Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].C[O:8][C:9](=O)[CH2:10][CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[OH:6][NH:5][C:9]([CH2:10][CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: COC(=O)CCSCCNC(=O)/C=C/C=C/c1ccccc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/C=C/c1ccccc1)NCCSCCC(=O)NO
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A solution of sodium methylate (6 mmol) in methanol (5 ml) was added to a solution of hydroxylamine hydrochloride (0.28 g, 4 mmol) in methanol (8 ml). A mixture was stirred for 10 min. and the precipitate was filtered off. 3-{2-[(2E)(4E)-5-phenylpenta-2,4-dienoylamino]ethylsulfanyl}propionic acid methyl ester (3/28) (1 mmol) was added to the filtrate and the mixture was heated to the complete dissolving. The resultant mixture was stirred for 4 hours at ambient temperature and the solvent was removed under reduced pressure. The product was dissolved in water (10 ml) and acidified with 3% HCl. Precipitate was filtered off and crystallized from methanol. Yield 47%, m.p. 158-160° C. 1H NMR (90 MHz, DMSO-d6) δ: 2.24 (2H, t, J=6.8 Hz, CH2); 2.56-2.87 (4H, m, CH2); 3.29 (2H, q, J=6.0 Hz, CH2); 6.14 (1H, d, J=15.0 Hz, CH); 6.83-7.14 (2H, m, CH—CH); 7.14-7.66 (6H, m, C6H5, CH); 8.21 (1H, t, J=5.5 Hz, NH); 8.74 (1H, s, NH), 10.42 (1H, s, OH). HPLC analysis on Symmetry C18 column: impurities 2.6% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; detector UV 230 nm; sample concentration 0.3 mg/ml). Anal. Calcd for C16H20N2O3S: C, 59.98; H, 6.29; N, 8.74. Found: C, 59.82; H, 6.23; N, 8.68.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[O:5].[I:15]N1C(=O)CCC1=O>CN(C=O)C>[OH:1][C:2]1[C:9]([I:15])=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=Cc1cc(OC(F)(F)F)cc(I)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.2 %

Procedure:
A mixture of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (5.09 g, 24.7 mmole) and N-iodosuccinimide (13.9 g, 61.8 mmole) in anhydrous DMF (50 mL) was stirred at room temperature for 2 days under a dry N2 atmosphere. The solvent was removed in vacuo and the residue was dissolved in EtOAc (200 mL), washed with 0.5 N HCl (200 mL), H2O (200 mL), aqueous sodium thiosulfate (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. Purification by sublimation under vacuum at 85° C. gave 7.97 g (97% yield) of the product as a white solid: EIHRMS m/z 331.9159 (M+, C8H8F3O4, Calc'd 331.9157).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give the title compound. LC-MS: 708.3 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[C:11]1([CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH:20]([C:24](O)=O)[CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:24]([CH:20]3[O:21][CH2:22][CH2:23][N:18]([CH2:17][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:19]3)=[N:10][C:5]=2[CH:4]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Yield: 78.3 %

Procedure:
A solution of 4-methoxybenzene-1,2-diamine (0.5 g, 2.369 mmol) and 4-(phenylmethyl)-2-morpholinecarboxylic acid (1.221 g, 4.74 mmol) in 6N HCl (10 mL) was stirred at 105° C. overnight. The reaction mixture was neutralized with aqueous NaOH and partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (50 mL), dried (MgSO4), and evaporated in vacuo to give the crude product as a black oil. The crude product was added to a silica gel column and was eluted with 90:10 CH2Cl2/CH3OH to afford the title compound (0.6 g). LC-MS (ES) m/z=324 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[CH2:14][CH2:15][CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].C(O)COCCOCCO>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:26][CH:27]=1
Reactant: O=C(CCCN1CCCCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(CCCCN2CCCCCC2Cc2ccc(Cl)cc2)cc1
Yield: 62.2 %

Procedure:
Heat 0.5 g of the title compound of Example 39 with 1 ml of hydrazine hydrate, 0.5 g of potassium hydroxide and 5 ml of triglycol for 2 hours at 165°. Cool the resulting reaction mixture to ambient temperature. Mix the cooled reaction mixture with water and diethyl ether. Dry the ether phase over sodium sulfate and then concentrate it to obtain 0.3 g of the title compound as a viscous oil.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:23].O>C1(C)C=CC=CC=1>[NH2:23]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)=[O:6]
Reactant: CCOCCOc1ccc(C=CCOC(=O)CC(C)=O)cc1
Reactant: N
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(C=CCOC(=O)/C=C(/C)N)cc1

Procedure:
10 Grams of 4-[(1-ethoxy)ethoxy]cinnamyl acetoactate was dissolved in 20 ml of toluene, then 2 g of ammonia gas was passed through this solution at about 80° C. with stirring condition. The water formed during the reaction was removed by azeotropic distillation with toluene. 2 Hours after the azeotropic distillation, the toluene was removed by distillation under reduced pressure to yield 10 g of 4-[(1-ethoxy)ethoxy]cinnamyl 3-aminocrotonate as in the form of an oily substance.
Reaction SMILES: N[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1N=CC=[N:7]2.Cl[Sn]Cl>>[NH2:7][C:8]1[C:3]2[C:2](=[CH:11][CH:2]=[CH:3][CH:8]=2)[C:11]([O:12][CH3:13])=[CH:10][CH:9]=1
Reactant: COc1ccc2nccnc2c1N
Agent: Cl[Sn]Cl
Product: COc1ccc(N)c2ccccc12

Procedure:
5-amino-6-methoxyquinoxaline (Compound 18), SnCl2 being replaced by TiCl3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1C=CC(O)=CC=1.O>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Oc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(Br)c1
Yield: 30 %

Procedure:
A mixture consisting of 53% of meta bromophenol and 47% of para bromophenol (30.15 g, 0.174 mol) was dissolved in 150 ml of 50% sodium hydroxide and 30 ml of water and cooled to 25° C., whereupon a white solid precipitated. The white solid was filtered and slurried with 20 ml of 50% sodium hydroxide and 5 ml of water. The white solid was then crystallized again in a similar manner and methylated with an excess of dimethylsulfate and sodium hydroxide to yield 9.72 g (30%) of meta bromoanisole after distillation, containing less than 2% of the para isomer.
Reaction SMILES: O.[ClH:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([OH:11])=[O:10].[CH3:12]O>S(Cl)(Cl)=O>[ClH:2].[Cl:2][C:6]1[CH:7]=[CH:8][N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1
Reactant: O=C(O)c1ccccn1
Reactant: CO
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Yield: 85 %

Procedure:
H2O (18 mL) was added dropwise to a stirred suspension of picolinic acid hydrochloride, compound 1 (157.9 g, 1.0 mol) in thionyl chloride (400 mL). The resulting mixture was heated under reflux for 4 days giving a clear orange solution. After cooling to ambient temperature, the solution was concentrated to a syrup and the residue coevaporated with toluene (2×500 mL). The residue was dissolved in toluene (1 L) and cooled to 0-5° C. Methanol (44.0 g, 1.0 mol) was added dropwise to the ice cold reaction mixture giving a heavy white precipitate. This precipitate was collected by filtration, washed with toluene (3×100 mL) and dried at 40° C. for 24 hr to give 176.5 g (85%) of compound 2 as a white crystalline solid.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[N:31]1([C:3]([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)=[O:30])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Reactant: C1COCCN1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1)N1CCOCC1
Yield: 40 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) was converted, using morpholine instead of cyclopropanemethylamine, to the title compound (32 mg, 40%) which was obtained as a white foam. MS: m/e=469.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH3:12])[CH2:9][CH2:8][N:7]1[CH3:13])=[O:5])C.[OH-].[Na+].Cl.CCOCC>CCO>[CH3:13][N:7]1[CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1CN(C)CCN1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CN1CCN(C)C(C(=O)O)C1
Yield: 48.2 %

Procedure:
Ethyl 1,4-dimethylpiperazin-2-yl carboxylic acid (1.86 g) was dissolved in EtOH (10 mL) and 5M aqueous NaOH (20 mL) added. The mixture was refluxed for 2 hours, allowed to cool, 10M HCl (9.1 mL) added to give pH4 and the mixture evaporated to dryness. The white solid was stirred with MeOH (25 mL), CH2Cl2 (10 mL) added and the filtrate evaporated to give, after trituration with Et2O, the title compound as a grey solid (761 mg, 48%).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1>C(O)C.[C].[Pd]>[CH3:1][N:2]([CH3:25])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:24])[C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CN(C)C1CCCN(C(=O)c2ccc(N)cc2)c2ccccc21
Yield: 96 %

Procedure:
5 g of 10% palladium-carbon was dispersed in 500 ml of ethanol. Thereto was added 64.1 g of 5-dimethylamino-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine. The mixture was subjected to catalytic reduction at normal temperature at normal pressure. After the reduction, 10% palladium-carbon was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 56.1 g of 5-dimethylamino-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO.ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(CC2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2

Procedure:
7-Methyl-5-piperidin-4-ylmethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (50.0 mg, 0.124 mmol) was dissolved in methanol (0.2 mL) and acetic acid (0.2 mL) and 37% formaldehyde (0.2 mL) was added at room temperature. The mixture was stirred for ten minutes and sodium cyanoborohydride (1M in THF, 0.2 mL, 0.20 mmol) was added and the mixture was allowed to stir overnight at room temperature. The reaction was diluted with dichloromethane, washed with sodium bicarbonate (sat) and brine dried over sodium sulphate, filtered and concentrated. Column chromatography provided the title compound as an off white foam (23.8 mg, 44%). 1H NMR (300 MHz, CDCl3): δ 7.37 (d, 2H), 7.21 (d, 2H), 6.99 (d, 2H), 4.77 (s, 2H), 4.22 (s, 2H), 2.91 (d, 1H), 2.77 (m, 4H), 2.58 (d, 2H), 2.30 (m, 3H), 1.99 (m, 1H), 1.67-1.27 (m, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[CH3:22][N:23]1[C:27]([CH3:28])=[C:26]([NH2:29])[C:25]([CH3:30])=[N:24]1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(OCC)(=O)C.CN1CCCC1=O>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]2[C:15]([CH3:16])=[C:5]([N:4]3[CH2:19][CH2:20][N:29]([C:26]4[C:25]([CH3:30])=[N:24][N:23]([CH3:22])[C:27]=4[CH3:28])[CH2:2][CH2:3]3)[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]=2[O:12]1
Reactant: Cc1nn(C)c(C)c1N
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(C)c1N1CCN(c2c(C)c(C)c3c(c2C)CC(C)(C)O3)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To 1-methyl-2-pyrrolidone (5.0 mL) solution of N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (660 mg, 2.0 mmol) synthesized in Reference example 146, 1,3,5-trimethyl-1H-pyrazole-4-amine (300 mg, 2.4 mmol), sodium hydrogen carbonate (400 mg, 4.8 mmol) and sodium iodide (300 mg, 2.0 mmol) were added, and stirred at 120° C. for 16 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 9:1). The resulting solids were recrystallized from ethanol-water to obtain the title compound 320 mg (yield 42%). Melting point was 162 to 164° C. (ethanol-water).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35]C)=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:22](=[O:27])[CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][C:17]4[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([OH:35])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:22](=[O:27])[CH2:23][N:24]([CH3:25])[CH3:26])[CH2:18][C:17]4[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)CN(C)C)Cc1cc(F)ccc1-3
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of methyl 14-cyclohexyl-6-(N,N-dimethylglycyl)-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate from (Step 6) in DCM (0.15 M) was added dropwise to a solution of BBr3 in DCM (1 M, 5 eq.). The solution was stirred at RT for 1 h. Some drops of saturated aqueous NaHCO3 were added before volatiles were removed in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 μm, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (28%).
Reaction SMILES: [CH:1]([C:3]1[C:20]([O:21]C)=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:2].[I-].[Mg+2].[I-].Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)c1cccc(COc2cccc(OC)c2C=O)c1
Agent: Cl
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(COc2cccc(O)c2C=O)c1

Procedure:
To a stirred solution of methyl 3-(2-formyl-3-methoxyphenoxy)methylbenzoate (3 g, 0.01 M) in dry tetrahydrofuran (30 ml) was added dropwise a solution of magnesium iodide (4.13 g, 0.015 M) in dry ether (65 ml). The mixture was then stirred under reflux (51/2 hr). The cooled mixture was poured into 10% hydrochloric acid (55 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solutions were washed with sodium bicarbonate solution, water, dried (magnesium sulphate) and evaporated. The residue was dissolved in chloroform-methanol (95:5) and filtered through a short pad of florisil. The pale yellow solution was evaporated to give methyl 3-(2-formyl-3-hydroxyphenoxy)methylbenzoate, m.p. 118°-120° C. from ethyl acetate/petrol.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([Cl:21])[CH:16]=[C:17]([C:18](O)=[O:19])[C:12]=2[O:11][C:10]([CH3:23])([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:38][CH:39]1[CH:44]2[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]2)[CH2:40]1>C(OCC)(=O)C>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([Cl:21])[CH:16]=[C:17]([C:18]([NH:38][CH:39]3[CH:44]4[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]4)[CH2:40]3)=[O:19])[C:12]=2[O:11][C:10]([CH3:22])([CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CN(Cc2ccccc2)c2cc(Cl)cc(C(=O)O)c2O1
Reactant: NC1CN2CCC1CC2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(Cc2ccccc2)c2cc(Cl)cc(C(=O)NC3CN4CCC3CC4)c2O1
Temperature: 25 °C

Procedure:
To a solution of 1.5 g of 4-benzyl-6-chloro-2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.2 ml of triethylamine, and 0.55 g of pivaloyl chloride was added dropwise thereto at -10° to -5° C. under cooling. After stirring for 15 minutes at the same temperature, 0.57 g of 3-aminoquinuclidine was added at -10° to -5° C. and the mixture was stirred at room temperature for an hour. The resultant mixture was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of isopropyl ether and ethanol to give 4-benzyl-6-chloro-2,2-dimethyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide as white crystals, melting at 174°-175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:11]2[CH2:12][CH2:13][N:14]3[C:18]([C:10]=2[NH:9][N:8]=1)=[CH:17][C:16]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])=[CH:15]3)=[O:5].Cl[CH2:32]Cl.CI>O>[CH3:1][C:2]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:11]2[CH2:12][CH2:13][N:14]3[C:18]([C:10]=2[N:9]([CH3:32])[N:8]=1)=[CH:17][C:16]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])=[CH:15]3)=[O:5]
Reactant: ClCCl
Reactant: Cc1ccc(C(=O)Nc2n[nH]c3c2CCn2cc(C(=O)N4CCCC4)cc2-3)c(C)c1
Solvent: O
Solvent: CI
Product: Cc1ccc(C(=O)Nc2nn(C)c3c2CCn2cc(C(=O)N4CCCC4)cc2-3)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving the compound 2,4-dimethyl-N-[8-(pyrrolidin-1-ylcarbonyl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizin-3-yl]benzamide (A35-M1-B8, Entry 200, Table III), obtained as described in the example 9, in dichloromethane 2 equivalent of methyl iodide were added. After four hours of stirring at room temperature, water was added and the phases were separated. The organic layer was Dried over Na2SO4 and the crude was purified through preparative HPLC. LCMS m/z 418 [M+H]+@ Rt2.87 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17].O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[N:17]/[NH:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N/N=C/c1ccc(-c2ccccn2)cc1
Yield: 97 %

Procedure:
4-(2-Pyridyl)benzaldehyde (15 g, 0.082 mol) was dissolved in ethanol (150 mL) and treated with t-butyl carbazate (10.3 g, 0.078 mol) at 80° C. for 4 h. The mixture was combined with water (200 mL), the solids were filtered, washed with water, and dried under vacuum to give 22.5 g (92%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:11]4[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=4)[CH:8]=3)[CH2:3]2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Product: O=C1CCC(c2ccc3c(c2)CC(NC(=O)Nc2ccccc2)C3)=NN1

Procedure:
2-Amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and phenyl isocyanate were treated in the same manner as in Example 29 to obtain 2-(phenylcarbamoyl)amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[O:11]=[CH:12][C:13](OCC)=O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[NH:9][C:12](=[O:11])[CH:13]=[N:10]2
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C=O
Solvent: CCO
Product: O=c1cnc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a stirred solution of 4,5-difluorobenzene-1,2-diamine (4.7 g, 32.6 mmol) in ethanol (75 mL) was added ethyl oxoacetate (50 wt % in toluene, 13.3 mL, 65.3 mmol). The reaction was stirred at room temperature overnight. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give 4.3 g (73%) of the product as a colorless solid.