Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[N+:12]([C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1)([O-:14])=[O:13].[H-].[Na+].[OH-].[Na+]>C1COCC1.O.C(O)C>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc([N+](=O)[O-])cc1

Procedure:
Alkylation of diethyl malonate with 4-nitrobenzyl bromide using sodium hydride in THF, followed by ester hydrolysis with sodium hydroxide in water and ethanol, then heating the resulting diacid to its melting point causing decarboxylation gives 3-(4-nitro-phenyl)-propionic acid. Conversion to the acid chloride with thionyl chloride in DCM and coupling with 2-amino-4,6-dimethylpyridine affords N-(4,6-dimethyl-pyridin-2-yl)-3-(4-nitro-phenyl)-propionamide. Amide reduction with borane-dimethylsulfide in THF at reflux, methylation of the resulting amine with methyl iodide and sodium hydride in THF and finally catalytic hydrogenation over Raney nickel in methanol gives the required aniline.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9].[CH3:21]O>>[ClH:3].[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][C:8]([O:10][CH3:21])=[O:9]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To 150 mL of stirred methanol at 0° C. under nitrogen was slowly added thionyl chloride (14.2 mL, 194.4 mmol). To the reaction mixture was then added 3-amino-3-(3,4-dimethoxyphenyl)propionic acid (15.5 g, 64.8 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature, and stirred overnight. The reaction solution was concentrated to an oil and then diluted with 200 mL of CH3OH/Et2O (1/3) and stirred. The resulting slurry was filtered ard the solid was washed with a copious amount of ether. The solid was dried in vacuo (60° C.,<1 mm) to afford 1.83 g (66%) of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride as a white powder: 1H NoM (DMSO-d6, 250 MHz)δ 8.59 (br s, 3 I, NH3), 6.9-7.3 (m, 3H, Ar), 4.52 (overlapping dd, 1H), 3.77 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 3.16 (dd, 1H, J1 =6 Hz, J2 =16 Hz), 2.98 (dd, 1H, J1 =8 Hz, J2 =16 Hz); 13C NMR (DMSO-d6)δ 169.6, 149.0, 129.0, 120.0, 111.5, 111.4, 55.7, 55.5, 51.7, 50.8, 38.5. Anal. Calcd for C12H18NO4Cl. Theoretical C, 52.27; H, 6.58; N, 5.08. Found C, 52.44; H, 6.53; N, 5.01.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH2:47][CH2:48][O:49]S(C)(=O)=O)[CH:44]=[CH:45][CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:54]1[CH2:60][O:59][CH2:58][CH2:57][NH:56][CH2:55]1>C1COCC1>[CH:48]([OH:49])=[O:59].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][N:56]3[CH2:55][CH2:54][CH2:60][O:59][CH2:58][CH2:57]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CNCCOC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCN5CCCOCC5)c4)c4ccccc43)cn12
Product: O=CO

Procedure:
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and homomorpholine (30.4 mg, 0.30 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (15 mg, 31%). LCMS (Method 5): Rt 3.66 min, m/z 746.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H, m), 1.73-1.97 (6H, m), 2.00-2.17 (2H, m), 2.66-2.81 (8H, m), 2.90 (1H, ddd, J=12.2, 9.0, 4.0 Hz), 3.16 (1H, dt, J=12.2, 4.4 Hz), 3.28-3.34 (1H, m), 3.56-3.59 (2H, m), 3.63 (2H, t, J=6.0 Hz), 4.82 (1H, td, J=8.6, 5.5 Hz), 5.52 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.08 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.8, 2.2 Hz), 7.24-7.42 (8H, m), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.69 (1H, dd, J=2.1, 0.9 Hz), 8.09 (1H, s), 8.18 (1.3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(#N)C>[NH:22]([C:2]1[N:7]=[N:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1)[NH2:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)nn2)CC1
Reactant: NN
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(NN)nn2)CC1
Temperature: 80 °C
Yield: 58.7 %

Procedure:
A stirred mixture of tert-butyl 4-(6-chloropyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (870 mg, 2.94 mmol) and hydrazine hydrate (4.29 mL, 88.25 mmol) in acetonitrile (15 mL) was heated at 80° C. for 4 hours. The mixture was partially evaporated (removing MeCN) and diluted with water (10 mL). The reaction mixture was extracted with DCM (3×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product as a gum, which crystallised on trituration with ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to afford tert-butyl 4-(6-hydrazinylpyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (503 mg, 58.7%) as a cream crystalline solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH:21]([CH3:23])[CH3:22])[C:18]([OH:20])=[O:19].C(C(C1C=CC(Cl)=CC=1)C(OC(F)C1C=CC=C(OC2C=CC=CC=2)C=1)=O)(C)C>>[F:16][C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH:21]([CH3:23])[CH3:22])[C:18]([O:20][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[O:19]
Reactant: CC(C)C(F)(C(=O)O)c1ccccc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: CC(C)C(C(=O)OC(F)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Product: CC(C)C(F)(C(=O)OCc1cccc(Oc2ccccc2)c1)c1ccccc1

Procedure:
This compound was prepared from 3-phenoxybenzyl bromide and α-fluoro-α-isopropylphenylacetic acid following the method used in Example 2 Method B for the preparation of α-fluoro-3-phenoxybenzyl α-isopropyl-4-chlorophenylacetate. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift ppm (solvent CDCl3): 0.69(3H, d, J=6 Hz, CH3); 1.05 (3H, d of d, J=6 Hz and J=2 Hz, CH3); 2.34(1H, m, CH(CH3)2); 3.27 (1H, d, J=10 Hz, CH); 7.17(1H, d of d, J=56 Hz and J=2 Hz, CHF) and c. 7.20(14H, m, aromatic protons).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](B(O)O)[C:5]([O:17][CH2:18][CH3:19])=[CH:4][C:3]1=2.[C:21](=[O:24])([O-])[O-].[Na+].[Na+].O.[CH2:28]([OH:30])[CH3:29]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([C:21]1[O:24][C:3]2[C:8]([C:6]3[C:5]([O:17][CH2:18][CH3:19])=[CH:4][C:3]4[C:2]([CH3:20])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=4[CH:7]=3)=[CH:9][CH:10]=[CH:11][C:2]=2[CH:1]=1)(=[O:30])[CH3:29]
Reactant: CCOc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: O=C([O-])[O-]
Reactant: CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1cc2c(cc1-c1cccc3cc(C(C)=O)oc13)C(C)(C)CCC2(C)C

Procedure:
A mixture of 1.08 mmol of (5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl)-boronic acid, 498 mg (1.62 mmol) of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan (see Example 4, step A) and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-7-(5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl)-benzo[b]furan as a clear yellow pasty solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9](SC)=[N:10][C:4]=2[CH:3]=1.[S:13]([O-:18])(O[O-])(=O)=[O:14].[K+].[K+].[CH3:21]C#N.O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9]([S:13]([CH3:21])(=[O:18])=[O:14])=[N:10][C:4]=2[CH:3]=1
Reactant: CSc1nc2cc(Cl)ncc2[nH]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC#N
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirring solution of 6-chloro-2-(methylthio)-3H-imidazo[4,5-c]pyridine (954.0 mg, 4.78 mmol) in 50% CH3CN/water (61.4 mL) was added potassium peroxymonosulfate (oxone, 6.46 g, 10.51 mmol). The reaction was stirred under N2 at RT for 15 h, then filtered and the filtrate added to a stirring mixture of EtOAc (1.27 L)/water (0.70 L). The aqueous layer was separated and back-extracted with EtOAc (0.25 L). The combined organic layers were evaporated under reduced pressure to afford the title compound. LC-MS: calculated for C7H6ClN3O2S 230.99 observed m/e: 231.98 (M+H)+ (Rt 1.72/2.0 min)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH2:9][C:10]1[C:15]([C:16]#N)=[CH:14][CH:13]=[CH:12][N:11]=1.C([Li])CCC.C1C[O:26]CC1>>[NH2:9][C:10]1[C:15]([C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)=[O:26])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Brc1cccc(Br)n1
Reactant: C1CCOC1
Reactant: N#Cc1cccnc1N
Agent: [Li]CCCC
Product: Nc1ncccc1C(=O)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A mixture of 2,6-dibromopyridine (16.92 g, 71.4 mmol) and 2-amino-3-cyanopyridine (5.0 g, 42.0 mmol) in THF (150 ml) was cooled to below −30° C. before n-butyl lithium (33.6 ml, 84 mmol, 2.5 M in hexanes) was added dropwise while maintaining temperature below −30° C. On complete addition, the reaction mixture was stirred at 0° C. on an ice bath for 1.5 hours. The reaction was then quenched by the addition of 2 M HCl (until pH=˜1) while keeping the temperature below 15° C., and stirred at below 15° C. for 15 mins. Additional 2M HCl (50 ml) was added and the mixture extracted with EtOAc (2×150 ml), the acidic aqueous was cooled on an ice bath before being basified by addition of 2M NaOH, causing precipitation of a brown solid. Resulting suspension was left to stand overnight, then solid product collected by filtration, washed with water and dried by suction, then under high vacuum to leave crude title compound as a brown solid (6.52 g, 56%). 1H NMR (DMSO-d6) 6.65 (1H, dd), 7.79 (2H, s), 7.93-7.83 (4H, m), 7.99 (1H, t), 8.28 (1H, dd). ES+ 280.80.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][C:10]#[CH:11])=[C:4]([Cl:12])[N:3]=1.[C:13]([O-:16])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([NH:1][CH:13]=[O:16])=[N:3][C:4]=1[Cl:12])[C:10]1[CH:10]=[CH:9][CH:5]=[CH:4][CH:11]=1
Reactant: C#CCc1c(Cl)nc(N)nc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=CNc1nc(Cl)c(Cc2ccccc2)c(Cl)n1

Procedure:
A flask was filled with 2.02 g (10 mmol) of 2-amino-4,6-dichloro-5-(prop-2-yn-1-yl)pyrimidine and 10 ml of 2 mol·l1 (20 mmol) of a solution of the Vilsmeier-Haack-Arnold reagent in chloroform. The reaction mixture was refluxed for eight hours. Having been cooled to laboratory temperature, the reaction mixture was poured onto ice and rapidly neutralized by NaHCO3. The obtained mixture was quickly transferred into a separatory funnel and immediately extracted by 3×20 ml of chloroform. The organic fractions were connected and dried using MgSO4. According to TLC, the reaction mixture contained another substance besides 4,6-dichloro-2-{[(dimethylamino)methylene]amino}-5-(prop-2-yn-1-yl)pyrimidine. The acquired mixture was therefore separated by column chromatography with a hexane/ethyl-acetate mobile phase (80/20 to 50/50). After evaporation of the organic solvents, the isolated substances were 686 mg of 4,6-dichloro-2-{[(dimethylamino)methylene]amino}-5-(prop-2-yn-1-yl)pyrimidine, 317 mg of 4,6-dichloro-2-formamido-5-(prop-2-yn-1-yl)pyrimidine and 458 mg of 4,6-dichloro-5-(2-chloroallyl)-2-formamidopyrimidine, which is created by the addition of hydrochloric acid (developed during the reaction) to the triple bond present. The hydrolysis to 2-formamido derivatives did not occur until during the chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO.Cl>O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1cc(CNC(=O)OCc2ccccc2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCC(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture comprising 23.56 of N-benzyloxycarbonyl-3-ethoxycarbonylmethyloxy-4-methoxybenzylamine, 7.29 g of sodium hydroxide, 300 ml of methanol and 30 ml of water, was stirred at 60° C. for one hour. The reaction solution was neutralized by an addition of hydrochloric acid, and the solvent was distilled off under reduced pressure. Dilute hydrochloric acid was added to the obtained residue, and the mixture was extracted with chloroform. The extract layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off. The obtained residue was crystallized from diethyl ether/n-hexane to obtain 21.55 g of the above-identified compound as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>O.CC(C)=O>[C:10]1([CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:5]1[C:4]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH3:9])=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=1
Reactant: Cc1ccccc1N
Reactant: Oc1cccnc1O
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccccc1NC1=CC(=O)C(=O)N=C1Nc1ccccc1C
Reaction time: 2 h
Yield: 27 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), o-methylaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml of water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(o-tolylamino)-2,3-pyridindione in a red powder. The yield was 27%-45%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1O.[C:10](=[O:13])([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([O:6][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:3]=1[O:13][CH2:10][C:2]1[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)c(O)c1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromoresorcinol (10.0 g) and potassium carbonate (21.9 g) in DMF (100 mL) was added benzyl bromide (13.2 mL), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (21.8 g) as a crude oil. This compound was used for the next step without further purification.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C2C=CC(C([O:23][C@@H:24]3[CH2:32][C@@H:27]4[O:28][C:29](=[O:31])[CH2:30][C@@H:26]4[C@H:25]3[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=O)=CC=2)C=CC=CC=1.CC(C)=O.C(=O)=O.CO>C1(C)C=CC=CC=1>[OH:23][C@@H:24]1[CH2:32][C@@H:27]2[O:28][CH:29]([OH:31])[CH2:30][C@@H:26]2[C@H:25]1[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: CC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](O)C[C@@H]2O1
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1.5 M solution of Diisobutylaluminum hydride in toluene (12.6 mL, 18.9 mmol) was added dropwise to a stirred solution of a compound [9a] (4.1 g, 7.2 mmol) in toluene (60 mL) at −70-−80° C. (acetone/dry ice bath). The mixture was stirred for 1 hour at the same temperature. Methanol (50 mL) was added dropwise to the stirred mixture at −70-−80° C. and the cooling bath was removed. The mixture was stirred for 1 hours at room temperature, filtered and evaporated under reduced pressure. A solution of the residue in dichloromethane (150 mL) was washed with brine (2×10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 1:2 v/v) to obtain compound [11a] (2.53 g, 90% yield).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].Cl>CN(C=O)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1)#[N:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
Diethyl malonate (44.6ml, 293 mmol) was added dropwise over 1.5 hours to a suspension of sodium hydride (11.7 g of a 60% suspension in mineral oil, 293 mmol) in DMF under argon and the reaction mixture was stirred at ambient temperature for 30 minutes. The resulting solution was added dropwise over 1 hour to a solution of 2-chloro-5-cyano-1-nitrobenzene (24.3 g, 133 mmol) in DMF (75 ml) cooled with a dry ice/acetone bath. The temperature of the cooling bath was adjusted to prevent the freezing of the red reaction mixture. After the addition was completed, the reaction was left to rise to ambient temperature over 2 hours. The resulting red solution was poured slowly into a stirred mixture of ice (100 ml) and 1M hydrochloric acid (10 ml). The resulting yellow precipitate was collected by filtration, washed with water until the filtrate was at pH7.0 and then dried under vacuum to give diethyl (4-cyano-2-nitrophenyl)malonate (39.6 g, 97%).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:26]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:28])[CH3:27]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 48.7 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 4. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with acetyl chloride (0.012 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.030 g of a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]1.O1CCCC1.O.O.[OH-].[Li+]>C(OC(=O)C)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCN(CCCOC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a stirred mixture of ethyl 1-(3-methoxy propyl)piperidin-4-carboxylate (33.0 grams, 144.1 mmol, obtained in the above step), tetrahydrofuran (200 mL) and water (200 mL) was added lithium hydroxide monohydrate (6.1 grams, 144.1 mmol). The reaction mixture was stirred at room temperature for 16 hours before being diluted with ethylacetate. The two layers were separated and the aqueous layer was acidified to pH: 3-4 with concentrated hydrochloric acid and the volatiles were removed under reduced pressure to obtain 1-(3-methoxy propyl)piperidin-4-carboxylic acid (35.0 grams).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH:15]1([C:18]2[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=2)[NH2:21])[CH2:17][CH2:16]1.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([CH:34]=O)[C:28]=2[CH:27]=[CH:26]1>>[CH:15]1([C:18]2[CH:19]=[C:20]([NH:21][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH:1][CH2:34][C:29]5[CH:30]=[CH:31][CH:32]=[C:33]6[C:28]=5[CH:27]=[CH:26][NH:25]6)=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:17][CH2:16]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Nc1cccc(C2CC2)c1
Product: c1cc(Nc2ccc3c(NCc4cccc5[nH]ccc45)cccc3n2)cc(C2CC2)c1

Procedure:
The title compound, MS: m/e=405.5 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 3-cyclopropylaniline and 4-indolecarbaldehyde as described in example 26.
Reaction SMILES: [C-:1]#[N:2].[Na+].C(O)C.Cl[CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17]>O>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=1[CH2:8][C:1]#[N:2]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(CC#N)c(C)c1

Procedure:
66 g of sodium cyanide is refluxed in 100 mL water and 140 mL of ethanol with stirring, until a clear solution is formed. 136 g of 2-chloromethyl-1,3,5-trimethylbenzene is slowly added dropwise to this solution and the mixture is refluxed for 3 hours with stirring. It is diluted with 1 L of water and extracted three times with 200 mL of benzene. The combined organic phases are washed with water and the solvent is distilled off under reduced pressure. The residue is fractionally distilled. Yield: 92 g (72%); bp15: 145° C.-153° C.