Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH2:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22])[CH3:17].[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36]Cl)[CH3:32]>>[CH2:29]([C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([CH2:16][CH3:17])[C:26]=1[O:27][CH3:28])[C:21]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22])[CH3:30].[CH2:29]([C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([CH2:16][CH3:17])[C:26]=1[O:27][CH2:36][CH2:35][CH2:34][N:33]([CH2:38][CH3:39])[CH2:31][CH3:32])[C:21]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22])[CH3:30]
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Reactant: CCc1cc(C(=O)Cl)cc(CC)c1OC
Reactant: CCN(CC)CCCCl
Product: CCc1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc(CC)c1OC
Product: CCc1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc(CC)c1OCCCN(CC)CC

Procedure:
3-(3,5-Diethyl-4-methoxybenzoyl)-2-phenylbenzofuran is prepared by acylation of 2-phenylbenzofuran with 3,5-diethyl-4-methoxybenzoyl chloride as described above. The subsequent steps of demethylation and reaction with 3-diethylaminopropyl chloride to give the title compound are accomplished as previously described.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].O[N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>C1COCC1>[O:15]=[C:10]1[CH2:11][CH2:12][C:13](=[O:14])[N:9]1[O:6][C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#CCCC(=O)ON1C(=O)CCC1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
4-pentynoic acid (5.0 g, 51 mmol) and N-hydroxy succinimide (5.87 g, 51 mmol) were added to a solution of DCC (12.6 g, 61.2 mmol) in THF (125 ml) at −10° C. The mixture was then stirred for 1 h at −10° C. then left to stir at room temperature overnight. (A white precipitate was observed after 15 min). Acetic acid (0.63 ml) was then added. The resulting DCU was removed by filtration. The filtrate was then evaporated to give 10a (10 g, 100% crude yield).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([OH:3])=O.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.ClC1C=CC=CC=1Cl.Cl>C(OCC)(=O)C>[CH3:16][C:15]1([CH3:19])[N:14]2[C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[CH:4]=[C:1]2[O:3][CH2:18]1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: CC(C)(N)CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1Cl
Product: CC1(C)COc2cc3ccccc3c(=O)n21

Procedure:
A mixture of 1 g. of 2-carboxymethylbenzoic acid, 0.5 g. of 2-amino-2-methylpropanol, and 5 ml. of o-dichlorobenzene was heated to 150°-160° C. for 4 hours. After cooling, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was dissolved in 30 ml. of ethyl acetate. Then, the solution was successively wased with diluted hydrochloric acid, a diluted sodium carbonate solution, and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. By recrystallizing the residue obtained from cyclohexane, 700 mg. of 3,3-dimethyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-b]isoquinoline was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:16][C:17]1[C:22]([N:23]=[C:24]=[S:25])=[CH:21][CH:20]=[CH:19][N:18]=1.CN(C=O)C>C(Cl)Cl>[ClH:16].[Br:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH:8][C:24]2[S:25][C:17]3[C:22]([N:23]=2)=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1Sc1ccccc1
Reactant: S=C=Nc1cccnc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Brc1cnc(Nc2nc3cccnc3s2)c(Sc2ccccc2)c1
Product: Cl
Temperature: 25 °C
Yield: 60.3 %

Procedure:
mL 5-Bromo-3-(phenylthio)pyridin-2-amine (1.0 g, 3.6 mmol), 2-chloro-3-isothiocyanatopyridine (0.61 g, 3.6 mmol), DMF (2 mL) were heated to 90° C. for 8 hours. Cooled to ambient temperature and the solids were diluted with mL CH2Cl2 (2 mL) and filtered and washed with small amount of CH2Cl2 to afford the title compound (0.98 g, 61% yield). 1H NMR (d6-DMSO) δ 8.50 (d, 1H), 8.39 (dd, 1H), 7.98 (s, 1H), 7.92 (dd, 1 h), 7.38-7.25 (m, 6H). Mass spectrum (apci) m/z=414.8 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[N:7][N:8]2C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][C:3]=1[NH2:39].[C:40]([OH:43])(=O)[CH3:41]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[NH:39][C:40](=[O:43])[CH3:41]
Reactant: Nc1cc2c(/C=C/c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Reactant: CC(=O)O
Product: CC(=O)Nc1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F

Procedure:
525 mg of 6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine and 80 μl of glacial acetic acid were dehydraing-condensed in accordance with Example 127, followed by deprotection in the similar method as described in Example 16, to afford 150 mg of the title compound as bright yellow crystals.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[C:25]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[N:24]=[CH:23]1>>[N:30]1([C:28](=[O:29])[CH2:27][C:25]2[N:24]=[CH:23][N:22]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][C:11]=3[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]4=[O:21])[CH:26]=2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: O=C(Cc1c[nH]cn1)N1CCOCC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cnc(CC(=O)N4CCOCC4)c3)cc2c1=O
Yield: 39 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-(1H-imidazol-4-yl)-1-morpholin-4-yl-ethanone according to the GPB affording 18.1 mg (39%) of a yellow powder. Rt=4.37 min
Reaction SMILES: CO[CH:3]([O:17]C)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1Br.[CH2:19]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][CH3:34])[CH:26]=O)[CH2:20][CH3:21].[C:35]([C:41]([O:43][CH3:44])=[O:42])#[C:36][C:37]([O:39][CH3:40])=[O:38]>>[CH2:19]([O:22][C:23]1[CH:24]=[C:25]([C:26]2[C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[C:6]=3[O:14][CH3:15])[C:3]([OH:17])=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:35]=2[C:41]([O:43][CH3:44])=[O:42])[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][CH3:34])[CH2:20][CH3:21]
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1cc(C(OC)OC)c(Br)c(OC)c1OC
Reactant: CCCOc1ccc(C=O)cc1OCCC
Product: CCCOc1ccc(-c2c(C(=O)OC)c(C(=O)OC)c(O)c3cc(OC)c(OC)c(OC)c23)cc1OCCC

Procedure:
2-Bromo-3,4,5-trimethoxybenzaldehyde dimethylacetal, 3,4-dipropoxybenzaldehyde and dimethyl acetylenedicarboxylate are treated in the same manner as described in Example 1-(1) and (2), whereby 1-(3,4-dipropoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene is obtained as colorless needles.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:29][CH3:30])=[CH:7][C:8]=2[NH:12][C:13]2[C:14]([C:26]([OH:28])=O)=[CH:15][C:16]3[C:21]([C:22]=2[N+:23]([O-:25])=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:30][O:29][C:6]1[CH:5]=[C:4]2[O:3][C:2]([CH3:1])([CH3:31])[CH:11]=[CH:10][C:9]2=[C:8]2[C:7]=1[C:26](=[O:28])[C:14]1[CH:15]=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]3=[C:22]([N+:23]([O-:25])=[O:24])[C:13]=1[NH:12]2
Reactant: COc1cc(Nc2c(C(=O)O)cc3ccccc3c2[N+](=O)[O-])c2c(c1)OC(C)(C)C=C2
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2c(c3[nH]c4c([N+](=O)[O-])c5ccccc5cc4c(=O)c13)C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
772 mg of the compound obtained in Step 4 are dissolved in 45 ml of anhydrous dichloromethane, and 3 ml of trifluoroacetic anhydride are added. After stirring for 5 minutes at ambient temperature, the reaction mixture is evaporated. The residue is taken up in a mixture of dichloromethane and saturated NaHCO3 solution. After extraction of the aqueous phase with dichloromethane, the combined organic phases are treated in conventional manner and then distilled, allowing the expected product to be isolated.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[N:18](OCCCC)=[O:19]>C(O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3](=[N:18][OH:19])[C:2](=[O:1])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:8]
Reactant: CCCCON=O
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(=NO)C(=O)CCc1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of 22.0 g. of ethyl 3-oxo-5-phenylvalerate in 100 ml. of ethanol is added 40 ml. of 38% hydrochloric acid, and after 10 minutes 11.3 ml. of n-butyl nitrite is added thereto. The resulting mixture is allowed to stand at room temperature for 45 minutes, and then the ethanol portion is essentially removed under reduced pressure to obtain an oily residue. The residue is poured into about 500 ml. of water and extracted 3 times with 200 ml. of chloroform. The combined extracts are dried over anhydrous sodium sulfate, then evaporated to obtain the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[C:11]([CH3:20])([CH3:19])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[C:26](=[O:28])=[O:27]>C1COCC1>[CH3:19][C:11]1([CH3:20])[CH2:10][CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:17]2[CH:16]=[C:15]([C:26]([OH:28])=[O:27])[CH:14]=[CH:13][C:12]1=2
Reactant: O=C=O
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)O)cc32)cc1
Temperature: 25 °C

Procedure:
A solution of 3,4-dihydro-1-(4-methylphenyl)-4,4-dimethyl-7-bromonaphthalene (Compound D) (250.0 mg, 0.764 mmol) in 2.0 ml of THF was cooled to -78° C. and 1.0 ml of t-butyllithium (1.68 mmol, 1.7M solution in pentane) was added slowly. After stirring for 1 hour at -78° C. gaseous CO2 (generated by evaporation of Dry-Ice, and passed though a drying tube) was bubbled through the reaction for 1 hour. The solution was then allowed to warm to room temperature and the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc was followed by washing the combined organic layers with H2O and saturated aqueous NaCl, and drying over MgSO4. Removal of the solvents under reduced pressure and washing of the solid with hexanes afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.94 (1H, dd, J=1.8, 8.1 Hz), 7.76 (1H, d, J=1.8 Hz), 7.45 (1H, d, J=8.1 Hz), 7.24 (4H, m), 6.01 (1H, t, J=4.7 Hz), 2.40 (3H, s), 2.36 (2H, d, J=4.7 Hz), 1.35 (6H, s).
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([CH3:18])[C:7]=1OS(C1C=CC=CC=1)(=O)=O)#[N:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)#[CH:20]>CCCCCCC.CCOC(C)=O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[C:20][C:7]2[C:6]([CH3:18])=[CH:5][S:4][C:3]=2[C:1]#[N:2])=[CH:22][CH:23]=1
Reactant: Cc1csc(C#N)c1OS(=O)(=O)c1ccccc1
Reactant: C#Cc1ccc(OC)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2c(C)csc2C#N)cc1

Procedure:
This product was prepared from benzenesulfonic acid 2-cyano-4-methyl-thiophen-3-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 9:1; yield (110 mg, 87%); 1H NMR δ (CDCl3): 7.51 (d, J=8.52 Hz, 2H), 6.88 (d, J=8.60 Hz, 2H), 6.81 (s, 1H), 3.84 (s, 3H), 2.51 (s, 3H); LCMS m/z: 253.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5]C(S(O)(=O)=O)=C[CH:2]=1.[CH3:12][C:13]([CH3:15])=[O:14].[OH2:16]>C(OCC)(=O)C.CCCCCC>[CH:1]12[CH2:11][CH:15]([CH:5]=[CH:6]1)[C:13](=[O:14])[CH2:12][C:2]2=[O:16]
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1CC(=O)C2C=CC1C2
Yield: 75 %

Procedure:
640 mg (3.55 mmol) of 4,4-(1′,2′-ethylenedioxy)-bicyclo[3.2.1]oct-6-en-2-one are heated for 16 hours at a temperature of 70° C. in the presence of 200 mg of p-toluenesulfonic acid in a 2:1 mixture of acetone and water. After hydrolysis is complete (TLC monitoring: ethyl acetate/hexane 1:1), the acetone is distilled off under reduced pressure and the aqueous phase is adjusted to pH 9 with saturated sodium hydrogen carbonate solution. After extraction of the aqueous phase three times with ethyl acetate, it is acidified to pH 5 with dilute hydrochloric acid. Extraction is carried out three times with fresh ethyl acetate, followed by drying over sodium sulfate and concentration by evaporation in vacuo. 364 mg (75%) of pure bicyclo[3.2.1]oct-6-ene-2,4-dione are obtained in the form of a yellow oil for further reaction to form compounds of formula I.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=1)[C:7]2=[O:12].[CH:24]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[CH:24]1([CH2:31][C:32]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]4[O:18][CH2:19][CH2:20][O:21][C:16]=4[CH:15]=2)[C:7]3=[O:12])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12
Reactant: O=C(O)CC1CCCCCC1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CCCCCC1)Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12

Procedure:
5-Amino-2-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-2H-isoquinolin-1-one (50 mg, 0.0002 mol), 2-cycloheptylacetic acid (63 mg, 0.00041 mol), fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (110 mg, 0.00041 mol) and N,N-diisopropylethylamine (100 mg, 0.0008 mol) were stirred in methylene chloride (3 mL, 0.05 mol) at room temperature for 72 hours. The mixture was purified via flash chromatography (12 g of silica gel, 50% EtOAc/Hexane) to give a light yellow solid.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2(C)C)=C(N)C=1.Cl.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:29](O)=O.FC1C=[C:47](C=CC=1OCCN1CCCCC1)[CH2:48][NH:49][C:50]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=1[CH:58]1[CH2:67][CH2:66][C:65]2[C:60](=[CH:61][CH:62]=[C:63]([O:68][CH3:69])[CH:64]=2)[C:59]1([CH3:71])[CH3:70]>>[CH2:48]([N:49]([CH2:29][C:28]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:26]([F:25])[CH:27]=1)[C:50]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=1[CH:58]1[CH2:67][CH2:66][C:65]2[C:60](=[CH:61][CH:62]=[C:63]([O:68][CH3:69])[CH:64]=2)[C:59]1([CH3:70])[CH3:71])[CH3:47]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2(C)C
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2(C)C)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1(C)C

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (306 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (253 mg). This compound (251 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (228 mg).
Reaction SMILES: [CH2:1]([N:3]([C:21]1[CH:26]=[C:25]([O:27]C)[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:39]C)[CH:35]=2)[CH2:30]1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)[CH3:2].B(Br)(Br)Br.CO.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:20])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:10]=1)[C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:38][CH2:37][C:36]2[CH:35]=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=2[CH2:30]1)[CH3:2]
Reactant: CCN(Cc1ccc(N(C)CCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN(Cc1ccc(N(C)CCN2CCCCC2)cc1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{4-[methyl(2-piperidin-1-ylethyl)amino]benzyl}amine (108 mg) in dichloromethane (5 ml) was added boron tribromide (1.0 M solution in dichloromethane) (1.0 ml) on an ice bath. The solution was stirred for 30 minutes while warming to room temperature, then methanol (2 ml) was added thereto on an ice bath. A saturated aqueous solution of sodium bicarbonate was added thereto, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The resulting residue was purified by NH silica gel column chromatography (chloroform-methanol system) to provide the title compound (58 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C(OCC)(=O)C.CO>[CH3:8][C:7]1[S:6][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:4][C:3]=1[CH2:2][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: Cc1sc(N2CCCCC2)nc1CCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1nc(N2CCCCC2)sc1C)OCC
Temperature: 160 °C
Reaction time: 20 h
Yield: 46.7 %

Procedure:
A mixture of 1-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperidine (2.7 g) and triethyl phosphite (1.5 g) was stirred at 160° C. for 20 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:1, v/v), then ethyl acetate-methanol (10:1, v/v) to give diethyl {[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]methyl}phosphonate as a brown oil (1.4 g, yield 35%). NMR (CDCl3) δ: 1.29 (6H, t, J=7.1 Hz), 1.53-1.74 (6H, m), 2.24 (3H, d, J=4.1 Hz), 3.10 (2H, d, J=20.9 Hz), 3.28-3.46 (4H, m), 4.00-4.21 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1.[CH2:23]1C[O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH:24]=[CH2:23])=[CH:11][CH:10]=2)#[N:13]
Reactant: N#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C#N)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 729 mg (2.56 mmol) 6-amino-4-[(3-cyanophenyl)amino]-3-quinolinecarbonitrile in 2 ml hot DMF, added 12 ml THF and cooled to 0° C. under N2. Added 392 μl (2.81 mmol) triethylamine and 234 μl (2.81 mmol) acryloyl chloride. Removed ice bath after 15 minutes and stripped solvent at 2 hours. Washed residue with water and collected solids. Recrystallized from ethyl acetate and dried in vacuo, giving 318 mg of yellow solid: mass spectrum (electrospray m/e): M+H=340.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([CH:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]([CH:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:24])=[CH:26][CH:27]=2)[CH2:16][CH2:17][CH3:18])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])=[CH:9][CH:10]=1
Reactant: CCCC(c1ccc(C(=O)O)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCC(c1ccc(C(=O)NCCC(=O)OCC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a solution of 4-{1-[2-tert-butoxy-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoic acid (17.8 g, 44 mmol) in DCM (175 mL) at room temperature was added β-alanine ethyl ester hydrochloride (6.6 g, 44 mmol), HOBt (7.85 g, 52.8 mmol), EDC (9.8 g, 53 mmol) and Et3N (30 mL, 220 mmol). After being stirred for 16 hours, the mixture was diluted with DCM then washed with water then saturated NaCl (aq). The organic layer was dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes. The two diastereomeric title compounds were separated by silica gel chromatography eluting with 40% EtOAc/hexanes. The slower-eluting diastereomer is readily resolved to provide enantiopure material by supercritical fluid chromatography on a ChiralPak IA column (3 cm×25 cm) eluting with 50 mL/min of 10% (2:1:3 MeOH:CH3CN:CHCl3) and 90% CO2 at 35° C. and 100 bar.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@H:36]3[CH2:41][CH2:40][C@@H:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH2:38][CH2:37]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][CH:20]=3)[C:11]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[CH3:48][N:45]1[CH2:44][CH2:43][N:42]([C@@H:39]2[CH2:40][CH2:41][C@H:36]([N:16]3[C:12]4=[N:13][CH:14]=[N:15][C:10]([NH2:9])=[C:11]4[C:18]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][CH2:26][CH2:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:23][CH:24]=4)=[N:17]3)[CH2:37][CH2:38]2)[CH2:47][CH2:46]1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC(=O)CCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NCCCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 34.1 %

Procedure:
Cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-3-phenylpropanamide diacetate (0.090 g, 0.000167 mol) was suspended in anhydrous tetrahydrofuran (5 mL), the suspension was cooled to 0° C. and lithium aluminum hydride (0.01 g, 0.00025 mol) was added at once. The resulting mixture was warmed up to ambient temperature and stirred under an atmosphere of nitrogen for 18 hours. It was quenched by dropwise addition of water, the solvents were removed under reduced pressure and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(3-phenylpropyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.037 g, 0.000057 mol) as a white solid.