Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[H][H]>[Pd].CO>[NH2:13][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NCCCO)c(N)c1
Yield: 91 %

Procedure:
A mixture of 70 parts of 3-[(4-methyl-2-nitrophenyl)amino]-1-propanol and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 54 parts (91%) of 3-[(2-amino-4-methylphenyl)amino]-1-propanol as a residue.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH3:24][O:25][CH2:26][CH2:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH:33]=[O:34]>C1COCC1.CCCCC>[OH:34][CH:33]([C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1)[C:29]1[N:28]([CH2:27][CH2:26][O:25][CH3:24])[CH:32]=[CH:31][CH:30]=1
Reactant: COCCn1cccc1C=O
Reactant: CN(c1ccc(Br)cc1)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCCn1cccc1C(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Temperature: -30 °C

Procedure:
To a solution of 1.49 g (4.59 mmol) of N-(4-bromophenyl)-N-methyl benzenesulfonamide (see Preparative Example A, Step C) in 37.5 mL THF at −78° C. was added dropwise 5.94 mL (10.10 mmol) of a 1.7 M solution of tert-BuLi in pentane and the resultant mixture was stirred at −78° C. for 15 min. To this mixture was then added a solution of 1.01 g (6.59 mmol) of N-methoxyethylpyrrole-2-carboxaldehyde in 6 mL THF and the mixture was allowed to gradually warm to −30° C. over a 4 h period. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 13:7) to give the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1nccs1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Product: c1cc(CN2CCCCC2)cc(OCCCNc2nccs2)c1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (7.45 g) and 2-bromothiazole (2.46 g) in pyridine (25 ml) were stirred under reflux for 20 hours. The reaction mixture was cooled, evaporated and partitioned between chloroform and water. The chloroform layer was evaporated and subjected to medium pressure column chromatography on silica (chloroform:methanol 19:1) to give the title compound as an oil. This was converted to 2-[3-[3(piperidinomethyl)phenoxy]propylamino]thiazole dihydrochloride, m.p. 192.5°-193.5° C. (recrystallised from isopropanol-ethyl acetate).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[H-].[Na+].[Cl:54][CH2:55][CH2:56]Cl.O>CN(C)C=O>[Cl:54][CH2:55][CH2:56][N:2]([CH3:1])[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: ClCCCl
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCl)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reaction time: 0.33 h

Procedure:
314 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) was dissolved in 8 mL N,N-dimethylformamide, then 21 mg sodium hydride was added thereto and stirred for 20 minutes, and 0.35 mL 1,2-dichloroethane was added thereto and stirred at room temperature for 2 hours. Further, 0.35 mL 1,2-dichloroethane was added thereto and stirred at 60° C. for 24 hours. Water was added to the reaction solution which was then extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated, and then the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 325 mg of the title compound as a colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:18]C(=O)OCC3C=CC=CC=3)[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.I[Si](C)(C)C.Cl>C(#N)C.C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCC1Cc2cccc(-c3ccccc3Cl)c2O1)OCc1ccccc1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CC(C)O
Solvent: CC#N
Product: NCC1Cc2cccc(-c3ccccc3Cl)c2O1
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
To a solution of (+)-benzyl {[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]carbamate (0.530 g, 1.34 mmol) in acetonitrile (25 mL) cooled to 0° C. was added iodotrimethylsilane (1.07 g, 5.38 mmol) and the reaction mixture was allowed to stir for 90 min. The reaction mixture was quenched by the addition of aqueous hydrogen chloride (25 mL, 2.0 N) and washed with diethyl ether (50 mL). The aqueous layer was neutralized with aqueous sodium hydroxide (50 mL, 2.5 N) and extracted with dichloromethane (2×100 mL). The combined organic fractions were washed with water (75 mL), saturated aqueous sodium chloride (50 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. The oil was re-dissolved in isopropanol (2 mL) and hydrogen chloride (5.0 mL, 1.0 M in diethyl ether) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.229 g (58%) of (−)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]D25=−11.06 (c 10.0 in dimethylsulfoxide); mp 186-188° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found C, 59.59; H, 5.13; N, 4.48.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]=[O:24])[CH3:21]>C1COCC1>[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=2)[N:9]=[CH:10][N:11]=1)[OH:24])[CH3:21]
Reactant: COc1ccc(Cn2cncn2)cc1
Reactant: CCC(C=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ncnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 114.1 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-1H-1,2,4-triazole (2.12 g, 11.2 mmol) in THF (120 mL) at −78° C. was added a solution of n-butyllithium (2.5 M in hexanes, 4.9 mL, 12.3 mmol) over a period of 20 min. The solution was stirred at −78° C. for 2h and 45 min. Then 2-ethylbutyraldehyde (0.65 mL, 5.3 mmol) was added. After 1.5 h the reaction mixture was warmed to room temperature, quenched with saturated aqueous ammonium chloride, extracted with EtOAc and dried over Na2SO4. After removal of the solvents, the product was purified by recrystallization from EtOAc/hexanes to give 1.75 g (54%) of 2-ethyl-1-[1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol as a white solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N+:15]=1[O-:6])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1ccc(OC)cn1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(OC)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Chloroperoxybenzoic acid (5.66 g, 32.8 mmol) was added to a stirred solution of 2-ethyl-5-methoxy-pyridine (3 g, 22 mmol) dissolved in CHCl3 (100 mL). The reaction was stirred at room temperature for 3 hours and then quenched with satd Na2SO3. The reaction mixture was partitioned between H2O and CH2Cl2. The organic layer was washed with 1N NaOH, dried over Na2SO4 and concentrated to an oil (3.3 g, 99%). 1H NMR (400 MHz, CDCl3): δ 1.29 (t, J=7.5 Hz, 3H), 2.89 (q, J=7.5 Hz, 2H), 3.82 (s, 3H), 6.86 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 8.04 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[C:11]([Cl:15])[N:10]=[C:9]2[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:5][CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[OH-:32].[Na+]>C1C=CC=CC=1>[CH:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[C:11]([Cl:15])[N:10]=[C:9]2[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:5][CH:4]=1)=[O:32]
Reactant: [OH-]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 5.05 g of 1-(4-cyanobenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole in 350 mL of benzene at 25° was added dropwise 22.8 mL of diisobutylaluminum hydride (0.15M in toluene). The mixture was warmed to 45° and stirred for 16 hours. After cooling, the reaction mixture was poured in ice-cold 20% aqueous sulfuric acid. This solution was allowed to warm to 25° and then stirred for 2 hours. The solution was cooled to 0°, neutralized using aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) provided 3.60 g of 1-(4-formyl-benzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3) δ : 9.96 (s, 1H); 7.47 (A2M2, 4H); 5.26 (s, 2H); 4.42 (s, 2H); 2.54 (t, 2H); 1.64 (quint., 2H); 1.32 (sext., 2H); 0.86 (t, 3H).
Reaction SMILES: [K].Br[CH:3]([CH:7]([CH3:9])[CH3:8])[C:4]([OH:6])=[O:5].[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([F:18])[CH:12]=1.[OH-].[Na+]>CCOCC.C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C@H:3]([C:4]([OH:6])=[O:5])[CH:7]([CH3:9])[CH3:8])=[C:13]([F:18])[CH:12]=1
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(Br)cc1F
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](Nc1ccc(Br)cc1F)C(=O)O
Temperature: 25 °C

Procedure:
To the potassium salt of α-bromoisovaleric acid (1.42 g) is added 4-bromo-2-fluoroaniline (1.9 g). The mixture is heated at 125° under nitrogen for 3.5 hr and then cooled to RT. The reaction product is poured into 2 M NaOH and ether/chloroform. The basic phase is separated and acidified with conc. HCl and then extracted into ether, washed with saturated NaCl solution, dried over calcium sulfate and evaporated to yield N-(4-bromo-2-fluorophenyl)valine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O.OS(O)(=O)=O.[CH3:34][C:35]([CH3:37])=O.[OH-].[NH4+]>C(O)(=O)C.O>[CH2:17]([N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:34][C:35]([CH3:37])=[N:1]2)=[CH:4][CH:5]=1)[CH3:16])[CH:18]=[CH2:19]
Reactant: CC(C)=O
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(N)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C=CCN(C)CCCCCCOc1ccc2c(-c3ccc(Br)cc3)cc(C)nc2c1
Temperature: 0 °C

Procedure:
A solution of 360 mg of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone in 1.6 ml of acetic acid is treated with 0.01 ml of H2SO4 and 0.4 ml of acetone and boiled at 95° C. for 21 hrs., with a further 0.4 ml of acetone being added after 6 hrs. At 0° C. the reaction is poured into an ice-cold solution of 1.2 ml of 25% ammonium hydroxide solution in 3.5 ml of water and the mixture is subsequently extracted with methylene chloride. After drying the organic phase is evaporated and the residue is purified over silica gel with methylene chloride/methanol (95:5). The title compound obtained (200 mg) is crystallized with 24.6 mg of fumaric acid from methylene chloride/methanol/ether. There are obtained 56 mg of allyl-[6-[4-(4-bromo-phenyl)-2-methyl-quinolin-7-yloxy]-hexyl]-methyl-amine.fumarate (1:2), m.p. 88°-93° C., MS: m/e 467 (M+H+, 1 Br).
Reaction SMILES: [CH3:1][CH:2]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:3].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[CH3:3][CH:2]([S:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)=[O:26])[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)SC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Product: CC(C)S(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
tert-Butyl 4-(propan-2-ylsulfanyl)piperidine-1-carboxylate (prepared in an analogous manner to Intermediate 245, 0.160 g, 0.62 mmol) was dissolved in DCM (3 mL) and cooled to 0 C. m-Chloroperbenzoic acid (0.138 g, 0.62 mmol) was added, the mixture was warmed to room temperature and stirred for 17 h. Further m-chloroperbenzoic acid (0.040 g, 0.18 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was then diluted with DCM (10 mL) and washed with saturated aq. sodium thiosulfate (10 mL). The organic layer was separated and purified by FCC, eluting with 50-100% EtOAc in heptane followed by 10% MeOH in EtOAc to afford the title compound as a colourless oil (0.124 g, 73%). Method C HPLC-MS: MH+ requires m/z=276 Found: m/z=298 (M+Na), Rt=1.14 min (100%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:45]([NH:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:46])[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Product: O=C(NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1)Nc1ccccc1
Reaction time: 8 h

Procedure:
Amine (22) (25.2 mg, 46 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamnine (16 μL, 114 μmole, 2.5 eq) and phenyl isocyanate (6 μL, 55 μmole, 1.2 eq) were added and the reaction stirred overnight. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 12.46 (s, 1H), 8.45 (s, 2H), 8.27 (s, 1H), 8.23 (s, 1H), 7.36 (d, 2H), 7.32 (d, 2H), 7.25 (t, 2H), 7.18 (m, 4H), 6.84 (t, 1H), 6.05 (t, 1H), 4.43 (s, 2H), 3.30 (water), 3.03 (s, 2H), 2.81 (t, 2H), 2.48 (DMSO), 1.60 (m, 4H), 1.30 (m, 1H), 1.21 (m, 1H), 0.64 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:33](=[O:41])[C:32]=1[C:42]#[N:43]>O1CCOCC1.CCOC(C)=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>[CH:38]1([CH2:37][N:34]2[CH:35]=[CH:36][C:31]([C:6]3[CH:5]=[CH:4][C:3]([NH:17][CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[C:2]([F:1])[CH:7]=3)=[C:32]([C:42]#[N:43])[C:33]2=[O:41])[CH2:39][CH2:40]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)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: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(NC3CCOCC3)c(F)c2)ccn(CC2CC2)c1=O
Yield: 28.4 %

Procedure:
To a solution of intermediate 15 (0.8 g, 2.55 mmol) in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml) was added intermediate 8 (0.58 g, 2.31 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.26 mg, 0.23 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 1 (0.241 g, 30%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[OH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][C:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:27][C:26]2=[O:39]>>[CH3:20][O:19][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[O:29][C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][C:26]3=[O:39])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:21]
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc3oc(-c4ccccc4)cc(=O)c3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and 6-hydroxyflavone in a manner analogous to that described for Example 24, Step B. MS(ES) for C30H26O6[M+H]+:483.2
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH:20]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)[CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CNCc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
Benzyl 4-formylbenzoate (618 mg, 2.57 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (622 mg, 3.09 mmol) were dissolved in 20 mL of toluene and 2.0 mL of methanol, and the solvent was evaporated under reduced pressure. The resulting white solid was dissolved in 15 mL of 2-propanol, sodium triacetoxyborohydride (1.64 g, 7.72 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure, and the resulting yellow oily substance was purified by silica gel chromatography (n-hexane:ethyl acetate, 90:10→80:20, v/v) to give the title compound (0.54 g; yield, 54%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:29]=[CH:28][C:6]2[N:7]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:8]3[C:9]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[O:10][C:5]=2[CH:4]=1.[C:30]([O-:33])(=[O:32])[CH3:31].[K+]>CN(C=O)C.[NH4+].[Cl-]>[C:30]([O:33][CH2:2][C:3]1[CH:29]=[CH:28][C:6]2[N:7]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:8]3[C:9]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[O:10][C:5]=2[CH:4]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(CBr)ccc1-n1c(C#N)ccc12
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1ccc(C#N)n1-2
Temperature: 80 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
tert-Butyl 7′-(bromomethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (33.0 mg, 0.0720 mmol) and potassium acetate (35.3 mg, 0.360 mmol) were combined in DMF (0.5 mL) and the mixture was stirred at 80° C. for 18 hours. The mixture was taken up in NH4Cl (10 mL) and was extracted with CH2Cl2 (10 mL). Solvent was removed under reduced pressure and the residue was purified by column chromatography (0-10% EtOAc/CH2Cl2) to obtain tert-butyl 7′-(acetoxymethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (19.5 mg, 62%) as a clear oil. ESI-MS m/z calc. 437.2. found 438.5 (M+1)+; Retention time 2.05 minutes (3 min run). tert-Butyl 7′-(acetoxymethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate was dissolved in CH2Cl2 (10 mL) before TFA (5.0 mL, 65 mmol) was added. The solvent was removed under reduced pressure to give (1′-cyanospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-yl)methyl acetate (15 mg, 62%). ESI-MS m/z calc. 337.1. found 338.3 (M+1)+; Retention time 1.16 minutes (3 min run).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1>>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: ClCc1cccs1
Reactant: O=C1CCNCC1
Product: O=C1CCN(Cc2cccs2)CC1

Procedure:
1-(2-Thiopheneyl)methyl-4-piperidone is prepared from 4-piperidone and 2-(chloromethyl)thiophene essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1ncc(-c2ccccc2)s1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1ncc(-c2ccccc2)s1
Yield: 17 %

Procedure:
This compound was synthesized from 2-methyl-2-(5-phenylthiazol-2-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (20 mg, yield 17%). 1H NMR (400 MHz, MeOD) δ 8.55 (m, 1H), 8.29-8.27 (m, 1H), 8.03-8.01 (m, 1H), 7.96 (s, 1H), 7.98 (s, 1H), 7.71-7.67 (t, J=7.8 Hz, 1H), 7.63-7.61 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.32 (m, 1H), 3.75 (s, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculated for C23H19F3N4O2S: 472.12. found: 473.1 (M+H)+.