Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N+:35]([O-:37])=[O:36])(=[O:28])=[O:27])[CH2:19][CH2:20]OS(C)(=O)=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:38].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:40]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:19][CH2:20][N:50]3[CH2:51][CH2:52][CH:47]([O:46][CH2:45][C:41]4[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=4)[CH2:48][CH2:49]3)[S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N+:35]([O-:37])=[O:36])(=[O:27])=[O:28])=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:38]
Reactant: c1cncc(COC2CCNCC2)c1
Reactant: Cn1c(=O)ccc2cc(OCCCN(CCOS(C)(=O)=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(=O)ccc2cc(OCCCN(CCN3CCC(OCc4cccnc4)CC3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Sodium iodide (2.93 g) was added to a acetonitrile solution (20 ml) of methanesulfonic acid 2-[[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)propyl]-(2-nitro-benzenesulfonyl)amino]-ethyl ester (4.37 g), and stirred at 60° C. for 1 hours. The reaction mixture was cooled to room temperature. 4-(pyridin-3-ylmethoxy)piperidine (1.87 g) and N-ethyl diisopropylamine (4.23 ml) were then added to the reaction mixture and stirred at 60° C. for 5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was washed with water, and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was concentrated under reduced pressure to give the title compound (3.48 g) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1CCCCC1.S(=O)(=O)(O)O>O>[CH:13](=[C:11]([C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10])[OH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCCCC1
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 40.0 g of 70% sorbitol, 29.4 g of benzaldehyde and 520 ml of cyclohexane under nitrogen gas was added 0.3 ml of 96% sulfuric acid dropwise with stirring, then the mixture was heated to allow to condense while eliminating the generated water by azeotropic distillation. After about 7 hours' continuation of the reaction, the reaction mixture was cooled to room temperature and then neutralized. The precipitate was settled and washed with water by decantation, then filtered and rinsed several times with hot water, further finally dried to obtain the reaction product as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.Cl.[F:25][C:26]([F:35])([F:34])[C:27]1[N:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([C:26]([F:35])([F:34])[F:25])[N:31]=3)=[O:15])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Product: C[C@H](Oc1ncc(C(=O)NCc2nc(C(F)(F)F)no2)nc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylic acid (example AG) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAN 944905-93-5; example AK) as starting materials. MS: 494.0 (M−H)−.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([NH:33][C:34](=[O:48])[C@@H:35]2[CH2:39][C@@H:38]([NH2:40])[CH2:37][N:36]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:24]=1.[OH:49][C@H:50]([CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:51](O)=[O:52]>ClCCl.C(Cl)(Cl)Cl>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([NH:33][C:34](=[O:48])[C@@H:35]2[CH2:39][C@@H:38]([NH:40][C:51](=[O:52])[C@H:50]([OH:49])[CH2:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH2:37][N:36]2[C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH:24]=1
Reactant: O=C(O)[C@H](O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)[C@H](O)CCc2ccccc2)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
1-Hydroxybenzotriazole (147 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (766 mg) were added to a stirred solution of trans-4-amino-N-tert-butoxycarbonyl-L-proline 3-quinolylamide(E, 1.30 g) and (R)-2-hydroxy-4-phenylbutanoic acid (F, 720 mg) in dichloromethane (40 mL) at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1, v/v) to give the title compound (1.85 g) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.45 (m, 9H), 1.70 (m, 2H), 1.94 (m, 1H), 2.15 (m, 1H), 2.75 (m, 2H), 3.29 (m, 1H), 3.80 (m, 1H), 4.11 (m, 1H), 4.53 (m, 1H), 4.60 (m, 1H), 6.76 (m, 1H), 7.15-7.26 (m, 5H), 7.48 (m, 1H), 7.57 (m, 1H), 7.73 (m, 1H), 7.95 (d, J=16.8 Hz, 1H), 8.68 (s, 1H), and 8.69 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.Cl[C:32]([O:34][C:35]1C=CC([N+]([O-])=O)=C[CH:36]=1)=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1c(C(=O)NC2CCNCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Yield: 87.7 %

Procedure:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide (1 eq, 61 mg, 0.132 mmol), p-nitrophenyl chloroformate (1.1 eq, 29 mg, 0.144 mmol), and triethylamine (3 eq, 0.06 mL, 0.395 mmol) were stirred for 16 h in THF (2 mL). The reaction was concentrated in vacuo. The crude material was purified by column chromatography 0-100% ethyl acetate/hexanes to yield 62 mg (75%) of desired product 4-nitrophenyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.54-1.74 (m, 2H) 2.18 (br s, 2H) 2.42 (s, 3H) 3.04-3.38 (m, 2H) 4.21-4.43 (m, 3H) 6.95 (d, J=7.91 Hz, 1H) 7.10 (d, J=8.29 Hz, 2H) 7.30-7.41 (m, 5H) 7.47 (s, 1H) 8.29 (d, J=9.04 Hz, 2H); [M+H]+ 628.7.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-])=O)(=[O:13])=[O:12].Cl.C(O)(=O)C>O>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])(=[O:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccccc1S(=O)(=O)c1cc(C(=O)O)ccc1Cl

Procedure:
A mixture of 4-chloro-3-(o-nitrophenylsulphonyl)benzoic acid (1.71g), stannous chloride (3.12g), concentrated hydrochloric acid (6.6 ml) and acetic acid (25 ml) was heated on the steam bath for 30 min., cooled, and diluted with water. 3-(o-Aminophenylsulphonyl)-4-chlorobenzoic acid was filtered off, washed with water and dried, m.p. 235°-238° C., providing on recrystallisation from acetic acid, m.p. 246°-248° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.Cl[CH2:30][C:31]1[CH2:35][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[O:33][N:32]=1>C(O)(CC)(C)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:30][C:31]4[CH2:35][CH:34]([C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][CH:37]=5)[O:33][N:32]=4)[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: FC(F)(F)c1ccc(C2CC(CCl)=NO2)cc1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Solvent: CCC(C)(C)O
Solvent: CCN(CC)CC
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CC4=NOC(c5ccc(C(F)(F)F)cc5)C4)CC3)ccc2s1
Temperature: 95 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
To a stirred mixture of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol (30 mg, 0.08 mmol) in tert-amylalcohol (5 mL) was added triethylamine (40 μL, 0.30 mmol), followed by 3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole (20 mg, 0.08 mmol). The resulting mixture was stirred at 95° C. for 12 hours, concentrated under reduced pressure, and purified by preparative chromatograph (1:19 MeOH:CH2Cl2) to afford (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[4-(trifluoromethyl)phenyl](4,5-dihydroisoxazol-3-yl)}methyl)piperazinyl]propan-2-ol (10 mg, M+1=535.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)=O)cc1
Reaction time: 1 h
Yield: 104.7 %

Procedure:
Paraanisidine (136.34 g, 1.108 mol) was dissolved in dichloromethane (500 ml), triethylamine (234 ml, 1.66 mol) and acetic anhydride (114.8 ml, 1.22 mol) were added thereto, and the resulting mixture was stirred for 1 hour. After completion of reaction, the reaction solution was concentrated. Water (800 ml) was added to the residue and the resulting mixture was stirred and filtered to give 168.0 g (1.16 mol, Yield 92%) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[N:23]([CH2:27]Cl)[CH:24]=[N:25][N:26]=1.O>CN(C)C=O>[Cl:21][C:22]1[N:23]([CH2:27][O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[CH:24]=[N:25][N:26]=1
Reactant: ClCn1cnnc1Cl
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nncn1COc1ccc(Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
5.6 g of p-phenoxyphenol and 4.2 g of potassium carbonate are heated for 1 hour at 70° C. in 50 ml of anhydrous dimethylformamide. Subsequently, 5.6 g of 2-chloro-1-chloromethyl-1,3,4-triazole is added and the mixture stirred for 6 hours at 70° C. and overnight at room temperature (about 20° C.). The mixture is then poured into 500 ml of water and extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated. The residue is purified by chromatography over silica gel using n-hexane/ethyl acetate (2:1) as eluant. There is obtained 2.8 g of 2-chloro-1-[(p-phenoxyphenoxy)-methyl]-1,3,4-triazole as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=2[O:3]1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:27])=S.[Na+].[Na+].[OH2:32]>C(OCC)(=O)C>[O:32]1[C@H:6]2[C@:7]1([OH:27])[C:2]([CH3:15])([CH3:1])[O:3][C:4]1[C:5]2=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: O
Reactant: O=S([O-])([O-])=S
Reactant: CC1(C)C=Cc2ccc([N+](=O)[O-])cc2O1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2[C@H]2O[C@]21O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of 2,2-dimethyl-7-nitrobenzopyran (11.1 g, 53.9 mmol) in ethyl acetate (165 mL), (Cyc, Ph)-salen manganese complex (XX) (405 mg, 0.431 mmol) and N-methyl imidazole (858 μL, 10.8 mmol) were added, and sodium hypochlorite aqueous solution (101 g, 162 mmol) was added dropwise at 20° C. thereto over 15 minutes. After stirring the resulting mixture at room temperature for 3 hours, saturated sodium thiosulfate aqueous solution was added thereto under cooling with water. The resulting reaction solution was filtered through celite, the organic phase was washed with saturated sodium thiosulfate aqueous solution and saturated sodium chloride solution, and then dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting solid was recrystallized in ethanol to obtain (3R*,4R*)-3,4-epoxy-2,2-dimethyl-7-nitro-3-chromanol (yield: 66%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:11][C:12]1[CH:13]=[C:14]([N:18]=[C:19]=O)[CH:15]=[CH:16][CH:17]=1.O1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][C:23](=O)N1.NC(N)=O>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[C:7]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:6]=[CH:5][C:3]=3[N:4]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C1Cc2ccccc2ON1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: NC(N)=O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2nc(Nc3cccc(Cl)c3)oc(=O)c2c1
Reaction time: 3 h

Procedure:
The anthranilic acid (200 mg, 0.8 mmol) was dissolved in anhydrous THF (1 ml), and to this was added 3-chlorophenylisocyanate (117 μl, 0.96 mmol). The mixture was stirred for 3 h before being concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate and brine then dried (MgSO4) and concentrated to give an orange solid. This was purified by flash chromatography on silica (15% EtOAc/hexane to 100% EtOAc, then 10% EtOH/EtOAc) which gave, in order of elution, the benzoxazinone (18 mg, 0.05 mmol); δH (400 MHz, CDCl3) 0.77-0.82 (3H, m, Me), 1.19-1.24 (10H, m, 5×CH2), 1.55-1.57 (2H, m, ArCH2CH2), 2.56-2.62 (2H, m, ArCH2), 7.00-7.32 (4H, m, 3×ArH, NH), 7.40-7.49 (2H, m, 2×ArH), 7.81-7.83 (2H, m, ArH); m/z (ES+) 385 (MH+) and the urea (160 mg, 0.4 mmol); m/z (ES−) 401 (M−H)−.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10]2.[CH2:24]([CH2:27][NH2:28])[CH:25]=C.[OH-].[Na+].[CH3:31]N(C=O)C>>[CH2:27]([N:28]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10]2)[CH3:31])[CH:24]=[CH2:25]
Reactant: CN(C)C=O
Reactant: Fc1cc2c(ccn2-c2ccc(Cl)cc2)cc1OCCCCBr
Reactant: C=CCCN
Agent: [Na+]
Agent: [OH-]
Product: C=CCN(C)CCCCOc1cc2ccn(-c3ccc(Cl)cc3)c2cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
30 mg (0.076 mmol) 5-(4-Bromo-butoxy)-1-(4-chloro-phenyl)-6-fluoro-1H-indole in 0.25 ml DMF were treated with 75 μl of N-Allylmethylamine and stirred at 80° C. during 1 h. The mixture was treated with 0.5M aqueous NaOH and extracted three times with Et2O. Drying of the combined organic layers with Na2SO4, evaporation of the solvent and column chromatography on silica gel with hexane/EtOAc 1:1 gave 25 mg (85%) Allyl-{4-[1-(4-chloro-phenyl)-6-fluoro-1H-indol-5-yloxy]-butyl}-methyl-amine as a light yellow oil, MS: 387 (MH+, 1Cl).
Reaction SMILES: Cl.C([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([NH:25][C:26]3[CH:41]=[CH:40][C:29]([O:30][C:31]4[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=4)=[C:28]([Cl:42])[CH:27]=3)=[N:22][CH:21]=[N:20][C:19]=2[CH:18]=[CH:17]1)(=O)C1C=CC=CC=1.[CH3:43][C:44]([NH2:47])([CH3:46])[CH3:45].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[ClH:42].[C:44]([NH:47][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([O:30][C:29]2[CH:40]=[CH:41][C:26]([NH:25][C:23]3[C:24]4[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][OH:10])[CH:17]=[CH:18][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:27][C:28]=2[Cl:42])=[CH:32][CH:33]=1)([CH3:46])([CH3:45])[CH3:43]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoic acid hydrochloride (183 mg), 2-methylpropan-2-amine (0.038 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg), 1-hydroxybenzotriazole monohydrate (55 mg), triethylamine (0.050 mL) and N,N-dimethylformamide (3 mL) was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (1 mL), 1N aqueous sodium hydroxide solution (0.6 mL) was added and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution (0.3 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (118 mg) as a white powder.
Reaction SMILES: S(=O)(=O)(O)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[N:21]1[C@@H:30]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:31]([N:33]1[CH:38]=[CH:37][CH2:36][CH:35]=[CH:34]1)=[O:32].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC>[O:29]=[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:19])[N:21]1[C@H:30]1[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH:34]2[CH2:35][CH2:36][CH:37]=[CH:38][N:33]2[C:31]1=[O:32]
Reactant: O=C([C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)N1C=CCC=C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Reaction time: 0.5 h

Procedure:
Combine sulfuric acid (3.0 mL, 96%) and trifluoroacetic anhydride (300 mL). Add (S)-N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,4-dihydro-pyridine (1.0 mmol). After 30 minutes, pour the reaction mixture into a mixture of saturated aqueous sodium bicarbonate and ice. Extract with ethyl acetate and then with methylene chloride. Combine the organic layers and filter through a plug of silica gel. Rinse the silica gel with dichloromethane. Evaporate the filtrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane and then 25% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5](O)=[O:6].CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1>CN(C)C(=O)C.O1CCCC1>[CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5]([NH:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1)=[O:6]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: CC1(C)CC1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5(C)C)cn4n3)ccc2F)n(C)n1
Yield: 16.1 %

Procedure:
Using 2,2-dimethylcyclopropanecarboxylic acid (82 mg, 0.72 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (63 μL, 0.72 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 239, the title compound (37 mg, 16%) was obtained as a white powder.
Reaction SMILES: CSC.B.[CH:5]([N:18]1[CH2:21][C:20]2([CH2:26][NH:25][C:24](=O)[CH2:23][O:22]2)[CH2:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO.CNCCNC>C1COCC1>[CH:5]([N:18]1[CH2:21][C:20]2([CH2:26][NH:25][CH2:24][CH2:23][O:22]2)[CH2:19]1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1COC2(CN1)CN(C(c1ccccc1)c1ccccc1)C2
Agent: B
Agent: CNCCNC
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(C(c2ccccc2)N2CC3(CNCCO3)C2)cc1
Temperature: 25 °C

Procedure:
Borane methyl sulfide complex (2M in THF, 10.7 mL) was added to a solution of 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one (example 33, step e) (2 g) in dry THF (40 mL) and the resultant solution was stirred at 70° C. under nitrogen for 50 minutes. The mixture was cooled to room temperature and treated dropwise with methanol (40 mL) followed by N1,N2-dimethylethane-1,2-diamine (3.43 g). The mixture was heated at 70° C. for 6 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 1% triethylamine and 5% methanol in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.35 g.