Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH:14]=[C:15]([S:17]([F:22])([F:21])([F:20])([F:19])[F:18])[CH:16]=2)=[O:10])=[CH:4][C:3]=1[N:36]1[C:43]2[N:39]([N:40]=[C:41]([C:44]3[CH:45]=[N:46][NH:47][CH:48]=3)[CH:42]=2)[CH:38]=[CH:37]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[C:13]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:14]=[C:15]([S:17]([F:20])([F:22])([F:21])([F:18])[F:19])[CH:16]=2)=[CH:4][C:3]=1[N:36]1[C:43]2[N:39]([N:40]=[C:41]([C:44]3[CH:45]=[N:46][NH:47][CH:48]=3)[CH:42]=2)[CH:38]=[CH:37]1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(N3CCNCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
210 mg (0.19 mmol, purity 61%) of the compound from Example 47A were stirred in 4.4 ml of a 25% strength solution of trifluoroacetic acid in methylene chloride at RT for 30 min. The mixture was then concentrated under reduced pressure. The residue was dissolved in a little methanol and added to semiconcentrated aqueous sodium bicarbonate solution. After 15 min of stirring at RT, 15 ml of ethyl acetate were added. The precipitate formed was filtered off, and the organic phase of the filtrate was separated off, washed with water, dried over sodium sulphate, filtered and concentrated. Drying of the residue under reduced pressure gave 41 mg (37% of theory) of the title compound.
Reaction SMILES: [NH4+:1].C([O-])(=O)C.ClC(Cl)(Cl)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:13][C:12]=1[C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=[O:9].O>CS(C)=O>[Cl:33][C:29]1[CH:28]=[C:27]([C:26]2[C:12]3[C:11](=[CH:16][CH:15]=[C:14]([C:17](=[O:25])[C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:13]=3)[NH:10][C:8](=[O:9])[N:1]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: [NH4+]
Reactant: O=C(c1ccc(F)cc1)c1ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c2cccc(Cl)c2)c1
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc2[nH]c(=O)nc(-c3cccc(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
Acetic acid, ammonium salt (0.135 mol) was added at room temperature to a mixture of intermediate 4 (0.0675 mol) in DMSO (300 ml). The mixture was stirred at 60° C. for 4 hours, then brought to room temperature and poured out into water. The precipitate was filtered, washed with water, taken up in warm CH3CN, filtered, washed again with CH3CN, then with diethyl ether and dried under a vacuo, yielding 18.5 g (72%) of intermediate 5. The mother layer was purified by column chromatography over silica gel (15-40 μm) (eluent DCM/MeOH:NH4OH 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1.8 g (7%) of 4-(3-chlorophenyl)-6-(4-fluorobenzoyl)-2(1H)-quinazolinone (intermediate 5), mp. 226° C.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([O:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)[CH3:7].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]C(Cl)=O)=[CH:18][CH:17]=1.Cl>O1CCCC1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:11](=[O:13])[CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:14])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cc1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1 l (2 mol) of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran is added dropwise to a solution of 125 g (0.95 mol) of malonic acid monoethyl ester in 1 l of tetrahydrofuran at 0° C. and the mixture is stirred at 20° C. for 1 hour. 146 g (0.63 mol) of 4-bromophenylacetyl chloride are then added dropwise at 20° C., and the reaction mixture is stirred at this temperature for 2 hours and brought to pH=3 with 1N hydrochloric acid. It is stirred overnight, the phases are separated, the aqueous phase is washed with diethyl ether, the combined organic phases are washed with water and aqueous sodium bicarbonate solution, the solvent is distilled off, the residue is dissolved in methylene chloride, the solution is dried with sodium sulphate and filtered over silica gel using methylene chloride and the solvent is removed on a rotary evaporator.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[CH2:37][N:38]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.NN>C(O)C.[OH-].[Na+]>[NH2:38][CH2:37][C@@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:52])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=2)([CH3:50])[CH3:49])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CN2C(=O)c3ccccc3C2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CN)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 103.6 %

Procedure:
A solution of 65 mg (0.089 mmol) (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 7.0 mg (0.14 mmol) hydrazine hydrate in 1 ml ethanol was stirred at room temperature over night. The reaction mixture was diluted with a 1 M aqueous sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated to give 55 mg of crude (S)-N-[6-(2-aminomethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide. This material was dissolved in 2 ml dichloromethane, followed by the addition of 0.013 ml (0.092 mmol) triethylamine and 0.009 ml (0.09 mmol) acetic anhydride at 0° C. The cooling bath was removed 5 min. after completed addition, and stirring was continued at room temperature over night. The reaction mixture was diluted with a 0.5 M aqueous sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated. Flash chromatography gave 44 mg (77%) of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30].C(N(CC)CC)C>C1COCC1.O>[OH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=[C:2]([N:35]4[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]4)[C:7]=3[N:8]=[C:9]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCN(c2cc(C(=O)O)nc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc23)CC1

Procedure:
A mixture of Example 9 (130 mg; 0.34 mmol), 1-(methylsulfonyl)piperazine (276 mg; 1.68 mmol) and N,N-diethylethanamine (170 mg; 1.68 mmol) in THF (3 mL) and water (3 mL) was stirred at 115° C. for 48 hours then concentrated in vacuo. The residue was taken up in EA, washed with aq. citric acid, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA/EtOH/AcOH, 90/10/1) afforded the title compound as an orange solid.
Reaction SMILES: [C:1]1(=[O:11])[CH:9]2[CH:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[C:3](=O)[O:2]1.[BH4-].[Na+]>CC(O)C>[C:1]1(=[O:11])[CH:9]2[CH:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3][O:2]1
Reactant: O=C1OC(=O)C2CC=CCC12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=C1OCC2CC=CCC12

Procedure:
4,7,3a,7a-Tetrahydroisobenzofuran-1,3-dione is added to a solution sodium borohydride in 2-propanol at room temperature and reacted to obtain 4,7,3a,7a-tetrahydroisobenzofuran-1(3H)-one.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:33])([F:32])[C:10]1[N:14]2[CH:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>ClCCl>[N:19]1([C:16]2[CH:17]=[CH:18][C:13]3[N:14]([C:10]([C:9]([F:8])([F:33])[F:32])=[N:11][N:12]=3)[CH:15]=2)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)(F)F)n3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
Trifluoroacetic acid (5 mL, 64.90 mmol) was added to a mixture of tert-butyl 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)piperazine-1-carboxylate (0.86 g, 2.32 mmol) and dichloromethane (20 mL). The resulting solution was stirred at 20° C. for 90 minutes and then evaporated to leave an involatile residue. The residue was purified by ion-exchange chromatography on an SCX column using aqueous ammonia (7M) in methanol as eluant to give 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (0.540 g, 86%) as a yellow solid that was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:10](O)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(C(O)CCc2ccccc2)n2cncn2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(C(=CCCc2ccccc2)n2cncn2)cc1

Procedure:
1-[1-(4-cyanophenyl)-2-hydroxy4-phenylbutyl]-1,2,4-triazole (0.42 g, 0.00132 mol) is dissolved into acetonitrile. Phosphorous pentachloride (0.27 g, 0.0013 mol) is added into the solution and the mixture is refluxed for 2 hours. Acetonitrile is evaporated, the residue is dissolved with 2 M aqueous sodium hydroxide and extracted with methylene chloride. Methylene chloride is dried and the product is crystallized from ethyl acetate as hydrogen chloride salt (isomer a).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15](O)[C:14]([C:23]3C=CO[CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C(C(OC)=O)=C(OS(C(F)(F)F)(=O)=O)C(CC)=CC=2)(=O)=O)C=CC=CC=1.[CH3:58][N:59]1[CH:63]=[CH:62][C:61](B2OC(C)(C)C(C)(C)O2)=[N:60]1>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:61]3[CH:62]=[CH:63][N:59]([CH3:58])[N:60]=3)[C:14]([CH2:23][CH3:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OS(=O)(=O)C(F)(F)F
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1-c1ccn(C)n1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-(trifluoromethanesulphonyloxy)benzoate (Intermediate 127) and 1-methyl-1H-pyrazole-3-boronic acid pinacol ester.
Reaction SMILES: [C:1]([OH:9])([OH:8])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Si:14](C1C=CC=CC=1)(C1C=CC=CC=1)Cl)(C)(C)C.N1C=CN=C1>CN(C)C=O>[SiH3:14][O:8][C:1]([OH:9])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCCC=C(O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCC=C(O)O[SiH3]

Procedure:
A solution of 6 g of the diol 5, 6.5 ml of t-butyldiphenylchlorosilane and 3.4 g of imidazole in 120 ml of dimethylformamide (DMF) was stirred at 0° C. for 2 hours. The mixture was then concentrated under vacuum and the residue was dissolved in 300 ml of 5 hexanes: 1 EtOAc. The solution was washed with 150 ml of water and then 150 ml of saturated aqueous sodium chloride solution (brine). The organic phase was dried over sodium sulfate and concentrated under vacuum to provide the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:15]=1)[O:12][C:11]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[CH:10][C:9]2=[O:34])=[O:5].C(Cl)Cl>O1CCOCC1>[O:31]1[CH2:30][CH2:29][N:28]([C:11]2[O:12][C:13]3[C:8]([C:9](=[O:34])[CH:10]=2)=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:15][C:14]=3[CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[CH2:33][CH2:32]1
Reactant: COC(=O)c1cc(C2CCCN2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Yield: 83.1 %

Procedure:
Hydrogen chloride (4M in dioxane) (2.4 mL, 9.6 mmol) was added to a stirred solution of tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (440 mg, 0.96 mmol) dissolved in dioxane (3 mL) and DCM (3 mL) at room temperature and the reaction mixture stirred for 4 h. The solvents were evaporated and the residue azeotroped twice with MeCN and dried under vacuum at 50° C. The remaining solid was then extracted with DCM. The DCM was dried over MgSO4 and concentrated to afford methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (286 mg, 83%) as a pale beige solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:16]=[C:15]3[N:10]([C:11](O)=[N:12][C:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)=[CH:14]3)[N:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:35])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:35][C:11]1[N:10]2[N:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=[C:15]2[CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(C(F)(F)F)cc2)cc2nc(CN3CCOCC3)nn12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: FC(F)(F)c1ccc(-c2cc3nc(CN4CCOCC4)nn3c(Cl)n2)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
850 mg (2.2 mmol) of 2-(morpholin-4-ylmethyl)-7-[4-(trifluoromethyl)phenyl][1,2,4]triazolo-[1,5-c]pyrimidin-5-ol (Example 135A) are introduced into phosphoryl chloride (20 ml), 1.98 g (8.7 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 2 h. The reaction mixture is slowly poured, while stirring vigorously, into ice-water, and solid sodium bicarbonate is added until a pH of 8 is reached. The reaction mixture is extracted with ethyl acetate (150 ml), and the organic phase is separated off, dried (magnesium sulphate) and concentrated. The residue is chromatographed on silica gel (mobile phase dichloromethane/ethanol 100:1 to 20:1). 650 mg (75% of theory) of the product are obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:33])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:33][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]1
Reactant: CC1CCN(CCc2ccc(N)cc2Cl)CC1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Product: CC1CCN(CCc2ccc(NC(=O)C#Cc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethyl]phenylamine. Yield: 0.21 g (45.3% of theory); C24H23Cl2F3N2O (M=483.36); calc.: molecular ion peak (M+H)+: 483/485/487; found: molecular ion peak (M+H)+: 483/485/487; Rf value: 0.65 (Alox, petroleum ether/ethyl acetate (1:1)).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[I:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3ccc(I)cc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Ic1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Yield: 95 %

Procedure:
The title compound (1.3 g, 95%) was prepared from the compound from step 1 (1.35 g, 3.8 mmol) and 4N HCl in dioxane by the procedure described in step 2 of Example 4: MS (ESI) m/z 381 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 3.22 (br, 4H), 3.32 (t, J=5.6 Hz, 4H), 6.74 (d, J=8.8 Hz, 2H), 6.98-7.03 (m, 4H), 7.65 (d, J=8.8 Hz, 2H), 9.05 (br, 1H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:17])([CH3:16])[NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-])=O.[H][H].C1(C)C=CC(S(O)(=O)=O)=CC=1>[Pd].CO>[F:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:13][C:3](=[O:2])[C:4]([CH3:17])([CH3:16])[NH:5]2
Reactant: [H][H]
Reactant: COC(=O)C(C)(C)Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC1(C)Nc2cc(F)ccc2NC1=O

Procedure:
A mixture of N-(5-fluoro-2-nitrophenyl)-2-methylalanine methyl ester (XI, EXAMPLE 7, 11.2 g), palladium on carbon (10%, 0.63 g), and methanol (350 ml) is shaken under 44 psi of hydrogen pressure for 1.5 hr. Additional palladium on carbon (10%, 0.23 g) is added and the mixture is shaken at 36 psi for another 45 min. p-Toluenesulfonic acid (0.46 g) is added and the catalyst is filtered off. The filtrate is concentrated to about 150 ml and warmed at 800 for 75 min. The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel (700 ml) eluting with dichloromethane/methanol (98/2). aaa a solid. The product is crystallized from methanol/dichloromethane/hexane to give the title compound, mp 148.5°-149.0°; NMR (CDCl3) 1.42, 3.80, 6.40, 6.46, 6.66 and 8.35 δ.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][CH2:18][OH:19])([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:19][CH2:18][CH2:17][C:11]1([CH2:14][CH2:15][OH:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OCCC1(CCO)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: OCCC1(CCO)CCNCC1

Procedure:
4,4-bis-(2-hydroxyethyl)piperidine is prepared by catalytic hydrogenation of 1-benzyl-4,4-bis-(2-hydroxyethyl)piperidine in ethanol in the presence of palladium on activated carbon (10% Pd).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.O>CN(C)C=O>[N:21]1([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]2=3)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: COC(=O)c1ccc2c(c1)C(Cl)c1ccccc1CO2
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)C(n1ccnc1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Add 4.0 gm of methyl 6,11-dihydro-11-chlordibenz[b,e]oxepin-2-carboxylate to a 78° C. solution of 2.0 gm of imidazole in 15 ml of dimethylformamide. Stir under a nitrogen atmosphere for 1 hour. Cool to room temperature and pour into 25 ml of water. Extract twice with 125 ml of ether. Wash the combined ether extracts twice with 50 ml of water and with 25 ml of saturated aqueous sodium chloride. Dry over anhydrous sodium sulfate and evaporate to dryness to obtain the title product (Yield 3.12 gm).
Reaction SMILES: Cl.Cl.NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3SC(CN5CCNCC5)=CC=3)=CC=CC=4)C)N=C(C3C=C(O)C=C(F)C=3)C=12.[CH3:46][N:47]([CH3:71])[CH2:48][CH:49]=[CH:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60](=[O:67])[O:59][C:58]=2[CH:68](O)[CH3:69])=[CH:53][CH:52]=1.[CH2:72]([O:79][C:80]1[CH:81]=[C:82]([C:87]2[C:95]3[C:90](=[N:91][CH:92]=[N:93][C:94]=3[NH2:96])[NH:89][N:88]=2)[CH:83]=[C:84]([F:86])[CH:85]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>>[NH2:96][C:94]1[N:93]=[CH:92][N:91]=[C:90]2[N:89]([CH:68]([C:58]3[O:59][C:60](=[O:67])[C:61]4[C:66]([C:57]=3[C:54]3[CH:53]=[CH:52][C:51]([CH:50]=[CH:49][CH2:48][N:47]([CH3:46])[CH3:71])=[CH:56][CH:55]=3)=[CH:65][CH:64]=[CH:63][CH:62]=4)[CH3:69])[N:88]=[C:87]([C:82]3[CH:83]=[C:84]([F:86])[CH:85]=[C:80]([O:79][CH2:72][C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=4)[CH:81]=3)[C:95]=12
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=CCN(C)C)cc1
Reactant: Nc1ncnc2[nH]nc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCNCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: Cl
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(C=CCN(C)C)cc1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Yield: 28.6 %

Procedure:
The title compound was made in a similar way as that of the compound of example 134, step a, from 4-(4-(3-(dimethylamino)prop-1-en-1-yl)phenyl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate B45, 220 mg, 0.630 mmol) and 3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G18, 0.63 mmol, 211 mg) to give 3-(1-(4-amino-3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(4-(3-(dimethylamino)prop-1-en-1-yl)phenyl)-1H-isochromen-1-one (120 mg, 0.18 mmol, 43.1% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:23])C(=O)C1>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Brc1cccc(NCC2CCOCC2)n1
Solvent: CC#N
Product: Clc1ccc(NCC2CCOCC2)nc1Br
Temperature: 80 °C
Yield: 53.1 %

Procedure:
To a solution of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (20 g, 74 mmol) in acetonitrile (240 mL) was added NCS (9.85 g, 74 mmol). The mixture was heated to 80° C. for 3 hr. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The resulting residue was diluted with brine (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, EtOAc/heptane= 0/100 to 50/50] providing 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (12 g) and a mixture of 6-bromo-3,5-dichloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine/6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (5 g, ratio ˜2:3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:28])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1C(OCC1C=CC=CC=1)=O)=[O:4]>C(O)C.[Pd].[C]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:28])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)=[O:4]
Reactant: COC(=O)c1ccccc1NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccccc1NC(=O)[C@@H]1CCCN1
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In 20 ml of ethanol was dissolved 1.9 g of N-benzyloxycarbonyl-(S)-proline 2-methoxycarbonylphenylamide prepared in Reference Example 39. To the solution was added 1 g of 10% Pd-carbon and the mixture was hydrogenated at ambient temperature and under atomspheric pressure. After 1.5 hours, the catalyst was removed by filtration and the filtrate was distilled off under reduced pressure. To the residue was added ether. The precipitated crystals were collected by filtration, giving 950 mg of (S)-proline 2-methoxycarbonylphenylamide.