Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1.Cl.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[O-:26].C(=O)(O)[O-].[Na+]>C(O)CCC>[OH:26][N:21]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]1[NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: CCOC(=O)c1ccc2c(cnn2CCN)c1
Reactant: [O-][n+]1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(=O)c1ccc2c(cnn2CCNC2C=CC=CN2O)c1
Reaction time: 24 h
Yield: 43.6 %

Procedure:
Ethyl 1-(2-aminoethyl)-1H-indazole-5-carboxylate (584 mg, 2.5 mmol, prepared as in step B), was added to dry n-butanol along with 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol). The reaction mixture was vigorously stirred and heated at 100 C for 21 hr. Additional aliquots of 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol) were added and heating continued for 24 hours. The reaction was cooled and filtered and the filtrate concentrated. The residue was purified by flash chromatography (5% methanol-dichloromethane) and the product fractions concentrated to afford the product as an orange solid (358 mg, 44%). LRMS (ES): 327.1 ([M+H]+, 100%), 653.3 ([2M+H]+, 40%) 1HNMR (600.1343 MHz, CDCl3): 8.44 (s, 1H), 8.12 (s, 1H), 7.97 (d of t, 2H), 7.56 (bs, 1H), 7.45 (d, 1H), 7.06, (m, 1H), 6.45 (m, 1H), 6.35 (t, 1H), 4.68 (t, 2H), 4.37 (q, 2H), 3.90 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: CCN(CC)CC.Br[CH2:9][CH2:10][OH:11].[OH:12][C@@H:13]1[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[C@H:27]([CH3:33])[C@@H:26]([OH:34])[C@@H:25]([CH3:35])[CH2:24][CH2:23][CH2:22][C@@H:21]2[C@@H:19]([NH:20]2)[CH2:18][C@@H:17](/[C:36](/[CH3:44])=[CH:37]/[C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[O:16][C:15](=[O:45])[CH2:14]1>C(#N)C>[OH:12][C@@H:13]1[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[C@H:27]([CH3:33])[C@@H:26]([OH:34])[C@@H:25]([CH3:35])[CH2:24][CH2:23][CH2:22][C@@H:21]2[C@@H:19]([N:20]2[CH2:9][CH2:10][OH:11])[CH2:18][C@@H:17](/[C:36](/[CH3:44])=[CH:37]/[C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[O:16][C:15](=[O:45])[CH2:14]1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2N[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@H]2[C@@H](CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)N2CCO
Temperature: 72.5 °C
Reaction time: 20 h
Yield: 68.2 %

Procedure:
Et3N (4.95 mL, 35.52 mmol) and 2-bromoethanol (3.02 mL, 42.62 mmol) were added to (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione (3.50 g, 7.10 mmol) in acetonitrile (35 mL) and heated to 72.5° C. After 20 hr, the reaction mixture was cooled to room temperature, concentrated to dryness through rotary vacuum distillation. The crude was dissolved in ethyl acetate (50 mL) and mixed with deionized water (35 mL). The mixture was extracted with ethyl acetate (3×35 mL), dried over Na2SO4, filtered, concentrated, crystallized in acetonitrile (35 mL), washed with acetonitrile (2×5 mL), and dried in vacuum oven at 45.5° C. overnight to isolate (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-17-(2-hydroxyethyl)-8,8,10,12-tetramethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione as a white crystalline powder (2.60 g, HPLC AP 97.1, 68.2% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1)=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[CH3:17][O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:18].[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]
Reactant: COCCN1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN1CCNCC1=O
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonyl-4-(2-methoxyethyl)-3-oxopiperazine (6.6 g) was dissolved in dichloromethane (100 ml), the resulting solution cooled in an ice-bath, and trifluoroacetic acid (145 ml) added. The mixture was stirred at the same temperature for 2 hours. Solvent was evaporated to yield 1-(2-methoxyethyl)-2-oxopiperazine product as a salt with 4 moles of trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([Cl:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O>C(O)C>[NH2:1][C:2]1[N+:7]([O-:22])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCNc1cc(Cl)nc(N)n1
Solvent: CCO
Solvent: O
Product: CCCCNc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
8.5 g of 2-amino-4-butylamino-6-chloropyrimidine are dissolved in 150 ml of ethanol. 19.95 g of meta-chloroperbenzoic acid are added dropwise as solution in 150 ml of ethanol. The reaction mixture is stirred at room temperature for 2 hours. 250 ml of water are added and ethanol is then evaporated off. The pH is adjusted to 1 with concentrated hydrochloric acid. After 1 hour's stirring, the precipitate is filtered off on sintered glass, rinsed with 50 ml of water and discarded. The pH of the solution is adjusted to 8 by adding sodium hydroxide. The mixture is extracted with 3×100 ml of dichloromethane. The organic phase is dried over sodium sulfate and then evaporated to dryness. The precipitate obtained is recrystallized from 50 ml of acetonitrile. 2.35 g of 2-amino-4-butylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:17]([S:21]([NH2:23])=[O:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl.O.[O-]S([O-])(=O)=O.[Cu+2]>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1/[CH:5]=[N:23]/[S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22]
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-bis trifluoromethyl benzaldehyde (10.0 g, 41.3 mmol), tert butyl sulfinamide (4.5 g, 37.2 mmol) and anhydrous CuSO4 (13.1 g, 82.6 mmol) in DCM (100 ml) was stirred at room temperature overnight. The fine suspension was diluted with water and extracted with DCM. The extracts were washed with water, dried (MgSO4) and evaporated in vacuo to afford the desired N-{(1E)-[2,4-bis(trifluoro methyl)phenyl]methylene}-2-methylpropane-2-sulfinamide as an off white solid (7.62 g, 53%), with no further purification. 1H NMR δ (ppm)(CDCl3): 8.99 (1 H, d, J=1.9 Hz), 8.35 (1 H, d, J=8.2 Hz), 8.02 (1 H, s), 7.92 (1 H, d, J=8.2 Hz), 1.28 (9 H, d, J=4.6 Hz); m/z (ES+) 346 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:46][CH2:47][CH:48]([OH:59])[CH2:49][N:50]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](=[O:14])[NH:46][CH2:47][CH:48]([OH:59])[CH2:49][N:50]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:51]2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(O)CN1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(O)CN2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (300 mg, 1.3 mmol) in DCM (8 mL) was added EDCI (383 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), Et3N (263 mg, 2.6 mmol), 1-amino-3-(isoindolin-2-yl)propan-2-ol (499 mg, 2.6 mmol), and the mixture was stirred at 25° C. for 16 h. The crude reaction mixture was washed with water and extracted with DCM. The combined organic layers were concentrated, and the residue was purified by column chromatography to yield the desired product (DCM:MeOH=10:1). (260 mg, yield 49%) MS (ESI+) e/z: 412.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.87 (s, 1H), 7.58-7.50 (m, 1H), 7.45-7.38 (m, 1H), 7.34-7.28 (m, 1H), 7.25-7.14 (m, 4H), 4.08-3.96 (m, 5H), 3.63-3.53 (m, 1H), 3.45-3.37 (m, 1H), 2.94-2.80 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[O:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 83 °C
Reaction time: 19 h
Yield: 25 %

Procedure:
To a solution of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.150 g, 0.340 mmol) in ethylene glycol dimethyl ether (3 mL) and water (1.5 mL) under nitrogen was added N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine (0.151 g, 0.425 mmol), tetrakis(triphenylphosphine)palladium (0) (0.020 mg, 0.017 mmol), and sodium carbonate monohydrate (0.105 mg, 0.850 mmol). The solution was stirred at 83° C. for 19 h. The resulting yellow mixture was concentrated in vacuo to give a yellow oil. Purification by preparative RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min using a 8 m Hypersil HS C18, 250×21 mm column, tr=5.7-8.1 min.) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine as an off-white solid (0.046 g, 25%): 1H NMR (DMSO-d6, 400 MHz) δ 10.65 (s, 1H), 8.49 (m, 1H), 8.25 (s, 1H), 7.53 (d, 2H), 7.48 (d, 2H), 7.26 (t, 1H), 7.20 (t, 1H), 4.80 (m, 1H), 3.51-2.50 (m, 11H), 2.33-2.32 (m, 4H), 2.09-2.06 (m, 2H), 1.80-1.40 (m, 3H); 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=6.95 min., 99%; m/z 542 (MH+).
Reaction SMILES: Br[CH:2]([C:4]1[C:5]([F:27])=[CH:6][C:7]2[O:16][CH2:15][CH2:14][N:13]3[C:9](=[N:10][C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)=[CH:12]3)[C:8]=2[CH:26]=1)[CH3:3].[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([CH:2]([C:4]2[C:5]([F:27])=[CH:6][C:7]3[O:16][CH2:15][CH2:14][N:13]4[CH:12]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[N:10]=[C:9]4[C:8]=3[CH:26]=2)[CH3:3])[CH2:32][CH2:31]1)[CH3:29]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)Br)c(F)cc2OCC3)n(C(C)C)n1
Reactant: CCN1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(C(C)c2cc3c(cc2F)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Yield: 65 %

Procedure:
A solution of 9-(1-bromoethyl)-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (85 mg, 0.20 mmol), N-ethylpiperazine (27 μL, 0.22 mmol) and DIPEA (54 μL, 0.30 mmol) in dioxane (2 mL) was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (Si-PPC, gradient 0-10% 2 M NH3/MeOH in DCM) to give 374 (61 mg, 0.13 mmol, 65% over 2 steps) as a white solid. LCMS (Method K): RT 2.74 min [M+H]+ 468.2. 1H NMR (CD3OD, 400 MHz): δ 8.55 (1H, d, J=8.2 Hz), 7.68 (1H, s), 6.76 (1H, d, J=11.1 Hz), 5.83 (1H, sept., J=6.7 Hz), 4.48 (4H, br s), 3.84 (1H, q, J=6.8 Hz), 2.50 (8H, br s), 2.38 (2H, q, J=7.4 Hz), 2.33 (3H, s), 1.53 (3H, d, J=6.7 Hz), 1.52 (3H, d, J=6.7 Hz), 1.40 (3H, d, J=6.8 Hz), 1.03 (3H, t, J=7.4 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CC(N(C)C)=O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([NH:1][CH2:12][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc(N)cc1OC
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Reaction time: 8 h
Yield: 66.8 %

Procedure:
In a 50 ml flask, a mixture of 4-aminoveratrole (1.53 g, 10 mmol), 4formyl-benzoic acid (1.50 g, 10 mmol), dibutyltin dichloride (304 mg, 1 mmol), phenylsilane (2.47 ml, 20 mmol) in anhydrous THF (10 mL) and DMA (10 ml) was stirred overnight. at room temperature. After solvents removal, the crude residue was dissolved in ethyl acetate (100 ml) and then washed with saturated aqueous solution of NaHCO3 (50 ml×3). The combined aqueous layers were acidified with 6% of NaHSO4 to pH=4. The resulting white suspension was filtrated and then the filter cake was washed with water (5 ml×3). The cake was dried over freeze dryer to afford acid (1.92 g, 67%) white solid product. LRMS=288 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[NH2:23][OH:24]>CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:23][OH:24])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC1CN(Cc2ccccc2)CCC1=NO

Procedure:
To a solution of 1-benzyl-3-methyl-piperidin-4-one (2.04 g, 10 mmol) in EtOH (20 mL), was added pyridine (20 mL, 0.25 mol) and hydroxylamine hydrochloride (0.70 g, 10 mmol). After being stirred at 90+ C. overnight, the resultant solution was concentrated in vacuo to give the crude product 1-benzyl-3-methyl-piperidin-4-one oxime. LC/MS m/z: 219 (M+H)+. This material was used without further purification.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=CC=2)C=1C#N.[NH2:70][C:71]1[N:75]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[N:74]=[C:73]([C:83]2[CH:88]=[CH:87][C:86](O)=[CH:85][CH:84]=2)[C:72]=1[C:90]#[N:91].[S:92]1[C:96]2[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=2[N:94]=[C:93]1[N:101]([CH2:130][O:131][CH2:132][CH2:133][Si:134]([CH3:137])([CH3:136])[CH3:135])[C:102]([C:104]1[CH:105]=[CH:106][CH:107]=[C:108]2[C:113]=1[CH2:112][N:111]([C:114]1[S:115][C:116]([CH2:126][CH2:127][CH2:128][OH:129])=[C:117]([C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[N:118]=1)[CH2:110][CH2:109]2)=[O:103].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC=C(O)C=2)C=1C#N>>[NH2:70][C:71]1[N:75]([C:76]([O:78][C:79]([CH3:80])([CH3:81])[CH3:82])=[O:77])[N:74]=[C:73]([C:83]2[CH:88]=[C:87]([CH:86]=[CH:85][CH:84]=2)[O:129][CH2:128][CH2:127][CH2:126][C:116]2[S:115][C:114]([N:111]3[CH2:110][CH2:109][C:108]4[C:113](=[C:104]([C:102](=[O:103])[N:101]([C:93]5[S:92][C:96]6[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=6[N:94]=5)[CH2:130][O:131][CH2:132][CH2:133][Si:134]([CH3:136])([CH3:135])[CH3:137])[CH:105]=[CH:106][CH:107]=4)[CH2:112]3)=[N:118][C:117]=2[C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[C:72]=1[C:90]#[N:91]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO
Agent: CC(C)(C)OC(=O)n1nc(-c2cccc(O)c2)c(C#N)c1N
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1cccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)c1

Procedure:
The title compound 39A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with compound 38E and compound 36A, respectively as a mixture of two inseparable isomers: MS (ESI(+)): 934 (M+H).
Reaction SMILES: Br[C:2]([Br:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[Si](CC)(CC)CC.[C:18]1(=[O:23])[CH2:22][CH2:21][CH:20]=[CH:19]1>[Zn].C(#N)C>[Br:9][C:2]([F:8])([CH:20]1[CH2:21][CH2:22][C:18](=[O:23])[CH2:19]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)C(F)(Br)Br
Agent: CC[Si](Cl)(CC)CC
Agent: [Zn]
Solvent: CC#N
Product: CCOC(=O)C(F)(Br)C1CCC(=O)C1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, 40.4 g of ethyl dibromofluoroacetate was added dropwise to a suspension of 22.4 mL of chlorotriethylsilane, 8.0 g of zinc, and 250 mL of acetonitrile, over 2 hours at −20° C. The mixture was further stirred for 1.5 hours at −20° C. 2-cyclopenten-1-one in an amount of 5.0 g was added dropwise to the reaction solution, and the mixture was stirred for 15 hours at −20° C. The reaction was quenched with 1M hydrochloric acid, followed by concentration under reduced pressure. After extraction of the residue with diethyl ether twice, the organic layers were combined. The combined organic layer was washed with a saturated aqueous solution of sodium chloride, and was subsequently dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=10:1 to 8:1), thereby yielding 6.2 g of (2SR)ethyl 2-bromo-2-fluoro-2-[(1RS)-3-oxocyclopentyl]acetate and 4.4 g of (2RS)ethyl 2-bromo-2-fluoro-2-[(1RS)-3-oxocyclopentyl]acetate.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:2][CH3:3].[C:11]([OH:17])(=O)[CH2:12][C:13]([OH:15])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([N:4]1[C:11](=[O:17])[CH2:12][C:13](=[O:15])[N:7]([CH2:8][CH2:9][CH3:10])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)NCCC
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCN1C(=O)CC(=O)N(CCC)C1=O

Procedure:
Synthesis was carried out according to the procedure of Goldner, Ann. Chem., 691, 142 (1966) using 1,3-di-n-propylurea (777 g., 5.38 mole), malonic acid (660 g., 6.34 mole), glacial acetic acid (1050 ml.) and acetic anhydride (2160 ml.) to obtain 790 g. (69.2%) of product, melting point 77° - 80° C. NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:6]1)[CH3:4].[C:19]([C:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:26]=[C:25]([C:27]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:6]2)[CH3:4])=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 18.2 %

Procedure:
(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (217 mg, 0.416 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (128 mg, 0.832 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water) to yield 30 mg (18%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.62 (d, 3H), 2.55 (s, 3H), 3.74-3.83 (m, 1H), 3.90-3.99 (m, 1H), 4.58-4.69 (m, 1H), 6.61 (d, 1H), 7.29 (bs, 1H), 7.50 (d, 1H), 7.68 (d, 1H), 7.77 (dd, 1H), 8.09 (s, 1H), 11.1 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:17])[O:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:14][CH2:15][O:16][C:11]([CH3:17])([CH3:10])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC1(C)CNCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CN(Cc2ccc(Br)cc2)CCO1
Temperature: 85 °C
Yield: 96.8 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.5 g, 6.0 mmol), 2,2-dimethylmorpholine (0.69 g, 6.0 mmol) and potassium carbonate (0.99 g, 7.2 mmol) in acetonitrile (60 mL) was heated at 85° C. for 20 h. The mixture was allowed to cool to ambient temperature and the solid was removed by filtration and the filtrate evaporated. The resultant residue was dissolved in DCM/methanol and loaded onto a 20 g SCX-2 cartridge which was washed with methanol then 2N ammonia in methanol. Concentration of the combined basic fractions afforded the title compound (1.65 g, 97%) as an orange oil. 1H NMR (CDCl3, 300 MHz): 7.44 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 3.75 (t, J=4.8 Hz, 2H), 3.39 (s, 2H), 2.37 (t, J=4.6 Hz, 2H), 2.16 (s, 2H), 1.23 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.CC1C=CC(S([CH2:23][N+:24]#[C-])(=O)=O)=CC=1.C(O[K])(C)(C)C>COCCOC.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[CH:7]([C:23]#[N:24])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)cc(Cl)c21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CCc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5,7-dichloro-1-indanone (2.24 mmol) and TosMIC (6.71 mmol) in 25 mL 1,2-dimethoxyethan and 1 mL EtOH was added tBuOK (6.71 mmol) at 5° C. The cooling bath was removed and the reaction mixture was stirred at RT for 1 h. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC using Hept/EtOAc (7/3) gives the desired compound as yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:11]([O:12][CH2:13][CH:14]([NH2:16])[CH3:15])=[C:10]([CH3:17])[CH:9]=[CH:8][CH:7]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>O>[CH3:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:17])[C:11]=1[O:12][CH2:13][CH:14]([NH:16][C:1](=[O:3])[CH3:2])[CH3:15]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(C)c1OCC(C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NC(C)COc1c(C)cccc1C
Temperature: 17.5 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
Acetyl chloride (99 ml, 1.39 mol, 1.5 eq) was added to a stirred suspension of mexiletine hydrochloride (200 g, 0.927 mol), ethyl acetate (750 ml), and 5N sodium hydroxide (750 ml) over a period of 35 minutes while keeping the temperature at ≤10° C. After the addition was complete, the reaction was allowed to stir for 45 minutes at 15-20° C. The mixture was then added to water (1 1) and the ethyl acetate layer separated. The aqueous layer was washed with ethyl acetate (2×300 ml) and the combined ethyl acetate layers were washed with saturated aqueous sodium bicarbonate until the washings were no longer acidic. The ethyl acetate solution was then washed with brine, dried over MgSO4, and concentrated to give N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-acetamide (197 g, 96% yield, mp 85-85.8° C.).