Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.C(N1CCNCC1)C.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.[CH2:36]([N:38]1[CH2:43][CH2:42][N:41]([S:44]([C:47]2[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH2:40][CH2:39]1)[CH3:37]>>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][C:47]([S:44]([N:41]3[CH2:40][CH2:39][N:38]([CH2:36][CH3:37])[CH2:43][CH2:42]3)(=[O:46])=[O:45])=[CH:48][CH:49]=2)=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: CCN1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: CCN1CCNCC1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CCN1CCN(S(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 570 mg of 1-ethylpiperazine via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(4-ethylpiperazin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazin-1-ylsulfonyl). MS (Q1) 485 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH:20]=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N+:23]([C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]([N:34]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH:36]=[CH2:37])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][N:41]2[CH2:42][CH2:43][CH:38]([N:34]([C:32]([O:31][CH2:30][C:29]3[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:45][CH:44]=3)=[O:33])[CH2:35][CH:36]=[CH2:37])[CH2:39][CH2:40]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC(C=O)C(c2ccccc2)C1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(NC(=O)OC(C)(C)C)CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.2 %

Procedure:
To a solution of 1-((SR)-((t-butoxycarbonyl)amino)-3-(SR)-(formyl)-4-(SR)-phenylcyclopentane (from Step G, derived from Higher Rf isomer in Step E) (30 mg, 0.11 mmol) in 1,2-dichloroethane (3 mL) was added 4-(N-(4-nitrobenzyloxycarbonyl)(N-allyl)amino)piperidine hydrochloride (45 mg, 0.126 mmol) and DIPEA (0.022 mL, 0.126 mmol). After 15 min, sodium triacetoxyborohydride (45 mg, 0.22 mmol) was added and the reaction was stirred at RT for 6 h. The reaction was diluted with methylene chloride, quenched with aq. sodium carbonate and extracted 3 times with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by Prep TLC eluting with 5% methanol in methylene chloride to give the title product (66 mg) as the free amine.
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[O:13][CH2:14][C:15](=[O:22])[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH3:23])[CH:6]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][N:33]=2)[C:28]([CH:35]=O)=[CH:27]1.N1CCCCC1>C(O)C>[NH:26]1[C:34]2=[N:33][CH:32]=[CH:31][CH:30]=[C:29]2[C:28]([CH:35]=[C:14]2[O:13][C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:24][OH:25])=[CH:6][C:7]=3[CH3:23])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]2=[O:22])=[CH:27]1
Reactant: CCOC(=O)C1=C(Nc2ccc(OCC(O)CO)cc2C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(OCC(O)CO)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22.5 %

Procedure:
To a stirred solution of ethyl 2-{[4-(2,3-dihydroxypropoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.17 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.070 g, 0.50 mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound as solid (0.054 g, y. 23%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>O.[OH-].[Na+]>[N+:17]([C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4](=[O:9])[NH:5][CH:6]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]cccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(trifluoromethyl)pyridin-2(1H)-one 2 (2.00 g, 12.26 mmol) and sulfuric acid (H2SO4, 3.5 ml, 30%) was heated to 90° C. and nitric acid (HNO3, 2.5 ml, 65%) was added. The mixture was stirred at 90° C. for 8 hours and additional nitric acid (1 ml, 65%) was added. The mixture was stirred for an additional 6 hours at 90° C. and was then poured into a beaker containing ice (30 ml). The mixture was diluted with water (30 ml) and 6N aqueous NaOH was added until a pH of about 4 to about 5. The mixture was extracted with ethyl acetate (3×40 ml), the combined organic phases dried over Na2SO4 and all solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate and the product precipitated by the addition of hexane. After filtration, 5-nitro-3-(trifluoromethyl)pyridin-2(1H)-one 3 was obtained as a yellow powder (1.58 g, 7.59 mmol, 62%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:43]([F:46])([F:45])[F:44])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])[N:7]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][C:29]([NH:31][S:32]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)(=[O:34])=[O:33])=[O:30])=[CH:22][CH:21]=3)[C:6]=2[CH:42]=1.FC(F)(F)C(O)=O.O>C(Cl)Cl>[NH2:12][CH:10]([C:8]1[N:7]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][C:29]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])=[O:30])=[CH:22][CH:21]=2)[C:6]2[CH:42]=[C:2]([Cl:1])[C:3]([C:43]([F:45])([F:44])[F:46])=[CH:4][C:5]=2[N:9]=1)[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(C(C)NC(=O)OC(C)(C)C)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(C(C)N)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of 1,1-dimethylethyl 1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethylcarbamate (step 2, 190 mg, 0.28 mmol) in CH2Cl2 (2 ml) was added trifluoroacetic acid (1 ml) and stirred at room temperature for 2 h. The mixture was added water (10 ml) and extracted with CH2Cl2 (20 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2/MeOH (10:1/5:1) to afford 160 mg (99%) of the title compound as white solids.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH:12][CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:14]([NH:16][NH2:17])=[O:15]>C(O)C>[OH:9][C:8]1[CH:10]=[CH:11][C:3](/[CH:2]=[N:17]/[NH:16][C:14](=[O:15])[CH:13]([OH:12])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1ccc(C(O)C(=O)NN)cc1
Solvent: CCO
Product: COc1ccc(C(O)C(=O)N/N=C/c2ccc(O)c(OC)c2)cc1

Procedure:
Vanillin (23 g, 0.15 mol) is added to a solution of hydroxy-(4-methoxy-phenyl)-acetic acid hydrazide (30 g, 0.15 mol) in 300 ml of ethanol at room temperature. After heating this mixture to reflux for 4 hours, the reaction is poured on water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated. The residue, which is hydroxy-(4-methoxy-phenyl)-acetic acid [1-(4-hydroxy-3-methoxy-phenyl)-meth-(E)-ylidene]-hydrazide, is sufficiently pure to be directly used in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12](Br)[N:11]=2)=[O:9])=[CH:3][CH:2]=1.[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12]([C:27]3[CH:26]=[N:25][N:24]([CH2:23][CH:19]4[O:20][CH2:21][CH2:22][O:18]4)[CH:28]=3)[N:11]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccncc1
Reactant: CC1(C)OB(c2cnn(CC3OCCO3)c2)OC1(C)C
Product: Nc1ncc(-c2cnn(CC3OCCO3)c2)nc1C(=O)Nc1ccncc1

Procedure:
The reaction of 3-amino-6-bromo-pyrazine-2-carboxylic acid pyridin-4-ylamide (synthesis described for “A10”) with 1-[1,3]dioxolan-2-ylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A12”
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:17][C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].CC#N>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:16][NH:15][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:18]([NH2:17])=[O:19])[CH:25]=2)=[CH:3][CH:4]=1)[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CN[C@@H](CN1CCCC1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: CN[C@@H](CN1CCCC1)c1ccc(-c2cccc(C(N)=O)c2)cc1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
(1R)-1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine (2.65 g, 9.4 mmol) was dissolved in dioxane (100 mL) under argon at room temperature. The resulting solution was magnetically stirred and treated with [3-(aminocarbonyl)phenyl]boronic acid (1.7 g, 10.3 mmol) followed by 15 mL of a 1.88M solution of Na2CO3 (28.2 mmol) and PdCl2(dppf)2·CH2Cl2 (408 mg, 0.5 mmol) all at room temperature. The flask was placed in a preheated 100° C. oil bath and maintained at 100° C. for approximately 18 h after which time it was determined by LCMS to be 60% complete. Additional PdCl2(dppf)2·CH2Cl2, (408 mg, 0.5 mmol) was added and the reaction was allowed to continue at 105° C. for approximately another 6 h. The reaction was determined to be complete by LCMS (Eclipse XDB C18, 4.6×250 mm column, 1.5 mL/min, 10 minutes, gradient from 1-99% CH3CN (0.1% trifluoroacetic acid)/H2O (0.1% trifluoroacetic acid), ES, Rt=4.46 min and m/e 324 [M+1]+). The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under vacuum by rotary evaporation and purified by silica gel chromatography (120 g Redisep silica gel column, 40 um, 60 Å, 50 mL/min, A: (CH2Cl2) B: (Methanol with 1% NH4OH) gradient of 0% -20% B in A, 60 min run; detection at 254 nm) to give 4′-[(1R)-1-(methylamino)-2-(1-pyrrolidinyl)ethyl]-3-biphenylcarboxamide (2.0 g) as a brown oil:
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=O)=[CH:3][CH:2]=1.OS(O)(=O)=O.[H][H]>C1COCC1.CO.C1(C)C=CC=CC=1.[Pd]>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C1CCC(C(=O)c2ccc(-c3ccccc3)cc2)N1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1CCC(Cc2ccc(-c3ccccc3)cc2)N1
Temperature: 50 °C
Yield: 96.5 %

Procedure:
A mixture of 26.5 g (100 mmol) (R/S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one, 3.0 g Pd/C (10% PD CP 4505 D/R Catalyst, BASF), 5 g conc. H2SO4 in 300 ml THF and 300 ml MeOH are hydrogenated at 1 atm pressure and heated at 50° C. After 10 h the hydrogen uptake stops. The catalyst is filtered off, washed with methanol and the resulting filtrate is concentrated in vacuo. The evaporation residue is dissolved in toluene and is washed with aqueous Na2CO3 solution. A part of the product precipitates and is filtered and dried in vacuo (96.5% HPLC area %). The toluene phase is washed twice with H2O and evaporated completely, to yield further crude product. This further crude product is purified over silica gel chromatography with toluene/methanol=4:1, to yield the product. This product is stirred in 70 ml toluene at 60° C. for 2 h. Then 70 ml heptanes fraction are added and the precipitate is filtered. The precipitate is dried in vacuo to yield (R/S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (96.5% HPLC area %). 1H NMR (DMSO): 1.69 (1H), 1.96-2.05 (2H), 2.67 (1H), 2.84 (1H), 3.80 (1H), 7.31 (2H), 7.44 (2H), 7.57 (2H), 7.63 (2H), 7.74 (1H).
Reaction SMILES: N.[Li].[OH:3][C@H:4]1[C@:8]2([CH3:22])[CH2:9][C@H:10]3[C@H:19]([CH2:20][C@H:7]2[CH2:6][CH2:5]1)[C@@H:18]1[C:13](=[CH:14][C:15](=[O:21])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[NH4+].[Cl-]>C1COCC1>[OH:3][C@H:4]1[C@:8]2([CH3:22])[CH2:9][C@H:10]3[C@H:19]([CH2:20][C@H:7]2[CH2:6][CH2:5]1)[C@@H:18]1[C@H:13]([CH2:14][C:15](=[O:21])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: C[C@@]12C[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3C[C@H]1CC[C@H]2O
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@@]12C[C@@H]3CC[C@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CC[C@H]2O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A three-neck flask fitted with a dry ice condenser was cooled to −78° C., and anhydrous ammonia (100 mL) was condensed into the flask. Lithium (0.21 g, 30 mmol) was added, and the resulting blue solution was stirred for 0.5 h. To this was added a solution of compound 36 (820 mg, 3.0 mmol) in dry THF (30 mL). After 3 h, solid NH4Cl was added until the blue color disappeared. The cooling bath was removed and stirring was continued at room temperature overnight. Aqueous NH4Cl was added and the product was extracted into EtOAc (100 mL×3). The combined extracts were washed with brine, dried and the solvent evaporated. Flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) gave compound 37 (615 mg, 75%) as a white solid: [α]D25+52.3 (c 0.13, CHCl3); 1H NMR (CDCl3) δ 3.58 (t, J=7.7 Hz, 1H), 0.68 (s, 3H); 13C NMR (CDCl3) δ 211.7, 81.3, 48.3, 47.8, 45.7, 44.9, 44.5, 43.6, 42.9, 41.0, 37.8, 34.2, 33.7, 30.1, 29.9, 29.0, 25.3, 11.0; IR νmax 3419, 1713 cm−1. Anal. Calcd for (C18H28O2): C, 78.21; H, 10.21. Found: C, 78.29; H, 10.12.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][O:11][C:12]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]2[C:13]=1[C:14]([C:34](=[O:38])[C:35]([NH2:37])=[O:36])=[C:15]([CH2:32][CH3:33])[N:16]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C1C=CC=CC=1.C1CC=CCC=1>O1CCCC1.[Pd]>[NH2:37][C:35](=[O:36])[C:34]([C:14]1[C:13]2[C:17](=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:12]=2[O:11][CH2:10][C:9]([OH:39])=[O:8])[N:16]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]=1[CH2:32][CH3:33])=[O:38]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OCc3ccccc3)c3ccccc3cc2n1Cc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: C1CCOC1
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)c3ccccc3cc2n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A mixture of 2-[[3-(2-amino-1,2-dioxoethyl)-1-benzyl-2-ethyl-1H-benz[f]indol-4-yl]oxy]acetic acid benzyl ester (29 mg, 0.056 mmol), 10% palladium-on-carbon (30 mg), and 1,4-cyclohexadiene (1 mL) in tetrahydrofuran (1 mL) was warmed to 50° C. with stirring for 3 h. The mixture was filtered and the resulting solution concentrated in vacuo. The filtered solids were washed with methanol and the resulting solution concentrated in vacuo. Both residues were dissolved methylene chloride and diluted with hexane. The resulting precipitate was collected via vacuum filtration to provide 8.8 mg (37%) of the title compound as a solid: mp 243-253° C. (dec). 1H NMR (DMSO-d6) δ8.26 (m, 1H), 8.11 (bs, 1H), 7.89 (m, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.34 (m, 2H), 7.30 (m, 2H), 7.22 (t, J=7.0 Hz, 1H), 7.07 (d, J=7.3 Hz, 2H), 5.60 (s, 2H), 4.47 (s, 2H), 2.97 (q, J=7.7 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H); TOF MS ES+ exact mass calculated for C25H23N2O5: m/z=431.1607 (p+1). Found: 431.1605.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=[C:17]([Cl:26])[CH:16]=1>>[Cl:26][C:17]1[CH:16]=[C:15]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1
Reactant: Oc1cccc2ccccc12
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc(Cl)cc1Oc1cccc2ccccc12
Yield: 62.4 %

Procedure:
Using the method of Example 3, Step A, naphthalen-1-ol (2.62 g, 18.2 mmol), 60% sodium hydride in mineral oil (727 mg, 18.2 mmol), and ethyl 4,6-dichloronicotinate (4.00 g, 18.2 mmol) afforded ethyl 6-chloro-4-(naphthalen-1-yloxy)nicotinate (3.72 g, 62% yield) as an oil. 1H NMR (CDCl3) δ 8.86 (s, 1H), 7.94 (d, 2H), 7.82 (d, 1H), 7.49-7.61 (m, 3H), 7.22 (d, 1H), 6.54 (s, 1H), 4.43 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([C:29]#[N:30])=[C:24]([Cl:31])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:32])(C)(C)C.FC(CC(O)=O)(F)F.C(OCC)(=O)C>ClCCl>[Cl:31][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:21])([F:19])[F:20])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:33])=[O:5])=[C:8]([CH3:32])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[C:25]=1[C:29]#[N:30]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(C#N)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Agent: O=C(O)CC(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(C#N)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (763 mg) in dichloromethane (9 ml) was added trifluoromethyl acetic acid (“TFA”) (0.9 ml). The reaction mixture was stirred at ambient temperature for 20 hours. Ethyl acetate was added and the mixture was washed with water, dried over sodium sulfate and concentrated to give 4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid. 19F-NMR (CDCl3, 75 MHz): −78.91 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.O[C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:18]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: COC(=O)c1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl 4-hydroxybenzoate: ESMS m/e: 593.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[NH2:21]>>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:21][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[CH:22]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 24.2 %

Procedure:
Using 2-methoxy-5-sulfamoylbenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([NH:21]C(=O)C)[N:10]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=2)=[CH:4][CH:3]=1>C(O)C.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([NH2:21])[N:10]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCN1CCOCC1
Yield: 103.2 %

Procedure:
A solution of N-(3-(4-fluorophenyl)-1-(2-morpholinoethyl)-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (141 mg, 0.32 mmol) in ethanol (1.5 mL) and 25% NaOH (1.5 mL) was heated to 83° C. for 16 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate and the organic phases combined, dried over MgSO4, filtered and evaporated to give 3-(4-fluorophenyl)-1-(2-morpholinoethyl)-4-(phenylethynyl)-1H-pyrazol-5-amine as a solid (129 mg) which was used as such in the subsequent step.
Reaction SMILES: [F:1][C:2]1[C:3]([I:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C>[F:1][C:2]1[C:3]([I:11])=[C:4]2[CH:10]=[CH:9][N:8]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]ccc2c1I
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(I)c(F)cnc21
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine (5.0 g, 0.019 mol) in DMF (30.0 mL) cooled at 0° C. under nitrogen was portionwise added sodium hydride (1.13 g, 0.0282 mol). The reaction was stirred for 1 hour. To the mixture was slowly added [β-(trimethylsilyl)ethoxy]methyl chloride (4.05 mL, 0.0229 mol). The reaction was stirred at 0° C. for 1 hour and quenched with water. The resulting solution was extracted with EtOAc (2 times). The combined extracts were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-25% EtOAc/hexanes to afford 7.1 g (95%) of 5-fluoro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine as a yellowish oil. LC/MS found: 393.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1.[OH-].[Na+].CN(C)C=O>O>[C:11]([C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)[O:15][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(OCc2ccc(C#N)cc2)cc(C(C)(C)C)c1
Temperature: 120 °C
Yield: 12.4 %

Procedure:
A mixture of 5.1 g (25 mmole) of 3,5-di-t-butylphenol, 4.2 g (25 mmole) of alpha-bromo-p-tolunitrile, 1.0 g (25 mmole) sodium hydroxide and 75 ml of dimethylformamide was heated at 120° C. for about sixteen hours. The mixture was poured into 700 ml of water to give an oil which rapidly solidified. The solid was collected, rinsed with water, and recrystallized once from ethanol and twice from hexane to give 1.0 g of white crystalline 4-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile, m.p. 118°-121° C. Analysis: Calculated for C22H27NO: %C, 82.2; %H, 8.5; %N, 4.4; Found: %C, 82.7; %H, 8.6; %N, 4.1.