Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:7][C:6]=1[NH2:18])=[O:4].[OH-].[Na+]>C1COCC1>[NH2:18][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccccc2F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc(-c2ccccc2F)ccc1C(=O)O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
Step 2 A solution of methyl-3-amino-2′-fluorobiphenyl-4-carboxylate (0.425 g, 1.73 mmol) in 1 M aqueous sodium hydroxide (6.9 mL, 6.9 mmol) and THF (3.5 mL) was heated at reflux overnight. The mixture was cooled to rt and concentrated almost to dryness. 6 M hydrochloric acid (0.1 mL) was added to the solution at 0° C. and the precipitate was collected by filtration, washed with water and dried to give 3-amino-2′-fluorobiphenyl-4-carboxylic acid (0.338 g, 84%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.87, d, 8.25, 1H), 7.50 (t, J=7.97, 1H), 7.47-7.55 (m, 1H), 7.25-7.36 (m, 2H), 6.92 (br s, 1H), 6.76 (s, 1H), 6.59 (d, J=7.70, 1H). Mass spectrum m/z 232.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]2)[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:28][C:26]1[CH:25]=[N:24][N:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:27]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN1CCC(n2cc(N)cn2)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cnn(C2CCN(C)CC2)c1
Yield: 79 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (216 mg, 1.2 mmol) to afford the desired product (304 mg, 76%) as a light orange solid: 1H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.56-7.48 (m, 2H), 7.42 (d, J=0.6 Hz, 1H), 4.18-4.11 (m, 1H), 3.00 (d, J=11.4 Hz, 2H), 2.67 (s, 3H), 2.34 (s, 3H), 2.26-2.02 (m, 6H); ESI MS m/z 385 [M+H]+
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)([OH:13])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: OC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: OC1(c2ccc(F)c(F)c2)CCNC1
Temperature: 25 °C
Yield: 105.7 %

Procedure:
To a mixture of 1-benzyl-3-(3,4-difluorophenyl)pyrrolidin-3-ol (0.55 g, 1.9 mmol) and ammonium formiate (0.36 g, 5.7 mmol) in ethanol (20 mL) was added palladium on carbon (0.11 g) and the mixture was refluxed for 1 h, cooled to ambient temperature and filtered through a pad of celite. The filtrate was evaporated to give the title compound (0.4 g). MS m/z (rel. intensity, 70 eV) 199 (M+, bp), 180 (51), 150 (60), 141 (90), 113 (75).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH3:14])[C@H:9]1[C:15]([O:17]CC1C=CC=CC=1)=[O:16])C1C=CC=CC=1>CO.[Pd]>[CH3:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@@H:9]1[C:15]([OH:17])=[O:16]
Reactant: C[C@H]1OCCN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1OCCN[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
A mixture of (2R,3S)-benzyl 4-benzyl-2-methylmorpholine-3-carboxylate (10 g, 30.76 mmol) and Pd/C (10%, 1 g) in anhydrous methanol (100 mL) was stirred at 25° C. for 12 hours under H2. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (3.8 g, 85%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[C-:12]#[N:13].[K+].O1CCOCC1>O>[S:7]1[C:3]([CH2:2][C:12]#[N:13])=[CH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]1=2
Reactant: ClCc1cc2ccccc2s1
Reactant: [C-]#N
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1cc2ccccc2s1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of 2-chloromethylbenzo[b]thiophene (21 g), potassium cyanide (11.7 g), 1,4-dioxane (200 ml) and water (100 ml) was stirred and heated under reflux for 4 hours, then cooled to ambient temperature and diluted with water (200 ml). The product was extracted into toluene (3×200 ml), then the combined extracts were washed with water (2×300 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified via flash chromatography over silica using a 1:4 mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined and the solvents were removed in vacuo to give benzo[b]thiophen-2-acetonitrile as a yellow solid (8.9 g), m.p. 59-61° C.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C>CC(O)C.O.CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccc(Oc2ccc(Cl)cc2)nc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(OCc2ccc(Oc3ccc(Cl)cc3)nc2)c(Cl)c1=O
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To 20 ml of N,N-dimethylformamide were added 2.1 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone, 2.5 g of 5-chloromethyl-2-(4-chlorophenoxy)-pyridine and 1.5 g of potassium carbonate, and the mixture was stirred at 80° to 90° C. for 2 hours. After cooling, the reaction mixture was poured into 50 ml of water and extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to obtain 3.9 g of a crude product. The crude product was added with a mixed solvent of isopropyl ether and 2-propanol and recrystallized therefrom to give 3.3 g of 2-t-butyl-4-chloro-5-[{6-(4-chlorophenoxy)-3-pyridyl}methyloxy]-3(2H)-pyridazinone, m.p. 150.0°~154.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C=C(C)C=CC=3S([O-])(=O)=O)[CH2:12]2)=[O:10])=[C:4]([C:34](=[O:41])[NH:35][CH:36]([CH:38]2[CH2:40][CH2:39]2)[CH3:37])[CH:3]=1.C(O)(=O)C.[BrH:46].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:46])[CH2:12]2)=[O:10])=[C:4]([C:34](=[O:41])[NH:35][CH:36]([CH:38]2[CH2:40][CH2:39]2)[CH3:37])[CH:3]=1
Reactant: Br
Reactant: Cc1ccc(S(=O)(=O)[O-])c(C2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 2.5 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl4-methylbenzene sulfonate was dissolved in 0.7 mL of acetic acid, and 0.3 mL of a 33 mass % hydrogen bromide acetic acid solution was dropwise added, followed by stirring for about 2.5 hours. After completion of the reaction, ethyl acetate, water and 2 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 260 mg of the desired product in a paste form.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][CH:12]([F:30])[C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH2:22][C:23]2([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[N:14][C:13]([CH:12]([F:30])[F:11])=[N:18][CH:17]=1)[CH2:22][C:23]1([C:26]([F:29])([F:27])[F:28])[CH2:25][CH2:24]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=434.0, tR (minutes, Method F)=2.42. [α]D20=+25.30 (c=3.75 mg/mL,CHCl3)
Reaction SMILES: Br[C:2]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.O=C1CC(=O)CN(C(OCC2C=CC=CC=2)=O)C1.[CH3:32][N:33]([CH3:53])[CH2:34][CH2:35][N:36]1[CH2:48][C:47]2NC3C=CC=C4C(=O)[NH:50][N:51]=[C:38]([C:39]=2C=34)[CH2:37]1>>[CH3:32][N:33]([CH3:53])[CH2:34][CH2:35][N:36]1[CH2:48][C:47]2[NH:12][C:11]3[CH:10]=[C:9]([F:13])[CH:8]=[C:3]4[C:4](=[O:6])[NH:50][N:51]=[C:38]([C:39]=2[C:2]=34)[CH2:37]1
Reactant: COC(=O)c1cc(F)cc(N)c1Br
Reactant: CN(C)CCN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Agent: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Product: CN(C)CCN1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 61 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoate and benzyl 3,5-dioxopiperidine-1-carboxylate according to the procedures similar to those for Compound 60. 1H NMR δ 10.1 (s, 1H), 7.58 (dd, 1H, J=1.8, 10.2 Hz), 7.21 (dd, 1H, J=1.8, 10.2 Hz), 4.20-4.22 (m, 2H), 4.03 (s, 2H), 3.42 (s, 2H), 2.51-2.54 (m, 2H), and 2.19 (s, 6H). MS (ESI) m/e [M+1]+316.
Reaction SMILES: NC1C=C(CC2CC3CCN2CC3)C=CC=1.[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)([O-:19])=[O:18].[N:28]12[CH2:35][CH2:34][CH:31]([CH2:32][CH2:33]1)[C:30](=[O:36])[CH2:29]2.[OH-].[K+]>C(O)C>[N+:17]([C:20]1[CH:21]=[C:22]([CH:23]=[C:29]2[C:30](=[O:36])[CH:31]3[CH2:34][CH2:35][N:28]2[CH2:33][CH2:32]3)[CH:25]=[CH:26][CH:27]=1)([O-:19])=[O:18]
Reactant: O=C1CN2CCC1CC2
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Nc1cccc(CC2CC3CCN2CC3)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2cccc([N+](=O)[O-])c2)N2CCC1CC2

Procedure:
The manner in which 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane is synthesized can vary. For example, in one method, 3-nitrobenzaldehyde can be condensed with 3-quinuclidinone in an aldol reaction using potassium hydroxide and ethanol to yield 2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one. The latter compound can be converted to the corresponding dithioketal by treatment with 1,2-ethanedithiol and boron triflouride etherate. Reduction and desulfurization can be effected by hydrogenation using Raney nickel to yield 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane. Alternatively, in another method, the aldol product, 2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one can be reduced by treatment with sodium borohydride in methanol to give the alcohol, 2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-ol. The latter compound can be converted to the chloro intermediate, 3-chloro-2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octane dihydrochloride upon treatment with thionyl chloride. Dechlorination by hydrogenation with Raney nickel and carbon-carbon double bond reduction by hydrogenation over 10% palladium on carbon can then be effected to yield 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane. Replacement of 3-nitrobenzaldehyde with 2-nitrobenzaldehyde or 4-nitrobenzaldehyde in the above synthetic approach affords the isomeric compounds, 2-[(2-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane and 2-[(4-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane, respectively.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][C@H:18]1[O:58][C@@H:22]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C@H:31]2[CH2:55][CH2:54][C@@:53]3([CH3:56])[C:33](=[CH:34][CH2:35][C@@H:36]4[C@@H:52]3[CH2:51][CH2:50][C@@:49]3([CH3:57])[C@H:37]4[CH2:38][CH2:39][C@@H:40]3[C@H:41]([CH3:48])[CH2:42][CH2:43][CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:32]2)[C@H:21]([OH:59])[C@@H:20]([OH:60])[C@H:19]1[OH:61].[C:62](O)(=[O:80])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69]/[CH:70]=[CH:71]\[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]>C(Cl)(Cl)Cl>[C:62]([NH:16][CH2:17][C@H:18]1[O:58][C@@H:22]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C@H:31]2[CH2:55][CH2:54][C@@:53]3([CH3:56])[C:33](=[CH:34][CH2:35][C@@H:36]4[C@@H:52]3[CH2:51][CH2:50][C@@:49]3([CH3:57])[C@H:37]4[CH2:38][CH2:39][C@@H:40]3[C@H:41]([CH3:48])[CH2:42][CH2:43][CH2:44][CH:45]([CH3:46])[CH3:47])[CH2:32]2)[C@H:21]([OH:59])[C@@H:20]([OH:60])[C@H:19]1[OH:61])(=[O:80])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69]/[CH:70]=[CH:71]\[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CN)[C@H](O)[C@H](O)[C@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NC[C@H]1O[C@@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 3 h
Yield: 55.1 %

Procedure:
A solution of dicyclohexylcarbodiimide (106 mg.) in chloroform (5 ml.) is added to a solution of 6-(5-cholesten-3β-yloxy)hexyl 6-amino-6-deoxy-1-thio-β-D-galactopyranoside (309 mg.) and oleic acid (131.5 mg.) in chloroform (20 ml.). After 3 hours at room temperature, the reaction mixture is filtered and washed with water (20 ml.) and methanol (25 ml.). The organic layer is dried and evaporated in vacuo to a syrup which is crystallized from methanol to give the title compound (238 mg., 55%); m.p. 160°-163° C., [α]D27 -5.0° C. (C 1.0, chloroform).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[F:18]C1(CC(C2C=CC=CC=2)=O)C=CN=CC1>>[F:18][C:12]1([C:3](=[N:2][OH:1])[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[CH:13]=[CH:14][N:15]=[CH:16][CH2:17]1
Reactant: O=C(CC1(F)C=CN=CC1)c1ccccc1
Reactant: O=C(C(=NO)c1ccncc1)c1ccccc1
Product: O=C(C(=NO)C1(F)C=CN=CC1)c1ccccc1

Procedure:
The title compound was prepared using the same procedure (U.S. Pat. No. 3,940,486) employed to prepare 2-hydroxyimino-2-(4-pyridyl)acetophenone, except using 4-fluoro-2-(4-pyridyl)-acetophenone.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[N:8]=1.[F:15][C:16]([F:33])([F:32])[C:17](=[O:31])[CH2:18][C:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH3:30])([CH3:21])[CH3:20]>C1COCC1>[F:33][C:16]([F:15])([F:32])[C:17]([CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[N:8]=1)([OH:31])[CH2:18][C:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH3:30])([CH3:21])[CH3:20]
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cc1cc(C)nc(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(C)cc(C)n1)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
tert-Butyl lithium (1.7 M in pentane, 0.5 mL) was added dropwise to a solution of 2,4,6-trimethylpyridine (0.12 g) in THF (0.5 mL) cooled to −70° C. under argon. The mixture was stirred at −70° C. for 15 minutes and 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4methylpentan-2-one (0.10 g) (Example 1) in THF (0.5 mL) was added. The reaction mixture was stirred for 20 minutes and then quenched with acetic acid. The mixture was diluted with EtOAc, washed with water, dried, filtered, and concentrated in vacuo. Fractionation by preparative layer chromatography on silica gel (methylene chloride-hexanes) followed by crystallization gave 43 mg of the title compound, m.p. 95° C.-98° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([F:20])[F:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH:22]([O:25][C:26]1[CH:32]=[C:31]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:30]([CH3:39])=[CH:29][C:27]=1[NH2:28])([CH3:24])[CH3:23].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([F:20])[F:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:28][C:27]2[CH:29]=[C:30]([CH3:39])[C:31]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:32][C:26]=2[O:25][CH:22]([CH3:24])[CH3:23])=[N:3][CH:4]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)C(F)F
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(F)F)n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a suspension of 2,5-dichloro-N-(2-(difluoromethylsulfonyl)phenyl)-pyrimidin-4-amine (0.5 mmol) in 1 mL of isopropanol, was added 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (0.5 mmol) and 4-methylbenzenesulfonic acid (0.5 mmol). The suspension was stirred at 150° C. for 3 hours. After work-up and prep-HPLC, product was obtained. MS (ES+): 566.17 (M+1)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[CH2:44][CH2:45][OH:46].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:46][CH2:45][CH2:44][C:37]3[CH:38]=[C:39]([F:43])[C:40]([F:42])=[CH:41][C:36]=3[F:35])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1cc(F)c(F)cc1F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2cc(F)c(F)cc2F)cc1
Reaction time: 18 h
Yield: 79.2 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), 2-(2,4,5-trifluorophenyl)ethanol (47.0 mg, 0.267 mmol) and Ph3P-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DIAD (0.052 mL, 0.267 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(2,4,5-trifluorophenethoxy)phenyl)pyridin-3-yl)acetic acid (25.2 mg, 0.042 mmol, 79% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.60-7.46 (m, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.08-6.87 (m, 3H), 5.85 (br. s., 1H), 4.26 (q, J=6.2 Hz, 2H), 3.23 (br. s., 1H), 3.07 (t, J=6.2 Hz, 2H), 2.85-2.73 (m, 1H), 2.43 (s, 3H), 2.16 (br. s., 1H), 2.05 (s, 3H), 1.96-1.86 (m, 1H), 1.48 (br. s., 1H), 1.29 (br. s., 1H), 1.17 (d, J=13.6 Hz, 1H), 1.13 (s, 9H), 1.01 (d, J=12.5 Hz, 1H), 0.84 (br. s., 3H), 0.59 (br. s., 3H). LCMS (M+H)=599.2.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C:10]1[C:11]([F:27])=[CH:12][C:13]([Cl:26])=[C:14]([CH:25]=1)[O:15][CH2:16]/[C:17](/[O:23][CH3:24])=[CH:18]\[C:19]([O:21][CH3:22])=[O:20]>C(OCC)(=O)C>[Cl:26][C:13]1[CH:12]=[C:11]([F:27])[C:10]([N:9]=[C:2]=[O:3])=[CH:25][C:14]=1[O:15][CH2:16]/[C:17](/[O:23][CH3:24])=[CH:18]\[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)/C=C(\COc1cc(N)c(F)cc1Cl)OC
Solvent: CCOC(C)=O
Product: COC(=O)/C=C(\COc1cc(N=C=O)c(F)cc1Cl)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trichloromethyl chloroformate (1.37 g) is added dropwise to a solution of methyl (2E)-4-(5-amino-2-chloro-4-fluorophenoxy)-3-methoxybut-2-enoate (2.0 g) in ethyl acetate (30 ml). The mixture is stirred overnight at room temperature. It is concentrated under vacuum and the residue obtained (2.3 g) is used as such in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].C(N(CC)CC)C.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=CC(C)C(C)=C1c1ccccc1N
Solvent: CCN(CC)CC
Product: CC1=CC(C)C(C)=C1c1ccccc1NC(=O)C(C)(C)C
Yield: 88.7 %

Procedure:
0.534 g of (2.68 mmol) of 2-(2,3,5-trimethylcyclopenta-1,4-dienyl)phenylamine, 0.325 g (3.22 mmol) of triethylamine, and 0.388 g (3.22 mmol) of pivaloyl chloride were used in the same manner as in Example 11. The resultant reaction product was purified through a column chromatography using a hexane/ethyl acetate (v/v, 5:1) solvent, and then the solvent in the purified product was removed in vacuum, thereby obtaining white solid (0.674 g, 89%).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:16]4[CH:17]=[CH:18][N:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[C:11]=3[N:25]=2)=[C:6]([CH3:26])[N:5](C2CCCCO2)[N:4]=1.CO.Cl.C([O-])(O)=O.[Na+]>>[F:33][CH:2]([F:1])[C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:16]4[CH:17]=[CH:18][N:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[C:11]=3[N:25]=2)=[C:6]([CH3:26])[NH:5][N:4]=1
Reactant: Cc1c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(C(F)F)nn1C1CCCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1[nH]nc(C(F)F)c1-c1nc2c([nH]1)-c1ccncc1Nc1ncccc1-2
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.1 %

Procedure:
2-[3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine (1.69 g, 3.76 mmol) was dissolved in methanol (50.00 mL, 1.234 mol) and concentrated HCl (2.00 mL) was added. The reaction was stirred at 25° C. for 20 h. The reaction was neutralized with NaHCO3 and was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4), concentrated in vacuo to a reduced volume and crystallized from MeOH/EtOAc to give the desired product (1.10 g). A portion of this (0.70 g) was suspended in methanol and 1.00 M of HCl in ether (6.00 mL) was added at which time the compound was completely dissolved. The reaction was concentrated in vacuo to reduce solvent to a minimal volume and ether was added. The crystallized solid was washed with ether and dried to give the bis hydrochloride salt (0.82 mg). Free base 1H NMR (DMSO-d6): δ 8.72 (br s, 1H), 8.14 (d, 1H), 8.01 (s, 1H), 7.95 (dd, 1H), 7.80 (m, 1H), 7.76 (d, 1H), 7.11-7.38 (t, 1H), 6.90 (dd, 1H), 2.48 (s, 3H). Mass spec (EI) m/z=366 (M+1).