Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH3:13][O:14][C:15](=[O:37])[C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([OH:25])[CH:19]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:37])[C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[NH:24][C:1](=[O:2])[O:25][C:20]=2[CH:19]=1
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(O)c1)NC(=O)OCc1ccccc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
A methylene chloride (15 mL) solution of carbonyl diimidazole (498 mg, 3.07 mmol) was added at 0° C. to a solution of (R)-3-(4-amino-3-hydroxy-phenyl)-2-benzyloxycarbonylamino-propionic acid methyl ester (1.17 g, 3.07 mmol), diisopropylethylamine (1.60 mL, 9.21 mmol), and methylene chloride (85 mL). The mixture was stirred at 0° C. for 4 h. The solvents were removed in vacuo and the residue was purified by silica gel chromatography using ethyl acetate/hexanes as eluent to afford the title compound as a white solid (51%). 1H-NMR (CDCl3, 500 MHz) δ 9.07 (s, 1H), 7.37-7.29 (m, 5H), 6.96 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 5.36 (d, J=8.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.07 (d, J=12.5 Hz, 1H), 4.65 (dd, J=13.5, 5.5 Hz, 1H), 3.74 (s, 3H), 3.17 (dd, J=14.0, 5.5 Hz, 1H), 3.07 (dd, J=14.0, 6.0 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 171.9, 155.7, 155.5, 144.1, 136.2, 130.8, 128.6, 128.42, 128.38, 128.2, 125.1, 111.1, 109.8, 67.2, 55.1, 52.6, 38.3. Mass spec.: 371.18 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: C1COCCN1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1C1=NCc2nnc(CN3CCOCC3)n2-c2ccc(Br)cc21

Procedure:
In the manner given in Preparation 48, 8-bromo-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and morpholine in tetrahydrofuran are reacted to give 8-bromo-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:7])[CH3:6].[C:17](Cl)(=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl[CH:31](Cl)C>>[C:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:31])=[CH:13][CH:12]=1)(=[O:7])[CH3:6]
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: CC(=O)OCCc1ccccc1
Reactant: CC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCCCCC(=O)c1ccc(CCOC(C)=O)cc1
Temperature: 25 °C

Procedure:
Aluminum chloride (48.2 g) was added to dichloroethane (400ml) in a stream of nitrogen and the mixture was stirred at room temperature. Then, phenethyl acetate (39.6 g) and undecanoyl chloride (52.7 g) were dropwise added thereto under ice-cooling and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with diethyl ether. The ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:20) to give the subject compound (34.5 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: CN(C)CCN
Reactant: CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
N,N-Dimethylethylenediamine (3.30 ml) was added to 4-chloro-N-methyl-3-nitrobenzamide (3.220 g) and the mixture was stirred for 14 hours at 100° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (3.687 g) as yellowish orange solid.
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.O=S(Cl)[Cl:19].[CH3:21]O>O.CCOC(C)=O>[ClH:19].[NH2:1][C@:2]1([C:14]([O:16][CH3:21])=[O:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: NC1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@]1(N)CC[C@H](c2ccc(Br)cc2)C1
Product: Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of (3S)-1-amino-3-(4-bromophenyl)cyclopentanecarboxylic acid (10.2 g, 35.9 mmol) in MeOH (100 mL) was cooled in an ice bath, followed by addition of SOCl2 (15.72 mL, 215 mmol) dropwise. After the addition was complete, the solution was refluxed for 3 hrs at which time the reaction was determined to be complete by HPLC. The solution was concentrated to remove methanol to afford a solid. The solid was taken in 50 ml of 3% H2O in EtOAc and stirred well for 30 mins. The white solid formed was collected by filtration. The wet white solid was taken in 50 ml of 4% H2O in 1,2-dimethoxyethane and heated to 50° C. for 3 hrs, and then stirred at room temperature overnight. The resulting white solid was collected by filtration and dried to afford (1R,3S)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate hydrochloride (3.5 g, 10.35 mmol). HPLC retention time=6.6 min (Condition H) LC/MS M+1=298/300. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (br. s, 3H) 7.50-7.53 (m, 2H), 7.35-7.37 (m, 2H), 3.81 (s, 3H) 3.17-3.28 (m, 1H), 2.57 (dd, J=14, 7 Hz, 1H), 2.0-2.28 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([Cl:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.O>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([O:14][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30])[CH:8]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(N)n(-c2cc(O)cc(Cl)c2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c2)n1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of Intermediate 62b (615 mg, 2.31 mmol) and imidazole (189 mg, 2.78 mmol) in DMF (4.5 mL) was added tert-butyl dimethylchlorosilane (384 mg, 2.55 mmol). The solution was stirred for 2 h then added tert-butyl dimethylchlorosilane (192 mg, 1.28 mmol). After 1.5 h, the solution was diluted with water and extracted with EtOAc. The combined organics were dried and concentrated in vacuo to give the title compound (831 mg, 94%). LCMS (Method 3): Rt 5.21 min, m/z 380 [MH+].
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[F:24])[CH2:10]1)=[O:8]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C2CN(Cc3ccccc3F)c3ccccc3C2=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
In 3 mL of anhydrous dimethylformamide was suspended 16 mg (0.4 mmol) of sodium hydride (60%), 86 mg (0.31 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a was added and the mixture was stirred at rt. After 30 minutes, 75.6 mg (0.40 mmol) of 2-fluorobenzylbromide was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was quenched by the addition of 10 mL of water. The crude product precipitated out were isolated by filtration and purified by flash chromatography to yield 25 mg of colorless solid 41: LC-MSD, m/z for C25H20FNO2 [M+H]+=386.4, [M+2H]+=387.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.526 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.2-2.3 (d, 6H), 5.7 (s, 2H), 7.1-7.3 (m, 4H), 7.3-7.4 (m, 1H), 7.4-7.5 (m, 2H),7.54 (s, 1H), 7.6-7.66 (d, 1H), 7.67-7.74 (t, 1H), 8.2 (d, 1H), 8.58 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([NH2:10])[C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([NH2:10])[C:5]([CH2:8][CH3:9])=[C:6]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(Cl)c(CC)c1N
Agent: O=S(=O)(O)O
Product: CCc1c(Cl)cc([N+](=O)[O-])c(CC)c1N
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.3 %

Procedure:
1.83 ml (10.9 mmol) 3-Chloro-2,6-diethyl-phenylamine (1) is dissolved on an ice-bath at 0° C. in 8 ml conc. H2SO4. 562 μl (12.0 mmol; 1.1 eq.) 90% ige HNO3 is added and the reaction mixture is stirred for 2.5 hours at 0° C. The reaction mixture is pored on ca. 200 ml ice and the obtained solution is extracted 8 times with 50 to 100 ml EE each. The combined organic layers are dried over magnesium sulphate and the solvent is removed under reduced pressure yielding 2.1 g of crude product. After purification by flash chromatography 1.24 g (5.42 mmol; 50%) of 2 could be obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[C:17]([O:16][C:14]([NH:13][C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:12][C:8]=1[C:9]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:24]1)=[O:11])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)O)c1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Step 3): A mixture of 5-isopropyl-N-tert-butoxycarbonylanthranilic acid (1.0 g, 3.58 mmol), 4-aminomethyl-1-diphenylmethylpiperidine (1.0 g, 3.57 mmol), triethylamine (0.37 g, 3.66 mmol) and DPPA (1.0 g, 3.63 mmol) in DMF was stirred at 0° C. for 30 mins and at room temperature for 2 hours. The mixture was poured into H2O and extracted with AcOEt. The extract was washed with H2O, dried over MgSO4 and evaporated and then the residue was purified by column chromatography on silica gel to give 2-(tert-butoxycarbonyl)amino-5-isopropyl-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 1.86 g (96.4%): mp 88°-90° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([O:15][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cc1c(C)cc(C(C)(C)C)c(O)c1C

Procedure:
10.68 grams of the compound of Example 5, 11.4 grams of n-octadecanol and 0.8 grams of p-toluene sulfonic acid monohydrate were dispersed in 150 ml of toluene and heated at reflux for seven hours during which the water collected by azeotropic distillation was almost equal to the theory. The reaction mixture was successively washed with water, aqueous saturated sodium bicarbonate solution, and then with water once again until the wash water was neutral. After drying over anhydrous sodium sulfate and filtering free of the drying agent, the clear filtrate was evaporated at reduced pressures to yield the desired product as residue. After successive crystallizations from acetonitrile and n-heptane, the desired compound was isolated as white crystals melting at 57° to 59° C (Compound 1).
Reaction SMILES: C([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:10]1=[O:25])[C:6](O)=[O:7])(=O)C.[H][H].[NH3:28]>CO.[Ni]>[NH2:28][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:11][C:6](=[O:7])[C@H:5]([OH:4])[C@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[C:10]2=[O:25])=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(C(F)(F)F)cc3)C2=O)cc1

Procedure:
To Compound 99-1 in 15 mL of 7M NH3 in MeOH was added excess Raney Ni (an aq. suspension) and the mixture stirred under a balloon of hydrogen for two hours. The mixture was filtered and evaporated to dryness yielding a white solid. Purification by RP-HPLC yielded 34 mg of EXAMPLE 99 as a white solid after conversion to the HCl salt by the addition of 1N HCl in diethyl ether and evaporation to dryness.
Reaction SMILES: [Si]([O:18][C:19]1[CH:62]=[CH:61][C:22]([O:23][CH2:24][C@@H:25]([OH:60])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:59]=[CH:58][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]4[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH3:57][O:56][C:50]1[CH:49]=[C:48]([CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:58]=[CH:59][C:30]([CH2:29][CH2:28][NH:27][CH2:26][CH:25]([OH:60])[CH2:24][O:23][C:22]4[CH:61]=[CH:62][C:19]([OH:18])=[CH:20][CH:21]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])[CH:53]=[CH:52][C:51]=1[O:54][CH3:55]
Reactant: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCNCC(O)COc4ccc(O)cc4)cc3)CC2)cc1OC
Yield: 89.4 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-[4-(3,4-dimethoxyphenyl)butyl]-1-piperidinecarboxamide (0.40 g, 0.47 mmol) was reacted according to Procedure H (eluant: 10:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.26 g, 0.42 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](NC(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.C(OC(OC(C)(C)C)N(C)C)(C)(C)C.CCOCC>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccccc1

Procedure:
A solution of 3.50 g of (S)-4-carboxymethyl)alpha-[[(1,1-dimethylethoxy)carbonyl]amino]benzenepropanoic acid methyl ester in 40 mL of dry toluene and 10 mL of dimethylformamide di-t-butyl acetal was heated to a bath temperature of 80° C. for 4 hours. After cooling, the mixture was diluted with 100 mL of ether and was washed with water and saturated sodium chloride solution and was dried over magnesium sulfate. The residue obtained after filtration and evaporation was chromatographed over 150 g of silica gel, eluting with 20% ethyl acetate-hexane to give 2.663 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-]2-(1,1-dimethylethoxy) 2-oxoethyl]benzenepropanoic acid methyl ester.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]([F:20])([F:19])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.C(OCC)C>O1CCCC1>[CH:16]1([C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]([F:19])([F:20])[F:5])=[CH:13][CH:12]=2)([OH:15])[CH:1]=[CH2:2])[CH2:18][CH2:17]1
Reactant: C=C[Mg]Br
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)C1CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(O)(c1ccc(OC(F)(F)F)cc1)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 550 ml (0.55 mole) of 1M vinylmagnesium bromide in tetrahydrofuran was cooled to 10°-15° C., and a solution of 115.0 grams (0.5 mole) of cyclopropyl 4-trifluoromethoxyphenyl ketone in 100 ml of tetrahydrofuran was added dropwise during a 30 minute period. Upon completion of addition the reaction mixture temperature was maintained at less than 20° C. where it was stirred for one hour. The reaction mixture was poured into a mixture of 2000 ml of pH5 buffer in 1000 ml of ice. To this was added 1000 ml of diethyl ether. The mixture was stirred until the ice melted. The aqueous layer was separated and was washed with two 500 ml portions of diethyl ether. The ether washes were combined with the original organic layer, and the combination was washed in turn with two 500 ml portions of the pH5 buffer solution, two 500 ml portions of water, and one 300 ml portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with ground sodium carbonate and filtered. The filtrate was concentrated under reduced pressure yielding 130.0 grams of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-2-propen-1-ol.
Reaction SMILES: [CH3:1][N:2](C)[OH:3].[CH3:5][Al](C)C.C(O[C:12]([CH:14]1[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1)=[O:13])C>C(Cl)Cl>[CH3:5][O:3][N:2]([CH3:1])[C:12]([CH:14]1[O:19][CH2:18][CH2:17][N:16]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15]1)=[O:13]
Reactant: CN(C)O
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCO1
Reactant: C[Al](C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of N,N-dimethylhydroxylamine (6.6 g, 67.6 mmol) in anhydrous DCM (200 mL) under nitrogen at 0° C. is added dropwise a solution of trimethylaluminium (2M solution in hexane, 34 mL, 67.6 mmol) over 30 minutes. The reaction mixture is allowed to warm up to room temperature and left stirring for 1 hour. A solution of the ester 1 (6.74 g, 27 mmol) in anhydrous DCM (100 mL) is then added dropwise over 30 minutes and the reaction mixture is left stirring overnight before quenching by cautious addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution. The precipitate is removed by filtration through a celite pad and the residue washed with chloroform. The organic phase is then concentrated in vacuo and washed with water. The aqueous layer is re-extracted with chloroform and the organic phases are combined, washed with brine, dried over magnesium sulphate and the solvent evaporated in vacuo to give 2 as a yellow oil. Alternatively, the reaction could be worked up as follows: upon addition of a solution of the ester 1 (1 eq) the reaction mixture is left stirring for 1 hour before quenching by addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution, followed by addition of water. The aqueous layer is re-extracted with DCM and the organic phases are combined, dried over magnesium sulphate and the DCM evaporated in vacuo to give 2 as a yellow oil (3.36 g, 47%). MW 264.33; C14H20N2O3; 1H NMR (CDCl3): 7.47-7.22 (5H, m), 4.55 (1H, d, 1.5 Hz), 4.00 (1H, dd, 11.5 Hz, 1.7 Hz), 3.75 (1H, dt, 11.5 Hz, 2.2 Hz), 3.65 (3H, s), 3.56 (2H, m), 3.17 (3H, s), 2.93 (1H, d, 11.3 Hz), 2.68 (1H, d, 11.3 Hz), 2.30 (2H, 11.3 Hz); LCMS: (6 min method) m/z 265 [M+H]+, RT 0.65 min.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]([CH3:28])[CH3:27])=[C:10](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>CO.CC(O)=O.[OH-].[Pd+2].[OH-]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]([CH3:28])[CH3:27])=[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(C(C)C)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CCc1c(C(C)C)nc2c(cnn2CC)c1-c1cncc(C)c1
Yield: 45.7 %

Procedure:
A solution of ethyl (2E)-3-[1-ethyl-6-isopropyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]acrylate (268 mg) in MeOH-AcOH (90:10, 10 ml) was hydrogenated (3 atm) over palladium hydroxide (38 mg) at room temperature for 8 hours. The reaction mixture was filtered through celite pad and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3, water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:2) to give ethyl 3-[1-ethyl-6-isopropyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (123 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:17])[C:14](=[O:16])[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].[N:30]1([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:17][N:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:18]([NH:42][C:39]3[CH:38]=[CH:37][C:36]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:41][CH:40]=3)=[O:19])=[CH:7][CH:6]=2)[CH2:9]1)[C:14](=[O:16])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N(C)C1CCN(c2ccc(N)cc2)C1
Reactant: Nc1ccc(N2CCCCC2)cc1
Product: CC(=O)N(C)C1CCN(c2ccc(NC(=O)Nc3ccc(N4CCCCC4)cc3)cc2)C1

Procedure:
N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-piperidin-1-ylphenylamine by method A. This resulted in the product with the molecular weight of 435.57 (C25H33N5O2); MS (ESI): 436 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][NH:24][CH3:25]>C(O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:25])[CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Reactant: CNC
Solvent: CCO
Product: CN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and N,N-dimethylamine in ethanol were converted to yield [4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl]-dimethyl-amine as light yellow semisolid, MS: 404 (MH+, 1Br).