Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:32]5[CH:31]=[N:30][C:29]([N:24]6[CH2:25][CH2:26][CH2:27][CH2:28]6)=[CH:34][CH:33]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2ccc(N3CCCC3)nc2)OC1(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc(N4CCCC4)nc3)cc1-2
Yield: 62 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were reacted to give 399 (0.078 g, 62%). 1H NMR (400 MHz, DMSO) δ 8.57 (d, J=2.4, 1H), 8.41 (d, J=2.2, 1H), 8.08 (d, J=24.7, 1H), 7.78 (dd, J=8.7, 2.6, 1H), 7.52 (dd, J=8.4, 2.5, 1H), 7.13 (d, J=8.4, 1H), 6.57 (d, J=8.7, 1H), 5.79 (dt, J=13.1, 6.5, 1H), 4.35 (dd, J=39.9, 34.8, 2H), 3.65-3.37 (m, 6H), 2.11-1.80 (m, 4H), 1.58 (d, J=6.6, 6H). MS (ESI(+)): m/z 459.2 (M+H)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].O.[CH3:20]N(C)C=O>>[CH3:20][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([CH:1]=[CH:13][N:14]([CH3:16])[CH3:15])=[CH:7][N:6]=1)=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CN(C)C=O
Reactant: Cc1cnc(C(=O)O)cn1
Solvent: O
Product: COC(=O)c1cnc(C=CN(C)C)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 5-methylpyrazine-2-carboxylic acid (1.38 g, 10 mmol) in anhydrous N,N-dimethylformamide (5 mL) was treated with dimethylformamide dimethylacetal (5 mL). The resulting mixture was heated at 90° C. for 1 h and then at 125° C. for 2 h. The mixture was cooled to 25° C. and then was poured into water (100 mL). This solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting dark oil was triturated with diethyl ether/hexanes (5/1) to afford 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylic acid methyl ester (1.3 g, 63%) as an orange solid which was used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)[C:19]([C:33](O)=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN.O1CCCC1.C[CH2:44][N:45](CC)CC.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:29]([CH3:30])[CH3:31])=[O:32])=[CH:24][CH:23]=5)[C:19]([C:33]([NH:45][CH3:44])=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C(=O)O)cc1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Reaction time: 3 h
Yield: 10.3 %

Procedure:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)biphenyl-2-carboxylic acid (47 mg, 0.10 mmol) and 75 μl of a 2.0 M solution of methylamine in tetrahydrofuran (0.15 mmol) were dissolved in DMF (1.0 mL) containing Et3N (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-N2,N4′,N4′-trimethylbiphenyl-2,4′-dicarboxamide (5.0 mg, 10%). ESI-MS m/z calc. 485.5. found 486.5 (M+1)+; retention time 2.54 minutes.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[O:14][CH2:13][CH:12]([CH3:15])[NH:11][C:10]=12)=[O:4].ClS([N:22]=[C:23]=[O:24])(=O)=O.C(N(CC)CC)C>ClCCl>[F:17][C:7]1[CH:6]=[C:5]2[C:10]3[N:11]([CH:12]([CH3:15])[CH2:13][O:14][C:9]=3[C:8]=1[F:16])[C:23](=[O:24])[NH:22][C:3]2=[O:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1cc(F)c(F)c2c1NC(C)CO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COc2c(F)c(F)cc3c(=O)[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.9 %

Procedure:
A solution of 1.5 g (6.2 mmol) of 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid methyl ester (Example 32a) in 25 mL of dichloromethane is cooled to −20° C. and treated dropwise with 0.92 g (6.5 mmol) of chlorosulfonyl isocyanate. The reaction is stirred at room temperature for 18 hours and the solvent removed in vacuo. The residue is treated with a saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer is dried (MgSO4), filtered, and concentrated in vacuo. The residue is dissolved in 50 mL of tetrahydrofuran, and the resulting solution is treated with 5.0 g (5.0 mmol) of triethylamine. After heating at reflux for 4 hours, the solvent is removed in vacuo, and the residue is triturated with 5 mL of dichloromethane/ethyl acetate (80:20). The insoluble material is removed by filtration, washed with the above solvent mixture (2 mL) to give 0.25 g of the title compound, mp 259–261° C. The filtrate is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethyl acetate (80:20) to give 0.38 g of starting material. Continued elution afforded an additional 0.2 g of the title compound. 1H NMR (400 MHz, CDCl3): 11.78 (s, 1H), 7.50 (m, 1H), 4.68 (m, 1H), 4.52 (d, 1H), 4.17 (d, 1H), 1.23 (d, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>C1COCC1.CO>[CH3:21][O:20][C:17]1[N:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(N2CCC(N)CC2)nn1
Temperature: 60 °C
Yield: 140 %

Procedure:
[1-(6-Methoxy-pyridazin-3-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.37, 1.2 mmol) was dissolved in THF:MeOH 9:1 (15 ml) and HCl in 1,4-dioxane (4M, 1.2 ml, 4.8 mmol) was added. The reaction mixture was heated to 60° C. with for 3 h. The solvent was evaporated to yield the title compound (0.35 g, 100%) as the dihydrochloric salt. 1H-NMR (CD3OD, 500 MHz): δ 8.04 (d, 1H), 7.57 (d, 1H), 4.34-4.26 (m, 2H), 4.00 (s, 3H), 3.62-3.55 (m, 1H), 3.50-3.40 (m, 2H), 2.30-2.23 (m, 2H), 1.90-1.79 (m, 2H); 13C-NMR (CD3OD, 125 MHz): δ 159.7, 152.1, 129.8, 127.0, 62.1, 55.9, 46.2, 45,9, 45.7, 30.9, 30.3, 30.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.N1CCCCC1.[O:25]1[CH2:37][CH:26]1[CH2:27][CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>C1(C)C=CC=CC=1>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[O:30][CH2:29][CH2:28][CH2:27][CH:26]([OH:25])[CH2:37][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: C1CCC(OCCCC2CO2)OC1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CCCOC3CCCCO3)ccc12
Temperature: 100 °C

Procedure:
A solid mixture of 7-hydroxyflavone (32.0 g, 0.134 mol), piperidine (0.5 ml), and 2-(4,5-epoxypent-1-oxy)tetrahydropyran (50 g, 0.268 mol) was stirred and heated under nitrogen at 100° C. for 14 hours; it became a stirrable mixture after 6 hours heating at 100° C. The cooled reaction mixture was purified through a pad of silica gel eluting with CH2Cl2 initially and then CH2Cl2 --EtOAc (1:1). The resulting solid was stirred with ether and filtered, giving 43.9 g (77% crude yield) of an off-white solid; pure white crystals, mp 110°-112° C., were obtained from recrystallization from toluene.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:37])[N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][CH2:35][OH:36])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[OH:36][CH2:35][CH2:34][CH2:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][N:22]([CH3:23])[C:21](=[O:37])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CN(CCc1ccccc1OCCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1OCCCO
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 69.4 %

Procedure:
A solution of N-[(1R)-1-(N-{2-[2-(3-hydroxypropoxy)phenyl]ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl]-N-methylcarbamic acid tert-butyl ester (383 mg, 0.74 mmol) in dichloromethane (4 ml) was cooled to 0° C. Trifluoroacetic acid (4 ml) was added. The reaction mixture was stirred for 105 min at 0° C. Dichioromethane (40 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (40 ml) was added dropwise. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×60 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 216 mg of (2R)-N-(2-(2-(3-hydroxypropoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][C:12]([NH2:14])=[S:13])([CH3:3])[CH3:2].[N:15]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[CH:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)[N:27]=2)=[CH:22][CH:21]=1)=[C:16]=[O:17].Br[CH:43]([CH3:48])[C:44](OC)=[O:45]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:44](=[O:45])[CH:43]([CH3:48])[S:13]/[C:12]/1=[N:14]\[C:16]([NH:15][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[CH:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:33][CH:32]=3)[N:27]=2)=[CH:22][CH:21]=1)=[O:17])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)C)c(NC(N)=S)c1
Reactant: O=C=NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: COC(=O)C(C)Br
Product: Cc1ccc(C(C)C)c(N2C(=O)C(C)S/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared from 1-(2-isopropyl-5-methylphenyl)thiourea, 3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C34a), and methyl 2-brompropanoate and isolated as a clear sticky oil (0.192 g, 49%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([O:14][CH2:15][C:16]2[N:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:18]=[N:19][C:20]=2[CH3:21])=[CH:10][N:9]=1)=[O:7]>O.C1COCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([N:17]2[C:16]([CH2:15][O:14][C:11]3[N:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=3)=[C:20]([CH3:21])[N:19]=[N:18]2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1cnc(OCc2c(C)nnn2-c2ccc(F)cc2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A solution of lithium hydroxide monohydrate (180 mg, 4.25 mmol) in water (7.3 mL) was added dropwise to a suspension of 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (730 mg, 2.13 mmol) in THF (7.3 mL). The reaction mixture was then stirred at room temperature for 30 min and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (700 mg, 100%) as a white solid. MS: m/e=330.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15].S(=O)(=O)(O)O>>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.5 %

Procedure:
400 g (1.98 mol) of 4-chloro-3-nitrobenzoic acid were suspended in 1025 g of a 25-30% aqueous solution of methylamine. After heating to reflux temperature, an orange solution was obtained. The solution was kept at reflux temperature for 4 hours. The solution was cooled to room temperature, and pH was adjusted to about 2 by addition of 2M aqueous sulphuric acid. Precipitation of an orange solid was observed, which was isolated by filtration. The filtered cake was washed with 500 mL of water. The wet solid was mixed with 1.5 L of ethanol and heated to reflux temperature for 1 hour. After cooling to room temperature, the resulting suspension was filtered and the cake was dried at 60° C. under vacuum to obtain 371 g of 4-(methylamino)-3-nitrobenzoic acid as an orange powder. Yield: 95.5%. Purity (HPLC, method 2): 99.4%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)[CH3:9].Cl[C:25]1[C:34]([F:35])=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1.O>C(#N)C>[CH2:8]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:25]2[C:34]([F:35])=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=2)[CH2:15]1)[CH3:9]
Reactant: COC(=O)c1cnc(Cl)c(F)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)OC)cc2F)C1
Temperature: 50 °C
Yield: 66.8 %

Procedure:
Triethylamine (0.45 mL, 3.3 mmol) was added to a stirred solution of (R)-3-(2-ethoxy-phenoxy)-piperidine (0.41 g, 1.6 mmol) and methyl 6-chloro-5-fluoronicotinate (0.30 g, 1.6 mmol) in acetonitrile (15 mL) at 0° C. The reaction mixture was heated at 50° C. for 18 h. The mixture was cooled to ambient temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (30% ethyl acetate-hexanes) to afford methyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinate (0.40 g). MS (ES+) 375.2 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])(C(C)(C)C)(C)C.Cl>CO.O.C(OCC)C>[OH:8][CH2:9][C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1CO
Reaction time: 0.17 h

Procedure:
To a solution of 15.021 g (39.368 mM) of N-[2-(tert-butyldimethylsilyloxymethyl)benzyl]phthalimide in 50 ml of methanol was added 5 ml of concentrated hydrochloric acid at room temperature and the mixture was stirred at the prevailing temperature for 10 minutes. This reaction mixture was poured in water-diethyl ether and the resulting precipitate was recovered, rinsed serially with water and diethyl ether, and dried to provide the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]2[O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:17][N:18]([CH3:19])[CH2:9][CH:8]([OH:10])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C(c2ccccc2)C2CO2)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
1,1-Diphenyl-2,3-epoxy-propane prepared as described in Example 21, was further reacted with dimethylamine in ethanol by the procedure described in Example 8 to give 3-dimethylamino-1 1-diphenyl-propan-2-ol (90%) m.p. 72° - 73°
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]=[C:7](Cl)[C:8]([F:11])([F:10])[F:9].Cl[C:18](=[CH2:21])[C:19]#[N:20].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[CH:21][C:18]=2[C:19]#[N:20])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: C=C(Cl)C#N
Reactant: FC(F)(F)C(Cl)=NCc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of N-(3,4-dichlorobenzyl)-2,2,2-trifluoroacetimidoyl chloride (20.0 g, 0.069 mol) and 2-chloroacrylonitrile (7.2 g, 0.082 mol) in N,N-dimethylformamide is cooled to 5° C. and treated with a solution of triethylamine (22 mL, 0.16 mol) in N,N-dimethylformamide (38 mL). When the addition is half complete, the cooling bath is removed and the reaction mixture is treated with the remaining triethylamine solution, stirred for two hours and diluted with water. The aqueous mixture is filtered to obtain the title product as a tan solid (18.38 g, mp 230°-232° C.).
Reaction SMILES: [C:1]([N:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][S:12]([C:9]2[CH:10]=[CH:11][C:6]([N:4]([C:1](=[O:3])[CH3:2])[CH3:5])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:18][CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)cc1

Procedure:
N-(1-Benzyl-4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide was prepared as a colorless oil from the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (20.0 g, 80.8 mmol) and 4-amino-1-benzylpiperidine (18.16 ml, 88.9 mmol) in a similar manner to that described in Preparative Example 16. This oil was dissolved in ethanol (200 ml), followed by the addition of glacial acetic acid (10.0 ml). The obtained mixture was stirred in the presence of 10% palladium/carbon (water-containing one, 2.00 g) in a hydrogen atmosphere (1 atm) at 50° C for 5 hours and filtered to remove the catalyst. The filtrate was concentrated to precipitate a crystal. The resulting mixture was washed with ethyl acetate and filtered to give the title compound as a white crystal (29.70 g, overall yield of two steps: 100%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[N:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].[NH:44]1[CH2:49][CH2:48][CH:47]([N:50]2[CH2:54][C:53](=[O:55])[NH:52][C:51]2=[O:56])[CH2:46][CH2:45]1>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[N:24][N:25]=[C:20]2[C@H:19]([NH:31][C:32]([N:44]2[CH2:45][CH2:46][CH:47]([N:50]3[CH2:54][C:53](=[O:55])[NH:52][C:51]3=[O:56])[CH2:48][CH2:49]2)=[O:33])[CH2:18][CH2:17]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1CN(C2CCNCC2)C(=O)N1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CN(C2CCN(C(=O)N[C@@H]3CC[C@@H](c4cccc(F)c4F)Cn4c(CC(F)(F)F)nnc43)CC2)C(=O)N1
Temperature: 60 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
Triethylamine (42 μL, 0.298 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (50 mg, 0.119 mmol) and 1,1′-carbonyldiimidazole (44 mg, 0.271 mmol) in tetrahydrofuran (4 mL) at 0° C. After 1 h, 1-piperidin-4-ylimidazolidine-2,4-dione (27 mg, 0.149 mmol) and dichloromethane (3 mL) were added and the mixture heated to 60° C. After 2 h, the reaction was concentrated. Purification by reverse phase HPLC (C-18, 90% water/acetonitrile→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (28 mg). MS 556.2126 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH2:18][OH:19])=[N:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[N:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(CO)nc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(C=O)nc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (5-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)methanol (0.266 g, 0.676 mmol) in DCM (3.38 mL) was added manganese dioxide (1.176 g, 13.52 mmol) and the reaction was stirred at room temperature for 48 h. Upon completion the reaction was was filtered over Celite™ and concentrated in vacuo to afford crude 5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)picolinaldehyde which was used without further purification. LC/MS (m/z, MH+): 392.2.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:9][O:10][C:11]1[C:12]([Br:29])=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([C:25]([F:28])([F:27])[F:26])[O:17][C:15]=2[CH:16]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:29][C:12]1[C:11]([O:10][CH2:9][C@@H:8]([NH2:7])[CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:16][C:15]2[O:17][CH:18]([C:25]([F:27])([F:28])[F:26])[C:19]3[C:24]([C:14]=2[CH:13]=1)=[CH:23][CH:22]=[N:21][CH:20]=3
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)-c1ccncc1C(C(F)(F)F)O2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)COc1cc2c(cc1Br)-c1ccncc1C(C(F)(F)F)O2
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a stirred solution of tert-butyl((2S)-1-((9-bromo-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.092 mmol) in dichloromethane (10 mL) at room temperature was added TFA (0.035 mL, 0.458 mmol) and stirred overnight. The solvent was removed under reduced pressure to afford a residue which was purified by preparative HPLC using 0.1% TFA in MeOH. The purification afforded (2S)-1-((9-bromo-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (15 mg, 0.033 mmol, 36% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.64 (m, 1 H), 8.54 (m, 1 H), 8.23 (m, 1 H), 7.88 (s, 1 H), 6.91 (s, 1 H), 6.10 (m, 1 H), 4.3 (m, 1 H), 4.12 (m, 1 H), 3.52 (m, 1 H), 1.85 (m, 1 H), 1.72-1.69 (m, 1 H), 1.61-1.56 (m, 1 H), 1.05 (m, 6 H). LCMS (ESI) m/e 445.2 [(M+H)+, calcd for C19H21BrF3N2O2 445.1]; LC/MS retention time (Method C): tR=1.74 min; HPLC retention time (method A): tR=5.66 min, 5.75 min (diastereomeric mixture); HPLC retention time (method B): tR=6.27 min, 6.34 min (diastereomeric mixture).