Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:28]([CH3:29])[N:27]=[N:26][N:25]=3)[CH:19]=2)=[O:16])[C@H:10]([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][C@@H:33]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:32]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][C@@H:33]2[CH2:34][CH2:35][CH2:36][N:31]([CH2:30][C@H:10]3[C@H:11]([NH:14][C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]5[N:28]([CH3:29])[N:27]=[N:26][N:25]=5)[CH:19]=4)=[O:16])[CH2:12][CH2:13][NH:8][CH2:9]3)[CH2:32]2)=[CH:39][CH:40]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCNC[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 3 h
Yield: 55 %

Procedure:
In a dry flask (3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid t-butyl ester (48 mg, 0.079 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated in vacuo then purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (22 mg, 38%). 1H NMR (500 MHz, CD3OD, 30° C.), δ: 8.01 (t, 1H, J=1), 7.59 (dq, 1H, J=8, J′=1), 7.52 (t, 1H, J=8), 7.43 (dt, 1H, J=8, J′=1), 7.17 (m, 2H), 6.96 (t, 2H, J=9), 4.18 (s, 3H), 3.73 (m, 2H), 3.51 (m, 3H), 3.38 (d, 1H, J=13), 3.13 (m, 2H), 2.99 (m, 2H), 2.64 (dd, 2H, J=14, J′=6), 2.50 (bs, 2H), 2.21 (m, 1H), 2.11 (bs, 1H), 1.92 (m, 2H), 1.76 (m, 2H), 1.19 (m, 1H). HRMS (ESI), C27H36FN8O M+/z: calc. 507.2996, found=507.2976.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[S:18][CH:19]=[CH:20][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.Cl.[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[S:18][CH:19]=[CH:20][C:11]2=3)=[O:9])=[CH:21][CH:22]=1
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccsc21
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCCC(=O)c3sccc32)cc1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a mixture of 2.0 g of 4-(4-nitrobenzoyl)-4,5,6,7-tetrahydro-8H-thieno-[3,2-b]azepin-8-one in 40 ml of glacial acetic acid is added 20 ml of 6N-hydrochloric acid. The mixture is cooled and 3.53 g of iron powder added in portions. The mixture is allowed to warm to room temperature and is heated at 70°-80° C. for 1 hour and then cooled to 0° C. To mixture is basified with 10N NaOH (pH 14) and extracted with 200 ml of ethyl acetate. The aqueous layer is again extracted with 200 ml of ethyl acetate and the extracts combined. The combined extract is washed with 100 ml each of H2O and brine and dried (Na2SO4). The extract is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to give a solid which is crystallized from ethyl acetate-hexane to give 1.24 g of crystals, m.p. 216°-218° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:4]=2[O:3]1.Cl.[OH-].[Na+]>O.C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:4]2[O:3][C:2]([CH3:1])([CH3:15])[CH:7]=[CH:6][C:5]=2[CH:8]=1
Reactant: CC1(C)C=Cc2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)C=Cc2cc(N)ccc2O1
Temperature: 60 °C
Reaction time: 0.83 h

Procedure:
2,2-dimethyl 6-nitro 2H-1-benzopyran (3), 40.1 g (185 mmol) was mixed with 120 g of ethanol, 28.0 g of water and 36.1 g of reduced iron, the resulting mixture was heated to 60° C., and a mixed solution of 4.0 g of 35% (w/w) hydrochloric acid, 16.0 g of ethanol and 4.0 g of water was added dropwise thereto over 50 minutes. After stirring at the same temperature for 2 hours, 10.0 g of 15% (w/w) sodium hydroxide aqueous solution was added dropwise thereto, the resulting mixture was filtered through celite, and then the solvent was distilled off. To 112 g of the resulting residue, 160 g of toluene and 68.0 g of 10% (w/w) sodium hydroxide aqueous solution were added, the resulting mixture was shaken, left and separated into phases. The aqueous phase was extracted with 68 g of toluene again. The organic phases were combined and washed with 68 g of 5% (w/w) sodium chloride solution, and the solvent was distilled off to obtain a solution of the intended product, 6-amino 2,2-dimethyl 6-2H-1-benzopyran (4) (68.0 g).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([OH:12])([CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[C:4]#[CH:5].[Cl:15][O-].[Na+]>C(Cl)Cl>[Cl:15][C:5]#[C:4][C:3]([OH:12])([CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[C:2]([CH3:14])([CH3:13])[CH3:1]
Reactant: [O-]Cl
Reactant: C#CC(O)(Cn1cncn1)C(C)(C)C
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(O)(C#CCl)Cn1cncn1
Yield: 86 %

Procedure:
9,65 (50 mmol) of 4,4-dimethyl-3-hydroxy-3-[(1,2,4-triazol-1-yl)-methyl]-1-pentine in 20 ml of methylene chloride are stirred for 3 days with 400 ml (150 mmol) of a solution of sodium hypochlorite at room temperature. The reaction mixture is then extracted by shaking with methylene chloride. After drying the organic phase and stripping off the solvent in vacuo, there are obtained 9.8 g (43 mmol; 86% of theory) of 1-chloro-4,4-dimethyl-3-hydroxy-3-[(1,2,4-triazol-1-yl)-methyl]-1-pentine having a melting point of 88° C.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4](F)=[N:5][C:6]([F:13])=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(O)C>[NH2:1][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[C:6]([F:13])[N:5]=1
Reactant: N
Reactant: Fc1nc(F)c(C(F)(F)F)cc1Cl
Solvent: CCO
Product: Nc1nc(F)c(C(F)(F)F)cc1Cl
Temperature: 55 °C
Reaction time: 2 h

Procedure:
12.5 g (0.74 mol) of gaseous ammonia were passed into a stirred mixture of 40 g (0.184 mol) of 3-chloro-2,6-difluoro-5-trifluoromethylpyridine in 200 ml of ethanol in the course of 45 minutes at 50°-60° C. After the reaction mixture had been stirred for 11/2 hours at 55° C., it was cooled and concentrated. The residue was stirred in water, filtered off with suction and dried, giving 36.7 g (93% of theory) of the title compound of m.p. 101°-103° C.
Reaction SMILES: [C:1]([C:5]1[C@H:6]2[CH2:11][C@H:9]([CH:10]=1)[N:8]([C@H](C1C=CC=CC=1)C)[C@H:7]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([CH:5]1[CH2:10][C@@H:9]2[CH2:11][C@@H:6]1[C@H:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@H](C=C2C(C)(C)C)N1[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1N[C@@H]2CC(C(C)(C)C)[C@@H]1C2
Temperature: 45 °C
Reaction time: 62 h
Yield: 23.4 %

Procedure:
To a solution of ethyl (1R, 3R, 4R)-5-(tert-butyl)-2-[(S)-1-phenylethyl]-2-azabicyclo [2.2.1]hept-5-ene-3-carboxylate (1.22 g, 3.74 mmol) in ethyl acetate (43 ml) was added 20 wt % Pd(OH)2 (0.578 g), and the mixture was stirred under a hydrogen atmosphere at 45° C. for 62 hours. After a filtration through Celite, the solvent was evaporated. The residue was purified by silica gel column chromatography (1%–5% methanol/chloroform), to give ethyl (1R, 3R, 4S)-5-(tert-butyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.197 g, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[N:29]([CH3:40])[C:30]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:31][CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[N:29]([CH3:40])[C:30]([CH2:33][N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[N:31][CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: Cn1c(C(=O)Oc2ccccc2)cnc1CN1CCOCC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cnc(CN4CCOCC4)n3C)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 3-methyl-2-morpholin-4-ylmethyl-3H-imidazole-4-carboxylic acid phenyl ester, the title compound was obtained as off-white solid (21% yield). MS: m/e=473(M+H+), mp 244-246° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:12][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in ethyl acetate. (20 ml) were added 3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (471 mg, 84%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:16]Br>C(Cl)Cl>[Br:16][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CCOC(=O)Cc1ccc(C(C)=O)cc1
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
Ethyl 4-acetyl-phenylacetate from Example 25 Part A (489 mg, 2.4 mmol) was dissolved in CH2Cl2. Bromine (379 mg, 2.4 mmol) was added dropwise. The reaction was stirred at rt for 16 h. The reaction had decolorized from rust red to light yellow. The solvent was evaporated in vacuo to yield 680 mg (99%) of ethyl 2-(4-(2-bromoacetyl)phenyl)acetate as a light yellow oil. The product was used in the next step without further purification. MS 287.0 and 289.0 of equal intensities (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a mixture of ethyl 3-[({4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]phenyl}carbonyl)amino]propanoate (273 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (253 mg, 97%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:17]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=[N:17][C:6]=1[CH3:7]
Reactant: N
Reactant: Cc1cccc(C(=O)c2cc(C)c(C)o2)n1
Solvent: CO
Product: Cc1cccc(-c2nc(C)c(C)cc2O)n1
Temperature: 160 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanone (810 mg), methanol (7 ml), and a 28% aqueous ammonia solution (7 ml) were placed in a sealed tube, and the mixture was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6,6′-trimethyl-[2,2′]bipyridin-3-ol (753 mg, yield 93%).
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]CC3C=CC=CC=3)[C:23]=2[O:36]CC2C=CC=CC=2)[CH:13]=[C:12]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]>[Pd].O1CCCC1>[C:7]([CH2:6][N:5]([C:10]1[CH:11]=[C:12]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]=2[OH:36])[CH:15]=1)[CH2:4][C:1]([OH:3])=[O:2])([OH:9])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(N(CC(=O)O)CC(=O)O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCc2cccc(O)c2O)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 4 h
Yield: 90.2 %

Procedure:
A mixture of 0.918 g of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[5-[2,3-bis(phenylmethoxy)phenyl]pentoxy]phenyl]glycine and 0.3 g of 10% palladium on carbon in 50 ml of tetrahydrofuran was stirred under a hydrogen atmosphere for 4 hours when absorption ceased. The catalyst was removed by filtration through a Celitepad and the filtrate was concentrated to a solid which was triturated with hexane and filtered to give 0.653 g (92% yield, mp 129°-131°) of N-(carboxymethyl)-N-[3-[5-(2,3-dihydroxyphenyl)pentoxy]-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[C:20](Cl)(=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:29])=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(OC)cc1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (244 mg, 1.26 mmol) in CH2Cl2 (5 mL), SnCl4 (1.0M solution in CH2Cl2 ; 2.5 mL 2.5 mmol) and 4-anisoyl chloride (220 μL, 1.62 mmol) as a white solid (110 mg, 27%). 1H NMR (CDCl3) 7.78 (d, 2H, J=8.6), 6.93 (d, 2H, J=8.6), 6.86 (s, 1H), 6.83 (s, 1H), 6.03 (s, 2H), 3.88 (s, 3H), 3.75 (s, 2H), 3.59 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.[N:15]#[C:16][NH2:17].[N+:18]([O-:21])([OH:20])=[O:19]>C(O)C>[N+:18]([O-:21])([OH:20])=[O:19].[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:16]([NH2:17])=[NH:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Reactant: N#CN
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reaction time: 24 h
Yield: 36.1 %

Procedure:
A suspension of 3-fluoro-4-(4-methyl-imidazol-1-yl)-phenylamine (500 mg, 2.62 mmol), of 50% aqueous cyanamide solution (249 mg, 2.96 mmol) and of 65% aqueous nitric acid (253 mg, 2.62 mmol) in ethanol (2.6 mL) was heated for 5 days to reflux under an atmosphere of nitrogen. Twice the same amounts of cyanamide and nitric acid were added to the reaction mixture after 2 and 4 days, respectively. The mixture was cooled and let stand at 20° C. for 1 d. The precipitated solid was filtered off (Caution: the filtrate may contain the ethyl ester of nitric acid) and washed with ethanol to yield the title compound (280 mg, 36%) as an off-white solid.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]3[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]=2[CH3:27])=[CH:6][CH:5]=1>C1COCC1.CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]3[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:21][C:22]([OH:24])=[O:23])[C:12]=2[CH3:27])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(n1CC(=O)O)CCCC2=O
Reaction time: 1 h

Procedure:
A solution of LiOH (1.79 g, 1.77 g corrected for assay, 42.2 mmol) was added to a stirred solution of ethyl [3-(4-chlorophenylsulfanyl)-2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (7.5 g, 5.33 g corrected for assay, 14.1 mmol) in a mixture of THF (27 mL) and MeOH (27 mL). The mixture was stirred for 1 h. The solvents were removed in vacuo (45 mbar) at 45° C. until the volume of the mixture was ˜20 mL. Water (27 mL) and CH2Cl2 (27 mL) was added and the mixture stirred for 5 mins. The layers were allowed to separate, concentrated aqueous hydrochloric acid (5 mL) was added to the aqueous layer and the resulting solid product was collected by filtration and washed with water (5 mL). This crude damp product was slurried in a mixture of EtOAc (20 mL), CH5Cl2 (20 mL) and heptane (20 mL) at r.t. The product was dried briefly on the filter to give the title compound; 4.64 g; assay by 1H NMR: 89.3% w/w; yield corrected for assay: 4.14 g (84%); purity by LC 99.1 area %; m/z: 350 (MH+); 1H NMR: 1.99-2.05 (2H, m), 2.16 (3H, s), 2.26-2.31 (2H, t), 2.73-2.77 (2H, t), 4.83 (2H, s), 6.95-6.99 (2H, d), 7.23-7.27 (2H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][N:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:33]2[CH:32]=[N:31][C:30]([Cl:29])=[CH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: ClCc1ccc(Cl)nc1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccc(Cl)nc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 2-chloro-5-chloromethylpyridine gave the title compound. ES-MS m/e (%): 524.1(M+H+).
Reaction SMILES: [Na].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[F:14][C:15]([F:47])([F:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38](O)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=1>C(OCC)(=O)C>[F:14][C:15]([F:46])([F:47])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CC(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
The [4-(polyfluoroalkylamino)phenyl]alkenoic acids may be prepared by condensation of the appropriate aldehydes or by dehydration of the corresponding substituted-phenyl-hydroxyalkanoic acids. For examle, ethyl 5-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-2,4-pentadienoate is obtained by the Wittig reaction of 4-[15-(trifluoromethyl)pentadecylamino]benzaldehyde with the Wittig reagent, triethyl 4-phosphonocrotonate. Alternatively, these alkenoic acids are obtained by heating 4-[N-polyfluoroalkyl-N-(methyl or acetyl)amino]benzaldehydes with the sodium salt of the carbanion of ethyl acetate or with a mixture of ethyl acetate, acetic anhydride and potassium acetate. The second method is illustrated by dehydration of ethyl 3-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-3-hydroxypropionate to yield ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[NH2:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C@@H:22]([NH2:24])[CH3:23])[C:13]=2[N:25]=1>>[C:1]([NH:8][C:9]1[C:10]([C:26]([NH2:28])=[O:27])=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C@@H:22]([NH2:24])[CH3:23])[C:13]=2[N:25]=1)(=[O:2])[CH3:3]
Reactant: C[C@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)N
Yield: 63 %

Procedure:
xxxi-a (44 mg, 0.104 mmol) was deprotected using the TFA conditions detailed in the preparation of 30 to afford the title compound (66, 29 mg, 63%). NH4OAc standard conditions. DAD Retention time=4.98 min. M+H=326. 1H NMR (300 MHz, DMSO-d6): δ 12.27 (br s, 1H), 9.05 (br s, 1H), 8.41 (br s, 1H), 8.31 (br s, 3H), 8.03 (d, J=7.6 Hz, 1H), 7.80 (br s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.51 (dd, J=7.6, 7.6 Hz, 1H), 7.32 (dd, J=7.0, 7.0 Hz, 1H), 4.53 (br s, 2H), 3.87-3.75 (br m, 1H), 2.32 (s, 3H), 1.16 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]=1[CH:30]=O>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:30][C:22]1[NH:23][C:24]2[C:29]([C:21]=1[CH2:20][CH2:19][CH2:18][N:17]([CH3:32])[CH3:16])=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:5])=[O:4]
Reactant: CN(C)CCCc1c(C=O)[nH]c2ccccc12
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1CCCN(C)C)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (98 mg, 0.43 mmol) was condensed with 3-(3-dimethylaminopropyl)-1H-indole-2-carbaldehyde (100 mg) to give the title compound as an orange solid.