Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11](=[O:19])[C:12]2[CH:18]=[CH:17][CH:16]=[N:15][C:13]=2[N:14]=1.[OH-].[NH4+:23]>>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:14][C:13]1[N:15]=[CH:16][CH:17]=[CH:18][C:12]=1[C:11]([NH2:23])=[O:19])=[O:10]
Reactant: O=c1oc(-c2ccccc2C(F)(F)F)nc2ncccc12
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cccnc1NC(=O)c1ccccc1C(F)(F)F
Yield: 33 %

Procedure:
2-(2-Trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.51 g) is stirred in 30% ammonium hydroxide (25 ml) at room temperature overnight. The resulting precipitate is filtered and rinsed with water and diethyl ether. The precipitate is dried under vacuum at 50 C overnight to give 2-(2-trifluoromethylbenzoylamino)-nicotinamide (850 mg, 33% yield)
Reaction SMILES: [CH3:1][C:2]1[C:13](=[O:14])[C:6]2[N:7]3[CH2:12][CH2:11][CH2:10][C:8]3=[N:9][C:5]=2[C:4](=[O:15])[CH:3]=1.[CH3:16][NH:17][CH3:18].CCCCCC.[K+].[Br-]>CN(C=O)C.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl.CO>[CH3:16][N:17]([CH3:18])[C:3]1[C:4](=[O:15])[C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[C:13](=[O:14])[C:2]=1[CH3:1]
Reactant: CC1=CC(=O)c2nc3n(c2C1=O)CCC3
Reactant: CNC
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CO
Product: CC1=C(N(C)C)C(=O)c2nc3n(c2C1=O)CCC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 50 mg (0.24 mmol) of 26 in 3 mL of dry DMF, chilled to 0° C., was added an excess of methanolic dimethylamine. After the addition, the reaction mixture was stirred at room temperature for about 30 min and then the solvent was evaporated in vacuo. The residue was chromatographed on silica gel employing chloroform as the eluant. The blue-colored 27 was obtained in 42 mg (71%) yield. An analytical sample was prepared by dissolving the residue in a small amount of chloroform, adding hexane, and then chilling the mixture overnight in the refrigerator: mp 158° C. dec; TLC (chloroform/methanol[90:10]), Rf =0.56, IR(KBr pellet) 1675, 1659, 1623, 1524, 1314, 1067 cm-1 ; 1H NMR (CDCl3) δ4.16 (2 H, t, J~7 Hz, C(1) methylene), 3.04 (6 H, s, dimethylamino), 2.87 (2 H, t, J~7 Hz, C(3) methylene), 2.64 (2 H, quintet, J~7 Hz, C(2) methylene); 1.93 (3 H, s, 7-methyl); mass spectrum (EI mode) m/z 245 (P+), 230 (P+ -CH3), 217 (P+ -CO). Anal. Calcd for C13H15N3O2.0.25: C, 62.50; H, 6.15; N, 16.82. Found: C, 62.78; H, 6.32; N, 16.64.
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1>Cl.O1CCOCC1>[F:19][CH:2]([F:1])[CH2:3][CH2:4][C:5]1([OH:18])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCC(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OC1(CCC(F)F)CCNCC1
Yield: 156.2 %

Procedure:
A solution of tert-butyl 4-(3,3-difluoropropyl)-4-hydroxypiperidine-1-carboxylate (293 mg, 1.075 mmol) in 5 mL of 3.5 N HCl in dioxane was stirred at r.t. for 30 min. The reaction mixture was concentrated in vacuo to give 301 mg of the title product which was used in the next step directly.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:47][C:48]1([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>ClCCl>[CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([NH:47][C:48]3([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[O:8])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1(N)CCCCC1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ccc3c(c2)OCO3)CCCCC1
Reaction time: 18 h
Yield: 98.9 %

Procedure:
2.74 g (16.5 mmol) of 3,4-methylenedioxybenzoic acid was dissolved in anhydrous dichloromethane and then was ice cooled. 4.62 ml (33.0 mmol) of triethylamine, 2.53 g (16.5 mmol) of 1-hydroxybenzotriazole hydrate, 3.57 g (17.3 mmol) of N,N'-dicyclohexylcarbodiimide and 3.20 g (16.5 mmol) of ethyl 1-aminocyclohexanecarboxylate hydrochloride were successively added to the above reaction mixture and were stirred for 18 hours gradually rising the temperature up to the room temperature. The reaction mixture was concentrated under reduced pressure and was dissolved in ethyleacetate, and the insoluble components were removed therefrom by filtration. After the ethyl acetate solution was washed successively with 1N-hydrochloric acid, saturated brine, aqueous solution of saturated sodium hydrogen carbonate and saturated brine, the resultant organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, whereby 5.21 g of ethyl 1-[N-(3,4-methylenedioxyphenylcarbonyl)amino]cyclohexanecarboxylate was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCc2ccc(Cl)cc2)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
2-(4-Chloro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester (2.98 g, 10.68 mmol) was dissolved in glacial acetic acid (20 mL) and sodium triacetoxyborohydride (6.79 g, 32.04 mmol) was added at 0° C. The solution was allowed to warm to 25° C. and stirred for 3 h. The acetic acid was removed in vacuo and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution followed by saturated aqueous brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product, 2-(4-chloro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (2.43 g, 8.64 mmol, 80.9%), as a yellow oil. LC-MS (ESI) calcd for C15H20ClNO2 281.12, found 282.0 [M+H+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:15][CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:2]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:2]1
Reactant: ClCc1ccccc1
Reactant: O=C1NCCNC1c1c[nH]c2ccccc12
Product: O=C1NCCN(Cc2ccccc2)C1c1c[nH]c2ccccc12

Procedure:
21.5 g (0.1 mol) of 3-(3-indolyl)-piperazin-2-one, prepared in accordance with Example 30, are alkylated with benzyl chloride as described in Example 2.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[N+](=[C:7]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:2]([C:1]1[O:18][C:13]([C:14]([F:15])([F:16])[F:17])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:4]=1)[CH3:3]
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)C(F)(F)F
Reactant: CCC#N
Agent: [Rh+3]
Agent: CC(=O)[O-]
Product: CCOC(=O)c1nc(CC)oc1C(F)(F)F
Temperature: 80 °C
Reaction time: 120 h
Yield: 43 %

Procedure:
To a mixture of rhodium acetate (100 mg) and propionitrile (15 mL) was added ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate (4.20 g, 20.0 mmol) over 12 hr, and the mixture was stirred at 80° C. for 5 days. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate=90/10→0/100) to give the title compound (2.03 g, 43%) as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C(O)C>[C:5]([C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)#[C:4][CH:3]=[CH2:2]
Reactant: ClCCC#Cc1ccc(-c2cccs2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CC#Cc1ccc(-c2cccs2)s1
Temperature: 75 °C

Procedure:
5-(4-chloro-1-butynyl)-2,2'-bithiophene was dissolved in ethanol. KOH dissolved in ethanol was then added in and heated at 75° C. for 15 minutes. The remaining process was as described in procedure(a) and the same product was obtained. The yield was above 90%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1)#[N:28]>>[NH2:20][C:13]1[CH2:14][O:15][CH2:16][C:17]([F:19])([F:18])[C@@:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:31]4[CH:32]=[N:33][CH:34]=[C:29]([CH:30]=4)[C:27]#[N:28])[CH:3]=3)[O:8][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10]2)[N:12]=1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)COC1
Reactant: N#Cc1cncc(B(O)O)c1
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CC(c4ccccc4)O3)N=C(N)COCC2(F)F)c1
Yield: 15 %

Procedure:
The cross coupling reaction of (2RS,4R)-6-bromo-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.4) with 5-cyanopyridin-3-ylboronic acid yielded the title compound (15% yield) as a colorless solid. MS (ISP): m/z=447.4 [M+H]+.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([CH3:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29].CO[Na].CO>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[C:10]([CH3:26])=[N:9][C:8]=1[C:6]([NH:27][C@@H:28]([CH3:29])[C:30]([OH:32])=[O:31])=[O:7]
Reactant: CCCCOC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: CO[Na]
Solvent: CO
Product: Cc1nc(C(=O)N[C@@H](C)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A mixture of 4-Hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (176 mg, 0.5 mmol), (S)-alanine (225 mg, 2.5 mmol) and a 0.5 N solution of MeONa in MeOH (5 ml, 2.5 mmol) was heated in a microwave oven with stirring for 20 min at 120° C. before the mixture was concentrated in vacuo. To the residue was added water (15 ml) and the mixture was washed with Et2O (3×30 ml). The so purified aq. solution was acidified by the addition of 6 N HCl and extracted with EtOAc (1×30 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (108 mg); MS-(−)-ion M−1=365.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19]C(OC(C)(C)C)=O)=[CH:17][CH:16]=[C:15]([F:27])[C:14]=3[Cl:28])[CH3:12])=[CH:9][N:8]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:5]2=[N:6][CH:7]=1.N1CCCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:27])[C:14]=3[Cl:28])[CH3:12])=[CH:9][N:8]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C:5]2=[N:6][CH:7]=1
Reactant: C[C@H](c1c(OC(=O)OC(C)(C)C)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Solvent: C1CCNCC1
Solvent: ClCCl
Product: C[C@H](c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 5-bromo-3-[(1S)-1-{6-[(tert-butoxycarbonyl)oxy]-2-chloro-3-fluorophenyl}ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.982 g, 3.478 mmol) in CH2Cl2 (40 mL) was charged with piperidine (12 mL, 120 mmol) and was stirred at rt for 16 h. The reaction mixture was diluted with CH2Cl2 and washed with 0.5 N HCl (4×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled silica gel loading cartridge [RediSepRf, 5 g] and purified using the Teledyne/ISCO system [RediSepRf 24 gram silica], eluting with a 10-50% EtOAc:Heptane solvent gradient. Fractions containing the desired product were pooled together and concentrated in vacuo, yielding the title material as a white solid. 1H NMR (400 MHz, CDCl3): δ=8.39 (d, J=2.3 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 6.97 (dd, J=8.8, 8.3 Hz, 1H), 6.67 (dd, J=8.8, 4.5 Hz, 1H), 4.93 (qd, J=7.1, 1.3 Hz, 1H), 1.78 (d, J=7.1 Hz, 3H), 1.68 (s, 9H). MS (ES+): m/z 412.78/414.75/416.76 (75/100/27) [MH+−C4H8]. HPLC: tR=4.13 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[CH:12]/[C:5]2[N:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[C:7]([OH:9])=[O:8])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Cl)cnc1C
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cnc1/C=C/c1ccc(Br)cc1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of methyl 5-chloro-2-methylnicotinate (7.26 kg, 96.4 wt %, 37.7 mol) and 4-bromobenzaldehyde (6.98 kg, 37.7 mol, 1.0 equiv) in THF (112 L) was put under a nitrogen atmosphere, and then cooled to −5° C. A solution of potassium tert-butoxide (8.46 kg, 75.4 mol, 2.0 equiv) in THF (53 L) was then added via a 1 μm filter, whilst maintaining the internal temperature at <0° C. The resulting reaction mixture was warmed to 25° C., and then aged at this temperature until the reaction was complete (typically 1 h). The reaction was then quenched by addition of water (54 L), ensuring the batch temperature remained <30° C. The biphasic mixture was stirred for ˜10 min, and the lower aqueous layer was then removed. The remaining THF layer was diluted with ethyl acetate (54 L), and then washed with 2 M hydrochloric acid (27 L) followed by half-saturated brine (20 L). The resulting organic layer was solvent-switched to ethyl acetate (to a final volume of 27 L), and then to methanol (to give a final volume of ˜106 L). The temperature of the resulting slurry was adjusted to ˜20° C., and it was then filtered, washing the filter-cake with methanol (11 L). The resulting solid was dried under vacuum at 50° C. to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([O:11][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:13][CH:14]=1)=[O:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
Combine 6-chloronicotinamide (4.53 g, 28.9 mmol), 4-hydroxybenzaldehyde (3.5 g, 28.9 mmol), potassium carbonate (6 g, 43.4 mmol), and dimethylformamide (200 mL). Heat the reaction mixture to 130° C. under nitrogen, and stir for 18 h. Dilute the reaction mixture with 200 mL of water, extract with diethyl ether (4×100 mL) and dichloroethane (2×100 mL). Combine the organics, and dry over magnesium sulfate. Filter, and concentrate in vacuo. Adsorb the residue on silica, and purify by Biotage Flash 40L (elute with 50:50 hexanes/ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid (3.2 g, 46%): 1H NMR (DMSO-d6): 10.0 (s, 1H), 8.59 (d, 1H), 8.26-8.22 (dd, 1H), 7.98-7.95 (m, 2H), 7.10-7.07 (d, 1H), 6.15-5.65 (br m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.CC1OCCC1.Cl.O1CCOCC1>CCOC(C)=O>[NH:5]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ncccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC1CCCO1
Product: O=C1CCNc2cccnc21

Procedure:
To a solution of tert-butyl 4-oxo-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (1 eq.) and 2-MeTHF (0.2 M) is added 4M HCl in dioxane (5 eq.). The reaction is monitored by TLC. The reaction is diluted with EtOAc and washed with saturated NaHCO3. The organic solution is dried over MgSO4 and concentrated in vacuo. The compound that may be thus obtained is purified by column chromatography to give the title compound.
Reaction SMILES: [CH3:1][NH2:2].Br[CH:4]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:7]=2[NH:6][C:5]1=[O:23]>C1COCC1.CCOC(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[NH:6][C:5](=[O:23])[CH:4]([NH:2][CH3:1])[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:8]=2[CH:18]=1
Reactant: CN
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=CC1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC1C=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Reaction time: 0.17 h

Procedure:
A solution of methyl amine (16.0 mL of a 1.1N THF solution, 17.6 mmole) in 50 mL of dry THF was cooled to 0°-5° C. in an ice-water bath. To this solution was added, over a ten minute period, a solution of crude rac-3-bromo-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2-H1-benzazepin-2-one (3.36 g estimated to be 85% pure, 7.36 mmole), dissolved in 55 mL of THF. After 10 minutes, the reaction solution was diluted with 300 mL of EtOAc, washed with water and brine, and dried (sodium sulfate). Concentration and drying under high vacuum yielded 2.98 g of crude material, which was used as is in the next step.
Reaction SMILES: Br[CH2:2][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][C:4]=1[N+:19]([O-:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:41]([C:43]1[C:48]([CH3:49])=[CH:47][C:46](/[CH:50]=[CH:51]/[C:52]([O:54][CH3:55])=[O:53])=[CH:45][C:44]=1[CH3:56])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:55][O:54][C:52](/[CH:51]=[CH:50]/[C:46]1[CH:45]=[C:44]([CH3:56])[C:43](/[CH:41]=[CH:2]/[C:3]2[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:5][C:4]=2[N+:19]([O-:21])=[O:20])=[C:48]([CH3:49])[CH:47]=1)=[O:53]
Reactant: O=C(OCc1ccccc1)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: COC(=O)/C=C/c1cc(C)c(C=O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cc(C)c(/C=C/c2ccc(C(=O)OCc3ccccc3)cc2[N+](=O)[O-])c(C)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of benzyl 4-bromomethyl-3-nitrobenzoate (2.06 g, 5.88 mmol) and triphenylphosphine (1.54 g, 5.87 mmol) in DMF (10 mL) was heated at 100° C. for 1 h. To this solution was added methyl (E)-3-(4-formyl-3,5-dimethylphenyl)-acrylate (1.28 g., 5.86 mmol) and potassium carbonate (1.63 g, 11.8 mmol) and the mixture was heated and stirred at 100° C. for 18 h. The reaction was poured into ethyl acetate and extracted with water once and brine.five times. The organic layer was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography using a 0-40% gradient of heptane/ethyl acetate to give benzyl 4-{(E)-2-[4-((E)-2-methoxycarbonylvinyl)-2,6-dimethylphenyl]-vinyl}-3-nitrobenzoate.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH3:15][C:16]1[S:17][C:18]([CH3:34])=[C:19]2[CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][C:20]=12.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:15][C:16]1[S:17][C:18]([CH3:34])=[C:19]2[CH2:23][NH:22][CH2:21][C:20]=12
Reactant: Cc1ccc(S(=O)(=O)N2Cc3c(C)sc(C)c3C2)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1sc(C)c2c1CNC2
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A mixture of 38 ml of a 3.4M solution of sodium bis(2-methoxyethoxy)aluminium hydride in toluene and 10 ml of dry toluene is added, at room temperature, to a suspension of 9.1 g (0.03 mol) of 1,3-dimethyl-5-tosyl-5,6-dihydro-4H-thieno [3,4-c]pyrrole in 42 ml of dry toluene. The mixture is then heated at reflux for 2 h 30 min, cooled to room temperature, and poured into 400 ml of 1N sodium hydroxide. The organic phase is washed with 3 times 50 ml of water and extracted with a 0.5N hydrochloric acid solution. The solid, precipitated by addition of a sodium carbonate solution, is filtered off, washed with water and dried. 3.12 g of product are obtained. Melting point: 110°-112° C. (with decomposition).
Reaction SMILES: [O:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CO.C(#N)C.[Pd]>[O:1]1[CH2:2][CH2:3][CH2:4][C@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1=COCCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CCCOC1
Temperature: 40 °C
Reaction time: 10 h
Yield: 58.6 %

Procedure:
Pd/C (10%, 3 g) was added to a solution of 3,4-dihydro-2H-pyran-5-carboxylic acid (7.0 g, 55 mmol) in MeOH (100 mL). The suspension was stirred under hydrogen atmosphere (100 psi) at 40° C. for 10 h. The catalyst was filtered off and washed with MeOH (50 mL). The filtrate and washings were combined and concentrated to dryness to afford crude product. The crude product was dissolved in acetonitrile (200 mL) and benzyl bromide (9.9 g, 58 mmol) and K2CO3 (19.0 g, 138 mmol) were added. The resulting suspension was heated at 50-60° C. for 4 h and then cooled to ambient temperature. The mixture was filtered and the filtration cake was washed with acetonitrile (50 mL). The filtrate and washings were combined and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc=20:1) to afford a mixture (7.1 g) of (S)-benzyl tetrahydro-2H-pyran-3-carboxylate and (R)-benzyl tetrahydro-2H-pyran-3-carboxylate, which was separated by chiral prep-HPLC to afford (S)-benzyl tetrahydro-2H-pyran-3-carboxylate (2.1 g, 17% yield) and (R)-benzyl tetrahydro-2H-pyran-3-carboxylate (2.0 g, 16% yield), respectively.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]1=[O:15].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]1=[O:15]
Reactant: COCCn1ccc(C(=O)OC)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCn1ccc(C(=O)O)cc1=O
Temperature: 80 °C
Yield: 68.6 %

Procedure:
Methyl 1-(2-methoxyethyl)-2-oxo-pyridine-4-carboxylate (1.56 g, 7.39 mmol), dioxane (16 mL) and NaOH (20 mL of 1 M, 20 mmol) were combined and the mixture was heated at 80° C. for 50 min. The solvent was evaporated under reduced pressure and the residue was dissolved in water before it was washed with EtOAc (3×). The aqueous layer was acidified with 1N HCl and was washed with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to yield 1-(2-methoxyethyl)-2-oxo-pyridine-4-carboxylic acid (1.0 g, 69%) as a white solid. ESI-MS m/z calc. 197.2, found 198.3 (M+1)+; Retention time: 0.29 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.59 (s, 1H), 7.72 (d, J=7.0 Hz, 1H), 6.84 (d, J=1.6 Hz, 1H), 6.53 (dd, J=7.0, 1.6 Hz, 1H), 4.08 (t, J=5.2 Hz, 2H), 3.58 (t, J=5.2 Hz, 2H), 3.23 (s, 3H).