Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 97.1 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (10 mg, 0.0315 mmol) obtained in Example 1, (3), and benzenesulfonyl chloride (8.3 mg, 0.0473 mmol) were treated by heating in pyridine (1.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (14 mg, yield 97%) as slightly brown amorphous.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH:9]([OH:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]1CCCN(C)C1(C)C.ICC>CO>[CH2:14]([N:11]1[CH2:12][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C@H:9]([OH:13])[CH2:10]1)[CH3:15]
Reactant: OC1CNCC(c2ccccc2)C1
Reactant: CC1CCCN(C)C1(C)C
Solvent: CCI
Solvent: CO
Product: CCN1C[C@@H](O)C[C@@H](c2ccccc2)C1

Procedure:
5-Phenyl-3-piperidinol (5.2 g), tetramethylpiperidine (8.3 ml) and iodoethane (1.97 ml) was stirred at room temperature in methanol (100 ml) for 48 hours. The methanol was removed under reduced pressure and excess 2 M NaOH added. The oil was extracted with ether and washed with brine. After drying (MgSO4) the ether was removed and the product crystallised affording, after recrystallisation from cyclohexane, 3.2 g of pure title compound which could be converted to the hydrochloride salt m.p. 182°-4° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:10](O)(=[O:14])[C:11]([CH3:13])=[CH2:12]>ClCCl>[CH3:12][CH:11]1[CH2:13][C:4]2[C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[S:1][C:5]=2[C:10]1=[O:14]
Reactant: C=C(C)C(=O)O
Reactant: c1ccc2sccc2c1
Solvent: ClCCl
Product: CC1Cc2c(sc3ccccc23)C1=O
Temperature: 67.5 °C
Yield: 78.9 %

Procedure:
A solution of 66.9 g of benzo[b]thiophene (0.5 mol) and 46.3 g of methacrylic acid (0.537 mol) in 60 ml of dichloromethane was added dropwise starting at 70° C. within 20 minutes to 1000 g of super-PPA. The temperature was maintained at 65-70° C. during the addition. Methylene chloride was distilled off. After 2 h of reaction time, the reaction mixture was poured onto crushed ice and stirred until the polyphosphoric acid had completely dissolved. The aqueous phase was extracted with a dichloromethane/hexane solvent mixture (30 parts by volume/70 parts by volume). The combined organic phases were washed with a saturated aqueous solution of sodium hydrogen-carbonate and with water and dried over magnesium sulfate. After removing the solvents under reduced pressure, 79.8 g of a dark orange oil (71%) were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].[Li+].CC([N-]C(C)C)C.[CH:22](OC)=[O:23]>O1CCCC1>[CH2:12]([O:11][P:6]([C:2]1[S:1][C:5]([CH:22]=[O:23])=[CH:4][CH:3]=1)([O:7][CH2:8][CH3:9])=[O:10])[CH3:13]
Reactant: COC=O
Reactant: CCOP(=O)(OCC)c1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(C=O)s1
Reaction time: 1 h

Procedure:
A solution 1.0 mmol of diethyl 2-thiophenephosphonate in tetrahydrofuran was treated with 1.12 mmol LDA at −78° C. for 20 min. 1.5 mmol methyl formate was added and the reaction was stirred for 1 hr. Extraction and chromotagraphy gave 5-diethylphosphono-2-thiophenecarboxaldehyde as a clear yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[C@H:46]([CH3:47])[CH2:45][CH2:44][CH2:43][C@@H:42]5[CH3:48])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:14]([C:49]2[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=2)[O:52][CH2:53][CH2:54]OS(C)(=O)=O)[N:13]=1)([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[C@H:42]([CH3:48])[CH2:43][CH2:44][CH2:45][C@@H:46]5[CH3:47])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:14]([C:49]2[CH:62]=[CH:61][CH:60]=[C:51]([O:52][CH2:53][CH2:54][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:50]=2)[N:13]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: CN1CCNCC1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCN(C)CC5)c4)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
1-Methylpiperazine (48 μL, 0.43 mmol) was added to a solution of Intermediate 96f (111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to 60° C. in a sealed vial overnight. 1-Methylpiperazine (48 μL, 0.43 mmol) was added and the reaction continued for a further 24 h. The mixture was cooled, evaporated in vacuo and the residue was purified by FCC, using 0-15% MeOH in DCM, then triturated with Et2O to give the title compound (42 mg, 38%) as an off-white solid. LCMS (Method 5): Rt 3.76 min, m/z 775.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.60 (3H, d, J=6.0 Hz), 0.63 (3H, d, J=6.0 Hz), 1.28 (9H, s), 1.36-1.62 (3H, m), 1.65-1.75 (2H, m), 1.76-1.99 (3H, m), 2.03-2.12 (2H, m), 2.14-2.26 (3H, m), 2.34-2.61 (5H, m, obscured by solvent), 2.63-2.74 (3H, m), 3.11-3.24 (2H, m), 3.28-3.38 (2H, m), 4.1 (2H, t, J=5.8 Hz), 4.78-4.87 (1H, m), 5.50-5.56 (1H, m), 6.33 (1H, s), 6.93-7.00 (1H, m), 7.05-7.13 (3H, m), 7.20 (1H, dd, J=9.9, 2.4 Hz), 7.23-7.31 (2H, m), 7.34 (2H, t, J=8.0 Hz), 7.40 (1H, t, J=8.0 Hz), 7.67 (1H, d, J=9.9 Hz), 7.87-7.91 (1H, m), 8.11 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].I[CH2:24][CH:25]([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[F:20]
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(F)c3nn2CC(C)C)c(OC)c1
Yield: 12.7 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and 1-iodo-2-methylpropane (0.23 mL, 2.00 mmol) to give the title compound (0.046 g) as a white solid.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]3[NH:25][N:24]=[N:23][N:14]=3)=[CH:11][CH:10]=2)=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(COc2ccc(-c3ccccc3)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2ccc(OCc3ccc(-c4nnn[nH]4)cc3)cc2)cc1
Temperature: 125 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
The above benzonitrile (3.00 g, 10.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), and sodium azide (1.03 g, 15.8 mmol) and ammonium chloride (0.84 g, 15.8 mmol) were added and the mixture was stirred 16 hours at 125° C. The mixture was cooled to room temperature and water (50 mL) was added. The suspension was stirred overnight, filtered, washed with water and dried in vacuo at 50° C. for 3 days to give crude 3.07 g (89%) of the title compound. From the mother liquor crystals were collected and washed with water, dried by suction to give 0.18 g (5%) of the title compound as a solid.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH:14]1([C:17]2[CH:22]=[N+:21]([O-])[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)[CH2:16][CH2:15]1.O>CN(C)C=O>[CH:14]1([C:17]2[CH:18]=[CH:19][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:21][C:22]=2[OH:4])[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(C2CC2)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C2CC2)c(O)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Trifluoroacetic anhydride (23 mL) was added to a solution of ethyl 5-cyclopropylpyridine-2-carboxylate 1-oxide (15.4 g) in N,N-dimethylformamide (45 mL), and the mixture was stirred at 50° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give ethyl 5-cyclopropyl-6-hydroxypyridine-2-carboxylate (12.4 g, 78%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: N#Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C#N)c3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-cyano-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.95 min; [M+H]+=402.40.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C@@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][N:10]2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:17][CH2:16][CH2:15][C@H:14]1[O:13][CH2:12][CH2:11][N:10]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:42])=[O:41]
Reactant: COc1cc(C(=O)N2CCO[C@H](CCO)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCO[C@H](CCOS(C)(=O)=O)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
30.0 g (63.8 mmole) of 2-[(2 R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol [prepared as described in step (d) above] were dissolved in 500 ml of methylene chloride. 11.5 ml (83.0 mmole) of triethylamine and 5.93 ml (76.6 mmole) of methanesulfonyl chloride were then added, in that order, to the mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was then diluted with methylene chloride and washed with 1 N aqueous hydrochloric acid, and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:4 to 1:9 by volume as the eluent, to give 34.8 g of the title compound.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][CH:5]1[O:10][C:9]([CH2:18][NH2:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7][O:6]1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[CH3:4][CH:5]1[O:10][C:9]([CH2:18][NH:19][C:22](=[O:23])[CH2:21][Cl:20])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7][O:6]1
Reactant: O=C(Cl)CCl
Reactant: CC1OCCC(CN)(c2ccccc2Cl)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1OCCC(CNC(=O)CCl)(c2ccccc2Cl)O1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Fifteen milliliters (ml) of water, 25 ml of dichloromethane, 4 ml (0.075 mole) of 50% sodium hydroxide and 7.2 grams (g) (0.03 mole) of 2-methyl-4-(aminomethyl)-4-(2-chlorophenyl)-1,3-dioxane were added to a reaction flask and cooled to 5° C. with an ice bath. Four and a half g of chloroacetyl chloride in 10 ml of dichloromethane were added at a rate slow enough to keep the temperature under 10° C. The reaction mixture was stirred for 1/2 hour and allowed to come to room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([CH:19]([OH:23])[CH2:20][CH2:21][CH3:22])=[C:11]2[O:12][C:13]=1[CH3:14]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([C:19](=[O:23])[CH2:20][CH2:21][CH3:22])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: CCCC(O)c1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCC(=O)c1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Temperature: 60 °C

Procedure:
To a solution 1-[3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazol-7-yl]-butan-1-ol (0.700 g, 1.982 mmol) in CHCl3 (15 ml) is added manganese dioxide (3.45 g, 39.6 mmol); the reaction mixture is heated to 60° C. for 18 hours and filtered through Celite® (filter material) 521, washing through with chloroform (75 ml). The solvent is removed in vacuo to yield the title compound as a white solid; MS: m/z 351.04 [M+H]+
Reaction SMILES: [NH2:1][CH:2]([C:11](O)=[O:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:1][CH:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][OH:12]
Reactant: NC(CCc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NC(CO)CCc1ccccc1
Yield: 78.1 %

Procedure:
Following the general procedure of example 40b, DL-homophenylalanine (5.0 g, 27.9 mmol) was reduced with LiAlH4 to give (RS)-2-amino-4-phenyl-butan-1-ol (3.6 g, 78%, MS: m/e=166 (M+H+)) as a light yellow solid.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1>C(O)C>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:13][O:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: CO[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CO[C@H]1CCNC1

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.207 g, 1.09 mmol), crude tert-butyl (3S)-3-methoxypyrrolidine-1-carboxylate (See Intermediate 60) (0.50 g, 1.09 mmol) and ethanol (2 mL) to give the title compound as a dark orange coloured oil (0.42 g): MS (m/e): 102 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:19]([OH:24])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:17][CH:18]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:32]([O:24][CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[CH:14]=1)[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCC(O)c1cccc(COc2cccc3cccnc23)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(OC(=O)c1ccccc1)c1cccc(COc2cccc3cccnc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g (10 mmol) of 1-[3-(quinolin-8-yloxymethyl)phenyl]-pentanol are dissolved in 50 ml of dichloromethane. After the addition of 2.8 ml of triethylamine and 1.16 ml of benzoyl chloride, the mixture is stirred for 2 hours at 25° C. and then heated under reflux for 5 hours. The reaction mixture is washed three times with water, dried over sodium sulphate and evaporated down. The residue is chromatographed over silica gel 60 (mobile phase: 100:2 dichloromethane/methanol). An oil is obtained.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.COCCOC.[Cl:23][C:24]1[S:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[S:28][C:27]([C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)Nc1nc2ccc(-c3ccc(Cl)s3)cc2s1
Temperature: 25 °C
Yield: 16 %

Procedure:
A 40 ml pressure tube was charged with about 100 mg N-(6-bromo-1,3-benzothiazol-2-yl)-N′-ethylurea, and about 2 ml ethylene glycol dimethyl ether. The slurry was stirred via magnetic stirbar followed by evacuation then release to nitrogen atmosphere (3 times). Next about 6 mol percent Pd(PPh3)4 was added, followed by about 1.1 eq of 5-chlorothiophene-2-boronic acid. Following addition of about 3 equivalents sodium carbonate in about 0.5 ml water, the suspension was evacuated and released to nitrogen atmosphere 3 times. The pressure tube was then sealed tightly and heated to about 85–90° C. for about 12–20 hours. The reaction was cooled to room temperature then purified by preparative HPLC to yield 16% of N-[6-(5-chloro-2-thienyl)-1,3-benzothiazol-2-yl]-N′-ethylurea. 1H NMR 1.1 (t, 3H), 3.2 (m, 2H), 6.75 (m, 1H), 7.18 (d, 1H), 7.38 (m, 1H), 7.6 (m, 2H), 8.19 (d, 1H), 10.75 (br s, 1H); LC/MS 3.86 min, 338 (M+1), 336 (M−1).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[O:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:40]#[C:39][C:37]([C:33]4[O:32][CH:36]=[CH:35][N:34]=4)([OH:41])[CH3:38])[CH:10]=3)[C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2nc(C(=O)N3CCOCC3)c3ccc(I)cc32)n1
Reactant: C#CC(C)(O)c1ncco1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2c(C(=O)N3CCOCC3)nn(-c3ccnc(N)n3)c2c1)c1ncco1
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 40.9 %

Procedure:
To a pressure tube was added 4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine (150 mg, 0.33 mmol) followed by piperidine (2.0 mL), tetrakis(triphenylphosphine)palladium(0) (38.5 mg, 0.03 mmol), copper(I) iodide (6.35 mg, 0.03 mmol) and 2-(1,3-oxazol-2-yl)but-3-yn-2-ol (68.53 mg, 0.5 mmol). The reaction was capped and stirred at 35° C. for 2.5 hr. The reaction mixture was concentrated in vacuo. DCM (5 mL×2) added and the mixture was concentrated in vacuo. Purification by column chromatography (1% to 10% MeOH in DCM), followed by trituration with a mixture of MeCN/diethyl ether mixture (3/1) gave the title compound as an off-white solid (62 mg): 1H NMR (500 MHz, DMSO) delta 3.67 (2H, d, J=4.26 Hz), 3.75 (4H, d, J=5.67 Hz), 3.94 (2H, d, J=3.94 Hz), 4.06 (3H, s), 6.72-6.89 (1H, m), 6.93-7.33 (4H, m), 7.45 (1H, d, J=7.57 Hz), 8.04 (1H, d, J=7.88 Hz), 8.11-8.23 (1H, m), 8.97 (1H, s); LC-MS: m/z=+460.15 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]([CH3:16])([C:10](OC)([O:12]C)[CH3:11])[CH3:9])=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([CH3:9])([CH3:16])[C:10](=[O:12])[CH3:11])=[CH:17][CH:18]=1
Reactant: COC(C)(OC)C(C)(C)OCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(C)(C)OCc1ccc(Cl)cc1
Yield: 86.5 %

Procedure:
134 g (0.5 mol) of 2-(4-chlorobenzyloxy)-3,3-di- methoxy-2-methyl-butane are stirred in 1 liter of toluene with 100 g of ion exchanger (Levatit SP C118) and 200 ml of water at 60° C. for 8 hours. After the ion exchanger has been filtered off with suction, the organic phase is separated off, washed with water and concentrated in vacuo. The residue is distilled. 98 g (87% of theory) of 3-(4-chlorobenzyloxy)-3-methyl-2-butanone of boiling point 95° C. to 100° C./0.03 mm Hg are obtained.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1/[CH:30]=[CH:31]\[C:32]#[N:33]>>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]2[CH:10]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:31]=[C:32]([NH2:33])[N:12]2[N:13]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccc(F)cc2F)n1)c1ccccc1
Reactant: N#C/C=C\c1ccccn1
Product: Nc1cc(-c2ccccn2)cc2nc(-c3ccc(F)cc3F)nn12

Procedure:
The title compound, MS m/e (%): 324(M+H+,100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole and (E)/(Z)-3-pyridin-2-yl-acrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:9]([NH:12][CH2:13][C:14]2[C:15]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:16]3[CH:24]=[N:23][N:22]([CH2:25][CH3:26])[C:17]3=[N:18][C:19]=2[CH2:20][CH3:21])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:34]([NH:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([F:65])=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]3[CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[C@@H:53]([CH3:64])[CH2:52]3)[CH:45]=2)[CH:43]=1)=[O:35]>O1CCOCC1.CO.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:9]([NH:12][CH2:13][C:14]2[C:15]([NH:27][CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[C:16]3[CH:24]=[N:23][N:22]([CH2:25][CH3:26])[C:17]3=[N:18][C:19]=2[CH2:20][CH3:21])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]3[CH2:56][CH2:55][NH:54][C@@H:53]([CH3:64])[CH2:52]3)[CH:45]=2)[C:41]([F:65])=[CH:40][CH:39]=1)=[O:35]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c(Cl)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c(Cl)cc1F
Temperature: 60 °C
Yield: 75.4 %

Procedure:
345(c) The 1,1-dimethylethyl (2S)-4-[(5′-{[({2-chloro-5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-4-fluorophenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate was dissolved in 2 mL of dioxane:MeOH (3:1). Three drops of HCl (concentrated) were added to the resultant solution and heated at 60° C. for 1 h. The solution was applied to the amine column, rinsed with 10 mL of dioxane:MeOH (3:1) to afford 63.0 mg (75.4%) the title compound. LC-MS m/z 837 (M+H)+, 1.29 min (ret time).