Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[N+:8]([CH:11]=[C:12]1[NH:17][CH2:16][CH2:15][CH2:14][S:13]1)([O-:10])=[O:9].[Cl:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Cl:18][CH2:19][CH2:20][CH2:21][S:22]([N:17]1[CH2:16][CH2:15][CH2:14][S:13][C:12]1=[CH:11][N+:8]([O-:10])=[O:9])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 ml of triethylamine was added to a solution of 4.8 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine in 100 ml of dichloromethane at -15° C. under nitrogen. Then a solution of 5.9 g of 3-chloropropylsulfonyl chloride in 50 ml of dichloromethane was added drop-by-drop over 25 minutes. The resulting mixture was allowed to warm to room temperature, stirred for one hour and washed with 2% hydrochloric acid solution. The organic phase was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with methanol to give N-(3-chloropropylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (1A), as a solid, m.p.: 99°-99° C.
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.[N:25]1([CH:31]2[CH2:37][CH2:36][C:35]3[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:34]=3[CH2:33][CH2:32]2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:42][C:39]3[CH:40]=[CH:41][C:34]4[CH2:33][CH2:32][CH:31]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH2:37][CH2:36][C:35]=4[CH:38]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ccccc1CNc1cccn2nc(Nc3ccc4c(c3)CCC(N3CCOCC3)CC4)nc12)S(C)(=O)=O

Procedure:
N-Methyl-N-(2-{[2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-phenyl)-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 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (75.0 mg, 0.304 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 tan foam (0.019 g, 12%). MP=118-135° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (d, J=6.8 Hz, 1H), 7.55-7.50 (m, 1H), 7.37-7.28 (m, 5H), 7.07 (d, J=7.8 Hz, 1H), 6.67 (t, J=7.0 Hz, 1H), 6.62 (s, 1H), 6.36 (d, J=7.4 Hz, 1H), 5.26-5.20 (m, 1H), 4.72 (d, J=5.1 Hz, 2H), 3.70 (br s, 4H), 3.31 (s, 3H), 3.01 (s, 3H), 2.91-2.50 (m, 9H), 2.15-2.00 (m, 2H), 1.53-1.35 (m, 2H). MS=576 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1.II.[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Br)[CH3:30]>O.C1(C)C(C)=CC=CC=1>[C:32]([CH2:33][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([O:31][CH2:29][CH3:30])=[O:35]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)COc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g. 4.09 M), xylene (2.5 L), p-toluenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylbromoacetate (341 g, 2.05 M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water while monitoring the reaction on TLC. After the completion of the reaction, water was added and the organic layer separated while the aq. layer was extracted with xylene (2×500 ml). The combined organic layers were washed with brine and concentrated under vacuum to yield 4-((carboethoxy)methoxy)benzaldehyde as an oily material (408 g, Y=97%, P=99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:23])[C:11]([C:13]1[CH:20]=[C:19]([CH3:21])[C:16]([C:17]#[N:18])=[C:15]([CH3:22])[CH:14]=1)=[O:12].[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:23])[C:11]([C:13]1[CH:14]=[C:15]([CH3:22])[C:16]([C:17]#[N:18])=[C:19]([CH3:21])[CH:20]=1)([OH:12])[C:25]([F:27])([F:26])[F:24]
Reactant: COc1ccc(C(C)C(=O)c2cc(C)c(C#N)c(C)c2)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: COc1ccc(C(C)C(O)(c2cc(C)c(C#N)c(C)c2)C(F)(F)F)c(Cl)c1

Procedure:
In analogy to Example 1, step 3, 4-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-2,6-dimethyl-benzonitrile was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=395.9 [M−H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[NH:8]2)[CH3:2].[Mg].ClCCl.[NH4+].[Cl-]>CO>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[NH:8]2)[CH3:2]
Reactant: CCOc1cccc2[nH]c(C(=O)OC)cc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CCOc1cccc2c1CC(C(=O)OC)N2
Temperature: 25 °C

Procedure:
Methyl 4-ethoxyindole-2-carboxylate (1.02 g, 4.568 mmol) was dissolved in methanol (20 ml) and magnesium shavings (0.55 g, 22.6 mmol) were then added, with stirring, at room temperature under nitrogen. After the reaction started, a water bath was used to maintain the reaction temperature between 15-20° C. At the end of the reaction, dichloromethane (200 ml) was added to the mixture, followed by NH4Cl solution (200 ml). The organic phase was separated out and the aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed in order to give a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[C:11]=2[CH3:18])[CH2:4][O:3]1.C(OC(=O)C)(=[O:22])C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:19])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:17][OH:22])[C:11]=2[CH3:18])[CH2:4][O:3]1
Reactant: Cc1c(OCC2COC(C)(C)OC2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(OCC2COC(C)(C)OC2)ccnc1CO
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
The 4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-2,3-dimethylpyridine 1-oxide (3.84 g, 14.4 mmol) obtained in the step (12a) was mixed with acetic anhydride (50 ml, 530 mmol). The mixture was stirred at 85° C. for 1.5 hours. After cooled to room temperature, the reaction mixture was concentrated. To the residue, methanol (50 ml) and a 5N aqueous sodium hydroxide solution (20 ml, 100 mmol) were added and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with a 1N aqueous sodium hydroxide solution twice, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (2.97 g, yield: 77.2%) as a brown solid.
Reaction SMILES: C(OC(NC(C1NC(C2C=CC=C3C=2N=C(NCC(F)(F)F)C(C)=N3)=CC=1C(OCC)=O)C)=O)(C)(C)C.Br[CH2:39][C:40]([C:42]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]2)=[O:41].[C:59]([O:63][C:64]([NH:66][C@H:67]([CH3:76])[C:68](=[O:75])[CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:65])([CH3:62])([CH3:61])[CH3:60].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCO.CC(O)=O>[C:59]([O:63][C:64]([NH:66][CH:67]([CH3:76])[C:68](=[O:75])[CH:69]([CH2:39][C:40]([C:42]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]2)=[O:41])[C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:65])([CH3:61])([CH3:62])[CH3:60]
Reactant: CCOC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC(C)(C)C
Agent: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1c(F)ccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C(C)NC(=O)OC(C)(C)C
Yield: 66 %

Procedure:
This compound (245 mg, 46% yield) as a yellow foam was prepared according to the procedures described for 293b, using 2-bromo-1-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (605) (366 mg, 1.03 mmol), (R)-ethyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (602) (322 mg, 1.24 mmol) and K2CO3 (357 mg, 2.58 mmol) in DMF (3.5 mL), followed by the subsequent treatment of the resulting ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (297a) (360 mg, 0.68 mmol, 65% yield, m/z 533.2 (ESI, +ve) (M+H)+) with NH4OAc (637 mg, 8.27 mmol) in 2 mL of EtOH and AcOH (1 mL). 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (dd, J=9.00, 5.67 Hz, 1H), 7.32-7.36 (m, 1H), 7.20 (dd, J=11.54, 9.00 Hz, 1H), 6.97 (d, J=9.98 Hz, 1H), 5.09-5.21 (m, 1H), 4.96 (s, 1H), 4.36 (qd, J=7.14, 2.05 Hz, 2H), 2.54 (s, 3H), 1.72 (s, 9H), 1.53 (d, J=6.85 Hz, 3H), 1.36-1.46 (m, 12H). 19F NMR (376 MHz, CDCl3) δ ppm −107.07 (s, 1F). m/z 514.2 (ESI, +ve) (M+H)+.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:30]>C(O)C.[Pd]>[ClH:30].[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][C:11]4[CH2:10][CH2:9][NH:8][CH2:21][CH2:20][C:19]=4[C:18]=3[CH:17]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2ccc3[nH]c4c(c3c2)CCN(Cc2ccccc2)CC4)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccc3[nH]c4c(c3c2)CCNCC4)cc1
Yield: 82.4 %

Procedure:
A mixture of 3-benzyl-9-(4-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.22 g, 0.62 mmol), 1 N hydrochloric acid (0.65 mL, 0.65 mmol) and Pd/C (10%, 0.24 g) in ethanol (50.0 mL) was reacted in a manner similar to Example 8 to give 0.168 g (80%) of a greenish solid: mp 258-5 260° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.08, 9.62, 7.64, 7.59, 7.31, 6.99, 3.79, 3.37-3.27, 3.22-3.12; IR (drift) 2986, 2957, 2921, 2893, 2829, 2752, 1514, 1476, 1456, 1273, 1250, 1239, 1180, 836, 800 cm−1; MS (EI) m/z 292 (M+); HRMS (FAB) calcd for C19H20N2O+H: 293.1654, found: 293.1651; Anal. Calcd for C19H20N2O.HCl: C, 69.40; H, 6.44; N, 8.52; Found: C, 68.37; H, 6.53; N, 8.27.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:12]Br>C(O)(=O)C>[C:1]([C:4]1[N:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([Br:12])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)c1ccc(N)c(Cl)n1
Solvent: CC(=O)O
Product: CC(=O)c1cc(Br)c(N)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
15 g (88 mmol) of 6-acetyl-3-amino-2-chloropyridine are suspended in 88 ml of glacial acetic acid and 4.5 ml (88 mmol) of bromine are added dropwise. The mixture is subsequently stirred at room temperature for a further 30 minutes and then filtered off with suction and the filter cake is partitioned between NaHCO3 solution and CHCl3. The organic phase is separated off, dried with Na2SO4 and evaporated.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13](I)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:19]([Si:22]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][N:30]=2)[CH:25]=[CH:24]1)([CH3:21])[CH3:20].CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([NH:32][C:28]2[CH:27]=[C:26]3[CH:25]=[CH:24][N:23]([Si:22]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[CH:19]([CH3:20])[CH3:21])[C:31]3=[N:30][CH:29]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1I
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N)cnc21
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Nc3cccnc3Oc3ccccc3C(C)(C)C)cnc21

Procedure:
A mixture of 2-(2-tert-butylphenoxy)-3-iodopyridine (prepared as above) (177 mg, 0.50 mmol), N-triisopropylsilyl 5-amino-7-azaindole (see Heureux, A. L. et al., Tetrahedron Lett. 2004, 45, 2317) (145 mg, 0.50 mmol), dppf (8.2 mg, 0.015 mmol), Pd2(dba)3 (9.1 mg, 0.010 mmol), sodium tert-butoxide (72 mg, 0.64 mmol) in toluene (8.0 mL) was heated in a seal tube at 110° C. for 16 h. The mixture was allowed to cool and saturated ammonium chloride (30 mL) was added and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (anhydrous sodium sulfate), filtered and evaporated to yield a residue was purified by reverse phase preparative HPLC to provide 141b. (M+H)+=375.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:5][CH2:4]1.[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]=O)=[CH:25][CH:24]=1)[CH:20]([CH3:22])[CH3:21].Cl>>[CH2:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH2:31][N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]3[CH:18]=[CH:17][C:12]4[NH:13][C:14](=[O:16])[O:15][C:11]=4[CH:10]=3)[CH2:7][CH2:8]2)=[CH:27][CH:28]=1)[CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)Cc1ccc(CCC=O)cc1
Reactant: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Agent: Cl
Product: CC(C)Cc1ccc(CCCN(C)[C@H]2CC[C@H](c3ccc4[nH]c(=O)oc4c3)CC2)cc1

Procedure:
Condensation of 15 (1.0 g, 3.6 mmol) and 3-(4-isobutylphenyl)-propionaldehyde (700 mg, 3.6 mmol), following the procedure described in Example 45, Step 2, followed by conversion to the HCl salt, gave 6-(trans-4-{[3-(4-isobutylphenyl)propyl]methylamino}cyclohexyl)-3H-benzoxazol-2-one (977 mg, 61%), as an off-white solid: mp 162-165° C.; IR (KBr): 2953, 1773, 1498, 1451 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 11.55 (s, 1H), 10.00 (s, 1H), 7.17-7.08 (m, 5H), 7.00 (s, 2H), 3.32-3.28 (m, 1H), 3.21-3.08 (m, 1H), 3.08-2.95 (m, 1H), 2.70 (d, J=5 Hz, 3H), 2.65-2.52 (m, 3H), 2.41 (d, J=7 Hz, 2H), 2.14-1.73 (m, 7H), 1.68-1.49 (m, 4H), 0.85 (d, J=7 Hz, 6H); HRMS-API (m/z): [M+H]+ calcd for C27H36N2O2, 421.2855; found, 421.2858; HPLC: method A, 7.49 minutes (>99%); method B, 13.59 minutes (>99%); Anal. Calcd for C27H36N2O2.HCl.0.5H2O: C, 69.58; H, 8.22; N, 6.01. Found: C, 69.23; H, 8.20; N, 5.87.
Reaction SMILES: [Li].[NH3:2].[NH2-].[Li+].C[C:6]1[C:14]2[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[C:12]([C:19](O)=[O:20])[S:11][C:10]=2[CH:9]=[C:8]([O:22][CH3:23])[CH:7]=1>O1CCCC1>[CH3:23][O:22][C:8]1[CH:7]=[CH:6][C:14]2[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[C:12]([C:19]([NH2:2])=[O:20])[S:11][C:10]=2[CH:9]=1
Reactant: N
Reactant: COc1cc(C)c2c(OC(C)C)c(C(=O)O)sc2c1
Agent: [Li+]
Agent: [Li]
Agent: [NH2-]
Solvent: C1CCOC1
Product: COc1ccc2c(OC(C)C)c(C(N)=O)sc2c1
Yield: 66 %

Procedure:
Excess lithium (74 mg, 10 mM) is added portionwise to a -78° C. solution of a catalytic amount of ferric nitrate in 10 mL of liquid ammonia. The dry ice/acetone bath is removed to allow the reaction to warm to reflux. When the gray color of lithium amide remains for 10 minutes, 2 mL of freshly distilled tetrahydrofuran is added slowly followed by a solution of methyl 6-methoxy-3-(-methylethoxy)benzo[b]thiophene-2-carboxylic acid (200 mg, 0.71 mM) in 2 mL of tetrahydrofuran. The ammonia is allowed to evaporate. The reaction solution is diluted with ethyl acetate, washed with aqueous hydrochloric acid, followed by water, then brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crystalline residue is suspended in 1:9 ethyl acetate:hexane, filtered, and dried at 50° C. in vacuo affording 125 mg (66%) of colorless crystals, mp 164°-166° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([O:35]C)=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:33]([OH:35])=[O:34])=[CH:20][C:19]=3[CH:37]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(CC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(CC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(1-ethylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (382 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-ethylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (287 mg) as yellow crystals.
Reaction SMILES: OC[C:3]1([OH:14])[CH2:9][O:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[O:5][CH2:4]1>C1COCC1.O>[O:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[O:8][CH2:9][C:3](=[O:14])[CH2:4]1
Reactant: OCC1(O)COc2ccccc2OC1
Solvent: C1CCOC1
Solvent: O
Product: O=C1COc2ccccc2OC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
A solution of Example 280B (5.29 g, 27 mmol) in THF (50 mL) was treated with a suspension of NaIO4 (6.33 g, 30 mmol) in water (10 ml) and THF (50 mL), then stirred at rt for 1.5 h. Diluted with water, extracted twice with ether. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The residue was suspended in ether, filtered and the filtrate was concentrated to give 2.75 g (55%) of the title compound as a yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]1([CH3:34])[CH2:32][NH:31][C:30](=[O:33])[NH:29]1>>[CH3:27][C:28]1([CH3:34])[N:29]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]5)[CH2:12][CH2:11]3)[CH:3]=2)[C:30](=[O:33])[NH:31][CH2:32]1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Reactant: CC1(C)CNC(=O)N1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)NCC5(C)C)c4)CC3)cccc2n1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}2-methylquinoline and 4,4-dimethyl-2-imidazolidinone.
Reaction SMILES: C(=O)(OCC(Cl)(Cl)Cl)N.C(=O)([O-])OCC(Cl)(Cl)Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:32][CH:31]3[N:33](C(OCC(Cl)(Cl)Cl)=O)[CH:28]([CH2:29][CH2:30]3)[CH:27]2[O:42]C(OCC(Cl)(Cl)Cl)=O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH2:32][CH:31]3[NH:33][CH:28]([CH2:29][CH2:30]3)[CH:27]2[OH:42])=[CH:24][CH:25]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)OC1C(c2ccc(F)cc2)CC2CCC1N2C(=O)OCC(Cl)(Cl)Cl
Agent: NC(=O)OCC(Cl)(Cl)Cl
Agent: O=C([O-])OCC(Cl)(Cl)Cl
Product: OC1C2CCC(CC1c1ccc(F)cc1)N2

Procedure:
By cleavage of the 2,2,2-trichloroethyl carbamate and 2,2,2-trichloroethyl carbonate from 2,2,2-trichloro-ethyl (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-2-(2,2,2-trichloro-ethoxycarbonyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate in an analogous manner to that described in Example 12(d) there was obtained (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-2-ol as a colourless solid; MS: 221 (M)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22]([NH:25][C:26]1[CH:27]=[C:28](O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH3:23]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:30]2[CH:31]=[C:26]([NH:25][C:22](=[O:24])[CH3:23])[CH:27]=[CH:28][CH:29]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)Nc1cccc(O)c1
Product: CC(=O)Nc1cccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)c1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 3-acetamidophenol: MS (APCI) m/z 446 (M+1).
Reaction SMILES: C(NCCO)C1C=CC=CC=1.C([C@H]1OC1)Cl.[OH-].[Na+].C([N:26]1[CH2:31][CH2:30][O:29][CH:28]([CH2:32][OH:33])[CH2:27]1)C1C=CC=CC=1.C(N1CCCOCC1)C1C=CC=CC=1.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>[C].[Pd].CO.O.CC(O)C>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[OH:33][CH2:32][C@@H:28]1[O:29][CH2:30][CH2:31][NH:26][CH2:27]1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: ClC[C@@H]1CO1
Agent: OCCNCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)O
Product: OC[C@H]1CNCCO1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a mixture of N-benzylethanolamine (81.7 g, 0.540 mol), 2-propanol (50 ml) and water (50 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (50.0 g, 0.540 mol, 99% ee). After reaction at 10 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 28.1 g, 0.703 mol) was added at 5 to 10° C. After reaction at 25° C. for 20 hr, the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol. To the residue was added toluene (150 ml) and, after partitioning, the organic layer was concentrated under reduced pressure. The residue was distilled (0.5 mmHg, 150 to 180° C.) to give a mixture of N-benzyl-2-hydroxymethylmorpholine and N-benzyl-1,4-oxazepane compound (76.3 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=76.5:23.5). To this mixture were added methanol (153 ml), trifluoroacetic acid (44.1 g, 0.387 mol) and palladium carbon (15.3 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected twice to azeotropic distillation with dehydrating with 2-propanol (76 ml). To the residue after azeotropic distillation with dehydrating was added ethyl acetate (382 ml) at 40° C., and the mixture was cooled to 20° C. Seed crystal was added and, after crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (76 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (50.22 g) (yield from (S)-epichlorohydrin: 40.2%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee.