Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=[O:19])[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[OH-:30].[Na+]>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([OH:30])=[O:19])[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a suspension of 2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carbaldehyde (15 g, 38 mmol) in ethanol was added silver nitrate (8.1 g, 48 mmol) and a 1.5 M NaOH solution (150 mL). The resulting mixture was stirred at room temperature for 30 minutes prior to filtering through celite. The solution was then concentrated. To the residual solid was added water and made basic by adding 1M NaOH (cloudy mixture). The mixture was then washed with DCM. The aqueous layer was then made acidic (pH 2) by adding concentrated HCl. The acidic mixture was then concentrated under vacuum. A precipitate slowly formed during the concentration. After the volume was reduced by ⅓, the suspension was cooled in an ice-bath for 15 minutes before being filtered to collect the solid. The solid was then dried under vacuum to give 2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid as a beige powder (15.2 g, 97%). LCMS m/z: 408.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH2:38][C:39]2([OH:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:42]5[CH2:43][CH2:44][C:39]([OH:45])([CH2:38][N:33]6[CH:37]=[CH:36][N:35]=[CH:34]6)[CH2:40][CH2:41]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:3]=1
Reactant: OC1(Cn2ccnc2)CCNCC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(O)(Cn3ccnc3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-hydroxy-4-imidazol-1-ylmethyl-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-Imidazol-1-ylmethyl-piperidin-4-ol following General Procedure B.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(NCCN(C)C)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(NCCN(C)C)nc1
Yield: 15.8 %

Procedure:
Following general procedure D, 1-(6-bromo-4-(6-(2-(dimethylamino)ethylamino)pyridine-3-ylamino)quinolin-3-yl)ethanone (100 mg, 0.23 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (82 mg, 0.35 mmol) to afford the desired product (18 mg, 16%) as a green-yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.29 (s, 1H), 8.26-8.20 (m, 2H), 8.05-7.99 (m, 2H), 7.69 (dd, J=9.0, 2.7 Hz, 1H), 7.18-7.07 (m, 2H), 6.96 (d, J=9.0 Hz, 1H), 3.89-3.83 (m, 2H), 3.46-3.37 (m, 2H), 2.96 (s, 6H), 2.80 (s, 3H); ESI MS m/z 494 [C26H25ClFN5O2+H]+; HPLC 97.2% (AUC), tR=10.46 min.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[C:26]5[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=5[O:24][N:23]=4)[CH2:18][CH2:17]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=O)C>S(=O)(=O)(O)O.O>[F:31][C:29]1[CH:28]=[CH:27][C:26]2[C:22]([CH:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C:10]4[C:7]5[CH2:8][CH2:9][NH:4][CH2:5][C:6]=5[S:12][C:11]=4[CH3:13])[CH2:17][CH2:18]3)=[N:23][O:24][C:25]=2[CH:30]=1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(c3noc4cc(F)ccc34)CC2)C1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCNC2

Procedure:
A mixture of 4 g of 6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine in 4ml of conc. sulfuric acid and 80 ml of water was refluxed under heating for 3 hours. The mixture was poured into water, made alkaline and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated. To the residue was added isopropyl ether and the crystals were collected by filtration to give 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, m.p. 88°-90° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+]>CO>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:14]=1)[C:3]([OH:22])=[O:2]
Reactant: C=C(C)C(=O)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)C(=O)c1cc(C(=O)O)cc(C(=O)N(C)CCC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve N-methyl-5-(2-methylacryloyl)-N-propyl-isophthalamic acid methyl ester (50 mg, 0.16 mmol) in methanol (3 mL). Add 2 N NaOH (0.12 mL) and stir overnight at room temperature. Add 2 N NaOH (0.05 mL ) and stir for an additional 3 h. Acidify the mixture to about pH=6 using DOWEX® 50WX2-100 ion exchange resin and filter. Concentrate filtrate to give the title compound which is used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>CO.O1CCCC1.O>[I:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:4]([OH:14])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C=Cc1ccc(I)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C=Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.8 %

Procedure:
A solution of ethyl-4-iodo-cinnamate (3.2 g, 10.5 mmol) in methanol (25 mL), tetrahydrofuran (25 mL) and water (15 mL) was treated with lithium hydroxide monohydrate (4.2 g, 100 mmol) and the resulting reaction mixture was stirred at ambient temperature over 2 days. The volatiles were evaporated in vacuo and the residue was neutralized with saturated aqueous ammonium chloride solution. The precipitated solid was filtered, washed with water and hexane and dried to afford the title product as a white solid (2.9 g, 91%). It was used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[N:27][CH:28]=1)#[C:21][CH3:22]>>[CH3:17][C:13]1[C:14]([NH2:16])=[N:15][C:11]2([C:18]3[C:5](=[CH:4][CH:3]=[C:2]([C:25]4[CH:26]=[N:27][CH:28]=[C:23]([C:20]#[C:21][CH3:22])[CH:24]=4)[CH:19]=3)[CH2:6][C:7]32[CH2:10][CH2:9][CH2:8]3)[N:12]=1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Product: CC#Cc1cncc(-c2ccc3c(c2)C2(N=C(C)C(N)=N2)C2(CCC2)C3)c1
Yield: 67.7 %

Procedure:
The title compound (60 mg, 68% yield) was prepared by the method described in Example 55, starting from 6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 54) (80 mg, 0.25 mmol) and 5-(prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 53 mg, 0.33 mmol). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.59 (m, 4H) 1.83 (d, 1H) 2.09 (s, 3H) 2.16 (d, 1H) 2.21 (s, 3H) 3.23 (m, 2H) 6.60 (s, 2H) 6.89 (d, 1H) 7.41 (d, 1H) 7.54 (dd, 1H) 7.91 (t, 1H) 8.52 (d, 1H) 8.67 (d, 1H). MS (ES+) m/z 355 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[O:12])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (411 mg) and 2-bromo-4'-methylsulphonyl acetophenone (835 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one hour. The resulting suspension was concentrated at reduced pressure then diluted with water (100 ml). The collected precipitate was crystallised from acetone, then from ethanol to give the title pyrimidinone (235 mg); m.p. 257°-258°; λmaxEtOH 242 nm (ε 23650), 286 nm (ε 1950), 334 nm (ε 1680), λinf 293 nm (ε 1850).
Reaction SMILES: [SiH3]CC(N)=O.CN1CCOCC1.[CH3:13][O:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1.C(Cl)(=O)C([Cl:27])=O>C(#N)C.ClCCl.CN(C)C=O>[CH3:13][O:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([Cl:27])=[O:23])[CH2:17][CH2:16]1
Reactant: COC1CCC(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: NC(=O)C[SiH3]
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC1CCC(C(=O)Cl)CC1
Temperature: 45 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-[3(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-amino-β-alanine (250 mg, 0.55 mmol) in acetonitrile (8 mL) was added monosilylacetamide (1.0 g), then the mixture was stirred for 20 minutes at 45° C. After the mixture was allowed to cool to 0° C., N-methylmorpholine (73 mL, 0.66 mmol) and a solution of 4-methoxycyclohexanecarbonyl chloride (0.66 mmol) in dichloromethane (2 mL), which was prepared from 4-methoxycyclohexanecarboxylic acid, oxalyl chloride and N,N-dimethylformamide, were added successively via syringe. After stirring at ambient temperature for 4 hours, the mixture was extracted with ethyl acetate and dried over sodium sulfate. After evaporation of the solvent, the residue was treated with 4N hydrochloric acid in ethyl acetate. The insoluble material was collected by filtration, dried and dissolved in water. The solution was neutralized with a saturated aqueous NaHCO3 solution, purified by an ODS column chromatography using Daisogel-120SP (10% CH3CN/water) and freeze-dried to give N-[3(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(4-methoxycyclohexanecarbonyl)amino-β-alanine (244.4 mg, 89.8%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4](Cl)[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([N:16]=[N+:17]=[N-:18])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(Cl)CSCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(CSCc1ccccc1)N=[N+]=[N-]
Yield: 98.7 %

Procedure:
15.0 grams (61.3 mmoles) of the 2-chloro-3-benzylmercapto-propionic acid methyl ester produced in Example 3 were stirred with 5.98 grams (92.0 mmoles) of sodium azide and 1.5 grams of Aliquat 336 in 30 ml of water for 7 hours at 45° C. After working up according to Example 2 there were obtained 15.2 grams (99% of theory) of 2-azido-3-benzylmercapto-propionic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:31].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[F:31][C:3]1[CH:4]=[C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][OH:23])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:9][CH2:10]2)[CH:6]=[CH:7][C:2]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)c(F)c4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccccc5)c(F)c4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33.7 %

Procedure:
A solution of the compound (526 mg, 1.0 mmol) obtained in Example 25-3), phenylboronic acid (244 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2.0 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 3.5 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was partially purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 40:60, gradient). A solution of this partially purified product and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (138 mg, 34%) as a colorless solid.
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2)[CH2:3][CH3:4].O1CCCC1>CO.[Ni]>[ClH:1].[ClH:1].[CH2:20]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2)[CH2:21][CH3:22]
Reactant: CCCN(CCC)CCc1ccc([N+](=O)[O-])c2[nH]ncc12
Agent: [Ni]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCC)CCc1ccc(N)c2[nH]ncc12
Yield: 117.7 %

Procedure:
600 mg of N,N-dipropyl-N- 2-(7-nitro-1H-indazol-4-yl)ethyl amine, hydrochloride, in 10 ml of methanol and 10 ml of tetrahydrofuran is hydrogenated in the presence of 0.5 g of Raney nickel. The mixture is filtered off from the catalyst, combined with ethereal hydrochloric acid, and concentrated. The residue is recrystallized from methanol/diethyl ether, yielding 360 mg of N,N-dipropyl-N- 2-(7-amino-1H-indazol-4-yl)ethyl amine, dihydrochloride, mp 214°-218° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH2:4]1.[Sn]>Br.O>[CH2:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:6]1[CH2:7][CH2:8][C:3]([CH2:25][CH2:26][CH2:27][CH3:28])([N:2]([CH3:1])[CH3:29])[CH2:4][CH2:5]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCCC1(N(C)C)CC=C(c2[nH]c3ccccc3c2Cc2ccccc2)CC1
Agent: Br
Agent: [Sn]
Solvent: O
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2Cc2ccccc2)CC1
Reaction time: 0.33 h

Procedure:
Ex. 39 (438 mg, 1.133 mmol) was dissolved in hydrogen bromide/glacial acetic acid (33% HBr, 25 ml). Tin powder (1.345 g, 11.330 mmol) was then added to the mixture in portions at room temperature in the course of 40 min and the mixture was stirred for a further 20 min. The mixture was then diluted with water (100 ml). The mixture was stirred at 5° C. for 1 h. The product precipitated out as the hydrobromide. This was filtered off and washed with water (2×5 ml). 1 N NaOH (50 ml) was added to the moist yellow solid (4.0 g). The mixture was extracted with methylene chloride (3×30 ml). The combined organic phases were dried with Na2SO4 and filtered. The volatile constituents were removed completely in vacuo. An oil (425 mg) remained. After separation of this mixture by chromatography [silica gel 60 (40 g); ethyl acetate (500 ml), ethyl acetate/methanol 4:1 (750 ml)] 4-(3-benzyl-1H-indol-2-yl)-1-butyl-N,N-dimethylcyclohexanamine (less polar diastereoisomer, 210 mg, impure) and the more polar diastereoisomer (178 mg, 40%) was obtained as a yellow oil. The less polar diastereoisomer was purified further: Hot methanol (6 ml) was added and the mixture was left to stand at −10° C. overnight. The colourless solid which separated out (144 mg, 33%, melting point of 72-78° C. and 97-99° C.) was filtered off with suction and washed with cold methanol (2×0.5 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7](=[O:30])[C@H:8]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:9]([CH2:12][C:13]([NH:15][CH:16]([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([NH:40][C:41](=[O:42])[NH:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7](=[O:30])[C@H:8]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[N:9]([CH2:12][C:13]([NH:15][CH:16]([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(CC(=O)O)NC(=O)CN1C(=O)c2cc(N)ccc2NC(=O)[C@@H]1Cc1ccc(O)cc1
Solvent: CN(C)C=O
Product: CC(CC(=O)O)NC(=O)CN1C(=O)c2cc(NC(=O)NCc3ccccc3)ccc2NC(=O)[C@@H]1Cc1ccc(O)cc1
Temperature: 45 °C

Procedure:
To a solution of 3-(R,S)-{2-[7-Amino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid (0.2 mmol, 88mg). in DMF (6 ml) was added benzylisocyanate (158 μl 1.2 mmol). The mixture was shaken at 45° C. over night and then was evaporated to dryness. The crude product was purified by RP-HPLC to give 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid: MS (ISN) 572 (M−H)−.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:14]([CH3:26])=[C:13]([CH3:27])[N:12]=1>O1CCOCC1>[CH3:27][C:13]1[C:14]([CH3:26])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCO)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCO)c1C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
Sodium hydride (4.38 g of 60% dispersion in mineral oil, 109.6 mmol) was added to chilled dioxane (73 mL). Phenol (10.31 g, 109.6 mmol) was added in portions with cooling. 4-[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butan-1-ol (20.00 g, 93.07 mmol) and additional dioxane (˜30 mL) were added. The reaction mixture was heated at reflux for 3 hours and then allowed to stand at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and then extracted with ethyl acetate (300 mL). The extract was washed with water (2×100 mL) then with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide an oil. The oil was purified by flash chromatography (600 mL of silica gel, eluting initially with 2000 mL 1:3 ethyl acetate:hexanes, then with 2000 mL 1:1 ethyl acetate:hexanes and finally with 1000 mL 3:1 ethyl acetate:hexanes) to provide 13.46 g of 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butan-1-ol as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1C=CC=[CH:22][CH:21]=1.C([O-])(=O)C.[NH4+].C(CC(O)=O)#N>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])/[CH:16]=[CH:22]/[C:21]#[N:20])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: N#CCC(=O)O
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(/C=C/C#N)c1cccc(OCc2ccccc2)c1
Yield: 91 %

Procedure:
To a solution of benzyloxy aldehyde III (320 g, 1.26 mol) in toluene (1.2 L) was added pyridine (600 mL), ammonium acetate (15 g, 0.19 mol) and cyanoacetic acid (200 g, 2.35 mol) and the mixture was refluxed for 72 hours. The reaction was diluted with ethyl acetate (3.5 L), washed with water (2 L) and washed with 1N HCl (until pH of the water layer becomes acidic), washed with brine (1 L) and the organic layer was dried and concentrated under reduced pressure to yield 317 g (91 %) cyanide XXXIV. M+1=278
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([C:28]3[S:29][C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[O:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[CH:19]([O:20][CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1)[C:15]1[CH:14]=[C:13]([N:10]2[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CN1CCC(OC(c2cccc(N3CCC(NC(=O)OC(C)(C)C)C3)c2)c2nc3ccccc3s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(OC(c2cccc(N3CCC(N)C3)c2)c2nc3ccccc3s2)CC1

Procedure:
A solution of crude (1-{3-[benzothiazol-2-yl-(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (289 mg) in dichloromethane (3 mL) and trifluoroacetic acid (2.5 mL) is stirred at room temperature for one night. The mixture is concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous 1N sodium hydroxide, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 80/20/0.5). The base is converted into its dioxalate salt in acetone to give 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine, dioxalate melting at 145° C.