Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([OH:26])[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][C:10]=2[O:27][CH3:28])=[CH:5][CH:4]=1)[CH3:2].[ClH:31].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:31].[CH2:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([OH:26])[CH2:18][NH:17][CH2:16]3)=[CH:11][C:10]=2[O:27][CH3:28])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(COc2ccc(C3(O)CN(C(=O)OC(C)(C)C)C3)cc2OC)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1ccc(COc2ccc(C3(O)CNC3)cc2OC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]-3-hydroxyazetidine-1-carboxylate (0.88 g) prepared in (2) in ethyl acetate (4.0 mL) was added a solution of 4 N HCl/ethyl acetate (4.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 hr. Ethyl acetate was added to the reaction mixture. The precipitated solid was collected on a filter and dried to give the title compound (0.53 g, 71%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][CH:18]2OC(=O)C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl.CO>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
To a solution of 3-acetoxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3a) in dichloromethane (13 parts) under nitrogen are added at -5° to 0° C. pyridine (2 equivalents) and at -25° to -20° C. phosphorus pentachloride. After stirring at -15° to -10° C. for 4 hours, the mixture is diluted with a mixture of methanol (20 parts) and dichloromethane (5 parts) cooled at -40° to -30° C., and stirred at -30° to -25° C. for 3.5 hours. To the mixture keeping at -25° to -20° C. is dropwise added triethylamine (10.9 equivalents). After keeping at 0° to 5° C. overnight, the mixture is diluted with ice-water (20 parts) and stirred for 20 minutes. The formed organic layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate, and water, dried, and concentrated. The residue is crystallized from ethyl acetate to give 7betaamino-3-cephem-4-carboxylic acid diphenylmethyl ester (5). Yield: 60.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:38][CH:37]=[CH2:36])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: C=CCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Product: C=CCOc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with allyl bromide
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[S:5][C:6]=1[SH:7].Cl[CH2:13][C:14]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)=[O:15].S1C(SCC(N2C3C(=CC=CC=3)CCC2)=O)=CC2C=CC=CC1=2>>[N:16]1([C:14](=[O:15])[CH2:13][S:7][C:6]2[S:5][C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]=2[CH3:1])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: Cc1c(S)sc2ccccc12
Agent: O=C(CSc1cc2ccccc2s1)N1CCCc2ccccc21
Product: Cc1c(SCC(=O)N2CCCc3ccccc32)sc2ccccc12
Yield: 11.7 %

Procedure:
Crude compound 75 (0.55 g, 3.0 mmol) was coupled with compound 4 (0.48 g, 2.3 mmol) according to procedure used to synthesize compound 73. The product was purified by column chromatography to yield compound 76 (95 mg, 5% for two steps): MS: m/z+ 354.1 [M+H]+; Anal. Calcd (found) for C20H19NOS2.0.1H2O: C, 67.61 (67.59); H, 5.45 (5.48); N, 3.94 (3.94); S, 18.05 (17.75).
Reaction SMILES: [CH2:1]([N:4]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[N:5]1)[CH:2]=[CH2:3].[CH3:23][O:24][CH:25]([O:34][CH3:35])[CH2:26][NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([N:4]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:27]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:26][CH:25]([O:34][CH3:35])[O:24][CH3:23])=[O:19])=[N:5]1)[CH:2]=[CH2:3]
Reactant: COC(CNC1CCCCC1)OC
Reactant: C=CCn1nnc(-c2cccc(CCOCCC(=O)O)c2)n1
Product: C=CCn1nnc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCCC3)c2)n1

Procedure:
The subtitled compound (450 mg) was prepared from 3-(3-(2-allyl-2H-tetrazol-5-yl)phenethoxy)propanoic acid [Example 7, Step ii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 14, Step iii). 1H NMR (300 MHz, CD3OD) δ 8.04-7.92 (m, 2H), 7.49-7.36 (m, 2H), 6.29-6.11 (m, 1H), 5.47-5.30 (m, 4H), 4.56 and 4.39 (2×t, J=5.3 Hz, 1H), 4.09-3.94 (m, 1H), 3.81-3.67 (m, 4H), 3.372 and 3.368 (2×s, 6H), 3.34 and 3.29 (d, J=5.3 Hz, 2H), 3.00-2.91 (m, 2H), 2.72-2.64 (m, 2H), 1.84-1.02 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[NH2:12].[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[C:6]2[NH:12][C:15](=[O:16])[NH:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(Cc1cccc(N)c1N)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COC(Cc1cccc2[nH]c(=O)[nH]c12)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.6 %

Procedure:
3-(2,2-Dimethoxy-ethyl)-benzene-1,2-diamine (1.03 g, 5.26 mmol) was dissolved in dTHF and carbonyldiimidazole (935 mg, 5.77 mmol) added. The mixture was stirred at rt for 18 hours. The solvent was removed and the crude material chromatographed to afford 4-(2,2-dimethoxy-ethyl)-1,3-dihydro-benzoimidazol-2-one as a colorless solid (440 mg, 38%). 1H NMR (CDCl3) δ 3.03 (2H, d, J=5.2 Hz), 3.40 (6H, s), 4.58 (1H, t, J=5.2 Hz), 6.86-6.89 (m, 1H), 6.96-7.02 (m, 2H), 9.29 (br s, 1H), 10.28 (br s, 1H). MS: 221 (M−H)−.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=1)#[CH:12].N>>[F:19][C:17]1[CH:18]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:14]=[C:15]([F:21])[C:16]=1[F:20]
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1cc(F)c(F)c(F)c1
Agent: N
Product: Fc1cc(-c2cc(-c3cccnc3)no2)cc(F)c1F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 78 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (dd, J=7.9, 4.8 Hz, 1H), 7.85 (s, 1H), 7.95 (dd, J=8.7, 6.7 Hz, 2H), 8.35 (dt, J=8.1, 1.7 Hz, 1H), 8.79 (d, J=3.6 Hz, 1H), 9.11 (s, 1H) ppm; MS (DCI/NH3) m/z 277 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(CNC(=O)c2ccncc2Nc2ccc(I)cc2F)cc1

Procedure:
4-[({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}amino)methyl]benzoic acid was synthesized according to the procedure for General Method 1, outlined above, starting with 0.3 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of 4-aminomethylbenzoic acid. LC/MS [9.25 min; 492 (M+1)]
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[S:15](N)([NH2:18])(=[O:17])=[O:16]>O1CCOCC1>[NH2:18][S:15]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]1[CH3:1])(=[O:17])=[O:16]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(N)(=O)=O
Temperature: 110 °C

Procedure:
To a solution of tert-butyl (3S)-3-methylpiperazine-1-carboxylate (0.5 g) in dioxane (40 ml) was added sulfamide (0.29 g) and the reaction was heated at 110° C. for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow oil. Yield: 0.66 g
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:24].[K+].[K+].OO>CS(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH2:20])=[O:24])=[CH:21][CH:22]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 141.3 %

Procedure:
Combine 4-(1-benzyl-piperidin-4-yloxy)-benzonitrile (74 mg, 0.25 mmol), DMSO (2.5 mL) and powdered potassium carbonate (18 mg, 0.13 mmol). Cool the resulting mixture to 0° C. and add hydrogen peroxide (76 μL). After addition, stir the mixture at room temperature for 1 h. Quench the reaction mixture with water (2 mL). Filter the precipitate formed rinsing with diethyl ether to give the title compound (57 mg, 73%). Mass spectrum (ion spray): m/z=311.1 (M+1); 1H NMR (CDCl3): 7.79 (ad, J=8.6 Hz, 3H), 7.32–7.21 (m, 5H), 7.14 (bs, 1H), 6.95 (d, J=8.6 Hz, 2H), 4.49–4.42 (m, 1H), 3.31 (s, 2H), 2.69–2.62 (m, 2H), 2.27–2.19 (m, 2H), 1.96–1.89 (m, 2H), 1.66–1.56 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[CH2:11][CH:10]1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@H:9]1[CH2:11][C@H:10]1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:14]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C=NC1CC1c1c(F)cccc1Cl
Product: O=C(Nc1ccc(Cl)cn1)N[C@@H]1C[C@@H]1c1c(F)cccc1Cl

Procedure:
2-(2-chloro-6-fluorophenyl)cyclopropylisocyanate prepared as described above was condensed with 2-amino-5-chloropyridine according to the method used in Example 7 to provide N-(cis-2-(2-chloro-6-fluorophenyl)-cyclopropyl)-N'-(5-chloropyrid-2-yl)-urea: 1H-NMR (250 MHz, CDCl3): 1.3-1.4 (m, 1H), 1.5-1.6 (m, 1H), 2.0-2.1 (m, 1H), 3.3-3.4 (m, 1H), 6.7-6.8 (m, 1H), 6.9-7.0 (m, 1H), 7.15-7.30 (m, 2H), 7.4-7.5 (m, 1H), 7.7 (m, 1H), 8.8 (s, 1H), 9.1 (s, 1H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].OC(C(F)(F)F)=O.[NH2:30][CH2:31][C:32]([CH3:37])([CH3:36])[C:33]([OH:35])=[O:34].C[O-].[Na+]>CCO>[CH2:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:30][CH2:31][C:32]([CH3:37])([CH3:36])[C:33]([OH:35])=[O:34])=[O:4])[N:6]=[CH:7]2)=[CH:12][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 38.6 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (19 mg, 0.065 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (60 mg, 0.26 mmol) and NaOMe (28 mg, 0.52 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 9.5 mg of the title compound. MS: (+) m/z 379.17 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:15]1([C:20]2[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=2)[CH:19]=[CH:18][N:17]=[CH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:23]2[CH:24]=[CH:25][C:20]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:21][CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2ccc(-n3ccnc3)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.7 %

Procedure:
To a mixture of (3R)-1-t-butoxycarbonyl-3-hydroxypiperidine (4.10 g, 17.8 mmol), 4-(imidazol-1-yl)phenol (4.4 g, 1.5 eq.), triphenylphosphine (1.5 eq., 7.10 g), DMF (80 mL) was added DEAD (1.5 eq., 4.33 mL). The resulting reaction mixture were stirred at room temperature for two days. The solvent was evaporated, the residue was diluted with ethyl acetate, washed with 1N NaOH (45 mL×3), water and brine, and evaporated in vacuo. Purification by flash column chromatography on silical gel with gradient 1–3% methanol in CH2Cl2 gave (3R)-1-t-butoxycarbonyl-3-[4-(imidazol-1-yl)phenoxy]piperidine (420 mg, 1.19 mmol), which was treated with trifluoroacetic acid/CH2Cl2 (1:1) from 0° C. to ambient temperature for 2 hours. The solvents were evaporated. The residue was diluted with CH2Cl2, and washed with 1N HCl (10 mL). The aqueous phase was extracted with CH2Cl2 to remove by-product. The aqueous phase was re-adjusted to pH 9.5 to 10.0 with 1N NaOH. Extraction with CH2Cl2 (60 mL×3) and evaporation of the solvent in vacuo gave (3R)-3-[4-(imidazol-1-yl)phenoxy]piperidine (62 mg) as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:25])[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([OH:25])[CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2COc3cc(OC(C)=O)ccc3C2O)cc1OC
Yield: 98.8 %

Procedure:
In a similar manner to Example 4.1, 7-acetoxy-3-(3,4-dimethoxyphenyl)chromen-4-one (1.4 g) and 5% Pd—C (0.24 g) were suspended in absolute ethanol (200 mL) and hydrogen was introduced to the system for 55 h until the reaction was complete. Filtration and evaporation gave a cis- and trans-mixture of 7-acetoxy-3-(3,4-dimethoxyphenyl)chroman-4-ol (1.4 g, 100%). This mixture was used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH2:11])([O-])=O.[Na+].[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][C:17]([O-])=[O:18])[CH3:14].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)CC)C>C(#N)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([NH:10][C:17](=[O:18])[CH2:16][N:15]([CH2:20][CH3:21])[CH2:13][CH3:14])[CH:7]=[CH:6][C:5]=1[NH2:11]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC(=O)[O-]
Agent: [Pd]
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCO
Product: CCN(CC)CC(=O)Nc1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Nitrobenzene-1,4-diamine (1.55 g, 10.1 mmol), N,N-diethylglycine sodium salt (1.61 g, 10.6 mmol) and DEPBT (3.02 g, 10.0 mmol) were suspended in acetonitrile (75 mL). Triethylamine (2.8 mL, 20.0 mmol) was added and the solution stirred overnight at room temperature. The brown precipitate which was formed was filtered and discarded. The filtrate was concentrated and the residue partitioned between EA and saturated aqueous sodium bicarbonate. The organic phase was washed with water and then with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was dissolved in ethanol (50 mL) and hydrogenated at atmospheric pressure with 10% palladium on charcoal (1.0 g, 0.9 mmol) at room temperature overnight. Filtration and concentration under reduced pressure gave N-(3,4-diaminophenyl)-2-(diethylamino)acetamide as a light brown semi-solid, which solidified and turned blue on standing.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:32])=[O:5])[S:12][CH:13]=3)=[N:20][CH:21]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-{[4-(2-{[5-(4-Fluorophenyl)pyridin-2-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester obtained in Example 100-2 was dissolved in dichloromethane (2 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1 to 2:1) to give the title compound (201 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27]C(N1C[C@@H](C)N2[C@H](CC3C2=NC(O)=CC=3)C1)=O)(C)(C)[CH3:24].[H-].[Na+].C(Br)C>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:27][CH2:23][CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Agent: [H-]
Agent: [Na+]
Solvent: CCBr
Product: CCOc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 22 intermediate b), from (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and ethyl bromide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([O-:19])[CH:3]=1.[CH2:9]([N+:6]([CH2:5][CH2:4][CH2:3][CH3:2])([CH2:5][CH2:4][CH2:3][CH3:2])[CH2:14][CH2:13][CH2:12][CH3:11])[CH2:10][CH2:16][CH3:17]
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1[O-]
Reaction time: 8 h

Procedure:
To an ethanol (2 mL) solution containing 105 mg (0.379 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 0.19 mL (0.38 mmol) of 2 mol/L aqueous sodium hydroxide solution, then, 106 mg (0.381 mmol) of tetrabutylammonium chloride, and the resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was allowed to stand at room temperature overnight, and the solid was removed by filtration. The filtrate was concentrated to obtain N,N,N-tributyl-1-butanaminium 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinolate (Compound No. 3798).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([CH:15](OC)[O:16][CH3:17])=[CH:13][C:12]([I:20])=[C:11]2[C:7]=1[CH:8](OC)[N:9](C(C)(C1C=CC=CC=1)C)[C:10]2=[O:21])(=[O:4])=[O:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>[N+](C)([O-])=O.CCCCCC.C(OCC)(=O)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([CH2:15][O:16][CH3:17])=[CH:13][C:12]([I:20])=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:21])(=[O:3])=[O:4]
Reactant: COC(OC)c1cc(I)c2c(c1OS(C)(=O)=O)C(OC)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: COCc1cc(I)c2c(c1OS(C)(=O)=O)CNC2=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-methanesulfonyloxy-5-dimethoxymethyl-3-methoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (226 mg, 0.393 mmol) was dissolved in nitromethane (5 mL), and the solution was added with trifluoroacetic acid (0.775 mL, 10.1 mmol) and triethylsilane (0.406 mL, 2.51 mmol), followed by stirring at 50° C. for 1 hour. The reaction mixture was added with water, ethyl acetate and hexane. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-methanesulfonyloxy-5-methoxymethyl-7-iodoisoindolinone (113 mg, yield 72%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]3[CH2:33][CH2:34][CH2:35]3)[N:27]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C3CCC3)n2)c(C(N)=O)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
In a 25 mL round bottom flask, a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclobutylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (112 mg, 233 μmol) in CH2Cl2 (5.0 mL) was treated with TFA (2.22 g, 1.5 mL, 19.5 mmol) and the mixture stirred to room temperature for 18 h. Solvents evaporated and residue purified by flash chromatography (spherical silica 20-45 μM, 80 g, Versaflash Supelco) eluting with 0 to 10% over 30 min (MeOH containing 10% NH4OH)/CH2Cl2 to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-cyclobutylpyridin-2-ylamino)pyridazine-3-carboxamide (48 mg, 126 μmol, 54.1% yield) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 11.43 (br. s., 1H), 8.45 (s, 1H), 8.03 (br. s., 1H), 7.51 (t, J=7.7 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.68 (d, J=7.9 Hz, 1H), 5.62 (d, J=8.3 Hz, 1H), 5.37 (br. s., 1H), 3.88 (br. s., 1H), 3.65 (quin, J=8.5 Hz, 1H), 3.22 (d, J=4.9 Hz, 1H), 2.27-2.51 (m, 4H), 1.99-2.22 (m, 1H), 1.94 (dd, J=11.1, 5.5 Hz, 1H), 1.07-1.84 (m, 10H); LC-MS 382.0 [M+H]+.