Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[CH3:8].O.[OH-].[Na+]>O1CCCC1>[CH2:7]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12])[CH3:8]
Reactant: CCc1ccccc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccccc1CN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (7.4 g 196 mmol) in tetrahydrofuran (130 mL) was slowly treated with 2-ethylbenzonitrile (4.99 g 38 mmol) in tetrahydrofuran (40 mL) at 0° C. under nitrogen. The mixture was stirred for 30 minutes at 0° C., 2 hours at room temperature, recooled to 0° C., and then slowly treated in succession with water (7.4 mL), 15% sodium hydroxide (7.4 mL) and water (22 mL). Additional tetrahydrofuran (50 mL) was added to facilitate stirring. The reaction mixture was filtered through celite, the filter cake was washed with tetrahydrofuran (150 mL), the filtrate was concentrated under reduced pressure, and the residue was partitioned between methylene chloride/saturated sodium chloride. The organic phase was dried (potassium carbonate), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (CDCl3) δ 1.24 (t, 3H), 2.69 (q, 2H), 3.89 (s, 2H), 7.20 (m, 3H), 7.32 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19]([C:20]([O:22]C)=O)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)[CH3:3].O.[NH4+:25]>>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19]([C:20]([NH2:25])=[O:22])=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3ccc(CN(C)C)cc3)oc12
Solvent: O
Product: CN(C)Cc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1

Procedure:
Methyl 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate in ammonium water (10 mL) was stirred at 30° C. for 17 hr, then the solvents were evaporated and purified by pre-HPLC to obtain 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (10 mg). 1H-NMR (400 MHz, DMSO-d6) δ 2.18 (s, 6H), 3.5 (s, 2H), 7.47-7.49 (t, J=8 Hz, 1H), 7.54-7.56 (d, J=8.4 Hz, 2H), 7.79-7.81 (d, J=8 Hz, 1H), 7.86-7.90 (d, J=14.4 Hz, 2H), 7.94-7.96 (d, J=8 Hz, 1H), 8.24-8.26 (d, J=8 Hz, 2H); LC-MS (ESI) m/z 296 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=1.C([O-])([O-])=O.[K+].[K+]>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>[C:16]1([C:8]2([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]3[CH:22]=[C:2]([CH2:51][C:52]4[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=4)[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]=3[O:9]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: COC(=O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COC(=O)c1cc(Cc2ccc(C)cc2)cc2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (200 mg, 1.486 mmol, 1 eq.), Pd(PPh3)4 (57 mg, 0.049 mmol, 0.1 eq.), bis(pinacolato)diboron (160 mg, 0.632 mmol, 1.3 eq.) and KOAc (72 mg, 0.73 mmol, 1.5 eq.), then Pd(PPh3)4 (57 mg, 0.049 mmol, 0.1 eq.), 1-bromomethyl-4-methyl-benzene (117 mg, 0.63 mmol, 1.3 eq.) and K2CO3 (336 mg, 2.43 mmol, 5 eq.) were reacted according to GP6 to yield the title product as a colorless, very slowly solidifying oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][O:6][C@H:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:4]1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:3]1[CH2:8][CH2:7][O:6][C@H:5]([CH2:9][N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCO[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCO[C@H](CN2CCNCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-((2R)-4-ethylmorpholin-2-ylmethyl)piperazinecarboxylate (0.50 g, 1.60 mmol) prepared according to Process Step 1 was dissolved in dichloromethane (5 mL), and the solution was mixed with trifluoroacetic acid (2 mL) added dropwise under ice-cooling. After stirring at room temperature for one hour, the solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in dioxane (6 mL), and the solution was mixed with triethylamine (3 mL) to thereby yield (2R)-4-ethyl-2-(piperazinylmethyl)morpholine.
Reaction SMILES: [C:1]12([C:7]3[O:8][C:9]4[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[C:17](B5OC(C)(C)C(C)(C)O5)=[CH:16][C:10]=4[C:11]=3[C:12]([NH:14][CH3:15])=[O:13])[CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.Cl[C:36]1[CH:37]=[CH:38][C:39]2[O:52][CH2:51][N:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[C:47]([F:50])[C:48]=4[CH:49]=[C:41]3[C:40]=2[N:53]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:1]12([C:7]3[O:8][C:9]4[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:22])=[O:23])[C:17]([C:36]5[CH:37]=[CH:38][C:39]6[O:52][CH2:51][N:42]7[C:43]8[CH:44]=[CH:45][CH:46]=[C:47]([F:50])[C:48]=8[CH:49]=[C:41]7[C:40]=6[N:53]=5)=[CH:16][C:10]=4[C:11]=3[C:12]([NH:14][CH3:15])=[O:13])[CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(C23CCCC2C3)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(C23CCCC2C3)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a degassed solution of 2-(bicyclo[3.1.0]hexan-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.20 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (67 mg, 0.24 mmol), K3PO4 (109 mg, 0.41 mmol) in 1,4-Dioxane (5 mL) and H2O (0.5 ml) was added Pd(dba)3 (5 mg), X-Phos (5 mg) under N2, then the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O, brine, extracted with DCM, and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 2-(bicyclo[3.1.0]hexan-1-yl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 16%). 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.55 (s, 1H), 7.46 (s, 2H), 7.21 (s, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.86 (q, J=8.0 Hz, 1H), 6.17 (d, J=4.0 Hz, 1H), 5.60 (s, 2H), 3.38 (s, 3H), 3.05 (d, J=4.8 Hz, 3H), 2.67 (s, 3H), 2.14˜2.22 (m, 2H), 2.11˜2.16 (m, 2H), 2.01˜2.09 (m, 2H), 1.91˜1.98 (m, 1H), 1.84 (d, J=4.0 Hz, 2H). MS (M+H)+: 601.
Reaction SMILES: [S:1]1[C:5]([S:6]([Cl:9])(=[O:8])=[O:7])=[CH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[N+:14]([O-])([OH:16])=[O:15]>ClCCl>[N+:14]([C:4]1[C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=2[S:1][C:5]=1[S:6]([Cl:9])(=[O:8])=[O:7])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Solvent: ClCCl
Product: O=[N+]([O-])c1c(S(=O)(=O)Cl)sc2ccccc12
Temperature: 25 °C

Procedure:
To a solution of benzo[b]thiophene-2-sulfonyl chloride (1.165 g, 5 mmol) in 25 mL of dichloromethane was added 3.6 mL of concentrated nitric acid (≧22.05 mol/L) dropwise, the resulting mixture was refluxed overnight and cooled to room temperature before it was poured into 20 gram of crushed ice. The organic layer was separated and the aqueous layer was extracted by 220 mL 2 dichloromethane. The organic layers were combined and dried over MgSO4. Solvent was then removed by rotary evaporator. The crude product was purified by flash column chromatography with an eluent of hexane, followed by a gradient eluent of hexane/ethyl acetate (6/1-3/1) to afford 0.58 g of product (mixture of 65% of 4-nitro-benzo[b]thiophene-2-sulfonyl chloride and 35% of 7-nitro-benzo[b]thiophene-2-sulfonyl chloride).
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:20]([C:22]1([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=4)[C:41]=3[CH3:42])=[O:36])=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:21].C(=O)(O)[O-].[Na+]>ClCCl.O1CCCC1>[C:20]([C:22]1([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=4)[C:41]=3[CH3:42])=[O:36])=[CH:30][CH:29]=2)[CH2:23][CH2:24][N:25]([CH:3]2[CH2:2][O:1][CH2:4]2)[CH2:26][CH2:27]1)#[N:21]
Reactant: O=C1COC1
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(C4COC4)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reaction time: 6 h
Yield: 44.5 %

Procedure:
3-Oxetanone (316 mg) and sodium triacetoxyborohydride (112 mg) were added at room temperature to a solution of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (200 mg) described in Reference Example 169 in dichloromethane (20 ml) and tetrahydrofuran (20 ml), and stirred at the same temperature for eight hours. Further 3-oxetanone (316 mg) and sodium triacetoxyborohydride (112 mg) were added at room temperature and stirred at the same temperature for six hours. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and the resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (100 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:2]3[N:24]=[C:5]4[C:6]([NH:10][CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: Nc1ccc2cnccc2c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ccccc1CNc1cccn2nc(Nc3ccc4cnccc4c3)nc12)S(C)(=O)=O

Procedure:
N-(2-{[2-(Isoquinolin-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (100.0 mg, 0.2733 mmol) and isoquinolin-6-ylamine (45.0 mg, 0.312 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.079 g, 61%). 1H NMR (400 MHz, CDCl3, δ, ppm): 9.09 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.28 (s, 1H), 7.92-7.87 (m, 2H), 7.62 (d, J=5.3 Hz, 1H), 7.54 (d, J=6.8 Hz, 2H), 7.40-7.28 (m, 3H), 7.18 (s, 1H), 6.76 (t, J=7.0 Hz, 1H), 6.44 (d, J=7.3 Hz, 1H), 5.39-5.32 (m, 1H), 4.75 (d, J=5.4 Hz, 2H), 3.32 (s, 3H), 3.02 (s, 3H). MS=474 (MH)+.
Reaction SMILES: B.C1COCC1.[O:7]=[C:8]1[CH:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][NH:9]1.CO>C1COCC1>[OH:15][CH2:14][C:12]1[CH:11]=[CH:10][NH:9][C:8](=[O:7])[CH:13]=1
Reactant: O=C(O)c1cc[nH]c(=O)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=c1cc(CO)cc[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane-THF (29 mL, 1.0 M) was added to a solution of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (1 g, 7.19 mmol) in THF (15 mL) at 0° C. The mixture was stirred at 25° C. for 2 hours. Methanol was added and the mixture was concentrated under reduced pressure to afford 4-(hydroxymethyl)pyridin-2(1H)-one. MS ESI calc'd. for C6H8NO2 [M+H]+ 126. found 126. 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=6.8 Hz, 1H), 6.58 (s, 1H), 6.38 (d, J=6.4 Hz, 1H), 4.52 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[C@@:16]([CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:25])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[Cl:40][CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>CN(C)C=O.O>[Cl:40][CH2:41][CH2:42][CH2:43][S:44]([NH:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[C@@:16]([CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:25])[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:23]=3[OH:24])[NH:7][C:6]=2[S:5][CH:4]=1)(=[O:46])=[O:45]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN)csc3N2)=C(O)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CNS(=O)(=O)CCCCl)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 186B (64 mg, 0.14 mmol) in 1.5 mL of N,N-dimethyl formamide was cooled to 0° C., treated with triethylamine (30 μL, 0.28 mmol) and 3-chloropropylsulfonyl chloride (19 μL, 0.15 mmol), stirred for 30 minutes, allowed to warm to room temp, stirred for 2 h, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and concentrated in vacuo to afford a solid. This crude material was purified by chromatography on silica gel with a gradient of methanol in dichloromethane (0-2%) to afford the title compound as a pale compound (42 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (td, J=12.8, 3.5 Hz, 1 H), 0.72 (s, 9 H), 0.82 (m, 1 H), 1.56 (s, 3 H), 2.13 (m, 4 H), 3.21 (m, 2 H), 3.75 (t, J=6.4 Hz, 2 H), 4.28 (d, J=5.9 Hz, 2 H), 7.33 (s, 1 H), 7.51 (m, 1 H), 7.72 (m, 2 H), 7.90 (t, J=6.3 Hz, 1 H), 8.13 (d, J=7.7 Hz, 1 H), 14.09 (s, 1 H); MS (APCI−) m/z 612 (M−H)−; Anal calc'd for C26H32ClN3O6S3: C, 50.84; H, 5.25; N, 6.84. found: C, 51.07; H, 5.28; N, 6.51.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:22]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)(=[O:25])[CH:23]=[CH2:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([CH:24]=[CH:23][C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CC(=O)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)N3CCOCC3)cn2)CC1
Yield: 91.5 %

Procedure:
A solution of t-butyl 4-(5-bromo pyridin-2-yloxy)piperidine-1-carboxylate (1 gram, 2.80 mmoles), 4-acryloylmorpholine (0.63 gram, 4.46 mmoles), palladium acetate (13 mg, 0.061 mmoles) tri(o-tolyl)phosphine (25.6 mg, 0.084 mmoles) and potassium carbonate (0.62 g, 4.49 mmoles) in DMF (15 mL) was stirred for 3 hours at 140° C. The progress of the reaction was monitored by thin layer chromtography. After completion of reaction, the mass was quenched on to chilled water (30 mL) and the product was extracted with ethyl acetate (3×15 mL). The resulting organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The residue, thus obtained, was purified by flash chromatography using ethyl acetate:n-hexane in the ratio of 1:1 to afford the title compound (1.07 grams).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=O)[O:21]C3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]([C@H:37]1[CH2:42][CH2:41][C@@H:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36]>>[CH3:33][O:34][C:35]([CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:32])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)=[O:21])[CH2:39][CH2:38]1)=[O:36]
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: COC(=O)C1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-cyclohexane-carboxylic acid methyl ester was prepared starting from intermediate M and cis-4-amino-cyclohexane carboxylic acid methyl ester. MS calcd. for C25H27ClN3O4 [(M+H)+] 468.2, obsd. 468.0.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:20])([F:19])[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.[CH2:21](O)[CH3:22]>>[F:6][C:7]([F:19])([F:20])[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:21][CH3:22])=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(OC(F)(F)F)cc1
Yield: 91 %

Procedure:
Sulfuric acid (0.484 ml, 9.08 mmol) was added dropwise to a solution of 2-(4-(trifluoromethoxy)phenyl)acetic acid (2.0 g, 9.08 mmol) in ethanol (20 ml), and heated under reflux for 5 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (100 ml), washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 0/100 to 20/80) to give ethyl 2-(4-(trifluoromethoxy)phenyl)acetate (2.06 g, yield 91%) as yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)([CH3:3])[CH3:2].[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[Cl:28][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[N:6]([C:9]([C:7]4[NH:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=4)=[O:11])[N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)=[O:11])[CH3:29])[N:16]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)c1cc(C(=O)O)[nH]n1
Product: CC(C)c1cc(C(=O)n2nc(C(C)C)cc2C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 1.88 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-isopropyl-1-(3-isopropyl-1H-pyrazole-5-carbonyl)-1H-pyrazole-5-carboxamide was prepared using the method of Example 34(d) starting from 3-isopropyl-1H-pyrazole-5-carboxylic acid (0.284 g, 1.841 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.534 mmol). Yield 1.883%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (dd, 6H), 1.27 (d, 3H), 1.32 (dd, 6H), 2.94 (m, 1H), 3.81 (m, 1H), 4.32 (dd, 1H), 4.47 (dd, 1H), 4.63 (m, 1H), 6.63 (d, 1H), 6.81 (s, 1H), 7.08 (s, 1H), 7.44 (d, 1H), 7.51 (d, 1H), 7.64 (dd, 1H), 7.78 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:26])[C:10]([CH2:27][OH:28])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:26])[C:10]([CH:27]=[O:28])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cccc3c2c(=O)c(CO)nn3Cc2ccccc2)c(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2cccc3c2c(=O)c(C=O)nn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
To 0.20 g (0.54 mmol) of 1-benzyl-5-(2,4-dimethylphenyl)-3-(hydroxymethyl)cinnolin-4(1H)-one in 10 mL of dichloromethane was added 0.28 g (0.65 mmol) of Dess-Martin periodinane. The reaction was stirred at room temperature for 90 min before being diluted with sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography eluting with a 33% ethyl acetate/hexanes mixture to give 0.17 g (85%) of the title compound as a yellow powder.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]1([C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)([OH:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc(Cl)cc1

Procedure:
To 37 ml of a 2M solution of phenylmagnesium bromide in tetrahydrofuran was added, under argon atmosphere, 5.24 g (33.9 mmol) of p-chloroacetophenone, and the mixture was allowed to react at 0° C. for 3 hours. At the completion of this reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with water and then concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform, to give 6.99 g (30.0 mmol) of 1-phenyl-1-(p-chlorophenyl)ethanol. To a solution of 6.99 g (30.0 mmol) of the alcohol compound in ethanol (80 ml) was added 5.00 ml (93.8 mmol) of conc. sulfuric acid, and the mixture was reacted for 1 hour.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O)C.[H-].[Na+].Cl.[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:17]([O:18][CH2:19][CH3:20])=[O:21])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4′-fluoroacetophenone (57.8 g, 0.307 mol) and ethanol (1 ml) in diethyl carbonate (300 ml) was added sodium hydride (24.5 g, 60% in oil, 0.63 mol) by small portions. Because heat is gradually generated, the mixture was ice-cooled and stirred at room temperature for 2 hrs. To the reaction solution was added 6N hydrochloric acid to quench the reaction. Water (300 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl 3-(4-fluorophenyl)-3-oxopropionate (71.2 g, 89%).