Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:37])=[C:4]([S:9]([N:12]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(O)(=O)C.[Fe]>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][N:12]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=3[OH:37])(=[O:11])=[O:10])[CH:15]=2)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccc(CN(Cc3ccc(F)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(-c2cccc(CN(Cc3ccc(F)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
A mixture of 3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxy-N-((4′-nitrobiphenyl-3-yl)-methyl)benzenesulfonamide (0.2 g, 0.4 mmol) and iron (0.1 g, 2.1 mmol) in acetic acid (5 mL) was heated at 70° C., under a nitrogen atmosphere. After 40 minutes, the reaction mixture was cooled to room temperature and filtered through a pad of Celite®. The pad was thoroughly rinsed with EtOAc followed by CHCl3. The combined filtrates were concentrated in vacuo. The crude product was dissolved in CHCl3 then passed through a RediSep normal phase silica flash column (12 g) eluting with CHCl3. The appropriate fractions were concentrated in vacuo to afford the title compound (0.18 g, 84%) as an off-white solid. 1H NMR (DMSO-d6) δ 7.77 (d, J=2.2 Hz, 1H), 7.58 (d, J=2.7 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.24-7.03 (m, 8H), 6.93 (d, J=7.7 Hz, 1H), 6.63-6.58 (m, 2H), 4.46 (s, 2H), 4.43 (s, 2H). MS (ESI): 531.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([OH:22])=O)[C:15]([CH3:23])=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][CH:25]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:24][CH:25]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])=[O:22])[C:15]([CH3:23])=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ncc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)NC(Cc1ccccc1)C(=O)C(F)(F)F

Procedure:
2-(5-Benzyloxycarbomylamino-2-methyl-6-oxo-1,6-dihydro-1-pyrimidyl)-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, (5-benzyloxycarbonylamino-2-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl)-acetic acid (title compound in Reference Example 11, 3.00 g, 9.45 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 2.17 g, 9.90 mmol), WSCI hydrochloride (2.17 g, 11.3 mmol) and HOBT (2.56 g, 18.9 mmol) in DMF (30 mL) to give 4.44 g (91%) of the target compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CC(=O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: Cc1ccc(F)c(O)c1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(F)c(OCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
A 200 ml 3-neck round bottom flask equipped with a magnetic stirrer bar and a reflux condenser was charged with 4.99 g (40 mmol) of 2-fluoro-5-methyl phenol, 9.01 g (44 mmol) of ethyl 4-bromobutyrate, 6.63 g (48 mmol) potassium carbonate and 120 ml of 2-butanone. The slurry heated to reflux. After stirring for 14.5 hr at reflux, the reaction mixture was cooled to 25° C., filtered and concentrated. The residue was taken up in water (200 ml) and treated with 42 ml (84 mmol) 2N aqueous sodium hydroxide. The reaction mixture was heated to reflux for 2 hours and cooled to 25° C. The yellow solution was acidified with 45 ml 2N aqueous hydrochloric acid. The resulting white solid was isolated by filtration washing with twice with water then twice with hexanes to yield 7.64 g (90%), mp 62-64° C. Combustion analysis: Found: C, 62.2%; H, 6.19%; Calculated: C, 62.26%; H, 6.17%; 1H NMR analysis (d6-DMSO): δ 12.2, broad s, 1H, (COOH); δ7.0, m, 2H (aryl H); δ 6.7, s, 1H (aryl H); δ 4.0, t, 2H (CH2 α ArO); δ 2.4, t, 2H (CH2 α COOH); δ 2.21, s, 3H (CH3 para F); δ 1.90, m, 2H (CH2 β COOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15][NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:15][N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[S:28]([CH3:27])(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CNCC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: CC(C)CN(CC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step II (450 mg, 1.2 mmol) in CH2Cl2 (5 mL) was added TEA (0.35 mL, 2.44 mmol) and methanesulfonyl chloride (0.14 mL, 1.83 mmol). After stirring was 30 min at 23° C. the reaction was diluted with CH2Cl2 and washed with brine, dried (Na2SO4), and evaporated to give the title product as an oil. MS m/z 446.3 (M++1).
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]3[NH:14][CH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH:11]([CH3:22])[C:10]=3[C:6]=2[CH:5]=[C:4]([Cl:23])[CH:3]=1.[C:24]1([S:30]([O-:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[C:7]2[O:8][C:9]3[NH:14][CH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH:11]([CH3:22])[C:10]=3[C:6]=2[CH:5]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC1CC(C(=O)OC(C)(C)C)Nc2oc3c(Br)cc(Cl)cc3c21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC1CC(C(=O)OC(C)(C)C)Nc2oc3c(S(=O)(=O)c4ccccc4)cc(Cl)cc3c21
Temperature: 110 °C
Yield: 29.6 %

Procedure:
A mixture of the product of step B (560 mg, 1.39 mmol), sodium benzenesulfinate (275 mg, 1.67 mmol), di-palladium-tris(dibenzylideneacetone) (179 mg, 0.19 mmol), cesium carbonate (683 mg, 2.09 mmol) and xantphos (225 mg, 0.39 mmol) were suspended in anhydrous toluene (20 mL). The reaction flask was purged with argon and heated to 110° C. for 6 h. After cooling to ambient temperature, the reaction was diluted with dichloromethane and filtered through a celite bed. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 4:1 hexanes/ethyl acetate) to give tert-butyl 6-chloro-4-methyl-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-e]pyridine-2(1H)-carboxylate (190 mg, 29%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.01-7.93 (m, 3H), 7.84 (s, 1H), 7.61-7.47 (m, 3H), 4.63-4.47 (m, 2H), 4.08-3.75 (m, 1H), 3.58-3.27 (m, 1H), 3.21-3.08 (m, 1H), 1.51 (s, 9H), 1.33 (d, J=6.9 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([F:22])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[F:22][C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][C:17]=1[C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(N2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (6.97 g, 22.83 mmol) in methanol (250 mL) was saturated with HCl gas and stirred at ambient temperature overnight. The reaction was concentrated, saturated sodium bicarbonate (250 mL) was added and the slurry was stirred for 1 hour. The resulting solid was filtered off, rinsed well with water, air dried then evacuated overnight. As water was removed from the solid, it turned to a milky yellow solid which slowly solidified to give 2-fluoro-4-piperazin-1-yl-benzonitrile as a waxy solid (3.84 g, 82%).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:8][CH:9]=2)[N:4]([CH3:20])[N:3]=1.[C:21]([O:25][C:26](=[O:44])[NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[CH3:43])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:44])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[N:8][CH:9]=3)[N:4]([CH3:20])[N:3]=2)=[CH:30][C:29]=1[CH3:43])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: Cn1nc(Cl)c2cnc(NCCN3CCOCC3)nc21
Product: Cc1cc(-c2nn(C)c3nc(NCCN4CCOCC4)ncc23)ccc1NC(=O)OC(C)(C)C

Procedure:
Prepared as described above in Example 15 starting from (3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-morpholin-4-yl-ethyl)-amine and [2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester to give the title compound {2-methyl-4-[1-methyl-6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-phenyl}-carbamic acid tert-butyl ester; LC/MS (m/e)=468.2 (MH+), Rt=1.40 min
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:18]Br>ClCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[Br:18]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1ccc2nc(-c3ccc(N)c(Br)c3)sc2c1
Yield: 85.2 %

Procedure:
2-(4'-Aminophenyl)-6-methylbenzothiazole (0.6 g, 2.5 mmol) was treated with bromine (0.403 g, 2.5 mmol) in dichloromethane according to the above-described general procedure for bromination. Crude product was purified by flash chromatography on silica gel, using ethyl acetate-hexane (1:3) as eluent, to give brown small crystals (0.68 g, 85.3%), m.p. 187.9-189.5° C.
Reaction SMILES: ClC(OCC)=O.[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[CH2:16]C(O)=O.C([N:22](CC)CC)C.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.[Cl-].[Na+].O>[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[CH2:16][NH2:22]
Reactant: O=C(O)CC1Cc2ccccc2C1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Solvent: CC(C)=O
Solvent: O
Product: NCC1Cc2ccccc2C1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (3.3 ml, 34 mmol) is added to a cooled (0° C.) solution of indan-2-yl acetic acid (5.0 g, 28.4 mmol) and triethylamine (4.75 ml, 34 mmol) in acetone (40 ml) and water (8 ml). After 30 minutes, a solution of sodium azide (2.8 g, 42.6 mmol) in water (16 ml) is added and the reaction is stirred at 5° C. for 1 hour, prior to addition of brine and ice. The mixture is extracted with ether and the combined extracts are dried (Na2SO4) and evaporated. The resultant acyl azide is taken into toluene (50 ml) and heated at 100° C. until nitrogen evolution ceases. After evaporation of solvent, the resultant isocyanate is taken into 6N HCl (40 ml) and heated at 100° C. for 16 hours. The reaction mixture is evaporated to ⅓ volume and the resultant solid collected by filtration, washed with water and ether, then dried. The resultant hydrochloride salt is suspended in ether (20 ml) and ammonia is bubbled for 10 minutes. Water is added and the organic layer is separated, dried (Na2SO4) and evaporated to afford the title compound [MH+CH3CN]+189.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:3]=1.[OH-].[K+].[CH:24]([OH:27])([CH3:26])[CH3:25]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH:24]([O:27][C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([N:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:3]=1)([CH3:26])[CH3:25]
Reactant: CC(C)O
Reactant: CC(C)Oc1nc(Cl)nc(N2C(C)(C)CCCC2(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Oc1nc(OC(C)C)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 8 h

Procedure:
12.5 g of 2-chloro-4-isopropyloxy-6-(2,2,6,6-tetramethylpiperidin-1-yl)- 1,3,5-triazine (product from Example 55), 11.2 g of finely pulverized potassium hydroxide and 0.7 g of tetrabutylammonium hydrogen sulfate are initially introduced in 60 ml of toluene. 2.6 g of isopropanol are added dropwise during the course of 15 minutes to this orange-colored suspension: weakly exothermic reaction to about 30+. The pale brown contents of the flask are stirred at 60° for 8 hours, cooled to 0°-5°, and diluted with 80 ml of water and then with 40 ml of toluene. The brown, aqueous phase is separated off from the colorless, organic phase and the latter is washed four times, each with 80 ml of water, dried over sodium sulfate and completely evaporated in vacuo. A weakly yellowish oil is obtained which solidifies after a short time to give 2,4-bis-isopropyloxy-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine with a melting range of 70°-98°.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1>>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(C)c(Oc2ccnc(Cl)c2)c1
Yield: 93.8 %

Procedure:
Using the method of Example 3, Step A, ethyl 4-methyl-3-hydroxybenzoate (1.70 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.48 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide ethyl 4-methyl-3-(2-chloropyridin-4-yloxy)benzoate (2.59 g, 94% yield) as a clear oil. 1H NMR (CDCl3) δ 8.24 (d, 1H), 7.90 (d, 1H), 7.69 (s, 1H), 7.38 (d, 1H), 6.73 (d, 2H), 4.37 (quartet, 2H), 2.23 (s, 3H), 1.39 (t, 3H).
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:48]([CH2:61][CH2:62][CH:63]([CH3:65])[CH3:64])[S:49]([C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)(=[O:51])=[O:50])[CH2:21][CH2:22][CH:23]([F:47])[CH2:24][NH:25][C:26](=[O:46])[C@H:27]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:28][C:29]([O:31][CH3:32])=[O:30])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:47][CH:23]([CH2:22][CH2:21][C@H:20]([N:48]([CH2:61][CH2:62][CH:63]([CH3:65])[CH3:64])[S:49]([C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)(=[O:51])=[O:50])[CH2:19][OH:18])[CH2:24][NH:25][C:26](=[O:46])[C@H:27]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred solution of the material from Step 13 (80 mg, 0.086 mmol) in THF (1.7 mL) was added 1.0 M TBAF (104 μL, 0.104 mmol) in THF. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 45 mg of the title compound. LCMS (M+1)=687.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[N:12]=1.CCN(C(C)C)C(C)C>CCO>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[CH:14]=[C:13]([C:18]([F:21])([F:19])[F:20])[N:12]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 70 °C
Reaction time: 22 h
Yield: 51.5 %

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (1.42 g, 11.5 mmol), 2,4-dichloro-6-(trifluoromethyl)pyrimidine (2.50 g, 11.5 mmol), DIPEA (4.05 mL, 23.0 mmol), and anhydrous EtOH (35 mL) was stirred at 70° C. under N2 for 22 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and the organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Trituration with DCM afforded 1.80 g (51.5%) of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)pyrimidin-4-amine (186) as a white solid: 1H NMR (400 MHz, DMSO-d6): δ 12.35 (br d, J=30.2 Hz, 1H), 10.97 (s, 1H), 8.14 (s, 0.50H, rotamer), 7.13 (s, 0.50H, rotamer), 6.38 (s, 0.50H, rotamer), 5.73 (s, 0.50H, rotamer), 1.91 (s, 1H), 0.98-0.90 (m, 2H), 0.70 (q, J=5.5 Hz, 2H); MS (ESI) m/z=304.2/306.2 [M+1]+.
Reaction SMILES: CC1(C)CO[C:5]2([CH2:9][C@@H:8]([C:10]([NH:12][C:13]3[CH2:20][CH2:19][C:16]4([CH2:18][CH2:17]4)[CH2:15][C:14]=3[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:11])[CH2:7][CH2:6]2)[O:4]C1.Cl>C(O)C>[O:4]=[C:5]1[CH2:6][CH2:7][C@H:8]([C:10]([NH:12][C:13]2[CH2:20][CH2:19][C:16]3([CH2:18][CH2:17]3)[CH2:15][C:14]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:11])[CH2:9]1
Reactant: CCOC(=O)C1=C(NC(=O)[C@H]2CCC3(C2)OCC(C)(C)CO3)CCC2(CC2)C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(NC(=O)[C@H]2CCC(=O)C2)CCC2(CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-ethyl 6-(8,8-dimethyl-6,10-dioxaspiro[4.5]decane-2-carboxamido)spiro[2.5]oct-5-ene-5-carboxylate. (1.5 g, 11.50 mmol) in ethanol (25 ml) was added 1 N hydrochloric acid (7.5 ml) in portion wise manner at 0° C. and the reaction was allowed to stir at 25° C. for overnight. Organic solvent was removed under reduced pressure; the residue was diluted with dichloromethane (50 ml) and water (25 ml). The organic mass was extracted using dichloromethane (3×50 ml). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude compound, which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain (S)-ethyl 6-(3-oxocyclopentanecarboxamido)spiro[2.5]oct-5-ene-5-carboxylate. (1 g, 85%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(O)c1ccc(F)cc1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(F)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-[(4-fluoro-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-di-hydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 4-fluoro-benzoic acid. MS calcd. for C26H21ClFN3O3 [(M+H)+] 478.1, obsd. 477.9.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[CH:15][CH:14]=1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: Nc1ccc(Br)cc1
Product: Cn1c(Nc2ccc(Br)cc2)nc2ccccc21
Temperature: 170 °C
Yield: 96.5 %

Procedure:
A mixture of 2-chloro-1-methyl-benzimidazole (0.639 g, 3.84 mmol) and 4-bromoaniline (0.710 g, 4.12 mmol) was heated at 170° C. for 21 h. The resulting brown solid was cooled to room temperature, washed with three 5-mL portions of heptane, and then triturated with toluene to afford N2-(4-bromophenyl)-1-methyl-1H-benzo[d]imidazol-2-amine (1.120 g, 90%) as a brown powder. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=10.85 min, 96%; m/z 302 (MH+).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([CH:21]=O)[C:16](=[O:20])[NH:17]2)=[CH:12][CH:11]=1>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([CH3:21])[C:16](=[O:20])[NH:17]2)=[CH:12][CH:11]=1
Reactant: COc1ccc2cc(C=O)c(=O)[nH]c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(C)c(=O)[nH]c2c1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
30.7 ml of triethylsilane was added to a trifluoroacetic acid (300 ml) solution of 13 g of 7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde while being stirred under ice-cooling and stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with dichloromethane and, after washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), and 11.1 g of 7-methoxy-3-methyl-1H-quinolin-2-one was obtained in the form of a white powder.
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>>[F:1][S:2]([F:12])([F:13])([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:21]([O-:23])=[O:22])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pentafluorosulfanylbenzoic acid (5.0 g) was dissolved in fuming nitric acid (20 ml) and stirred at RT with exclusion of moisture. Then concentrated sulfuric acid (3 ml) was added and the mixture was stirred at 75° C. After stirring at 75° C. for 5 h, further sulfuric acid (1.5 ml) was added and, after stirring at 75° C. for 2 h, left to stand overnight. Then the mixture was added to ice-water and stirred for 2 h. The precipitate formed was filtered off with suction and dried under high vacuum. 4.2 g of 3-pentafluorosulfanyl-5-nitrobenzoic acid were obtained. A further 900 mg were obtained from the mother liquor after extracting three times with methylene chloride, drying the combined methylene chloride phases over magnesium sulfate and concentrating the solvent. The precipitate was used in the next stage without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24]([O:26]CC)=[O:25])=[CH:10]2)=[O:5].[OH-].[Li+]>>[CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]2)=[O:5]
Reactant: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1Cc1ccccc1F
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2Cc1ccccc1F

Procedure:
Preparation analogously to Example XXII using 12.50 g (31.53 mmol) of ethyl 5-[(3,3-dimethylbutanoyl)amino]-1-(2-fluorobenzyl)-1H-indole-2-carboxylate from Example XXXVII and 31.5 ml (63.0 mmol) of 2 M lithium hydroxide solution.