Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(N2CC[C@H](N[C@@H](C3C4C(=CC=CC=4)C=CC=3)C)C2)=CC=1)(=O)C.[C:28]([O:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].F[C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]([CH3:53])[CH3:52])(=[O:50])=[O:49])=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.O>[CH3:52][N:51]([CH3:53])[S:48]([C:45]1[CH:44]=[CH:43][C:42]([N:38]2[CH2:39][CH2:40][C@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:31])([CH3:29])[CH3:30])[CH2:37]2)=[CH:47][CH:46]=1)(=[O:49])=[O:50]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Agent: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 16.9 %

Procedure:
A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml of THF was cooled to 0° C., and then, 100 ml of an aqueous 50% dimethylamine solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried, the solvent was evaporated, and disopropyl ether and hexane were added to the residue. Then, the precipitates were collected by filtration and washed with hexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzene sulfonamide. (2) In 600 ml of DMSO were suspended 25 g of (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine, 47.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide and 139 g of potassium carbonate, and the mixture was stirred at 130° C. for 1 day. To the reaction mixture were added water and ethyl acetate, the resulting mixture was stirred and the liquids were separated. The organic layer was washed with water, and then dried, and the solvent was evaporated. The residue was dissolved in chloroform, NH silica gel was added thereto and the mixture was allowed to stand for a while, and silica gel was filtered off. The silica gel was further washed with ethyl acetate. The filtrate and the washed solution were combined, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→67:33) to obtain 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH:34]1[CH2:37][CH2:36][CH2:35]1>>[N:34]1([C:2]2[CH:3]=[C:4]([S:8]([N:11]3[CH2:20][CH2:19][C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]5[CH:23]=[N:22][N:21]([C:24]6[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=6)[C:16]=5[CH:17]=4)[CH2:12]3)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(Br)c1)C2
Reactant: C1CNC1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(N3CCC3)c1)C2

Procedure:
The title compound was prepared by the method of Preparation 12c using (R)-6-(5-bromopyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and azetidine. LCMS (Method C): 510 (M+H)+, Retention time 11.3 minutes.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.N1C=CC=CC=1.[O:27]=[C:28]1[N:32]([CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:31][CH2:30][N:29]1[C:39](Cl)=[O:40]>C(Cl)Cl.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:39]([N:29]4[CH2:30][CH2:31][N:32]([CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[C:28]4=[O:27])=[O:40])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
A 0° C. solution of Example A2 (6.4 g, 23.94 mmol) and pyridine (6 mL, 74.2 mmol) in DCM (150 mL) was treated with a solution of Example B2 (8.36 g, 35.9 mmol) in DCM (10 mL), stirred at 0° C. for 5 min, warmed to RT and stirred for 1.5 h. The mixture was diluted with water, stirred for 15 min, and the layers separated. The organic layer was washed with water and the combined aqueous layers were extracted with DCM (4×). The combined organics were dried over Na2SO4, concentrated to dryness, treated with MeOH and concentrated again to dryness. The residue was dissolved in DCM, sonicated, treated with MTBE, sonicated and the resulting solid collected via filtration. The solid was treated with Et2O, sonicated and again collected via filtration to afford N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (8.93 g, 80%). 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (dd, J=9.0, 0.7 Hz, 1 H), 7.96 (d, J=0.7 Hz, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 6.69 (dd, J=5.7, 2.5 Hz, 1 H), 3.93-3.87 (m, 3 H), 3.84 (s, 3 H), 3.83-3.77 (m, 2 H), 3.49-3.43 (m, 2 H) 3.42-3.34 (m, 2 H), 1.78-1.64 (m, 2 H), 1.59 (m, 2 H); MS (ESI) m/z: 464.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH3:20]>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:20])=[O:5]
Reactant: N
Reactant: Cc1cc(OC(F)(F)F)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(OC(F)(F)F)ccc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
795 mg (3.61 mmol) of 2-methyl-4-(trifluoromethoxy)benzoic acid are heated under reflux with 4 ml (54.8 mmol) of thionyl chloride and one drop of DMF for 30 minutes. After cooling, the reaction solution is slowly added dropwise into an ice-cooled concentrated aqueous ammonia solution. The resulting precipitate is collected by suction filtration, taken up in 30 ml of water and stirred at 60° C. for 1 h. The mixture is allowed to cool and the solid is collected by filtration and dried in vacuo. Yield: 562 mg (71% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]([Si](C)(C)C)([F:40])[F:39]>CN(C=O)C>[F:37][C:38]([F:40])([F:39])[CH:22]([C:20]1[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1)[OH:23]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(O)C(F)(F)F)n2)ccc1-n1cnc(C)c1
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
Molecular sieves were added to a solution of 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carbaldehyde (60 mg, 0.14 mmol) in dry DMF (1 mL) under argon atmosphere. The mixture was stirred for 30 minutes. Potassium carbonate (2 mg, 0.01 mmol) and (trifluoromethyl)trimethylsilane (0.427 mL, 0.21 mmol) were added. The mixture was stirred at ambient temperature for 2 days. The mixture was filtered and purified by preparative HPLC to yield the title compound (7 mg, 10%).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5]CC)=O.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18]Br)[C:14]([NH2:17])=[N:15][CH:16]=1>C1COCC1.C(OCC)(=O)C.[Zn]>[Br:10][C:11]1[CH:12]=[C:13]2[C:14](=[N:15][CH:16]=1)[NH:17][C:3](=[O:5])[C:2]([CH3:8])([CH3:9])[CH2:18]2
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)Cc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of activated Zn (1.0 g, 15 mmol) and ethyl 2-bromo-2-methylpropanoate (1.24 mL, 6.4 mmol) in THF (8 mL) were added together at 0° C. and stirred for 6 h while warming to room temperature. To this mixture a dropwise solution of 5-bromo-3-(bromomethyl)pyridin-2-amine in THF (5 mL) was added via canula and the reaction mixture was stirred for a further 19 h at rt. The mixture was diluted with ethyl acetate (25 mL) and washed with saturated aqueous NH4Cl (50 mL) and brine (50 mL), dried over magnesium sulphate, and concentrated in vacuo. The crude yellow solid product was triturated with diethyl ether and filtered to obtain the white solid product. Yield 158 mg (49%); 1H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.23 (s, 1H), 7.87 (s, 1H), 2.81 (s, 2H), 1.04 (s, 6H); ESI MS m/z 255, 257 [C10H11N2OBr+H]+
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH:13]=[C:14]([I:16])[S:15][C:3]=12.C1(C)C=CC=CC=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[S:15][C:14]([I:16])=[CH:13][C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cnc2cc(I)sc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)sc2c1O
Temperature: 190 °C

Procedure:
A stirring mixture of ethyl 7-hydroxy-2-iodothieno[3,2-b]pyridine-6-carboxylate (1.5 g, 4.29 mmol) in 4-chlorobenzylamine (15 mL) was heated at 190° C. for 1 hour. The resulting dark solution was cooled to ambient temperature and 100 mL toluene added. The resulting solid was collected by filtration and dried at 50° C. for 16 h to afford 0.875 g title compound as a yellow solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:11])[CH:6]=1.CS[C:14]1[CH:19]=CC=C[C:15]=1SC>>[C:10]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:11])[C:9]1[CH:8]=[CH:7][CH:19]=[CH:14][CH:15]=1
Reactant: CSc1ccccc1SC
Reactant: Oc1cccc2ccccc12
Product: O=C(c1ccccc1)c1ccccc1
Yield: 80 %

Procedure:
Thereafter, this naphthol compound was coupled with 1,2-dimethylthiobenzene in the same manner as in Example 17 to obtain a benzophenone derivative represented by the following formula (50) at a yield of 80%.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[N:19]=1)=[O:17]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:24][C:20]2[N:19]=[C:18]([C:16]([OH:17])=[O:15])[CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1cccc(CBr)n1
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3)cc2)n1

Procedure:
6-(Biphenyl-4-yloxymethyl)-pyridine-2-carboxylic acid was prepared using general procedure B from 4-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (Intermediate 2). Yield: 68 mg. Mass spectrum (ES) MH+=306.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH:22]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:14]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Add to a stirring solution of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid methyl ester (2.0 g, 5.22 mmol) in THF (50 mL) and MeOH (25 mL), 5N NaOH (3 mL, 2.9 eq.). Stir the solution for 2 h at room temperature and the remove solvents to give a paste. Treat the paste with 1N HCl (25 mL) and a solid results. Dilute further with water (50 mL). Filter the solid, back-wash with water, and dry (20 mm Hg, 60° C.) to provide the pure title compound (1.63 g, 84%); 1H NMR (DMSO-d6) δ 8.06 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.53 (s, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 3.17 (m, 1H), 2.08 (m, 2H), 1.69 (m, 6H); MS(ESI) m/z 368 (m−H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:16].[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([Cl:22])=[O:21]>O1CCOCC1>[ClH:22].[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:2]=1[F:1])=[O:21]
Reactant: CN1CCC(Oc2cccc(N)c2F)CC1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: C1COCCO1
Product: CN1CCC(Oc2cccc(NC(=O)c3ccc(F)cc3F)c2F)CC1
Product: Cl
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Heat a mixture of 2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenylamine (preparation 33, 0.126 g) and 2,4-difluorobenzoyl chloride (0.119 g) in 1,4-dioxane (5 mL) for 2.5 hrs. Cool to room temperature, collect the white crystals and wash with ether to give the free base of title compound (0.164 g). The free base is converted to the mono hydrochloric acid salt using a method similar to Example 52 to provide the title compound. Mass spectrum (electric spray) m/z=365 (M+1); 1H NMR (CD3OD-CDCl3): 8.04 (m, 1H), 7.85 (m, 1H), 7.05 (m, 3H), 6.88 (m, 1H), 4.69 (m, 1H), 3.37 (m, 2H), 3.31 (s, 2H), 2.84 (s, 3H), 2.34 (m, 2H), 2.20 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])[CH2:14][C@H:13]1[O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([OH:23])=[O:22])[CH2:14][C@H:13]1[O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CO[C@@H]1CN(c2cccc(C(=O)O)c2)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Methyl cis(±)-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (42a) (250 mg, 0.63 mmol) was dissolved in methanol (5 mL). A 1 N aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at 70° C. for one hour. The reaction solution was neutralized with 1 N hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH2:25]([NH-:29])[CH2:26][CH2:27][CH3:28]>>[CH2:25]([NH:29][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[NH-]
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Product: CCCCNC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride is reacted with butyl amide to produce 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl amide, m.p. 178° C.; and
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33](=[O:36])[N:32]([CH:37]([CH2:48][O:49][CH3:50])[CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1>[CH2:19]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33](=[O:36])[N:32]([CH:37]([CH2:48][O:49][CH3:50])[CH2:38][CH2:39][OH:40])[CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCC(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COCC(CCO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Yield: 76.9 %

Procedure:
3.22 ml (3.22 mmol, 1 M in tetrahydrofuran) tetrabutylammonium fluoride were added to a cooled solution (0° C.) of 1.36 g (2.93 mmol) (rac)-4-[3-(tert-butyl-dimethyl-silanyloxy)-1-methoxymethyl-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 29 ml tetrahydrofuran. After 50 min water was added and extracted with ethyl acetate (3×). The organic phases were washed with water (2×), dried over Na2SO4 and evaporated. Flash chromatography on silica gel with a gradient 2% to 4% methanol in dichloromethane yielded 0.79 g (77%) of the title compound as a colorless oil, MS: 263 (M).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[N:7]=1)=[O:19]
Reactant: CN1CCC(=O)CC1
Reactant: Nc1cccc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(Nc2cccc(NC(=O)c3c(Cl)cc(Cl)cc3Cl)n2)CC1
Yield: 38.3 %

Procedure:
Using a method similar to Example 104 using N-(6-amino-pyridin-2-yl)-2,4,6-trichloro-benzamide (Preparation 55, 375 mg, 1.18 mmol), 1-methyl-4-piperidone (270 mg, 0.29 mL, 2.37 mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g), glacial acetic acid (0.21 g, 0.20 mL, 3.54 mmol), sodium triacetoxyborohydride (625 mg, 2.95 mmol) gives the title compound (187 mg, 45% yield): dihydrochloride salt: mass spectrum (ion spray): m/z=412.0 (M+1), 1H NMR δ (CDCl3) 7.78 (s, 1H), 7.56 (d, 1H), 7.45 (t, 1H), 7.36 (s, 2H), 6.18 (d, 1H), 4.26 (d, 1H), 3.55 (m, 1H), 2.73 (d, 2H), 2.28 (s, 3H), 2.11 (m, 4H), 1.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37]>Cl.O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:37])([F:38])[F:39]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(N2CCOCC2)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccnc(N2CCOCC2)c1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 85 °C

Procedure:
4-Chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide from step 2 was dissolved in a mixture of 4 M HCl in dioxane (8 mL) and water (2 mL), heated to 85° C. for 2 h. The solvent was evaporated and the residue was purified with HPLC to give 4-chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. MS m/z: 561 (M+H)+.
Reaction SMILES: CO[C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].C(O)(=[O:18])C>Br>[N+:13]([C:4]1[CH:5]=[CH:6][C:7]([OH:18])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:3]=1)([O-:15])=[O:14]
Reactant: CC(=O)O
Reactant: COc1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: Br
Product: O=[N+]([O-])c1ccc(O)c(C(F)(F)F)c1

Procedure:
A solution of 24.73 g (110.7 mmol) 6-methoxy-5-nitrobenzotrifluoride in 260 ml acetic acid and 130 ml of aqueous HBr solution (62%) was heated to reflux for 96 h, cooled down, evaporated and taken up in aqueous saturated NaHCO3 solution/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over sodium sulfate, and evaporated to dryness to yield 19.27 g of the title compound as yellow solid of mp. 103–104° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:28][C:29]1[S:33][N:32]=[C:31]([CH2:34]Cl)[N:30]=1>CC(C)=O.CC(=O)CC>[Cl:28][C:29]1[S:33][N:32]=[C:31]([CH2:34][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[N:30]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: O=C1N(Cc2nsc(Cl)n2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a stirred solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.33 g, 4.73 mmol) in acetone (50 mL) and 2-butanone (10 mL) were added cesium carbonate (3.10 g, 9.46 mmol) and 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole (1.00 g, 5.92 mmol). The reaction was stirred at ambient temperature for 16 h, then filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (15% to 50% gradient) to afford 1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.43 g, 22%) as a colorless solid: mp 114-116° C.; 1H NMR (300 MHz, DMSO-d6) δ7.29 (dd, J=7.7, 7.7 Hz, 1H), 7.21 (d, J=7.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.71 (s, 1H), 6.32 (s, 1H), 5.93 (d, J=3.0 Hz, 2H), 5.24 (ABq, 2H), 4.78 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 174.2, 170.6, 155.7, 148.8, 142.4, 142.2, 132.2, 129.3, 124.1, 123.7, 120.4, 109.8, 103.5, 101.9, 93.8, 79.9, 57.9, 41.6; MS (ES+) m/z 414.1 (M+1), 416.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[OH:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]([NH2:35])=[NH:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:34]=[C:33]([NH:32][C:26]4[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([OH:23])[CH:25]=4)[N:35]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: COc1ccc(NC(=N)N)cc1O
Solvent: O=[N+]([O-])O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1O

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-hydroxy-4-methoxy-phenyl)-guanidine nitrate were converted to I-65 (69%): HRMS Calcd. for C19H15ClN4O3: 383.091, Found 383.0913.