Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(C(C)(C)C=O)C=CC=1)=CC.[CH:15]([CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:30])[CH2:27]C=O)[CH:21]=1)[CH3:19])=[O:16].O=[O+][O-]>>[CH2:27]=[C:26]([C:22]1[CH:21]=[C:20]([CH:18]([CH3:19])[CH2:17][CH:15]=[O:16])[CH:25]=[CH:24][CH:23]=1)[CH3:30]
Reactant: CC(CC=O)c1cccc(C(C)CC=O)c1
Agent: CC=Cc1cccc(C(C)(C)C=O)c1
Agent: O=[O+][O-]
Product: C=C(C)c1cccc(C(C)CC=O)c1

Procedure:
m-Diisopropenylbenzene (237 g), 0.2 g butylated hydroxytoluene, 0.1 g NaHCO3, 0.0918 g RhHCO(PPh3)3 and 20 g triphenylphosphine were heated under a pressure of 250 psi hydrogen and 250 psi carbon monoxide at 110° C. for five hours and then at 140° C. for six hours. The crude reaction product was distilled to give 215 g of a liquid which analyzed as 49.4% starting material, 40.8% lb, 1.9% 2-(3-propen-ylphenyl)-2-methylpropanal and 4.9% 1,3-di-(1-formylpropan-2-yl)benzene. The constituents were readily separated by fractional distillation to give pure lb, b.p 98° C./0.1 mm Hg. The starting material may be recycled to give further product in an overall yield of 71.0% lb. IR and NMR spectra were compatible with the assigned structure. Odor: ozone, stemmy-green floral, melon. Odor value: 35,514; Odor threshold value: 0.7 ng/L.
Reaction SMILES: [C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][CH2:3][C:2]2=O.CC(C)([O-])C.[K+].[C:14](OCC)(=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH2:24][NH2:25].Cl>C(O)C>[CH2:6]1[C@@H:5]2[CH2:4][C:3]3[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:24][NH:25][C:2]=3[C@H:1]12
Reactant: NN
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CC[C@H]2C[C@@H]12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2c1C[C@H]1C[C@@H]21
Temperature: 70 °C
Reaction time: 1 h
Yield: 17.8 %

Procedure:
(1R,5S)-Bicyclo[3.1.0]hexan-2-one (1.000 g, 10.40 mmol) was taken up in ethanol (40 mL) and potassium tert-butoxide (1.0 M in THF) (13.00 mL, 13.00 mmol) was added, followed by diethyl oxalate (1.413 mL, 10.40 mmol). The resulting solution was heated and stirred for 1 h at 70° C. Hydrazine (10.40 mL, 10.40 mmol) was then added, followed by hydrochloric acid (ca 3 M aqueous) (10.40 mL, 31.2 mmol). The solution was stirred at 70° C. for 1 h and purified by HPLC to give the title compound (356 mg, 1.852 mmol, 17.80% yield) as a solid. LCMS m/z=193.3 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([F:26])[CH:14]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:19][C:18]1[C:13]([NH:12][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=3[N:6]=2)=[CH:14][C:15]([F:26])=[C:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Reactant: Fc1ccc2sc(Br)nc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc(Cl)c(Nc2nc3cc(F)ccc3s2)cc1F
Yield: 33 %

Procedure:
In xylene (5 ml), 2-bromo-5-fluorobenzothiazole (548 mg, 2.36 mmol), ethyl 4-amino-5-chloro-2-fluorophenylacetate (547 mg, 2.36 mmol), and pyridinium p-toluenesulfonate (PPTS) (178 mg, 0.71 mmol) were heated under reflux for 3 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (7:1, v/v) eluate fractions, ethyl (5-chloro-4-(5-fluoro-2-benzothiazolyl)amino-2-fluorophenyl)acetate (298 mg, 33%) was obtained as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:30])/[C:5](=[N:25]/[O:26][CH2:27][CH:28]=[CH2:29])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[S:7][C:6](/[C:5](=[N:25]\[O:26][CH2:27][CH:28]=[CH2:29])/[C:4]([OH:30])=[O:3])=[CH:10][CH:9]=1
Reactant: C=CCO/N=C(/C(=O)OCC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCO/N=C(/C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 50 °C
Yield: 59.8 %

Procedure:
As in Example 306, a solution of (Z)-5-[2-(2-naphthalenyloxy)ethoxy]-alpha-[(2propenyloxy)imino]-2-thiopheneacetic acid ethyl ester (0.102 g) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with 4N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 50° C. for 30 minutes. After the normal work up, the product was crystallized from ethyl acetate-hexane to furnish 0.057 g of (Z)-5-[2-(2-naphthalenyloxy)ethoxy]-alpha-[(2-propenyloxy)imino]-2-thiopheneacetic acid, mp 114°-115° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.CC[O:18]CC.CCOC(C)=O>CC(O)=O.[Pd]>[C:1]1([C:7]2[CH:12]=[N+:11]([O-:18])[C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: Cc1ccc(-c2ccccc2)cn1
Agent: [Pd]
Agent: OO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2)c[n+]1[O-]
Temperature: 70 °C

Procedure:
To a solution of 100 g 5-phenyl-2-picoline in 170 mL of glacial HOAc was added 30% H2O2 and the resulting solution was heated at 70° C. overnight. After the reaction mixture was cooled to room temperature, 1 g of 10% Pd/C was added to destroy excess of H2O2. The reaction mixture was then filtered on celite, washed with toluene and the filtrate was evaporated to dryness affording a yellow solid residue. The crude material was swished with a mixture of Et2O/EtOAc (10:1) and filtered to afford the pure title product as a white solid, m.p.: 91° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([N+:28]([O-:30])=[O:29])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[N+:28]([C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 60 °C
Yield: 77.9 %

Procedure:
A 20 mL round bottom flask was charged with (S)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 0.25 g, 1.77 mmol), 2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Method 37, 0.3 g, 1.0 mmol), and DIEA (0.30 g, 2.34 mmol). Anhydrous n-BuOH (5 mL) was added, and the flask was heated at 60° C. for 4 hours. The reaction mixture was washed with brine (5 mL×3), and the organic layer was dried and concentrated. The resulting residue was separated by silica gel column to afford desired product (0.3 g, 75%). LC-MS, 386 (M+1). 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 10.5 (s, 1H), 9.1 (s, 1H), 9.0 (s, 1H), 8.80 (s, 2H), 6.1 (s, 1H), 5.2 (dd, 1H), 2.0 (m, 1H), 1.7 (d, 3H), 1.0 (m, 2H), 0.8 (m, 2H).
Reaction SMILES: [F:1][C:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]=[C:21]([C:23]#[N:24])[C:20]4[N:25]=[CH:26][N:27]([CH3:28])[C:19]=4[CH:18]=3)=[CH:13][C:12]=2[C:29]([F:32])([F:31])[F:30])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C=O.[C:35]([BH3-])#N.[Na+].[C:39](=[O:42])(O)[O-:40].[Na+]>C(#N)C.C1COCC1.C(O)(=O)C>[F:1][C:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]=[C:21]([C:23]#[N:24])[C:20]4[N:25]=[CH:26][N:27]([CH3:28])[C:19]=4[CH:18]=3)=[CH:13][C:12]=2[C:29]([F:30])([F:31])[F:32])[CH2:7][CH2:6][N:5]([CH3:35])[CH2:4][CH2:3]1.[C:39]([OH:40])([C:29]([F:32])([F:31])[F:30])=[O:42]
Reactant: O=C([O-])O
Reactant: [BH3-]C#N
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4(F)CCNCC4)c(C(F)(F)F)c3)cc21
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(F)(CCOc2ccc(-c3cc4c(ncn4C)c(C#N)n3)cc2C(F)(F)F)CC1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 6-(4-(2-(4-fluoropiperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (TFA salt, 100 mg) in acetonitrile/THF (2 ml, 1:1) was added formaldehyde (37%, 140 ul), acetic acid (0.3 ml), followed by sodium cyanoborohydride (100 mg). The mixture was stirred at room temperature for 2 hours, and then poured to aqueous sodium bicarbonate (10 ml). The mixture was then extracted with ethyl acetate (20 ml+10 ml×4). Combined organic layer was then dried over sodium sulphate. After removal of solvent under reduced pressure, the residue was purified by HPLC to give 6-(4-(2-(4-fluoro-1-methyl-piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a TFA salt. 1H NMR (CD3OD) δ: 8.45 (s, 1H), 8.38 (s, 2H), 8.35 (d, 1H), 7.35 (d, 1H), 4.39 (t, 2H), 4.02 (s, 3H), 3.50 (m, 2H), 3.3 (m, 2H), 2.93 (s, 3H), 2.25-2.4 (m, 4H), 2.0-2.25 (m, 2H). MS m/z 462 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=2)[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:15][CH:16]=2)[N:6]=1
Reactant: COC(=O)c1ccc(-c2nc(N)sc2-c2ccc(SC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ccc(-c2sc(N)nc2-c2ccc(CO)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-{2-amino-5-[4-(methylthio)phenyl]-1,3-thiazol-4-yl}benzoate (100 mg) in tetrahydrofuran (4 ml) was added portionwise lithium aluminium hydride (21.3 mg), and the mixture was stirred for 1 h at 20° C. To the reaction mixture were added ethyl acetate (10 ml) and water (3 ml). The resulting precipitate was removed by filtration, and the filtrate was washed with brine, dried over sodium sulfate and evaporated to give (4-{2-amino-5-[4-(methylthio)phenyl]-1,3-thiazol-4-yl}phenyl)methanol as a yellow solid, that was used as crude in the next reaction.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(O[C:17]([C:19]1[C:24]([CH2:25][N:26]([CH2:37][C:38]([O:40]C)=O)S(C2C=CC(C)=CC=2)(=O)=O)=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:18])(C)C.C(N(C(C)C)CC)(C)C.O.[Cl-].[Cl-].[NH3+:54][CH2:55][C:56]1[NH2+:60][C:59]2[CH:61]=[CH:62][CH:63]=[CH:64][C:58]=2[N:57]=1.[C:65]([OH:71])([C:67]([F:70])([F:69])[F:68])=[O:66]>CN(C=O)C>[F:68][C:67]([F:70])([F:69])[C:65]([O-:71])=[O:66].[OH:18][C:17]1[C:37]([C:38]([NH:54][CH2:55][C:56]2[NH2+:60][C:59]3[CH:61]=[CH:62][CH:63]=[CH:64][C:58]=3[N:57]=2)=[O:40])=[N:26][CH:25]=[C:24]2[C:19]=1[N:20]=[CH:21][CH:22]=[CH:23]2
Reactant: [NH3+]CC1=Nc2ccccc2[NH2+]1
Reactant: COC(=O)CN(Cc1cccnc1C(=O)OC(C)C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1=Nc2ccccc2[NH2+]1)c1ncc2cccnc2c1O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triphosgene (0.556 g, 1.87 mmol) was added over 20 mins to a solution of the acid from Step 1. (0.89 g, 4.68 mmol) and diisopropylethylamine 3.26 ml, 18.7 mmol) in DMF (22 ml) at 0° C. The dark solution was allowed to warm to room temperature and stirred a further 1 hr. 2-(ammoniomethyl)-1H-benzimidazol-1-ium dichloride hydrate (25.0 mg, 1.05 mmol) was treated with a portion of the above solution (0.58 ml, 0.07 mmol) and the resulting mixture was stirred at room temperature for 16 hrs. The solution was treated with TFA (0.025 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) (available from Waters) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the trifluoroacetate salt of the title compound after lyophilization.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:27]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: C=Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: C=Cc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
White solid. MS (ESI): 431.3 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chloro-benzenesulfonyl chloride and 4-amino-styrene.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:17][C:18]1[C:23]([CH2:24][C:25](O)=[O:26])=[CH:22][CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[N:19]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.BrC1C(C2C=CC(Cl)=CC=2)=CC(NNC(=O)CC2C=NC(C(F)(F)F)=CC=2)=NC=1>CC#N>[Br:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:4][C:5]([NH:8][NH:9][C:25](=[O:26])[CH2:24][C:23]2[C:18]([CH3:17])=[N:19][C:20]([C:28]([F:29])([F:31])[F:30])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Reactant: Cc1nc(C(F)(F)F)ccc1CC(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)ccc1CC(=O)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Yield: 97 %

Procedure:
The title compound (160 mg, 97%) as a beige powder was prepared from 5-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (100 mg, 0.33 mmol), 2-(2-methyl -6-(trifluoromethyl)pyridin-3-yl)acetic acid (75 mg, 0.33 mmol), (i-Pr)2EtN (86 mg, 0.66 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBop, 190 mg, 0.37 mmol) in CH3CN (2.5 mL) by the procedures analogous to those described for N′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide (Example 56C). LC/MS (method B): retention time=1.92 min, [M+H]+=499.0.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:49])[CH2:6][C:7]1[C:44]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:42]=[CH:41][C:8]=1[CH2:9][CH2:10][C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[N:12]=1>C1COCC1.CO.O>[C:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:8]4[CH:41]=[CH:42][CH:43]=[C:44]([C:45]([F:46])([F:48])[F:47])[C:7]=4[CH2:6][C:5]([OH:49])=[O:4])[C:16]([C:17]([F:18])([F:20])[F:19])=[CH:15][N:14]=3)=[CH:27][CH:26]=2)[CH2:33][CH2:32]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)Cc1c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(F)(F)F)c4CC(=O)O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
LiOH (31 mg, 1.3 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A95) (0.106 g, 0.159 mmol) in THF (2.0 mL), MeOH (1.0 mL) and water (1.0 mL) and the resulting mixture was stirred at room temperature for 16 hours. Water (20 mL) was added and the mixture extracted with EtOAc (2×20 mL). The combined organic extracts were concentrated under reduced pressure and the residue taken up in THF (2.0 mL), MeOH (1.0 mL) and water (1.0 mL). LiOH (0.103 g, 4.30 mmol) was added and the resulting mixture stirred for 136 hours at room temperature. The mixture was diluted with water (30 mL) then extracted with EtOAc (3×30 mL). The combined organic extracts were passed through a phase separation cartridge then concentrated under reduced pressure to give the title compound A96 (0.104 g, 99%); 1H NMR (400 MHz, d6-DMSO) δ 10.27 (bs, 1H), 8.65 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.45 (d, J=7.7 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.25 (dd, J=7.6, 7.6 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H), 4.06 (m, 2H), 3.48 (s, 2H), 3.14 (m, 2H), 3.05 (m, 2H), 2.80 (m, 2H), 2.61 (m, 1H), 1.74 (m, 2H), 1.48 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.78 min; m/z 653.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O1CCCC1>[CH2:1]([NH:5][C:6]([NH:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NC1CCCCC1
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Product: CCCCNC(=O)NC1CCCCC1
Reaction time: 1 h

Procedure:
One hundred mL of tetrahydrofuran (THF) was added to a dry 500 mL round bottom 3-neck flask equipped with a thermometer, pressure equalizing addition funnel capped with a drying tube, nitrogen inlet and magnetic stirrer. Then 17.24 mL (0.15 moles) of 98% n-butyl isocyanate was added under nitrogen. A solution of 17.33 mL (0.15 moles) of 99% cyclohexylamine in 46 mL of THF was added to the addition funnel and slowly dropped into the stirred solution of n-butyl isocyanate at a rate (about 20 min.) which maintained the temperature below 40° C. The reaction mixture was stirred for one hour after completion of the addition. The solvent was removed by rotary evaporation. The white residue was vacuum dried for 12 hours at room temperature. The yield of dried, crystalline white product was quantitative. The product melted sharply at 107°-108° C. (uncorrected).
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[Li]>C1COCC1>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:26]5[S:25][CH:29]=[CH:28][CH:27]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Reactant: [Li]c1cccs1
Solvent: C1CCOC1
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5cccs5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (ice/water) solution of 3-cyclobutyl-1-quinolin-7-ylimidazo[1,5-a]pyrazin-8-ylamine (52.7 mg, 0.167 mmol) in THF (5 mL) was added 2-thienyllithium (1 M in THF; 0.6 mL, 0.6 mmol), then the cooling bath was removed, and the solution was stirred overnight at ambient temperature. After 1 d and 2 d, more 2-thienyllithium (0.2 mL, 0.2 mmol) was added, and stirring was continued. The reaction was quenched by adding water and sat. NH4Cl solution, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were washed with brine and dried over MgSO4. Air was bubbled into the solution for 8 h. The crude material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-6)→1% MeOH in CH2Cl2 (7-21)→2% MeOH in CH2Cl2 (22-43)], yielding a yellow film. Further purification by preparative TLC (20×20 cm silica gel plates, 500 μM thickness, eluting with 3% MeOH in CH2Cl2 four times) yielded the title compound as a yellow solid;
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(NC(=O)C5C=CC(C(O)(C)C)=CC=5F)C=4C(C4C=CC=CC=4)(C4C=CC=CC=4)O[SiH2]C(C)(C)C)C=3C=2)CC1)=O.[C:60]([O:64][C:65]([N:67]1[CH2:72][CH:71]=[C:70]([C:73]2[NH:90][C:76]3[N:77]=[CH:78][N:79]=[C:80]([C:81]4[CH:86]=[C:85]([F:87])[CH:84]=[C:83]([NH2:88])[C:82]=4[CH3:89])[C:75]=3[CH:74]=2)[CH2:69][CH2:68]1)=[O:66])([CH3:63])([CH3:62])[CH3:61].FC1C=C(C(O)(C)C)C=CC=1C(O)=O.[F:105][S:106]([F:119])([F:118])([F:117])([F:116])[C:107]1[CH:115]=[CH:114][C:110]([C:111](O)=[O:112])=[CH:109][CH:108]=1>>[C:60]([O:64][C:65]([N:67]1[CH2:68][CH:69]=[C:70]([C:73]2[NH:90][C:76]3[N:77]=[CH:78][N:79]=[C:80]([C:81]4[CH:86]=[C:85]([F:87])[CH:84]=[C:83]([NH:88][C:111](=[O:112])[C:110]5[CH:114]=[CH:115][C:107]([S:106]([F:119])([F:105])([F:116])([F:117])[F:118])=[CH:108][CH:109]=5)[C:82]=4[CH3:89])[C:75]=3[CH:74]=2)[CH2:71][CH2:72]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Reactant: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Agent: CC(C)(O)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)O)cc5F)c4C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)ncnc3[nH]2)CC1
Product: Cc1c(NC(=O)c2ccc(S(F)(F)(F)(F)F)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12

Procedure:
Intermediate 23 was prepared analogue to Intermediate 9 by replacing Intermediate 7 with Intermediate 20 and Intermediate 8 with 4-(pentafluoro-sulfanyl)-benzoic acid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]=[CH:10][CH2:11][NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH:9]=[CH:10][CH2:11][NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC=CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC=CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-but-2-enyl}-carbamic acid tert-butyl ester (1.6 g, 4.3 mmol) was dissolved in dry CH2Cl2 (50 ml) followed by addition of TFA (20 ml). The resulting solution was stirred at room temperature for 2 hrs. The solution was concentrated under reduced pressure. The resulting residue was dissolved in water (20 ml) and pH of the solution was adjusted to 10. The water phase was extracted with CH2Cl2 (100 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product in almost quantitative yield.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:19][O:20][C:21]1[C:22]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:24]#[N:25]>ClCCl>[C:24]([C:23]1[C:22]([O:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[C:21]([O:20][CH3:19])[C:28]([O:29][CH3:30])=[CH:27][C:26]=1[N+:1]([O-:4])=[O:2])#[N:25]
Reactant: COc1ccc(C#N)c(OCC(F)(F)F)c1OC
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])c(C#N)c(OCC(F)(F)F)c1OC
Yield: 73 %

Procedure:
Ammonium nitrate (2.82 g, 0.035 mol) and trifluoroacetic anhydride (12.4 ml, 0.088 mol) were added to a solution of 3,4-dimethoxy-2-(2,2,2,-trifluorethoxy)benzonitrile in dichloromethane. The temperature was maintained between 20° C. and 30° C. for 2 hours, after which time the reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried (MgSO4) and evaporated under reduced pressure. Trituration with diethyl ether followed by filtration afforded a first crop of product. The filtrate was purified on silica gel, eluting with dichloromethane to afford the subtitle compound as a colourless solid (combined yield 6.56 g, 73%). Rf 0.31 (ethyl acetate:hexane 20:80, v/v). MS m/z 324 (MNH4)+