Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]3[C:23]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=3[N:19]=2)=[O:13])=[CH:10][CH:9]=1)[CH3:6])=[O:4].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH3:39].C(=O)([O-])O.[Na+]>ClCCl>[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH2:2][C:3]([N:5]([CH2:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]3[C:23]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=3[N:19]=2)=[O:13])=[CH:10][CH:9]=1)[CH3:6])=[O:4])[CH3:39]
Reactant: CNCCOC
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)CCl)cc3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCN(C)CC(=O)N(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
4-[(Chloroacetyl-methyl-amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (100 mg, 205 mmol) are dissolved in N-(2-methoxyethyl)-methylamine (1.8 ml, 21 mmol) and the mixture stirred for 2 h at 55° C. Saturated aqueous sodium hydrogen carbonate is added (50 ml) and dichloromethane (50 ml) are added, the phases are separated and the aqueous phase extracted twice with 50 ml dichloromethane. The combined organic layers are dried with magnesium sulfate and evaporated. Flash chromatography (silica, dichloromethane containing 5% methanol) afforded the title compound as white crystals (74% yield), mp 171-173° C. MS: m/e=542 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH:26]=[C:25]([C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[N:24]=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:18]3[CH:26]=[C:25]([C:27]4[O:28][C:29]([CH3:32])=[N:30][N:31]=4)[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: Cc1nnc(-c2cc3c(Cl)ncnc3cn2)o1
Product: Cc1nnc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1

Procedure:
The title compound was prepared according to Procedure A from 4-benzyloxyaniline and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.33 (1H,s), 9.49 (1H,s), 9.39 (1H,s), 8.93 (1H,s), 7.80 (2H,d), 7.53 (2H,dd), 7.45 (3H,m), 7.20 (2H,d), 5.25 (2H,s), 2.75 (3H,s); m/z (M+1+) 411.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:36](C)=O.[Na+]>C(Cl)Cl>[CH3:36][N:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCNC3)ccc21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC[C@@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 93.4 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid ((R)-1-methyl-pyrrolidin-3-yl)-amide (42 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (R)-pyrrolidin-3-ylamide dihydrochloride (51 mg), 37% formaldehyde (500 uL), and Na(OAc)3BH (40 mg) in DCM (500 uL). LC/MS: m/z 440.5.
Reaction SMILES: C(OC(=O)CN1C2CCC[C@@H](N([S:17]([C:20]3C=C(C(F)(F)F)C=C(SCC)[CH:21]=3)(=[O:19])=[O:18])C)C=2C=N1)C.[CH2:34]([O:36][C:37](=[O:64])[CH2:38][N:39]1[C:47]2[CH2:46][CH2:45][CH2:44][C@@H:43]([N:48]([S:50]([C:53]3[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[C:55](F)[CH:54]=3)(=[O:52])=[O:51])[CH3:49])[C:42]=2[CH:41]=[N:40]1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:64])[CH2:38][N:39]1[C:47]2[CH2:46][CH2:45][CH2:44][C@@H:43]([N:48]([S:50]([C:53]3[CH:58]=[C:57]([C:59]([F:60])([F:61])[F:62])[CH:56]=[C:55]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:54]=3)(=[O:52])=[O:51])[CH3:49])[C:42]=2[CH:41]=[N:40]1)[CH3:35]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(SCC)cc(C(F)(F)F)c1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CC)c1

Procedure:
Starting with {(R)-4-[(3-ethylsulfanyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (1st step intermediate of example 8-1) using the method analogous to the one described for example 7-1, {(R)-4-[(3-ethanesulfonyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester was obtained as a white solid. MS cald. for C21H26F3N3O6S2 537, obsd. (ESI+) [(M+H)+] 538.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 97 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (1.0 g, 3.89 mM), 3-fluorobenzyl bromide (0.48 ml, 3.97 mM), and potassium carbonate (1.07 g, 7.78 mM) in 20 mL DMF was stirred at room temperature for 22 hours. The mixture was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous extracted with EtOAc. The combined EtOAc layers were extracted with 1N HCl, water, then brine. After drying (Na2SO4), evaporation in vacuo afforded 1.38 g (97%) of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ7.4-7.2 (m, 5H), 7.0 (m, 1H), 6.75 (m, 2H), 5.4 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.65-2.45 (m, 3H), 2.3 (dd, J=15 and 9 Hz, 1H), 1.1 (d, J=7 Hz, 3H). MS (ES) m/e 334, 366.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[P:11]([O-:16])([O:14]C)[O:12][CH3:13].C(N(CC)CC)C>C(#N)C.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>[PH:11](=[O:14])([O:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)[O:12][CH3:13]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: COP([O-])OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CO[PH](=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
1-Iodo-3-nitrobenzene (249 mg, 1 mmol) was dissolved in 10 mL of acetonitrile. Tetrakis(triphenylphosphine)palladium (58 mg, 3 mol %), dimethyl phosphite (0.138 ml, 1.5 mmol) and triethylamine (0.28 ml, 2 mmol) were added thereto and stirred at 70° C. overnight. After removing a solvent, the mixture was purified in accordance with the purification process A to obtain a mixture (0.222 g) of monomethyl (3-nitrophenyl) phosphonate and dimethyl ester. The obtained monomethyl phosphonate was dissolved in 10 mL of methanol. Pd/C in catalyst quantity was added thereto and stirred under hydrogen atmosphere overnight. After filtering out the catalyst, a solvent was removed to obtain a mixture of monomethyl (3-aminophenyl) phosphonate and dimethyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:15]([O:22][NH:23][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NOCc1ccccc1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=CNc1nc(Cl)c(NC=O)c(NOCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamido-pyrimidine (1.9 g, 8.09 mmol), benzyloxyamine (1 g, 8.13 mmol), triethylamine (2 ml) and dioxan (20 ml) was stirred at 100° C. for 1 hour. The cooled reaction mixture was filtered and the precipitate collected and washed with dioxan (2×5 ml). The filtrate and washings were combined and evaporated to a syrup. Column chromatography on silica gel (eluted with chloroform-ethanol, 30:1) afforded the title compound (1.2 g, 46%). IR: νmax (KBr) 3242, 1694, 1588, 1472 cm-1 ; 1H NMR δH [(CD3)2SO], 4.89 (2H, s, OCH2Ph), 7.4 (5H, m, Ph), 8.15 (1H, s, CHO), 9.18, 9.42 (1H, 2×br.s, D2O exchangeable, NH), 9.25 (1H, br.s, CHO), 10.91 (2H, br.s, D2O exchangeable, 2×NH). m/e (FAB+ve ion, thioglycerol) MH+ 322.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.CN(/[CH:12]=[N:13]/[C:14]1[C:23]([C:24]([O:26]C)=O)=[CH:22][C:21]2[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:28][CH3:29])[CH:20]=2)[N:15]=1)C.C(O)(=O)C>O1CCCC1>[CH3:29][O:28][C:19]1[C:18]([O:30][CH3:31])=[CH:17][C:16]2=[N:15][C:14]3[NH:13][CH:12]=[C:2]([C:1]#[N:3])[C:24](=[O:26])[C:23]=3[CH:22]=[C:21]2[CH:20]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2nc1/N=C/N(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3nc2cc1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
Acetonitrile (1.3 mL, 24.9 mmol) is added to a −78° C. solution of 9.0 mL of 2.5 M n-butyllithium (22.5 mmol) in 40 mL of tetrahydrofuran. After stirring at −78° C. for 15 min, a solution of 2.86 g (9.02 mmol) of methyl 2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarboxylate in 100 mL of tetrahydrofuran is added dropwise over 30 minutes. After stirring at −78° C. for 30 minutes, the reaction mixture is allowed to warm to room temperature and then stirred at room temperature for 1 hour. The reaction mixture is cooled to −78° C. and 3.0 mL of acetic acid is added. The mixture is then stirred at room temperature for 40 min. The solids are collected by filtration washing with water, methanol and ethyl acetate to provide 1.11 g (44%) of 7.8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile as a light yellow solid, mp>300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[CH:16](OCC)=[O:17].[H-].[Na+]>COCCOC>[CH:16]([CH:10]([CH2:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC(=O)CCc1ccc(OC)nc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccc(OC)nc1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A mixture of ethyl 3-(6-methoxy-3-pyridyl)propionate (32.74 g) and ethyl formate (17.22 g) was added dropwise over 1.5 hours to a stirred suspension of sodium hydride in oil (50%. 9.38 g) in 1,2-dimethoxyethane (50 ml) cooled to -2°, allowed to stand overnight at room temperature and was poured on to ice. The mixture was extracted with ether (discarded), and the aqueous phase was adjusted to pH 5 with 2 N sulphuric acid. An oil was precipitated and crystallised on standing to give ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (25.9 g, 70%) m.p. 91.5°-94°. A sample recrystallised from aqueous ethanol had m.p. 93°-94°.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: COc1ccccc1C(Cl)Cn1ccnc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
915 mg of methyl 4-mercaptobenzoate were dissolved in 6 ml of dry dimethylformamide, and 237 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling, to the resulting solution, followed by stirring at room temperature for 30 minutes. A solution of 1.17 g of 1-[2-chloro-2-(2-methoxyphenyl)ethyl]imidazole dissolved in 6 ml of dry dimethylformamide was added to the resulting solution. At the end of this time, the resulting mixture was treated and purified similarly to the procedure described in Example 1, to give 1.26 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([F:19])=[C:17]2[C:12]([C:13]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([F:28])[C:14]=3[C:15](=O)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC(OCC)=C(F)C=1.COCCOC.[BH4-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:18]([F:19])=[C:17]2[C:12]([C:13]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([F:28])[C:14]=3[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc2c(c1F)c(=O)oc1c(F)c(OCc3ccccc3)ccc12
Agent: CCOc1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1F)COc1c-2ccc(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
2.00 g (5.24 mmol) of 3-benzyloxy-8-ethoxy-4,7-difluoro-6H-benzo[c]chromen-6-one, the compound of Example 841, were dissolved in 12 ml of THF, and 2.37 ml (23.0 mmol) of boron trifluoride/THF complex were added with ice-cooling. 24 ml of ethylene glycol dimethyl ether and then in portions 530 mg of sodium borohydride were subsequently added. The mixture was subsequently stirred at room temperature for 18 hours and then transferred onto ice. The mixture was subjected to conventional purification, giving 1.5 g (78% of theory) of 3-benzyloxy-8-ethoxy-4,7-difluoro-6H-benzo[c]chromene as colourless crystals. These were dissolved in THF, hydrogenated at a pressure of 1 bar in the presence of 0.6 g of Pd/C (5%), filtered and evaporated, giving 1.2 g (99% of theory) of 8-ethoxy-4,7-difluoro-3-hydroxy-6H-benzo[c]chromene as colourless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH:15](=[N:24][NH:25][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C(=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1)c1ccccc1
Reaction time: 2 h

Procedure:
5-Chloro-7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidine (51.4 mg, 0.163 mM) was suspended in ethanol (1 mL) and then hydrazine monohydrate (15.8 μL, 0.326 mM) was added to the resulting suspension. This suspension was stirred for 2 hours and a half, while refluxing with heating, then hydrazine monohydrate (15.8 μL, 0.326 mM) was further added to the suspension, the mixture was stirred for additional 3 hours, hydrazine monohydrate (15.8 μL, 0.326 mM) was further added to the mixture and then the mixture was stirred for 18 hours. This reaction liquid was diluted with a saturated aqueous common salt solution and extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off. The resulting residue was suspended in ethanol (0.5 mL), then acetic acid (2.0 μL, 0.035 mM) and benzaldehyde (16.6 μL, 0.196 mM) were added to the suspension and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (16.5 mg, overall yield of these two steps: 25%).
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O>[CH3:22][CH:23]1[CH2:28][CH2:27][N:26]([C:4]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:5]=2[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])[CH2:25][CH2:24]1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2)CC1
Yield: 93.9 %

Procedure:
A mixture of 0.024 mole (0.96 g) of NaOH, 25 ml of water, 0.02 mole (5.92 g) of 2,4'-dichloro-5-nitro-benzophenone and of 0.022 mole (2.6 ml) of 4-methylpiperidine is heated to 80° C. for three and a half hours. After cooling the reaction medium to normal temperature the resulting precipitate is filtered, washed in water and dried giving 6.74 g (Yield: 94%) of the expected product. M.P.=138° C. (Ex. 25) The compounds listed hereunder are obtained by reacting, in the same conditions as above, the 2,4'-dichloro-5-nitro-benzophenone with other piperidine derivatives (2-methyl, 3-methyl, 3,5-dimethylpiperidine):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:34])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH:35]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:34])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH2:35][NH:40][CH:37]2[CH2:39][CH2:38]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C=O)C(C)C)cc21
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3CNC3CC3)C(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,4R)-3-formyl-4-({isopropyl-[1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carbonyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6 g, 10.9 mmol) in dichloroethane (100 mL), cyclopropylamine (0.85 mL, 12 mmol) and NaBH(OAc)3 (4.32 g, 15.3 mmol) are added. The solution is stirred at RT overnight, then diluted with CH2Cl2. A saturated solution of NaHCO3 is added, the layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluent: AcOEt/MeOH 100:0 to 85:15) to give the title compound. TLC, Rf (AcOEt)=0.1. MS (LC-MS): 541.3 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.52 min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[OH:20]O.O>C(O)(=O)C>[NH2:1][C:2]1[N+:10]([O-:20])=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: OO
Reactant: Nc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1c2ncn(Cc3c(Cl)cccc3Cl)c2nc[n+]1[O-]
Reaction time: 120 h
Yield: 40 %

Procedure:
The crude 6-amino-9-(2,6-dichlorobenzyl)purine obtained from the initial reaction was dissolved in one liter of acetic acid. A 30% aqueous solution of hydrogen peroxide was then added in the amount of 350 milliliters. The solution was allowed to stand for 5 days at room temperature, after which about 400 milliliters of water was added and the solution was cooled. The resulting precipitate was recovered by filtration, reslurried in 500 milliliters of a 30% aqueous solution of acetic acid, and then in one liter of water. The solids recovered from the aqueous slurry were vacuum dried to yield 75 grams of a crude 6-amino-9-(2,6-dichlorobenzyl)purine-N1 -oxide having a melting point of 296°-301° C, representing a 40 percent yield. An analytical sample of the same having a melting point of 298°-302° C. was prepared by recrystallization from acetic acid.
Reaction SMILES: [Cl:1][C:2](=[CH2:20])[CH2:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.[H-].[Na+].[CH2:23](I)[CH3:24]>CN(C)C=O>[Cl:1][C:2](=[CH2:20])[CH2:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([CH2:23][CH3:24])[C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2
Reactant: CCI
Reactant: C=C(Cl)CN1C(=O)c2ccccc2Nc2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)CN1C(=O)c2ccccc2N(CC)c2ncccc21
Temperature: 25 °C

Procedure:
9.7 g (0.034 mol) of 5-(2-chloro-2-propenyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, were suspended in 100 ml of anhydrous dimethylformamide. The mixture was thoroughly purged with dry nitrogen and stirred rapidly while 1.8 g (0.0375 mol) of a 50% dispersion of sodium hydride in mineral oil was slowly added portionwise through an inlet protected by a calcium chloride drying tube. Addition of the first portion sodium hydride resulted in an immediate exothermic reaction, and the temperature of the mixture rose rapidly to about 60° C. After addition of the sodium hydride was complete (30-35 minutes), the reaction mixture was cooled to room temperature, and 7.8 g (0.05 mol) of ethyl iodide were added dropwise. Thereafter, the flask was placed in an oil bath heated to 100° C., and the reaction mixture was stirred and heated for 2 hours, during which time a slow stream of dry nitrogen was passed through the apparatus. After this time no starting material was detected by thin-layer chromatography.