Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[C:3](=[O:5])[CH3:4].[CH2:8]([O:10][CH:11]=[CH2:12])[CH3:9]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[CH2:8]([O:10][CH:11]([O:7][C:2]([CH3:6])([CH3:1])[C:3](=[O:5])[CH3:4])[CH3:12])[CH3:9]
Reactant: CC(=O)C(C)(C)O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(C)(C)C(C)=O
Yield: 66.7 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 15 gm (147 mmol) of 3-methyl-3-hydroxy-2-butanone, 500 mg (2.0 mmol) of pyridinium p-toluenesulfonate and 100 ml of anhydrous methylenechloride were mixed with stirring under nitrogen stream, and 11.7 gm (162 mmol) of ethylvinylether was added dropwise at room temperature for 3 hours while stirring. After the reaction, the reaction mixture was washed with 5% aqueous sodium hydrogencarbonate, and then the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Distillation of the crude product afforded 17.09 gm of 3-(1-ethoxyethoxy)-3-methyl-butane-2-one (b.p. 38-40/1 mmHg, yield: 66%).
Reaction SMILES: Cl[C@H:2]1[C@@H:6](Cl)[CH2:5][S:4](=[O:9])(=[O:8])[CH2:3]1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>O1CCOCC1>[NH:12]1[CH2:11][CH2:10][NH:13][CH:2]2[CH2:3][S:4](=[O:9])(=[O:8])[CH2:5][CH:6]12
Reactant: O=S1(=O)C[C@@H](Cl)[C@@H](Cl)C1
Reactant: NCCN
Solvent: C1COCCO1
Product: O=S1(=O)CC2NCCNC2C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
cis-3,4-Dichlorotetrahydrothiophene 1,1-dioxide (5.0 g, 26.0 mmol) in dioxane (40 mL) was added dropwise to ethane-1,2-diamine (10.4 g, 173.0 mmol) in dioxane (25 mL) at 0° C. The mixture was heated at 100° C. for 3 h, followed by cooling to room temperature and continued stirring overnight. The two layers were separated and the bottom layer, containing ethylene diamine and amine salt, was washed twice with dioxane. The dioxane layers were combined and the solvent was removed in vacuo. The crude product was recrystallized from toluene to afford 2.7 g (59%) of the title compound as white crystals. HPLC 98%, RT: 0.292 (System B; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 2.67-2.76 (m, 2H) 2.86-2.96 (m, 2H) 3.13-3.20 (m, 2H) 3.33-3.44 (m, 2H) 3.63-3.70 (m, 2H). LC-MS 177 (M+H)+. *Previously described in U.S. Pat. No. 3,882,122.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C@@H:28](N)[CH2:29][CH3:30])=[N:26][CH:27]=1.C([N:35](C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C@H:28]([C:4]2[CH:3]=[C:2]([NH2:35])[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]=2[N+:18]([O-:20])=[O:19])[CH2:29][CH3:30])=[N:26][CH:27]=1
Reactant: CC[C@H](N)c1ccc(F)cn1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC[C@H](c1ccc(F)cn1)c1cc(N)nc(Nc2cc(OC(C)C)[nH]n2)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 7, 0.5 g) and [(15)-1-(5-fluoropyridin-2-yl)propyl]amine (Intermediate 35, 0.45 g) in n-BuOH (10 mL) with diisopropylethylamine (3 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.45 g of desired product. MS (electrospray): 416 (M+1) for C19H22FN7O3.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([S:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[NH2:25])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1>O>[F:5][C:6]1[CH:7]=[C:8]([S:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[NH:25][C:1](=[O:3])[CH3:2])(=[O:13])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[5-(3-Fluorobenzenesulfonylamino)-1H-indazol-3-yl)acetamide can be obtained in the following way: 0.037 ml of acetyl chloride is added dropwise to a solution, cooled to 0° C., of 0.16 g of 3-fluoro-N-(3-amino-1H-indazol-5-yl)benzenesulfonamide and of 3.2 ml of pyridine. The reaction medium is then maintained with stirring at a temperature in the region of 25° C. overnight. After addition of 20 ml of water, the medium is extracted with three times 10 ml of ethyl acetate. The pooled organic phases are dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (97.5/2.5 by volume) mixture as eluent. The solid obtained is recrystallized from 6 ml of isopropanol. 0.1 g of N-[5-(3-fluorobenzenesulfonylamino)-1H-indazol-3-yl)acetamide is thus obtained, after drying under reduced pressure at 60° C., in the form of a white solid melting at 246° C. (analysis C15H13FN4O3S.0.2H2O % calculated C, 51.73; H, 3.76; F, 5.45; N, 16.08; O, 13.78; S, 9.20. % found C, 51.75; H, 2.82; F, 5.07; N, 16.04; S, 8.13).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]1=[O:27])=[CH:8]2.O=P(Cl)(Cl)[Cl:30]>CC#N>[Cl:30][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1])[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[N:10]=1
Reactant: COc1nccc2cc(CCCN3C(=O)c4ccccc4C3=O)[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1nccc2cc(CCCN3C(=O)c4ccccc4C3=O)nc(Cl)c12

Procedure:
2-(3-(8-Methoxy-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)propyl)isoindoline-1,3-dione (200 mg, 0.55 mmol) is dissolved in CH3CN (2 mL) and POCl3 (59 uL, 0.64 mmol) The mixture is stirred at 80° C. for 3 hours. POCl3 is removed and neutralized with sat. NaHCO3. The compound is extracted with CHCl3 and the organic layer is dried (Na2SO4) and evaporated to yield the crude compound, which is used in the next step without any further purification. MS m/z 382.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=O)=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>CN(C)C=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([NH2:23])=[O:18])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
192.4 g (714.6 mmol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 900 ml of N,N-dimethylformamide, treated at room temperature with 116 g (715 mmol) of 1,1'-carbonyldiimidazole and stirred at 50° for 30 minutes. 173 ml of 25% ammonia were added dropwise at 25°-30° within 30 minutes. After stirring for 30 minutes the reaction mixture was concentrated and the residue was dissolved in 500 ml of alcohol. After adding 250 ml of ether the mixture was cooled to 0° and the crystallizate was filtered off under suction and dried. There were obtained 133.6 g (69%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. 228°-230°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: COc1ccccc1N
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: COc1ccccc1NC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using o-anisidine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-methoxyphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (84%) as a colorless solid: mp 172-174° C.; 1H NMR (300 MHz, DMSO-d6) δ9.66 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.49-7.32 (m, 2H), 7.24-6.86 (m, 8H), 6.52 (s, 1H), 6.40 (s, 1H), 5.19-5.00 (m, 2H), 4.86 (d, J=9.4 Hz, 1H), 4.70 (d, J=9.4 Hz, 1H), 3.79 (s, 3H), 2.93 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.9, 167.6, 161.6, 161.2, 152.1, 142.8, 136.5, 134.4, 132.6, 130.8, 129.1, 128.2, 127.8, 127.1, 126.8, 126.5, 124.9, 124.1, 123.6, 120.9, 120.7, 120.4, 119.6, 112.0, 109.7, 92.9, 80.4, 72.6, 57.4, 56.2, 41.4, 28.8; MS (ES+) m/z 519.2 (M+1).
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH3:18])[CH2:15][S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Si:25]([CH3:33])([CH3:32])NC(OCC)=O.C[Si](OS(O[Si](C)(C)C)(=O)=O)(C)C.NS(O)(=O)=O.[Br:52]N1C(=O)CCC1=O>ClCCl>[C:1]([NH:9][CH:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([O:21][Si:25]([CH3:33])([CH3:32])[CH3:24])=[O:20])=[C:14]([CH2:18][Br:52])[CH2:15][S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Reactant: CCOC(=O)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)O[Si](C)(C)C
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Yield: 65 %

Procedure:
A mixture consisting of 400.5 mg (1.20 mmoles) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide, 0.69 g (4.3 mmoles) of N-trimethylsilylurethane and 20 mg of bis-(trimethylsilyl)-sulfate in 40 ml of dichloromethane was refluxed for 3/4 hours after which a clear solution was obtained. This was cooled in an ice-bath and bromination was carried out after the addition of 200 mg (2.04 mmoles) of amidosulfonic acid using 325.3 mg (1.83 mmoles) of N-bromosuccinimide as the brominating agent. The bromination took half an hour to obtain a 65% yield of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:37]([NH:36][C:32]5[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=5)=[O:38])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(NC(=O)NCc2ccc(Nc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)cc2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 115 mg (0.3 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine hydrate (see Step 77.5), 0.041 ml (0.318 mmol) of 3-methoxy-phenyl isocyanate and 4 ml of THF is stirred at 20° C. for 15 hours and then concentrated by evaporation in vacuo. After recrystallization of the residue from ethyl acetate/hexane, 4-(3-chloro-phenylamino)-3-{4-[(3-methoxy-phenyl-amino)-carbonylamino-methyl]-phenylamino}-1H-pyrazolo-[3,4-d]pyrimidine is obtained in the form of the monohydrate; m.p. 157-160° C.; ESI-MS: (M−H)−=513.
Reaction SMILES: [Br:1][C:2]1[N:22]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([OH:21])=O)=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[N:22]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:23]3[CH2:26][CH2:25][CH2:24]3)=[O:21])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(Br)nc2c1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of 5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (929 mg, 2.54 mmol), azetidine (206 μl, 3.05 mmol), propylphosphonic anhydride (50% in ethyl acetate, 3.75 ml, 6.36 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.63 mmol) in tetrahydrofuran (20 ml) was stirred for 18 hours at 25° C. The solvent was evaporated, the residue was triturated with sat. sodium hydrogencarbonate solution. The solid was filtered off, washed with water and dried in vacuo affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (910 mg, 88.5%) as a light yellow solid. mp: >250° C., MS: m/z=402.2/404.0 (M−H+)
Reaction SMILES: C(S[N:6]=[N:7][C:8]1[C:9]([CH3:19])=[C:10]([C:15]([F:18])=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])(C)(C)C.CC(C)([O-])C.[K+]>CS(C)=O.O>[F:18][C:15]1[CH:16]=[CH:17][C:8]2[C:9](=[CH:19][NH:6][N:7]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(F)ccc(N=NSC(C)(C)C)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1c(F)ccc2n[nH]cc12
Reaction time: 12 h
Yield: 25.3 %

Procedure:
To a solution of a crudely purified product (18.5 g, 65.1 mmol) of methyl 3-[(tert-butylthio)diazenyl]-6-fluoro-2-methylbenzoate in dimethyl sulfoxide (200 mL) was added a solution of potassium tert-butoxide (10.6 g, 98.0 mmol) in dimethyl sulfoxide (125 mL) at room temperature, and the mixture was stirred for 12 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (3.20 g, yield 25%).
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[C:18]([SH:20])[NH:19][C:15]=2[CH:14]=1>>[Cl:12][C:13]1[CH:22]=[CH:21][C:16]2[NH:17][C:18]([S:20][CH2:2][C:3]3[C:4]4[N:5]([CH:9]=[CH:10][N:11]=4)[CH:6]=[CH:7][CH:8]=3)=[N:19][C:15]=2[CH:14]=1
Reactant: OCc1cccn2ccnc12
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Product: Clc1ccc2[nH]c(SCc3cccn4ccnc34)nc2c1

Procedure:
A solution of 20 g (0.12 mole) of 3-chloro-6-nitroaniline in 350 ml of methanol was hydrogenated over 5% palladium on carbon to yield 24.9 g of the corresponding diamino compound. Reaction of the diamino compound with potassium ethylxanthate using the method described in Example 10 yielded 19 g of 5-chloro-2-mercaptobenzimidazole, as confirmed by elemental analysis. The title compound (1.14 g) was prepared by the method of Example 6 using 8-hydroxymethylimidazo[1,2-a]pyridine as the hydrochloride salt (701 mg, 3.8 mmole) and using 701 mg (3.8 mmole) of 5-chloro-2-mercaptobenzimidazole instead of 2-mercapto-5-methoxybenzimidazole. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5]C=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33](O)=[O:34])[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH:8]1([CH2:9][NH:10][C:33]([CH:31]2[CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:20]([N:12]4[CH2:11][C:19]5[CH:18]=[CH:17][N:16]=[CH:15][C:14]=5[CH2:13]4)=[O:21])=[CH:28][CH:27]=3)[CH2:32]2)=[O:34])[CH2:5][CH2:6][CH2:1][CH2:7]1
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Reactant: NCCCc1ccccc1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(NCC1CCCC1)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting cyclopentylmethamine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.13 (s, 1H), 7.96 (t, J=5.7 Hz, 1H), 7.42 (d, J=4.7 Hz, 1H), 7.34-7.27 (m, 2H), 6.41-6.33 (m, 2H), 4.81-4.72 (m, 4H), 3.94-3.85 (m, 2H), 3.77-3.68 (m, 2H), 3.50-3.37 (m, 1H), 3.04-2.97 (m, 2H), 2.04-1.89 (m, 1H), 1.71-1.39 (m, 6H), 1.25-1.08 (m, 2H); MS (ESI(+)) m/e 420 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:22]([F:21])[CH:23]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: COc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1F

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3-fluoro-4-methoxybenzoic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH:29]1[CH2:34][C:33](=[O:35])[NH:32][C:31]([CH3:36])=[C:30]1[C:37](O)=[O:38]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:37]([C:30]3[CH:29]([C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[F:21])[CH2:34][C:33](=[O:35])[NH:32][C:31]=3[CH3:36])=[O:38])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)cc2F)CC(=O)N1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3=C(C)NC(=O)CC3c3ccc(F)cc3F)CC2)c1

Procedure:
Prepared by Procedure AC and Scheme AM using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide and 4-(2,4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid: ESMS m/e: 525.2 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>C(#N)C>[F:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([NH:21][CH:18]([CH3:20])[CH3:19])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of 2-(2,6-difluoro-3-nitrophenyl)pyridine (0.85 g, 3.6 mmol), isopropylamine (0.31 mL, 3.6 mmol) and DIPEA (0.63 mL, 3.6 mmol) in acetonitrile (10 mL) was stirred overnight at RT. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to afford the title compound as a yellow oil (0.49 g, 50%). 1H NMR (CDCl3, 400 MHz): δ 8.76 (1H, ddd, J=6.5, 3.7, 2.4 Hz), 8.26 (1H, dd, J=12.7, 8.1 Hz), 7.86 (1H, br s), 7.81 (1H, td, J=10.4, 2.5 Hz), 7.46 (1H, dq, J=10.5, 1.5 Hz), 7.34 (1H, ddd, J=10.2, 6.5, 1.6 Hz), 6.57 (1H, dd, J=12.7, 10.8 Hz), 2.70-2.54 (1H, m), 0.93 (6H, d, J=8.4 Hz)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[N:11][C:12]([O:22][CH3:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH:14]=2)=[CH:4][N:3]=1.C(#N)C.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31].C(N(C(C)C)C(C)C)C>CCOC(C)=O>[Cl:21][C:17]1[CH:16]=[C:15]([C:13]2[CH:14]=[C:9]([CH2:8][C:5]3[CH:4]=[N:3][C:2]([NH:31][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[N:7][CH:6]=3)[CH:10]=[N:11][C:12]=2[O:22][CH3:23])[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCN
Reactant: COc1ncc(Cc2cnc(Cl)nc2)cc1-c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ncc(Cc2cnc(NCCN(C)C)nc2)cc1-c1cccc(Cl)c1
Temperature: 180 °C
Yield: 28 %

Procedure:
A 5 mL microwave vial was charged with 2-chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine (Example 2, 50.00 mg, 0.14 mmol), ACN (1.44 mL), N1,N1-dimethylethane-1,2-diamine (0.03 mL, 0.29 mmol), and N-ethyl-N-isopropylpropan-2-amine (77.13 μL, 0.43 mmol). The vial was sealed, and the reaction mixture was heated at 180° C. for 15 minutes. EtOAc (5 mL) was added to the reaction mixture, and the reaction mixture was extracted with water (3×). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-15% MeOH/DCM) afforded the title compound (15.6 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 2H), 8.09 (s, 1H), 7.67 (br s, 2H), 7.58 (s, 1H), 7.51-7.34 (m, 2H), 6.79 (br s, 1H), 3.84 (s, 3H), 3.72 (s, 2H), 2.42-2.37 (m, 4H), 2.17 (s, 6H). [M+H]=398.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.[OH-].[K+]>C1C=CC=CC=1.C(O)C>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:6]2[CH:7]=[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCNc1ccc(OC)c(-c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Solvent: CCO
Product: COc1ccc(N(CCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1-c1ccccc1
Yield: 74.9 %

Procedure:
8.0 g of ethyl 4-(6-methoxybiphenyl-3-yl)aminobutyrate and, 3.3 g of ethyldiisopropylamine in 50 ml of benzene are reacted, analogously to Example 47b), with 4.6 g of p-chlorobenzoyl chloride. The reaction product is dissolved in 50 ml of benzene and, after the addition thereto of a solution of 2.3 g of potassium hydroxide in 20 ml of ethanol, is then stirred for 8 hours at room temperature. After distilling off the solvent, the residue is dissolved in water; the resulting solution is acidified with dilute hydrochloric acid and extracted with diethyl ether. The residue (remaining after evaporating off the ether) is recrystallized from ethyl acetate/petrol ether (1:1) to obtain 8.1 g (73.5% of theory) of 4-[p-chloro-N-(6-methoxybiphenyl-3-yl)-benzamido]butyric acid, MP 114° to 116°.