Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.Cl.[CH3:6][NH:7][O:8][CH3:9].[CH2:10]([C:13]1[N:14]([CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH2:11][CH3:12]>C1(C)C=CC=CC=1.ClCCl>[CH3:9][O:8][N:7]([CH3:6])[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:14]1[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=[C:13]1[CH2:10][CH2:11][CH3:12]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A solution of trimethylaluminum in toluene (80 mL of a 2 M solution, 160 mmol) was added dropwise to a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (15.6 g, 160 mmol) in dichloromethane (150 mL) at 0° C. After 15 minutes, the reaction flask was removed from bath and the solution stirred for 15 minutes at room temperature. The flask was then cooled in ice bath, and a solution of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate (34.7 g, 107 mmol) in dichloromethane (100 mL) was added rapidly dropwise. After 15 minutes, the ice bath was removed and the solution heated at reflux to cause considerable gas evolution. After 20 hours, a 10% solution of hydrochloric acid in water (15 mL) was added slowly, followed by a saturated solution of sodium bicarbonate in water (50 mL). The layers were separated, and the aqueous mixture was extracted with dichloromethane (2×50 mL). The combined organic solutions were washed successively with a 5% solution of sodium hydroxide in water (2×50 mL) and a saturated solution of sodium bicarbonate in water (1×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide N-methoxy-N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide (35.9 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:16])[C:3]=1[CH3:17].C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:16])[C:3]=1[CH3:17]
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n2c1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cl)c(C(=O)O)c2n(c1=O)CCC2
Yield: 94.8 %

Procedure:
Compound 8c (225 mg, 0.88 mmol) was stirred in a solution of THF (4 mL), MeOH (2 mL), and 1N NaOH (2 mL) at r.t. for 20 h. The solution was made acidic with 1N HCl and extracted (3×) with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo to give 190 mg (95%) of compound 8d as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.16 (s, 1H), 4.01 (t, 2H, J=6.9 Hz), 3.26 (t, 2H, J=7.6 Hz), 1.96-2.17 (m, 5H). MS (ES) [m+H] calc'd for C10H10ClNO3, 228. found 228.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:28][C:22]1[CH:21]=[C:20]([S:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=2)[CH2:15][CH:16]([CH3:17])[CH3:18])[CH:25]=[C:24]([CH3:26])[C:23]=1[C:36]1[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2cc(C)c(Br)c(C)c2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(SC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 358 starting from enantiomerically purified 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS: 542.2 [M−H]−; Isomer 2 MS: 542.2 [M−H]−.
Reaction SMILES: C(N(CC)CC)C.I.CS[C:11]1[NH:12][CH2:13][CH2:14][N:15]=1.[NH2:16][C:17]1[C:38]([Cl:39])=[CH:37][C:20]([C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:27][CH2:26]2)=[O:22])=[C:19]([O:40][CH3:41])[CH:18]=1.[OH-].[Na+]>CO>[NH2:16][C:17]1[C:38]([Cl:39])=[CH:37][C:20]([C:21]([NH:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[CH2:29][CH2:30]2)=[O:22])=[C:19]([O:40][CH3:41])[CH:18]=1
Reactant: CSC1=NCCN1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC2=NCCN2)CC1
Yield: 47.5 %

Procedure:
Triethylamine (0.59 g) and 2-methylthio-2-imidazoline hydroiodide (1.4 g) were added to a solution of 4-amino-N-((1-(5-aminopentyl)-piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (1.5 g) in methanol (20 ml), and the mixture was stirred at refluxing temperature for 4 hr. A 10% aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 0.84 g of 4-amino-5-chloro-N-((1-(5-(imidazolin-2-ylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: O[CH2:2][C:3]1[C:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=2[C:11]([S:19][CH3:20])=[C:5]2[O:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].CO>N1C=CC=CC=1>[Br:41][CH2:2][C:3]1[C:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=2[C:11]([S:19][CH3:20])=[C:5]2[O:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=12
Reactant: CSc1c2c(c(CO)c3c1OC(C)(C)O3)OC(C)(C)O2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CO
Product: CSc1c2c(c(CBr)c3c1OC(C)(C)O3)OC(C)(C)O2

Procedure:
4-Hydroxymethyl-8-methylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole is dissolved in pyridine. The solution is chilled and triphenylphosphine followed by carbontetrabromide are added the reaction is stirred for an appropriate time. Methanol is added and the product is isolated by a suitable method.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:29])([F:28])[C:23]1[CH:27]=[CH:26][NH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:21][C:22]([F:29])([F:28])[C:23]1[CH:27]=[CH:26][N:25]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[N:24]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3ccc(C(F)(F)F)n3)nc2c1
Temperature: 60 °C
Yield: 86 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of 3-trifluoromethylpyrazole, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60° C. for one hour. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.34 g of 2-[3-(3-trifluoromethylpyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 60”).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCOC(=O)CN(CC(C)C)S(=O)(=O)c1ccc(O)cc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(S(=O)(=O)N(CC(=O)OCC)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[[4-hydroxybenzenesulfonyl](isobutyl)amino]acetate (1.0 g, 3.17 mmol) is dissolved in dimethylformamide (16 mL). Cesium carbonate (1.03 g, 3.17 mmol) is added, followed by 1-iodohexane (0.47 mL, 3.17 mmol), and the reaction is stirred overnight at room temperature. The reaction is then partitioned between water and ethyl acetate, the aqueous layer is extracted well with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give ethyl 2-[[4-hexyloxybenzenesulfonyl](isobutyl)amino]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:19]2[CH2:22][CH2:21][CH2:20]2)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (100 mg, 0.389 mmol) in DCE (11 mL) was added azetidine (33 mg, 0.578 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (132 mg, 0.623 mmol) was added and stirring was continued for 2 h. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (102 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13](O)[CH2:14][CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: OCCCO
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1Nc2ccc(Br)cc2C12OCCCO2
Yield: 45.6 %

Procedure:
A mixture of 5-bromoisatin (5.00 g, 22.1 mmol), 1,3 propanediol (4.86 mL, 66.4 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (0.84 g, 4.42 mmol, 0.2 mole %) in benzene (430 mL) was refluxed with a Dean Stark Trap for 5 hr. The mixture was concentrated and washed with sat. aq. NaHCO3 (2×) and brine (1×) and flash chromatographed (Biotage KP silica gel, step gradient 70/30-60/40 Petroleum ether/EtOAc) to give the title compound as a bright yellow solid (2.86 g, 46% ). Anal. Calc'd for C11H10BrNO3: C, 46.50; H, 3.55; N, 4.93. Found: C, 46.82; H, 3.54; N, 4.82. IR: consistent. NMR (300 Mz, DMSO-d6): consistent. MS: (ESI−) m/z 281/283 [M−H], 1 Br pattern observed. m.p.: 202-203° C.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[C:4]([N+:14]([O-])=O)[CH:3]=1.[CH2:17]([OH:19])[CH3:18].[BH4-].[Na+]>C1COCC1>[C:17]([NH:14][C:4]1[CH:3]=[C:2]([F:1])[C:11]([CH3:12])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)(=[O:19])[CH3:18]
Reactant: CCO
Reactant: Cc1c(F)cc([N+](=O)[O-])c2c1C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)c(C)c2c1CCCC2
Temperature: 25 °C

Procedure:
The compound obtained in (4) above (1.35 gm) was dissolved into 5 ml of ethanol and 15 ml of THF. To the solution was added 114 mg of sodium borohydride while stirring at room temperature. After stirring for 20 minutes, the reaction mixture was concentrated. To the concentrate were added 25 ml of toluene and 840 mg of p-TsOH, followed by heating under reflux for 30 minutes. Upon the addition of 100 ml of ethyl acetate, the reaction product was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved into 20 ml of ethyl acetate and catalytically hydrogenated with the addition of 400 mg of platinum oxide for 4 hours. The catalyst was removed, the fitrate was concentrated, and 10 ml of dichloromethane was added to the concentrate. After the further addition of 1.2 ml of triethylamine and 0.81 ml of acetic anhydride, the mixture was stirred for 40 minutes. The reaction product was diluted with 50 ml of chloroform, washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 1.23 gm of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>O1CCCC1.CN(C)C=O>[F:21][C:19]1[CH:20]=[CH:13][C:14]([C:15]#[N:16])=[C:17]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:18]=1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
To a solution of imidazole (4.45 g, 65.4 mmol) in tetrahydrofuran (30 mL) and dimethylformamide (10 mL) was added potassium carbonate (9.95 g, 72 mmol) and the mixture was stirred for 30 min at room temp. To this was added 2,4-difluorobenzonitrile (10.0 g, 72 mmol) and the mixture stirred at 90° C. for 3 h then at room temp for 2 days. The mixture was filtered and concentrated and the residue was purified by flash chromatography (SiO2) eluting with 20% to 70% ethyl acetate/hexane to give the title compound as white needles (1.1 g, 9% yield). 1H-NMR (500 MHz, CDCl3) δ ppm: 7.94 (1H, s), 7.84 (1H, dd, J=8.7, 5.6 Hz), 7.37 (1H, t, J=8.7, 5.6 Hz), 7.37 (1H, t, J=1.4 Hz), 7.29 (1H, t, J=1.1 Hz), 7.27-7.21 (2H, m). LCMS [M+H]+ calcd for C10H7N3F: 188.058; found: 188.12.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([N+]([O-])=O)[CH:11]=1.O>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:11]=1
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: CC(C)=NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(ON=C(C)C)c1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
In 20 ml of DMF was dissolved acetone oxime (0.74 g), followed by sodium hydride (0.30 g). After this mixture had stirred for 30 minutes, 4-methoxy-2-nitro-benzonitrile (1.50 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of 4-methoxy-2-[[(1-methylethylidene)-amino]oxy]benzonitrile, m.p. 78-79° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>>[C:20]([O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)(=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: OCCN1CCN(Cc2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OCCN1CCN(Cc2ccccc2)CC1
Yield: 90.2 %

Procedure:
4-Benzyl-1-piperazineethanol was reacted with diketene in the same manner as Reference Example 1-(2) to give 2-(4-benzyl-1-piperazinyl)ethyl acetoacetate as an oil. Yield 90.2%. NMR(CDCl3)δ: 2.26(3H, s), 2.47(8H, s), 2.61(2H, t, J=6), 3.41(2H, s), 3.47(2H, s), 4.22(2H, t, J=6), 7.21(5H, s).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH:6]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].[C:19]1([C:25]2[N:26]=[C:27]([CH2:36]Br)[O:28][C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([N:5]([CH:6]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH2:36][C:27]1[O:28][C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]=1)=[O:4]
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COc1cccc2c1CCC2NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCC2N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(=O)C(F)(F)F
Reaction time: 12 h
Yield: 35.9 %

Procedure:
To a solution of 1-trifluoroacetamido-2,3-dihydro-4-methoxy-1H-indene (0.44 g) and 4,5-diphenyl-2-bromomethyloxazole (0.55 g) in DMF was added K2CO3 (0.30 g). After being stirred for 12 hours, the solution was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(N-trifluoroacetyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.30 g).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][OH:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[C:28]([CH3:29])=[C:27]([C:30](O)=[O:31])[C:26](=[O:33])[N:25]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[OH:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30]([C:27]4[C:26](=[O:33])[N:25]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:24]([CH3:23])[C:28]=4[CH3:29])=[O:31])=[CH:22][CH:21]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCO)ccc34)cc2)c(=O)n(-c2ccccc2)n1C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 2-((4-(4-aminophenoxy)quinolin-7-yl)oxy)ethanol (0.14 g, 0.5 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carb oxylic acid (0.11 g, 0.51 mmol) in DCM (1.5 mL) was added HOAT (0.014 g, 0.1 mmol), and EDCI (0.11 g, 0.6 mmol). The reaction was refluxed for 3 hours. The cooled mixture was diluted with water (30 mL) and filtered. The solid was collected and stirred in a mixture of EtOAc (3 mL) and water (3 mL) overnight. The solid was collected by filtration and dried in vacuo at 50° C. for 9 hours to afford the title compound as a gray-white solid (180 mg, 74.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]1O)=[O:5])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C1CCc2ccccc2C1O
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2ccccc2CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
A mixture of 2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-naphthol (2.45 g, 11.1 mmol), triethylamine (2.70 g, 26.7 mmol) and tetrahydrofuran (50 ml) was cooled to 0° C., followed by adding dropwise thereto methanesulfonyl chloride (1.53 g, 13.3 mmol). The reaction mixture was stirred at 0-5° C. for 1.5 hours and then at room temperature for 7 hours, and allowed to stand overnight at room temperature. The reaction mixture was poured into a cold aqueous ammonium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:99) to obtain 2.12 g of ethyl 3,4-dihydronaphthalene-2-carboxylate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Br.[NH2:56][C:57]1[S:58][CH:59]=[C:60]([C:62](O)=[O:63])[N:61]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH2:56][C:57]1[S:58][CH:59]=[C:60]([C:62]([N:50]2[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]3[CH:37]=[CH:38][C:39]4[NH:40][C:41]5[N:42]=[C:26]([NH:27][C:28]6[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=6)[CH2:33][CH2:34][C:35]=3[CH:43]=4)[N:25]=[CH:24][C:23]=5[Cl:22])=[O:53])[CH2:48][CH2:49]2)=[O:63])[N:61]=1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Nc1nc(C(=O)O)cs1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cs1
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-amino-1,3-thiazole-4-carboxylic acid hydrobromide as starting materials in 36% yield. LCMS for C28H29ClN9O2S (M+H)+: m/z=590.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.[C:16]([S:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CC(C)=O.CCOCC>[C:16]([S:24][CH2:25][CH2:26][C:27]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCSC(=O)c1ccccc1
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(SCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O)c1ccccc1

Procedure:
11.3 g of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid and 13.2 g of thriethylamine are dissolved in 200 ml of dehydrated acetone and 11.7 g of S-benzoyl-3-mercaptopropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour. 4 N Hydrochloric acid in ether is added to this mixture and the precipitate is filtered. The filtrate is concentrated in vacuo and the obtained oil is dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give the titled compound, yield 12 g (58%), mp. 100.5°-101° C. (dec.) (ethyl acetatebenzene), [α]D26 +130.8° (c=1.0, methanol).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:24][CH:25]2[CH2:27][CH2:26]2)[C:5]2[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[N:34][NH:35]2)=[CH:31][CH:30]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][C:2]3[N:3]=[C:4]([NH:24][CH:25]4[CH2:26][CH2:27]4)[C:5]4[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:37]=2)[CH:33]=[N:34]1
Reactant: CC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(NC3CC3)c12
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)c1c[nH]c2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CC3)c12
Temperature: 116 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A mixture of 1-(2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethanone (85 mg, 0.21 mmol), 6-aminoindazole (56 mg, 0.42 mmol) and TMSCl (0.070 mL, 0.55 mmol) in nBuOH (3 mL) was stirred at 116° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (30 mg). MS 348.1 (M+H); UV 248.7, 305.7 nm.