Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2ccccc2N)cc1
Yield: 72.9 %

Procedure:
A mixture of isatoic anhydride (4.894 g, 30 mmol), 4-methoxyaniline (3.695 g, 30 mmol) and toluene (60 mL) was heated to reflux for 5 h. After cooling, the reaction was filtered. The solid was triturated with CH2Cl2 (500 mL) This supernatant was combined with the above filtrate and concentrate. The residue was dissolved in CH2Cl2, decolorized with activated charcoal and crystallized from CH2Cl2/hexanes to give the title compound as a white solid (5.3 g, 73%); mp 116-7 C; MS(FD): 242.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([CH3:17])=[C:11]([F:18])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[F:18][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[CH3:17])[NH2:8]
Reactant: [H][H]
Reactant: COc1cc(NCc2ccccc2)cc(F)c1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N)cc(F)c1C
Yield: 82.9 %

Procedure:
To a solution of N-benzyl-3-fluoro-5-methoxy-4-methylaniline (223 mg, 0.91 mmol) in methanol (25 mL) prepared in a Parr shaker flask was added palladium hydroxide (20% on carbon). This was subjected to 45 psi of hydrogen gas overnight until the LCMS showed complete conversion. The catalyst was filtered and the solution concentrated in vacuo to yield 117 mg (83%) of 3-fluoro-5-methoxy-4-methylaniline as an oil. 1H NMR (300 MHz, CDCl3) δ 6.03 (d, J=12.0 Hz, 1H), 6.01 (s, 1H), 3.77 (s, 3H), 2.09 (s, 3H); LCMS (m/z): 156 (MH+). Compound I-120 was made using this aniline.
Reaction SMILES: [CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15](I)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[CH:40]1([Zn+])[CH2:43][CH2:42][CH2:41]1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:40]1([C:15]2[C:14]3[CH:13]=[C:12]([O:11][CH2:10][C:9]4[CH:33]=[CH:34][C:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[C:7]([C:35]([F:38])([F:37])[F:36])[CH:8]=4)[CH:20]=[CH:19][C:18]=3[N:17]3[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C:16]=23)[CH2:43][CH2:42][CH2:41]1
Reactant: [Zn+]C1CCC1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCn2c1c(C1CCC1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 70 °C
Yield: 39.1 %

Procedure:
tert-Butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50 mg, 0.078 mmol) was dissolved in THF (1.0 mL) in a heavy walled sealed microwave tube (0.5-2.0 mL) under N2. Cyclobutylzinc(II) bromide (0.156 mL, 0.078 mmol) and bis(tri-t-butylphosphine)palladium(0) (3.60 mg, 7.04 μmol) were added. The reaction mixture was heated to 70° C. for 2 h, quenched with saturated NaHCO3 and filtered through Celite®. The filtrate was then extracted with EtOAc (3×5 mL). The organic layers were combined and washed with saturated NaCl (10 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to provide the title compound as an amber oil (17.3 mg). LCMS m/z=568.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(cc(Cl)cc2[N+](=O)[O-])C1=O
Reaction time: 1 h
Yield: 94.11 %

Procedure:
To a solution of 5-chloro-1H-indole-2,3-dione (2.8 g, 15.46 mmol) in conc. H2SO4 (9 mL) was added fuming nitric acid (1.5 mL) very slowly at −5 to 0° C. The reaction mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice, and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (3.2 g, 94.11%) which was used for the next step directly.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N[C:17](=[O:52])[C@H:18]([CH3:51])[CH2:19][C@H:20]([OH:50])[C@@H:21]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:22][C@@H:23]([CH:39]([CH3:41])[CH3:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)CCC>C(Cl)(Cl)Cl>[C:46]([O:45][C:43]([NH:42][C@H:21]([CH:20]1[CH2:19][C@@H:18]([CH3:51])[C:17](=[O:52])[O:50]1)[CH2:22][C@@H:23]([CH:39]([CH3:40])[CH3:41])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCCCOC)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C2C[C@@H](C)C(=O)O2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.02 g of p-toluenesulfonic acid (monohydrate) are added to 5.6 g of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid (N-butyl)-amide (Example 32) in 240 ml of chloroform at room temperature and the mixture is stirred at room temperature for a further 18 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between diethyl ether and 0.1N hydrochloric acid. The organic phases are concentrated by evaporation and the title compound is obtained from the residue after FC (160 g of silica gel, eluant: ethyl acetate/hexane 1:1): Rf (ethyl acetate/hexane=2:1)=0.47; m.p. 86°-87° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:15]=23)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>[Pd].CCO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([NH2:20])=[CH:18][N:17]=[C:16]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:15]=23)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 105.6 %

Procedure:
A suspension of (R)-3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.90 g, 20.3 mmol) and palladium on carbon (1.0 g, 10%, wet, Degussa, E101 NE/W) in a 4:1 mixture of THF and EtOH (150 ml) was stirred under a hydrogen atmosphere (2 balloons) at 50° C. for 18 h. The reaction mixture was cooled to 25° C. and was filtered through Celite. The Celite was washed with THF (1×20 ml), and the combined filtrate and washings were concentrated under reduced pressure to give (R)-3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.81 g, 99%) as a brown foam. LCMS (Method G, ESI): RT=0.83 min, m+H=458.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[N:40][CH:41]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:41]=[N:40][C:39]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[N:38][CH:37]=2)[O:11][CH2:10]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN(C)C(=O)c1ncc(Br)cn1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Product: CN(C)C(=O)c1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cn1
Yield: 61 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 61% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)chroman-3-amine and 5-bromo-N,N-dimethylpyrimidine-2-carboxamide. The reaction mixture was irradiated in a microwave at 140° C. for 20 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (s, 2 H), 7.23-7.34 (m, 8 H), 7.15-7.22 (m, 3 H), 6.84-6.93 (m, 2 H), 4.31-4.39 (m, 1 H), 4.05 (t, 1 H), 3.60-3.76 (m, 4 H), 3.08-3.15 (m, 1 H), 3.06 (s, 3 H), 2.94-3.05 (m, 1 H), 2.88 (s, 3 H), 2.52-2.59 (m, 1 H); MS (ESI) m/z 452[M+H+].
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][S:17]([CH2:20][C:21](O)=[O:22])(=[O:19])=[O:18])=[CH:14][CH:13]=1>C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][S:17]([C:20]2[C:21](=[O:22])[O:4][C:3]3[C:2]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)(=[O:18])=[O:19])=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1O
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3ccccc3oc2=O)cc1
Yield: 87.5 %

Procedure:
A solution of salicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate an 87.5% yield of the title compound; m.p. 194-195° C.
Reaction SMILES: [C:1]1([CH:7]([OH:14])[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@H:22]1[O:27][C@@H:26]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@H:22]1[O:27][C@@H:26]([CH2:28][O:14][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Reactant: OC(Cn1ccnc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CO[C@@H]2CCC[C@H](COC(Cn3ccnc3)c3ccccc3)O2)c(Cl)c1
Temperature: 85 °C
Yield: 35.5 %

Procedure:
1 ml of a dimethylformamide solution containing 23 mg of 1-phenyl-2-(1-imidazolyl)ethanol was heated at 50° C. for 30 minutes with 5 mg of 55% sodium hydride, and then 1 ml of a dimethylformamide solution containing 65 mg of cis-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, prepared as described in Example 2(a), were added thereto. The mixture was heated at 85° C. for 3 hours and then the mixture was treated and the product purified essentially as described in (a) above, to give 20 mg of the title compound as a liquid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]([NH2:29])([CH3:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]([CH3:28])([NH:29][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ncnc2sc3c(c12)CCCC3
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Product: CC1(Nc2ncnc3sc4c(c23)CCCC4)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared (373.9 mg, 93%) from 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (224 mg, 1 mmol) and 4-amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (235.4 mg, 1.1 mmol) by following the procedure described for preparation 9. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.39 (s, 1H), 3.33 (m, 4H), 3.10 (m, 2H), 2.87 9M, 2H), 1.93 (m, 4H), 1.66 (m, 4H), 1.40 (s, 9H), 1.22 (s, 3H); MS (SEI): m/z: Calculated: 402.6; Observed: 403.2 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](B1OC(C)(C)C(C)(C)O1)=[CH:8][CH:7]=[CH:6]2.Cl[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:23]1[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=1)=[CH:8][CH:7]=[CH:6]2
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc2c1
Product: COc1ccc2c(-c3cnnc(Cn4ccnc4C)c3)cccc2c1

Procedure:
The title compound, MS: m/e=331.4 (M+H+), was prepared from 2-(6-methoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH:31]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CCO>[NH2:34][CH2:33][CH2:32][CH:31]([NH:30][C:26]1[CH:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][CH:27]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)c1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCCC(Nc1cccc(-c2n[nH]c3nc(NC4CCC(N)CC4)ncc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of (4-{3-[3-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-phenyl]-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (91 mg, 0.10 mmol) in EtOH (2.0 mL) was added conc. HCl (4 mL) at room temperature. The resulting mixture was stirred for 15 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue was washed with dichloromethane (10 mL), then purified by prep-HPLC to give N-{3-[3-(3-amino-1-phenyl-propylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 43 mg).
Reaction SMILES: [CH:1]([NH:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.Cl.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:22][NH2:23]>C(O)(=O)C>[CH2:5]([C:4]1[N:22]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=2[Cl:14])[N:23]=[CH:1][N:3]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NNc1cccc(Cl)c1Cl
Reactant: O=CNC(=O)Cc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: Clc1cccc(-n2ncnc2Cc2ccccc2)c1Cl

Procedure:
N-Formylphenylacetamide (Finkbeiner J. Org. Chem. 1965, 30; 2861) (200 mg, 1.22 mmol) and 2,3-dichlorophenylhydrazine hydrochloride (314 mg, 1.47 mmol) were combined in glacial acetic acid (8 mL) and refluxed under a nitrogen atmosphere for 1 hour and then concentrated under reduced pressure at 60° C. The residue was purified by flash chromatography eluting with hexanes/ethyl acetate (6/1) to provide the title compound. MS (ESI+) m/z 305 (M+1H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.02 (s, 2H) 6.97-7.02 (m, 2H) 7.16-7.25 (m, 3H) 7.52-7.58 (m, 2H) 7.88 (dd, J=6.8, 3.1 Hz, 1H) 8.16 9s, 1 H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[C:15](=[O:37])[C:16]([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)=[N:17][N:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:19]=1>CN(C=O)C>[CH3:12][O:13][C:14]1[C:15](=[O:37])[C:16]([C:26]2[N:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:29]=[CH:28][CH:27]=2)=[N:17][N:18]([C:20]2[CH:21]=[N+:22]([O-:9])[CH:23]=[CH:24][CH:25]=2)[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cn(-c2cccnc2)nc(-c2ccnn2-c2ccccc2)c1=O
Solvent: CN(C)C=O
Product: COc1cn(-c2ccc[n+]([O-])c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF solution (2.0 ml) of m-chloroperbenzoic acid (0.398 mg) was added a DMF solution (12.0 ml) of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-(pyridin-3-yl)pyridazin-4(1H)-one at 0° C., and the mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration to give the title compound (168 mg).
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH:7]=[CH:6][CH:5]([O:10][CH3:11])[O:4]1)[CH3:2].[OH:12]O>CO>[CH3:11][O:10][CH:5]1[O:4][CH:3]([CH2:1][CH3:2])[C:8](=[O:9])[CH:7]2[O:12][CH:6]12
Reactant: OO
Reactant: CCC1OC(OC)C=CC1=O
Solvent: CO
Product: CCC1OC(OC)C2OC2C1=O
Yield: 86.3 %

Procedure:
A 15.6 g quantity of 2-ethyl-6-methoxy-3-oxo-3,6-dihydro-2H-pyran, 15 g of 30% aqueous solution of hydrogen peroxide and 100 ml of methanol are cooled to a temperature of about 10° C with full stirring. The same procedure as in Example 6 is thereafter followed to obtain a concentrate, which is then distilled at a reduced pressure of 3 mm Hg to give 14.8 g of 6-methoxy-4,5-epoxy-3-oxo-2-ethyltetrahydropyran as a colorless liquid fraction at 83° to 88° C in a yield of 86.3%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCOCC1)CO2

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), morpholine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 313 (M+, 1), 101 (6), 100 (bp), 70 (2), 56 (4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:23][S:24]([CH2:27][CH2:28][O:29]C(=O)C)(=[O:26])=[O:25])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:22])[C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1.N>CO>[F:1][C:2]1[CH:3]=[C:4]([NH:23][S:24]([CH2:27][CH2:28][OH:29])(=[O:25])=[O:26])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:22])[C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)OCCS(=O)(=O)Nc1ccc(Cc2ccc(C(=O)c3ccccc3)n2C)c(F)c1
Agent: N
Solvent: CO
Product: Cn1c(Cc2ccc(NS(=O)(=O)CCO)cc2F)ccc1C(=O)c1ccccc1
Reaction time: 60 h
Yield: 74.8 %

Procedure:
N-{3-Fluoro-4-[5-benzoyl-1-methyl-1H-pyrrol-2-ylmethyl]phenyl}-2-(acetoxy)-ethanesulfonamide (0.415 g, 0.905 mmol) [prepared as in Example 18, Step (a)] was dissolved in methanol (5 ml) and a 2.0 M solution of ammonia in methanol (4.53 ml, 9.05 mmol) was added. The mixture was stirred for 60 h, after which it was concentrated to dryness. Purification of the residue by flash chromatography gave N-{3-fluoro-4-[5-benzoyl-1-methyl-1H-pyrrol-2-ylmethyl]phenyl}-2-(hydroxy)-ethanesulfonamide (282 mg, 75%) as a solid.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]3[C:29]#[N:30])=[CH:18][CH:17]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[C:23]3[C:29]3[NH:37][N:36]=[N:35][N:30]=3)=[CH:18][CH:17]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)c(Cl)c2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)c(Cl)c2-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 22 h
Yield: 95.9 %

Procedure:
A mixture of 2-butyl-3-[4-(3,4-dichloro-2-cyano-1-pyrrolyl)benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (490 mg) and trimethyltin azide (690 mg) in xylene (5 ml) was stirred at 120° C. for 22 hours. After cooled to ambient temperature, the mixture was treated with aqueous 1N sodium hydroxide (10 ml) for 4 hours. The suspension was filtered. The filtrate was washed with diisopropyl ether, adjusted to pH 4 with aqueous 1N-hydrochloric acid, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by methanol/dichloromethane=1/8) to give 2-butyl-3-[4-[3,4-dichloro-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (516 mg) as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cccc(Br)n1
Temperature: 70 °C
Yield: 87.8 %

Procedure:
A suspension of 2-(6-Bromo-pyridin-2-ylmethyl)-isoindole-1,3-dione (4000 mg, 12.61 mmol) in ethanol (60 mL ) was heated at 70° C. until complete dissolution was observed. Hydrazine hydrate (3156 mg, 63.06 mmol) was then added and the resulting mixture was heated at 70° C. for 5 h. The resulting solution was cooled to 0° C. and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by column chromatography with a gradient of 0 to 30% methanol/dichloromethane to give C-(6-Bromo-pyridin-2-yl)-methylamine as a yellow solid (2070 mg, 79%). MS ES (MH+187.1, RT=1.11 min).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][N:15]1[CH2:32][C:33]([OH:35])=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:47][CH2:46][CH2:45][NH:44]2)=[CH:39][CH:38]=1>ClCCl>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[CH2:47][CH2:46][CH2:45][N:44]2[C:33](=[O:35])[CH2:32][N:15]2[CH2:16][CH2:17][CH2:18][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]2=[O:13])=[CH:41][CH:42]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(C2CCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCCC1c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 68E, 0.050 g, 0.169 mmol) and 2-(4-fluorophenyl)pyrrolidine (0.028 g, 0.169 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF10-4 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.42-6.83 (m, 14H), 5.14 (m, 1H), 4.64-4.10 (m, 1H), 3.97-3.73 (m, 2H), 3.73-3.47 (m, 2H), 3.25-2.91 (m, 1H), 2.78-2.15 (m, 3H), 1.85 (m, 5H)); MS (DCI+) m/z 457 (M+H)+.