H).
Reaction SMILES: [C:1]([CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2].[CH2:18](O)[CH3:19]>>[C:1]([CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3][CH2:18][CH3:19])=[O:2]
Reactant: CCO
Reactant: CC(C)(CCCCC1CCCC1=O)CC(=O)O
Product: CCOC(=O)CC(C)(C)CCCCC1CCCC1=O

Procedure:
Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one with ethanol by the procedure of Example 456 is productive of the subject compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:3][C@H:4]4[F:35])=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@H]1F
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1S*,2R*,4S*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f73) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].CCN(C(C)C)C(C)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[O:24][CH3:25]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of 2-fluoro-5-nitroaniline (500 mg, 3.20 mmol) in THF (20 mL) was treated with DIEA (0.84 mL, 4.8 mmol) followed by methyl chloroformate (0.25 mL, 3.20 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, 40 g column, 30 min. gradient) to afford Intermediate 59A (450 mg, 65.6%). HPLC: Rt=2.868 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.94 (1H, s), 8.72 (1H, dd, J=6.80, 2.77 Hz), 7.87-8.09 (1H, m), 7.52 (1H, t), 3.72 (3H, s).
Reaction SMILES: [CH2:1]([NH:3][Si:4]([NH:11][CH2:12][CH3:13])([NH:8][CH2:9][CH3:10])[NH:5][CH2:6][CH3:7])[CH3:2].[C:14]1(C)C=CC=C[CH:15]=1>>[CH2:9]([NH:8][Si:4]([NH:5][CH2:6][CH3:7])([NH:11][CH2:12][CH3:13])[N:3]([CH2:14][CH3:15])[CH2:1][CH3:2])[CH3:10]
Reactant: CCN[Si](NCC)(NCC)NCC
Reactant: Cc1ccccc1
Product: CCN[Si](NCC)(NCC)N(CC)CC

Procedure:
A three-necked flask in which the internal atmosphere was sufficiently replaced with nitrogen gas was charged with 50 ml of a THF solution of diethylamine (0.1 mol/50 ml). The solution was cooled to −10° C. while stirring and 100 ml of a THF solution of BuMgCl (0.1 mol/100 ml) was slowly added dropwise using a dripping funnel. After the addition, the mixture was reacted at 40° C. for two hours to complete the reaction. A slurry of Mg salt of diethylamine obtained in this manner was slowly added to 50 ml of a 0.09 mol/50 ml toluene solution of tetrakis(ethylamino)silane synthesized according to the method of Example 33 at −10° C. while stirring. After the addition, the mixture was allowed to react at 50° C. for two hours. The reaction product was centrifuged in a nitrogen stream to separate a solid from liquid. The solid was washed twice with toluene. The solution was concentrated and purified by distillation under reduced pressure. Tris(ethylamino)(diethylamino)silane thus obtained was subjected to elementary analysis to confirm that the compound consists of C: 41.32% (51.67%), H: 12.10% (12.14%), and N: 23.98% (24.10%), wherein the percentages of the parentheses are theoretical values.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].COC1C=CC([Mg]Br)=CC=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=O)[C:31]=3[C:40]([O:42]CC)=[O:41])=[CH:24][C:23]=2[O:22]1>CCOCC.C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]([C:25]3[CH:26]=[CH:27][C:28]4[O:29][CH2:21][O:22][C:23]=4[CH:24]=3)[CH:31]2[C:40]([OH:42])=[O:41])=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Reactant: COc1ccc(Br)cc1
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O/THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10:1 Et2O/THF (55 ml) at 0° C. The resulting mtixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([NH:14][CH2:15][CH2:16][OH:17])[CH:6]=[CH:5]2.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>ClCCl>[C:18]([Si:22]([CH3:25])([CH3:24])[O:17][CH2:16][CH2:15][NH:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH2:1])[CH:3]=2)[N:8]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc2nc(NCCO)ccc2cc1N
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc2nc(NCCO[Si](C)(C)C(C)(C)C)ccc2cc1N
Temperature: 25 °C
Reaction time: 62 h
Yield: 34.5 %

Procedure:
A mixture of 2-(6-amino-7-methoxy-quinolin-2-ylamino)-ethanol (0.4 g, 1.72 mmol), tert-butyldimethylchlorosilane (0.8 g, 5.15 mmol) and imidazole (0.4 g, 5.15 mmol) in dichloromethane (20 mL) was stirred at room temperature for 62 hours. The resulting mixture was washed with water and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 3/7) to afford 206 mg of N2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methoxy-quinoline-2,6-diamine as a brown oil. MS=348 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[NH:8][C:6]1[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:2]([O:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=2)[N:7]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccc(C=O)cc3)n2)cc1Cl
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A mixture of compound 133 (1.8 g, 4.70 mmol), potassium carbonate (3.2 g, 23.45 mmol) in dimethylformamide (8 mL) was added 4-hydroxybenzaldehyde (0.69 g, 5.63 mmol). It is heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound as white solid (1.58 g, 72%). mp 218-220° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 265 nm, Rt 25.606 min, 98.06% purity; MS (CI): m/z 468 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.C(OC([N:39]1[CH2:44][CH2:43][N:42]([C:45]2SC(=CC3C=C4C(=CC=3)N(CC3C=CC(C(O)(C)C)=CC=3C(F)(F)F)N=C4)C(=O)N=2)[CH2:41][CH:40]1[CH2:76][OH:77])=O)(C)(C)C>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][C@@H:40]5[CH2:76][OH:77])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1CO
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)[C@@H](CO)C1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R) (4-Methyl-piperazin-2-yl)-methanol following General Procedure C.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:22](OC(C)(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH:25]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16])[CH3:24]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2cc(-c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
6-Phenyloxindole (0.053 mg, 0.25 mmol) and dimethylformamide di-t-butylacetal (0.08 mL, 0.32 mmol) were combined and dissolved in DMF. The reaction mixture was stirred at room temperature for 4 hours. The volatiles were removed in vacuo and the resulting residue was triturated with diethyl ether. The solids were collected by filtration (50 mg, 75% yield). ). 1H NMR 400 MHz (DMSO-d6) mixture of E and Z isomers: δ 10.09 (s, 1H); 10.02 (s, 1H); 7.59–7.51 (m, 4H); 7.45–7.22 (m, 1OH); 7.10–7.05 (m, 2H); 6.98 (s, 1H); 6.91 (s, 1H); 3.29 (s, 12H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Cl[CH2:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C(COC)OC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][C:23]3[S:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[N:27]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc2ccccc2s1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Oc1ccc(N2CCN(Cc3nc4ccccc4s3)CC2)cc1
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A solution of 1.05 g of triethylamine in 20 ml of absolute dimethoxyethane was added dropwise within 15 minutes with stirring to a mixture of 1.78 g (10 mmol) of 1-(4-hydroxyphenyl)piperazine, 2.48 g (13.5 mmol) of 2-chloromethylbenzothiazole and 80 ml of absolute 1,2-dimethoxyethane under reflux. The mixture was stirred for a further 5 hours under reflux, the solvent was evaporated in vacuo, the residue was taken up in CH2Cl2 /H2O, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated. The crystalline residue (3.2 g) was recrystallized from methanol. 2.64 g (81.2% of theory) of pure 1-(4-hydroxyphenyl)-4-(benzothiazol-2-ylmethyl)piperazine, melting point 175°-76° C., were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][C:41]=1[F:42])[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([OH:38])=[CH:24][C:25]=2[O:27][CH2:28][C@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[O:37])[CH2:35][OH:36])[N:20]=[CH:19][N:18]=1.O>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][C:41]=1[F:42])[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:38][CH2:4][CH2:3][O:2][CH3:1])=[CH:24][C:25]=2[O:27][CH2:28][C@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[O:37])[CH2:35][OH:36])[N:20]=[CH:19][N:18]=1
Reactant: COCCBr
Reactant: O=C(CO)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 40 °C
Yield: 64 %

Procedure:
2-Bromoethyl methyl ether (22 μl) and potassium carbonate (43 mg) were added to a mixture of 4-[3-chloro-4-fluoroanilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]-methoxy}-quinazolin-7-ol (70 mg) in DMF and the reaction mixture was heated at 40° C. for 16 hours. The reaction mixture was cooled to room temperature and then water (5 ml) was added to leave a white precipitate. The precipitate was filtered, washed with water and then purified by column chromatography using 2-5% methanol in DCM as eluent to give the title compound as a white solid (51 mg, 64%); NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.75 (t, 2H), 3.50-3.37 (m, 2H), 3.35 (s, 3H), 2.10-1.85 (m, 4H); Mass spectrum MH+ 505.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.CC1CCCC(N)C1>C(O)(=O)C>[CH3:24][CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CC1CCCC(N)C1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC1CCCC(n2cnc3c(-c4ccccc4)csc3c2=O)C1
Yield: 70.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 3-methylcyclohexanamine (0.120 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 98.4 mg (0.30 mmol, 70.5% yield) of the title compound.