Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C([O:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[C:18]([NH:20][S:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:40]3[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([O:41][Si](C(C)(C)C)(C)C)[CH2:27]1)(=[O:23])=[O:22])=[O:19])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CO.[Pd]>[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[OH:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[C:18]([NH:20][S:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:40]3[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[CH2:27]1)(=[O:22])=[O:23])=[O:19]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(=O)(=O)NC(=O)c2ccccc2OCc2ccccc2)O[C@H]1n1cnc2c(N)ncnc21
Agent: [Pd]
Agent: CC[NH+](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COS(=O)(=O)NC(=O)c2ccccc2O)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 5′-O—[N-(2-benzyloxybenzoyl)sulfamoyl]-2′-O-tert-butyldimethylsilyl-3′-deoxyadenosine triethylammonium salt (70 mg, 0.092 mmol, 1.0 equiv) in MeOH (10 mL) was added 10% Pd/C (20 mg) and the reaction was stirred under H2 (1 atm) for 8 hours at room temperature. The reaction mixture was filtered through a plug of Celite and the residue was washed with MeOH (4×10 mL). The combined filtrates were concentrated and the crude obtained was treated with 80% aq TFA (2.0 mL) for 8 hours. The reaction was concentrated in vacuo. Purification by flash chromatography (10:90:1 MeOH/EtOAc/Et3N) afforded the title compound (27 mg, 53%) as a viscous oil: Rf 0.3 (1:4 MeOH/EtOAc); [α]20D −10 (c 0.28, MeOH); 1H NMR (600 MHz, CD3OD) δ 1.26 (t, J=7.2 Hz, 9H), 2.05-2.20 (m, 1H), 2.40-2.55 (m, 1H), 3.15 (q, J=7.2 Hz, 6H), 4.32 (dd, J=11.4, 4.2 Hz, 1H), 4.46 (d, J=11.4 Hz, 1H), 4.60-4.80 (m, 2H), 6.00 (s, 1H), 6.70-6.85 (m, 2H), 7.27 (t, J=7.2 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 8.12 (s, 1H), 8.47 (s, 1H); 13C NMR (150 MHz, CD3OD) δ 9.3, 34.9, 47.9, 70.7, 76.9, 79.9, 92.9, 117.9, 119.3, 120.3, 120.7, 131.3, 134.3, 140.7, 150.2, 153.7, 157.3, 162.0, 174.9; HRMS (ESI+) calcd for C17H19N6O7S [M+H]+ 451.1030, found 451.1053 (error 5.1 ppm).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1.CCOCC>[CH3:12][O:11][C:1](=[O:10])[CH:2]([O:3][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 16 h
Yield: 90.9 %

Procedure:
To a solution of commercially available methyl (S)-mandelate (2.39 g, 14.4 mmol) in dichloromethane (50 mL) is added imidazole (1.18 g, 17.3 mmol), tert-butyldimethylsilyl chloride (2.38 g, 15.8 mmol) and 4-dimethylaminopyridine (176 mg, 1.44 mmol). The mixture is stirred for 16 hrs then diluted with ether, washed with water, brine, then dried (MgSO4), filtered and concentrated. The residue is purified by chromatography on silica gel; elution with EtOAc:heptane (25:75) gives 3.67 g of the product. 1H NMR (CDCl3) δ 7.45-7.40 (m, 2 H), 7.35-7.25 (m, 3 H), 5.20 (s, 1 H), 3.65 (s, 3 H), 0.90 (s, 9 H), 0.10 (s, 3 H), 0.05 (s, 3 H); MS: m/z 281 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:26]=[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][C:27](=[O:26])[CH2:28][CH2:29]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C1CCNCC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(=O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4-oxopiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.04 minutes; C22H20Cl2N4O3 (459.33); mass spectrum: (M−H)−=458/460/462 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][O:10][CH3:11])[C:4](=[O:12])[CH:3]=1.[I:13][C:14]1[N:15]=[C:16]([CH3:19])[NH:17][CH:18]=1>>[CH3:11][O:10][CH2:9][CH2:8][N:5]1[C:4](=[O:12])[CH:3]=[C:2]([N:17]2[CH:18]=[C:14]([I:13])[N:15]=[C:16]2[CH3:19])[CH:7]=[N:6]1
Reactant: Cc1nc(I)c[nH]1
Reactant: COCCn1ncc(Cl)cc1=O
Product: COCCn1ncc(-n2cc(I)nc2C)cc1=O

Procedure:
The title compound, light yellow oil, MS: m/e=361.1 (M+H+), was prepared in accordance with the general method of example 23b from 5-chloro-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 4-Iodo-2-methyl-1H-imidazole.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:21])[CH:14]([C:18](=O)[CH3:19])[C:15](=O)[CH3:16])[CH3:11].N1C=CC=CC=1>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15]([CH3:16])=[N:8][N:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=2)[C:18]=1[CH3:19])=[O:21])[CH3:11]
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2ccc(C)cc2)c1C

Procedure:
Similar to Example 1, p-tolylhydrazine (10 mmol, 1.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum. The named product was purified over silica gel (m.p. 47° C.–49° C.).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH3:27])([CH3:26])[CH3:25]>CCO.CCOC(C)=O>[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][NH:34][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 55.2 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (67 mg, 0.39 mmol) in EtOH (8 mL) was refluxed for 16 h. After cooling to r.t., mixture was diluted with EtOAc and washed with a pH 3 aqueous solution until the washes became acidic. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 80 mg of the title compound as a pale yellow solid. MS: (−) m/z 451.37 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH:14]=O)[C:4](=[O:16])[CH:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:5]4[C:6]5[C:11](=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=5)[C:2]([Cl:1])=[CH:3][C:4]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cc(Cl)c2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To 20 mL of a chloroform solution containing 0.71 g of (4-chloro-7-fluoro-2-oxoquinolin-1(2H)-yl)acetaldehyde, 1.03 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.18 g of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 0.99 g of sodium triacetoxyborohydride was added, and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate:hexane=4:1], to give 0.76 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][NH:13][CH3:14].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:7]2[C:6]3[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH3:11])[CH:8]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: CNCc1cn(C)c2c(F)cccc12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2c(F)cccc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 28.4 %

Procedure:
According to the procedure of Example 24, except substituting 7-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.1 g, 27%) was prepared as an off-white powder: MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1.[CH:41](=O)[CH3:42].[BH4-].[Na+].CO>C1COCC1>[CH2:41]([NH:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:37])([F:36])[F:38])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1)[CH3:42]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN[C@H]1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (4-(4-((3-((4S)-4-amino-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (42 mg) in THF (1.0 mL) was added acetaldehyde (37 μL), and the mixture was stirred overnight at room temperature. Sodium borohydride (28 mg) and methanol (0.20 mL) were added thereto, and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in TFA (0.70 mL), and the solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/hexane to give the title compound (14 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]=O.[OH-].[K+]>C(O)=O>[CH3:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: C=O
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CN1C(C)(C)CC(O)CC1(C)C
Yield: 91 %

Procedure:
1,2,2,6,6-pentamethyl-4-piperidinol was synthesized upon reductive-amination of 2,2,6,6-tetramethy-4-piperidinol. A mixture of 2,2,6,6-tetranmethyl-4-piperidinol (3.55 g, 0.02 M), 37% formalin (3.3 mL) and 1 mL formic acid was heated under a reflux condenser on the steam bath for 5 h. The reaction mixture was made basic with (1.0 M) potassium hydroxide solution and the product was extracted with ether (5×50 mL). The combined extract was washed with saturated solution of potassium carbonate (2×20 mL) and dried over anhydrous magnesium sulfate and finally the solvent was evaporated under vacuum. The residue was then sublimed at 0.05 mm, bath temperature 85° C. The white sublimate weighed 3.5 g to give 91% yield, mp=72-74° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1
Reactant: NCCc1ccc(N)cc1
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccc(CCNc2ncnc3cc(OCCCCl)ccc23)cc1

Procedure:
A solution of 4-chloro-7-(3-chloro-propoxy)-quinazoline (synthesized as reported in J. Med. Chem. 2007, 50, 2213-2224) (100 mg, 0.389 mmol), 2-(4-aminophenyl)ethyl amine (63.6 mg, 0.467 mmol) and triethylamine (118.1 mg, 1.167 mmol) in ethanol (3 mL) was heated at 120° C. for 3 hours. The solution was cooled and the solid formed was filtered, washed with ethanol and then with dichloromethane to give the title compound as light yellow solid product (34 mg, 25%). 1H-NMR (300 MHz, CD3OD): 7.93-8.37 (s, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.07-7.13 (m, 2H), 7.00-7.03 (d, J=8.1 Hz, 2H), 6.66-6.69 (d, J=8.4 Hz, 2H), 4.24-4.28 (t, 2H), 3.71-3.81 (m, 4H), 2.84-2.89 (t, 2H), 2.27-2.31 (m, 2H). LC-MS (ESI) m/z 357.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](O)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.C1C=CC2N(O)N=[N:27]C=2C=1.CCN=C=NCCCN(C)C.Cl.N.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:27])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxylic acid (36 mg, 0.1 mmol) in DCM (5 mL) was added HOBt (16 mg, 0.12 mmol), and EDC.HCl (23 mg, 0.12 mmol) and 2 M NH3 in methanol (0.2 mL, 0.4 mmol). The mixture was kept overnight at RT. The mixture was concentrated, and EtOAc and aq. NaHCO3 were added. The aqueous layer was extracted with ethyl acetate once. The combined organic layers were dried (MgSO4) and concentrated to give 36 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl.C1C(O)=CC=CC=1C.[CH3:19][NH:20][C:21]#[N:22].[OH-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:21]([NH:20][CH3:19])=[NH:22]
Reactant: CNC#N
Reactant: Cc1cccc(C)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: CNC(=N)Nc1c(C)cccc1C

Procedure:
To 40.5 g. (0.315 mole) of 2,6-dimethylaniline is added 0.4 moles of ethereal HCl and 200 ml. of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 17.7 g. (0.315 mole) of methyl cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml. of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 × 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dimethylphenyl)-3-methylguanidine.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:37])C(=O)C1.O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[N:8]2[N:26]=[C:27]([CH3:29])[C:28]([Cl:37])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nc(C)cc2n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nc(C)c(Cl)c2n1

Procedure:
5-n-Butyl-2-methyl-7-(3,4,5-trimethoxybenzoyl-amino) pyrazolo[1,5-a]pyrimidine (the compound of Example 53; 0.78 g) was dissolved in 10 ml of chloroform. After addition of 0.28 g of NCS, the mixture was refluxed with heating for 1 hour and allowed to cool. After addition of some water, the reaction mixture was extracted with chloroform. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:2) and recrystallized from ethanol-n-hexane to provide 0.61 g of the object compound as colorless crystals. Table 3 shows the structure and melting point of the compound obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]2[OH:25]>C(#N)C.CN(C)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([NH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]2[OH:25])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc2c(O)cccc12
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: O=C(Nc1cccc2c(O)cccc12)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 50 °C

Procedure:
22.4 g of 3-nitro-4-fluorobenzoyl chloride (0.12 mols) were added dropwise at 0° C. to a suspension of 19.1 g of 5-amino-1-naphthol (0.12 mols) in 120 ml of acetonitrile and 14.2 g of N,N-dimethylaniline. The mixture was further stirred until it reached room temperature, and then heated for 30 minutes at 50° C. The yellow deposit was suction filtered and washed with acetonitrile. The deposit was dissolved in tetrahydrofurane and stirred with charcoal, filtered and the product was precipitated from the filtrate with petrol 50/75. Yield: 25.8 g=66% of the theoretical yield; mp. 235°-238° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([NH2:27])=[C:22]([NH2:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.[CH3:37][O:38][C:39](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]4[NH:27][C:37]([O:38][CH3:39])=[N:28][C:22]=4[CH:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: COC(OC)(OC)OC
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]c(OC)nc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 1.00 g (2.02 mmol) (R)-2-(3,4-diamino-5-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 4a), 2.0 mL (15.0 mmol) tetramethoxymethane and 40 mg p-toluenesulphonic acid-monohydrate in 20 mL MeOH was refluxed for 1 h. The mixture was evaporated down i.vac. and the residue was purified by chromatography (Alox, activity stage II-III, DCM/MeOH 20:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[S:33]([C:29]2[S:28][CH:32]=[CH:31][N:30]=2)(=[O:35])=[O:34])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1nccs1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.80 (d, 2H), 8.30 (d, 2H), 7.96 (d, 1H), 7.59 (m, 1H), 7.24-7.13 (m, 4H), 7.05 (d, 1H), 6.96 (d, 1H), 6.92 (s, 1H), 4.54 (s, 2H), 4.49 (s, 2H), 3.64 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 509 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>CCO.C(Cl)(Cl)Cl>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([NH:11][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:13][CH:14]=1
Reactant: CSC(=C[N+](=O)[O-])N(C)C
Reactant: Nc1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(C)C(=C[N+](=O)[O-])Nc1ccc(Cl)nc1
Reaction time: 1 h

Procedure:
A mixture of 1.5 g (0.0093 mole) of 1-dimethylamino-1-methylthio-2-nitroethylene and 1.1 g of 5-amino-2-chloropyridine was heated at 110°-120° C. with stirring for 1 hour. After cooling, the reaction mixture was subjected to silica gel column chromatography using EtOH-CHCl3 (1:40) as the eluent to recover 0.38 g of the title compound as pale brown crystals. The NMR spectrum of this product showed that it was a 1:1 mixture of the title compound and N2 -(6-chloro-3-pyridyl)-N'-dimethyl-2-nitroacetamidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])[CH:7]=1.N[C:32]1C=C2C(=[CH:39][CH:40]=1)NN=C2C1C=CC=CC=1.FC1C=CC(S(C)(=O)=O)=C(S(Cl)(=O)=[O:55])C=1>N1C=CC=CC=1>[CH:40]([O:55][CH:26]([CH3:25])[CH3:21])([CH3:39])[CH3:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CS(=O)(=O)c1ccc(F)cc1S(=O)(=O)Cl
Agent: CS(=O)(=O)c1ccc(F)cc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Solvent: c1ccncc1
Product: CC(C)OC(C)C

Procedure:
5-Fluoro-2-methylsulfonyl-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be prepared as described in Example 2 from 0.52 g of 5-amino-3-phenyl-1H-indazole, 5 ml of pyridine and 0.68 g of 5-fluoro-2-methylsulfonylbenzenesulfonyl chloride. The residue obtained is purified by chromatography on a column of 50 g of silica (particle size 40-63 μm), eluting with pure dichloromethane. After recrystallization from 5 ml of acetonitrile and washing with acetonitrile and then with diisopropyl ether, 0.07 g of 5-fluoro-2-methylsulfonyl-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide is obtained in the form of a white solid melting at 224° C. (analysis: C20H16FN3O4S2, % calculated C, 53.92; H, 3.62; F, 4.26; N, 9.43; O, 14.37; S, 14.40. % found C, 53.74; H, 3.31; N, 9.35; S, 14.10).