Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[OH-].[Na+]>[C:8]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(N)CC(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(CC(=O)O)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a cooled solution of 3-aminobutyric acid (13 g) in 2M NaOH (130 ml) is added benzoyl chloride (19.7 g) over the course of two hours. The mixture is allowed to warm to room temperature. Washing with diethyl ether, acidifying of the aqueous phase with 20% HCI, extraction with diethyl ether, drying over MgSO4, evaporation of the solvent and recrystallization in ether/hexane gives the title compound m.p. 150°-152° C. (compound 1.16, Table 1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:30]2[CH:29]=[N:28][CH:27]=[C:26]([F:25])[CH:31]=2)[CH:3]=1)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cccc(F)c21
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cncc(F)c3)c2)c2cccc(F)c21
Yield: 25 %

Procedure:
The title compound was synthesized as described for Example 1 in 25% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (0.096 g, 0.25 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.061 g, 0.28 mmol):
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:47])[CH2:43][CH2:44][CH2:45]I)=[CH:38][CH:37]=1>CN(C)C=O.C(OCC)(=O)C>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:42](=[O:47])[CH2:43][CH2:44][CH2:45][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:22][CH:23]=4)[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:40][CH:41]=1
Reactant: CS(=O)(=O)Nc1ccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Reactant: O=C(CCCI)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(N2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a solution of N-(4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide (0.2 g, 0.46 mmol) and potassium carbonate (0.191 g, 1.38 mmol) in N,N-dimethylformamide (5 mL), was added 1-(4-fluorophenyl)-4-iodobutan-1-one (0.134 g, 0.46 mmol). After stirring at 65° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and isolated by pTLC (10% methanol/dichloromethane) to obtain the product (0.03 g, 12%); 1H NMR (DMSO-d6): δ 1.70-1.90 (m, 4H), 2.40-2.49 (m, 2H), 2.66-2.84 (m, 6H), 2.97 (s, 3H), 3.05 (br, 2H), 5.12 (s, 2H), 6.88 (t, 1H, J=7.6 Hz) 6.99-7.03 (m, 2H), 7.26 (d, 4H, J=9.2 Hz), 7.34 (t, 2H, J=8.4 Hz), 7.76 (d, 2H, J=8.8 Hz), 8.04-8.07 (m, 2H), 9.73 (s, 1H); MS for C30H33FN4O4S m/z 565.3 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[C:13]([CH:14]2[CH2:16][CH2:15]2)=[CH:12][S:11][C:10]=1[NH:17][C:18](=[O:21])[CH2:19]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:22]>>[NH2:22][CH2:19][C:18]([NH:17][C:10]1[S:11][CH:12]=[C:13]([CH:14]2[CH2:16][CH2:15]2)[C:9]=1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: N
Reactant: O=C(CBr)Nc1scc(C2CC2)c1C(=O)c1ccccc1
Product: NCC(=O)Nc1scc(C2CC2)c1C(=O)c1ccccc1

Procedure:
reacting the 3-benzoyl-2-(α-bromoacetamido)-4-cyclopropylthiophene with ammonia to obtain 2-(α-aminoacetamido)-3-benzoyl-4-cyclopropylthiophene (V),
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].C([O:23][C:24]1[C:33]([CH3:34])=[CH:32][C:27]([C:28]([NH:30][NH2:31])=O)=[CH:26][C:25]=1[CH2:35][CH3:36])C1C=CC=CC=1>>[CH2:35]([C:25]1[CH:26]=[C:27]([C:28]2[O:13][C:11]([C:9]3[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:10]=3)=[N:31][N:30]=2)[CH:32]=[C:33]([CH3:34])[C:24]=1[OH:23])[CH3:36]
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Reactant: COc1cc(CC(C)C)nc(C(=O)O)c1
Product: CCc1cc(-c2nnc(-c3cc(OC)cc(CC(C)C)n3)o2)cc(C)c1O

Procedure:
The title compound is prepared in analogy to Example 18 starting from 6-isobutyl-4-methoxy-pyridine-2-carboxylic acid and 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide; LC-MS: tR=1.04 min, [M+H]+=368.33.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2([CH2:16][CH3:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:27][CH2:26]1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Clc1ccccc1N1CCNCC1
Product: CCC1(CCCCN2CCN(c3ccccc3Cl)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(2-chlorophenyl)-piperazine.
Reaction SMILES: C1C2C(=CC=CC=2)C=C(N)[N:2]=1.[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[C:16](=[NH:18])[O-])[CH3:13].Cl.C1(CN)C=CC=CC=1.CO[Na]>CO>[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[C:16]([NH2:2])=[NH:18])[CH3:13]
Reactant: CCOC(OCC)C(=N)[O-]
Reactant: Nc1cc2ccccc2cn1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: NCc1ccccc1
Product: CCOC(OCC)C(=N)N
Temperature: 70 °C

Procedure:
Shown in scheme O is the synthesis of intermediates compounds O-1 containing isoquinolin-3-amine. In a 250 ml of three-neck round bottom flask equipped with magnetic stir bar was charged the 2,2-diethoxyacetimidate (O-3) (6.7 g, 41.6 mmol) and MeOH (20 ml) then the phenyl methanamine hydrochloride (0.5 eq., 20.8 mmol) and MeONa (1 eq., 20.8 mmol) were added. The mixture was heated to 70° C. for 1 hr. The solution appeared dark. After the reaction finished, the MeOH solvent was removed by vacuum and the residue was dissolved in CH2Cl2 (100 ml). The organic phase washed with water (3×50 mL), then brine (1×30 mL). The organic layer was dried over magnesium sulfate, and filtered and the solvent reduced under vacuum. The product was purified by a silica gel column with 100% EA to give about 40.0% of desired product of 2,2-diethoxyacetamidine (O-2). The 2,2-diethoxyacetamidine (O-2) was dissolved in 6 ml of concentrated H2SO4 (99.9%) and the reaction was stirred at 40° C. for 72 hours. The solution was neutralized by 1M NaOH aqueous to PH 7.0. The crude was purified by silica gel column with 50:50 (petroleum ether: EA) to give final product O-1; yield from 13% to 70% depending on the substitution of phenyl methane amidine.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Cs+].[CH2:11](Br)[CH:12]=[CH2:13]>CN(C)C=O>[CH2:11]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[I:1])[C:12]1[CH:13]=[CH:5][CH:3]=[CH:2][CH:8]=1
Reactant: Nc1ccccc1I
Reactant: C=CCBr
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1ccccc1NCc1ccccc1
Reaction time: 0.04 h

Procedure:
N-benzyl-2-iodoaniline was prepared using a system (FRX 200, Syrris Limited) including a microflow reactor. For this purpose, 329 mg (1.5 mmol) of 2-iodoaniline and 15 ml of dimethylformamide were added to the first storage unit of the system including the microflow reactor to dissolve the 2-iodoaniline, and then 112 mg (0.75 mmol) of cesium hydroxide was added thereto. Meanwhile, 156 μl (1.8 mmol) of allyl bromide and 15 ml of dimethylformamide were added to the second storage unit of the system, and then 112 mg (0.75 mmol) of cesium hydroxide was added thereto. The reactants included in the first and second storage units were transferred through the first and second flow channels to the mixing unit, and then transferred to the microflow reactor including microchannels through the third flow channel. The first and second flow channels could transfer 5 ml (2.5 ml for each flow channel) of the reactants to the microflow reactor. The microflow reactor was set at a capacity of 1 ml, a temperature of 236° C. and a pressure of 7 bar. The reactants in the first and second reactants were set such that they were passed through the first to third flow channels at a flow rate of 0.4 ml/min and introduced into the microflow reactor. Also, the residence time of the reactants in the microflow reactor was set to 2.5 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]C(=O)N(C)C)[CH:6]=1.[OH-].[K+]>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([SH:11])[CH:6]=1
Reactant: COC(=O)Cc1cccc(SC(=O)N(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Cc1cccc(S)c1

Procedure:
A mixture of (3-dimethylcarbamoylsulfanyl-phenyl)-acetic acid methyl ester (2.0 g, 7.9 mmol), potassium hydroxide (1.4 g, 24 mmol) methanol (50 mL), and water (5 mL) is stirred at reflux 3 hr. The mixture is concentrated, and product partitioned between 1M aqueous hydrochloric acid (50 mL) and ethyl acetate (3×75 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is taken up in methanol (50 mL), 2 mL concentrated sulfuric acid is added, and the mixture refluxed 3 hr. The mixture is concentrated, and the residue purified by silica chromatography eluting with 7:3 hexanes:ethyl acetate to afford the title compound as a pale yellow oil, 1.0 g, 69%. MS M++1 183. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:8]=[CH:9][CH:10]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(OCC)(=O)C>CC(N(C)C)=O.O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][C@H:29]([CH2:33][O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(CCc2ccccc2OC[C@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reaction time: 6 h
Yield: 96.5 %

Procedure:
0.295 g of a 50% w/w dispersion of sodium hydride in mineral oil was added to a solution of 1.55 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 21) in 60 ml of dimethylacetamide, whilst ice-cooling and stirring, and the mixture was stirred at the same temperature for 15 minutes. 2.50 g of (S)-1-t-butoxycarbonyl-3-(p-toluenesulfonyloxymethyl)piperidine were then added to the mixture, whilst ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 6 hours. At the end of this time, 250 ml of ethyl acetate and 150 ml of water were added to the reaction mixture, and the ethyl acetate layer was separated. The aqueous layer was extracted with 50 ml of ethyl acetate once, and the ethyl acetate layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride twice, dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.78 g (yield 96%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2](=[NH:15])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O=[C:17]1[CH2:22][CH2:21][O:20][CH2:19][CH:18]1[C:23](OC)=[O:24].C(=O)([O-])[O-].[K+].[K+]>CO>[O:24]=[C:23]1[NH:1][C:2]([CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:15][C:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]1=2
Reactant: COC(=O)C1COCCC1=O
Reactant: N=C(N)CNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(NCc1nc2c(c(=O)[nH]1)COCC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
To benzyl 2-amino-2-iminoethylcarbamate (1.77 g, 8.54 mmol) in methanol (67.5 mL) was added methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (1.35 g, 8.54 mmol) and potassium carbonate (3.54 g, 25.6 mmol). The reaction mixture was stirred 15 h at room temperature. The solution was filtered and concentrated under vacuum. Purification was accomplished on a 100 g Isco column with 0% to 10% methanol in dichloromethane over 20 column volumes to give title compound (1.63 g, 59% yield). Exact mass calculated for C16H17N3O4 315.3. found 316.2 (ESI, M+H); 1H NMR (400 MHz, MeOD) 8 ppm 7.17-7.46 (m, 5H) 5.11 (s, 2H) 4.47 (br. s., 2H) 4.22 (s, 2H) 3.92 (t, J=5.31 Hz, 2H) 2.65 (br. s., 2H).
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[C:3]([CH3:12])=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)c(C)cc1C
Temperature: 0 °C
Yield: 97 %

Procedure:
5-Iodo-2,4-dimethylbenzoic acid (2.78 g, 10.1 mmol) obtained in Step 1 of Example 1-1 was placed in a reaction vessel, and then methanol (20 ml) was added thereto. The resulting mixture was cooled to 0° C. Thionyl chloride (2.2 ml, 30.1 mmol) was added dropwise to the mixture over about 10 minutes. The resulting mixture was stirred under reflux for 3 hours. The reaction solution was distilled off under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to the obtained residue. The solution was extracted twice with ethyl acetate. The organic layers were combined together, and washed with a saturated aqueous sodium chloride solution. Then, the organic solution was dried over anhydrous magnesium sulfate. After removal of anhydrous magnesium sulfate by filtration, the liquid was washed with ethyl acetate. The filtrate and washing solution were combined together, and ethyl acetate was distilled off under reduced pressure to yield 2.85 g (97%) of 5-iodo-2,4-dimethylbenzoic acid methyl ester.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:9]=2[N:10]=[C:11]([NH2:13])[N:12]=1.[NH2:23][C:24]1[N:29]=[C:28](Cl)[N:27]=[CH:26][CH:25]=1>>[NH2:23][C:24]1[CH:25]=[CH:26][N:27]=[C:28]([NH:3][CH2:4][CH2:5][NH:6][C:7]2[C:8]3[CH2:18][CH2:17][CH2:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[N:29]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: NCCNc1nc(N)nc2c1CCCc1ccccc1-2
Agent: Cl
Product: Nc1ccnc(NCCNc2nc(N)nc3c2CCCc2ccccc2-3)n1

Procedure:
The product of Example 4B (67 mg, 0.196 mmol) and 6-amino-2-chloropyrimidine (33 mg, 0.254 mmol) were treated under the conditions of Example 1F to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.87 (d, J=5.55 Hz, 1H) 7.62-7.68 (m, 1H) 7.28-7.37 (m, 2H) 7.14-7.21 (m, 1H) 5.80 (d, J=5.55 Hz, 1H) 5.30-5.39 (m, 1H) 4.72 (s, 2H) 4.61 (s, 2H) 3.57-3.73 (m, 4H) 2.53 (t, J=6.94 Hz, 2H) 2.15 (t, J=6.35 Hz, 2H) 1.94-2.08 (m, 2H); MS (ESI+) m/z 363.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)c1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccccc1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of anthranilic acid methyl ester (5.0 g) and 4-fluorobenzaldehyde (3.55 ml) in 1,2-dichloroethane (50 ml) was added sodium triacetoxy-borohydride (10.5 g). The reaction mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium bicarbonate was added. Layers were separated and the aqueous layer was extracted with 1,2-dichloroethane. The combined organic layers were washed with water and brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (elution with EtOAc/petroleum ether 1/9) and gave 2-(4-fluoro-benzylamino)-benzoic acid methyl ester (6.22 g). The obtained ester was converted into the title compound using general procedure 2. 13C-NMR (DMSO-d6) δ 169.9, 161.1, 150.4, 135.5, 134.3, 131.6, 128.9, 115.2, 114.5, 111.6, 110.4, 45.0.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@@H:23]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH2:24][NH:25][CH2:26][CH2:27][C:28]2[CH:61]=[CH:60][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([C@@H:44]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[CH2:45][CH2:46][N:47]([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])[CH:38]=3)=[CH:30][CH:29]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[Si:63]([O:62][C@H:23]([C:11]1[CH:12]=[C:13]([OH:15])[CH:14]=[C:9]([OH:8])[CH:10]=1)[CH2:24][NH:25][CH2:26][CH2:27][C:28]1[CH:61]=[CH:60][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([C@@H:44]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:45][CH2:46][N:47]([CH:48]([CH3:50])[CH3:49])[CH:51]([CH3:53])[CH3:52])[CH:38]=2)=[CH:30][CH:29]=1)([C:66]([CH3:69])([CH3:67])[CH3:68])([CH3:65])[CH3:64]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3)cc2)ccc1O)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3cc(O)cc(O)c3)cc2)ccc1O)C(C)C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4-{4-[4-(2-{[(2R)-2-[3,5-bis(benzyloxy)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]amino}ethyl)phenoxy]butyl}-2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenol (Preparation 33, 720 mg, 0.76 mmol), ammonium formate (960 mg, 15.0 mmol) and 20% palladium hydroxide on carbon (110 mg) were mixed in methanol (8 ml) and stirred at 70° C. for 1 hour under nitrogen. Further ammonium formate (300 mg, 4.75 mmol) and 20% palladium hydroxide on carbon (30 mg) were then added and heating continued at 70° C. for further 1 hour. Reaction mixture was then cooled and filtered, the filtrate was collected and the solvent removed in vacuo. The residue was dissolved in methanol (8 ml) and ammonium formate (900 mg, 14 mmol) and 20% palladium hydroxide on carbon (100 mg) were added and stirred at 70° C. for 1 hour under nitrogen. Reaction mixture was then cooled and filtered, the filtrate was collected and the solvent removed in vacuo. The residue was dissolved in ethyl actate (25 ml) and saturated aqueous sodium hydrogen carbonate (25 ml). Organics were separated and washed with brine (15 ml), dried (magnesium sulphate) and solvent was removed in vacuo to furnish the title compound as an off-white foam, 555 mg.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][C:8]([C:16]2[N:17]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:18]3[C:23]([C:24]=2C)=[CH:22][C:21]([CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:40].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][C:8]([C:16]2[N:17]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:40]
Reactant: Cc1c(-c2cc(OCC3CO3)c(Cl)c3c2C(=O)NC3)n(C(=O)OC(C)(C)C)c2ccc(CN3CCCCC3)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCC3CO3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 79.2 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-chloro-5-(2,3-epoxypropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)methylindol-2-yl]isoindolinone (77.1 mg, 0.211 mmol) was dissolved in acetonitrile (2.3 mL), and the solution was treated with Compound BD (151 mg, 0.383 mmol), palladium acetate (3.8 mg, 0.017 mmol), tri(o-tolyl)phosphine (10.3 mg, 0.034 mmol) and triethylamine (0.294 mL, 2.11 mmol), followed by purification by slurry using diisopropylether to obtain 4-chloro-5-(2,3-epoxypropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (92.3 mg, yield 79%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8](O)=[O:9])[N:3]=1.C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8]([Cl:18])=[O:9])[N:3]=1
Reactant: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OCF)C(=O)Cl)ns1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 11.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 6.97 g of oxalyl chloride at 5° C. to a mixture of 80 ml of THF and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 400 ml of ice water to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water, and then stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 6.70 g (56.3%). Purity: 91.5%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(O[CH:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)(=O)C>C1(C)C=CC=CC=1>[C:8]1([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][CH:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[O:25][C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:3]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1CCCN(c2ccccc2)C1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: c1ccc(N2CCCC(NC3c4ccccc4Oc4ccccc43)C2)cc1

Procedure:
Refluxing 3-amino-1-phenylpiperidine with 9-acetoxyxanthene in dry toluene by the procedure of Example 1 gives N-(N-phenyl-3-piperidinyl)-9-xanthenylamine.