Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:44])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][O:38][CH3:39])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[C:8]=2[F:43])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][O:38][CH3:39])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:42])[C:8]=2[F:43])=[O:44])[CH2:2][CH2:3]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1
Yield: 97.8 %

Procedure:
A solution of intermediate 24 (0.92 mmol) and TFA (10 mL) in DCM (50 mL) was stirred at RT for 3 h. The reaction mixture was concentrated, diluted with a minimum of MeOH and water was added. The pH was adjusted to ca pH12 with 4N NaOH. The fine suspension was sonicated for 15 min, collected by filtration, rinsed with water and dried under high vacuum to afford the title compound 25 (578 mg, 0.9 mmol, 98% yield, TFA salt) as a pale ivory solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.78-8.61 (m, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 8.02 (t, J=7.8 Hz, 1H), 7.90 (dd, J=8.1, 2.1 Hz, 1H), 7.28 (td, J=9.0, 2.1 Hz, 1H), 7.16-7.01 (m, 1H), 6.75 (d, J=5.3 Hz, 1H), 3.78 (d, J=6.1 Hz, 2H), 3.41 (t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (q, J=6.0 Hz, 2H), 2.61-2.53 (m, 1H), 2.30-2.21 (m, 1H), 0.72-0.58 (m, 2H), 0.49-0.36 (m, 2H). MS (m/z): 526.6 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([O:18]O)(C)(C)C>ClCCl.O.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CCCc2ccc(Br)cc21
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 7-bromo-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Compound 2, 1.1 g, 4.62 mmol) in 10 mL of dichloromethane was added chromium (VI) oxide (72 mg, 0.46 mmol) and 5 mL of tert-butyl hydroperoxide solution (TBHP). After stirring at room temperature for 8 h, the mixture was diluted with water (20 mL), extracted with diethyl ether (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (90:10 hexane/ethyl acetate) yielded the title compound (920 mg, 79% yield) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)C(O)C1C2C(=CC=CC=2)C=CC=1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=[O:32]>>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([CH:18]=[CH:5][CH:4]=1)[CH:31]([OH:32])[C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=1
Reactant: COc1cccc(C(O)c2cccc3ccccc23)c1
Reactant: O=Cc1ccc2ccccc2c1
Product: COc1cccc(C(O)c2ccc3ccccc3c2)c1

Procedure:
The compound 6 was prepared by following the synthesis procedure as described for compound 1, but substituting 1-naphtaldehyde for 2-naphtaldehyde.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C:5]1[C:6](=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8].[Sn](Cl)Cl>C(O)C>[CH3:2][O:3][C:4](=[O:18])[C:5]1[C:6](=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)OC
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COC(=O)c1cccc(N)c1C(=O)OC
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 3:1 ethanol-conc. HCl (200 mL) was cooled to 0° C. and then 3-nitrophthalic acid dimethyl ester (15.0 g, 62.8 mmol) was added. Maintaining the cooling, tin (II) chloride (70.8 g, 314 mmol) was added portionwise, over a period of 15 min. Following completion of the addition, the cooling bath was removed and stirring proceeded at room temperature. After 2 h, the mixture was neutralized by the addition of solid sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (3×150 mL) and the combined extracts were washed with water (5×250 mL), were dried (MgSO4) and evaporated, providing 11.3 g of 3-aminophthalic acid dimethyl ester as a yellow oil, in 86% yield; 1H NMR (CDCl3) δ 3.84 (s, 3H), 3.86 (s, 3H), 5.20 (br, 2H), 6.78 (dd, J=8.5 Hz, J=1.0 Hz, 1H), 6.90 (dd, 1H, J=7.3 Hz, J=1.0 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[CH:39]1([NH:42][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH2:41][CH2:40]1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 73.7 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 42 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2-c2ccc([N+](=O)[O-])cc2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc2c(ccn2-c2ccc(N)cc2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
A mixture of tert-butyl 1-(4-nitrophenyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (35 mg, 0.10 mmol), zinc powder (80 mg), and NH4Cl (100 mg) in MeOH (3 mL) and THF (2 mL) was stirred at rt for 15 h. The mixture was diluted with EtOAc, filtered through a pad of Celite®. The filtrate was washed with brine, dried over MgSO4 and concentration in vacuo to afford the title compound as a solid (29 mg, 89%) was obtained. LC-MS: m/z 325 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([C:21]2[CH:33]=[CH:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=2)[CH:18]=[CH:17][N:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:15]2[CH:20]=[C:19]([C:21]3[CH:33]=[CH:32][C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=3)[CH:18]=[CH:17][N:16]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)c3)cc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(NS(=O)(=O)c4ccc(C)cc4)c3)cc2s1
Reaction time: 0.25 h

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-methylbenzenesulfonamide (0.170 g, 0.99 mmol) in DMF (3 ml). Then sodium hydride (0.047 g, 2.0 mmol) was added into the mixture and allowed to stir an additional 15 minutes. Then N-(6-(2-chloropyridin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.120 g, 0.40 mmol), palladium(II) acetate (0.0089 g, 0.040 mmol) and Xantphos (0.010 g) was added to the mixture. The vial was capped and placed into a CEM Microwave for 20 minutes at 120° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired product in the mixture. The mixture was placed into a round-bottom flask, then diluted with ethyl acetate (20 ml) and stirred 20 minutes. The precipitate was collected by filtration and then purified by reverse-phase HPLC. This gave N-(6-(2-(4-methylphenylsulfonamido)pyridin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.012 g, 6.9% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 439 (MH+). Calc'd exact mass for C21H18N4O3S2: 438. 1H NMR (400 MHz, DMSO-d6): 2.07 (s, 3H), 2.28 (s, 3H), 6.69 (s, 1H), 6.91 (s, 1H), 7.15 (d, J=6.53 Hz, 2H), 7.44 (d, J=8.03 Hz, 1H), 7.56 (d, J=7.53 Hz, 1H), 7.68 (d, J=7.03 Hz, 2H), 7.90 (s, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH:22]([F:24])[F:23])[CH2:9]1)(OC(C)(C)C)=O.Cl>>[F:24][CH:22]([F:23])[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccccc2OC(F)F)C1
Agent: Cl
Product: FC(F)Oc1ccccc1C[C@@H]1CNCCO1

Procedure:
Deprotection of intermediate (a), N-Boc-(R)-2-(2-difluoromethoxybenzyl)morpholine using hydrogen chloride (4M, in methanol), afforded the morpholine example 34 as a colorless oil (37 mg, 65%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[C:11]([C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]3[CH:29]=[C:30]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=4)[CH:31]=[CH:32][CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C#N)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M189) (278 mg, 0.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (185 mg, 84%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:24][C:20]=3[C:19](=[O:31])[N:18]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:17]2=[O:38])=[N:11]1)[CH3:9].[CH2:39]([O:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:49]2[C:48]([C:54]3[CH:62]=[CH:61][C:57]([C:58](O)=[O:59])=[CH:56][CH:55]=3)=[N:47][C@@H:46]3[CH2:63][CH2:64][S:65][CH2:66][C@@H:45]3[C:44]=2[CH:43]=1)[CH3:40].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[CH2:39]([O:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:49]2[C:48]([C:54]3[CH:55]=[CH:56][C:57]([C:58]([N:35]4[CH2:34][CH2:33][CH:32]([N:18]5[C:19](=[O:31])[C:20]6[S:24][C:23]([C:25]7[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=7)=[CH:22][C:21]=6[N:16]([CH2:15][C:12]6[CH:13]=[CH:14][N:10]([CH2:8][CH3:9])[N:11]=6)[C:17]5=[O:38])[CH2:37][CH2:36]4)=[O:59])=[CH:61][CH:62]=3)=[N:47][C@@H:46]3[CH2:63][CH2:64][S:65][CH2:66][C@@H:45]3[C:44]=2[CH:43]=1)[CH3:40]
Reactant: CCn1ccc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: O=S(=O)([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ccn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 1-[(1-ethyl-1H-pyrazol-3-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate (250 mg; compound B43), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (181 mg; compound C10), EDCI (87 mg) and HOBT hydrate (61 mg) in DCM (15 ml) DIPEA (0.24 ml) is added. After 14 h at RT additional EDCI (87 mg) and HOBT hydrate (61 mg) are added and the reaction mixture is stirred for additional 3 d at RT. Aqueous potassium hydrogen sulfate solution (10% w/w) is added and the mixture is filtered using a phase separator. The organic layer is concentrated under reduced pressure and the residue is purified by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][OH:14])[NH:8]2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>C(Cl)Cl>[Si:24]([O:14][CH2:13][CH2:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([N+:17]([O-:19])=[O:18])=[C:2]([F:1])[CH:10]=2)([CH3:16])[CH3:15])([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CCO)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52558400 %

Procedure:
To a solution of 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutan-1-ol (6.6 g, 25 mmol) in CH2Cl2 (80 mL) was added TBSCl (3.7 g, 25 nmol) and imidazole (4.2 g, 62 nmol) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The precipitate was filtered off and washed with the methanol. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give the desired product as a brown solid (5.0 g, 53%). 1H NMR (300 MHz, CDCl3) δ 9.80 (brs, 1H), 8.30 (d, J=7.2 Hz, 1H), 7.05 (d, J=11.7 Hz, 1H), 6.33 (t, J=1.2 Hz, 1H), 3.7 (t, J=6.0 Hz, 2H), 1.91 (t, J=6.0 Hz, 2H), 1.42 (s, 6H), 0.94 (s, 9H), 0.12 (s, 6H). MS (ESI) m/z (M+H+): 381.1.
Reaction SMILES: [Br:1]/[C:2](/[C:8]([OH:10])=[O:9])=[C:3](\[Br:7])/[C:4](O)=[O:5].[CH2:11]([CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][CH2:15][NH2:16])[CH3:12].BrC1=C(Br)C(OC1=O)=O>C(O)(=O)C>[C:17]1([CH:13]([CH2:11][CH3:12])[CH2:14][CH2:15][N:16]=[C:4]([OH:5])/[C:3](/[Br:7])=[C:2](/[Br:1])\[C:8]([OH:10])=[O:9])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)/C(Br)=C(/Br)C(=O)O
Reactant: CCC(CCN)c1ccccc1
Agent: O=C1OC(=O)C(Br)=C1Br
Solvent: CC(=O)O
Product: CCC(CCN=C(O)/C(Br)=C(/Br)C(=O)O)c1ccccc1
Temperature: 20 °C
Yield: 54.4 %

Procedure:
14 g (0.051 mol) of dibromomaleic acid are stirred in 100 ml of glacial acetic acid under reflux for 1 hour. 8.2 g (0.05 mol) of 3-ethyl-3-phenyl-propylamine are added to the cooled solution of the dibromomaleic anhydride thus prepared, and the mixture is stirred under reflux for a further 3 hours. The mixture is cooled to 20° C. and the precipitate is filtered off with suction. After drying, 11.4 g (56% of theory) of dibromomaleic acid N-3-phenylpentylimide of melting point 71°-73° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8](OCC)=[O:9])=[C:4]([CH:22]=O)[C:3]=1[F:24].C([BH3-])#N.[Na+].Cl.[C:30]([N:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1)(=[O:32])[CH3:31]>CO>[C:30]([N:33]1[CH2:36][CH:35]([N:37]2[CH2:22][C:4]3[C:3]([F:24])=[C:2]([Cl:1])[CH:15]=[C:14]([C:16]4([CH3:21])[O:20][CH2:19][CH2:18][O:17]4)[C:5]=3[O:6][CH:7]([CH3:13])[C:8]2=[O:9])[CH2:34]1)(=[O:32])[CH3:31]
Reactant: CCOC(=O)C(C)Oc1c(C2(C)OCCO2)cc(Cl)c(F)c1C=O
Reactant: CC(=O)N1CC(N)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CC(N2Cc3c(F)c(Cl)cc(C4(C)OCCO4)c3OC(C)C2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A solution of ethyl 2-[4-chloro-3-fluoro-2-formyl-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate (392 mg, 1.09 mmol) in methanol (21 mL) was treated with sodium cyanoborohydride (171 mg, 2.72 mmol) followed by 1-acetylazetidin-3-amine hydrochloride (360 mg, 2.39 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with acetic acid (200 μL) and concentrated in vacuo. The residue was diluted with toluene (60 mL) and heated at 110° C. for 2 h. The solvent was concentrated in vacuo, and the residue was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (142 mg, 32%) as a mixture of enantiomers. LCMS calculated for C19H23ClFN2O5(M+H)+: m/z=413.1; found: 413.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[C:10]([O:14][C:15]([NH:17][C@H:18]([C:23](O)=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:11][C:10]([O:14][C:15](=[O:16])[NH:17][CH:18]([C:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:24])[CH:19]([CH3:20])[CH2:21][CH3:22])([CH3:13])[CH3:12]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCCc1ccccn1

Procedure:
The title compound is prepared by the procedure of Example 1, using 1.0 g of 2-(2-amino-ethyl)pyridine, 2.163 g of N-(tert-butoxycarbonyl)-L-isoleucine, 6.15 g of BOP, 10.52 g of Hunig's base, and 15 ml of methylene chloride to give 2.5 g of the product as a white/yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:13](=[O:15])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=3[F:27])[CH:6]=[N:7]2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 47 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 32) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as an orange oil (555.9 mg, 47%); ES+-HRMS m/e calcd for C29H39N5O5SiF2 [M+H+] 488.2104 found 488.2103. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.07 (s, 6H) 0.80 (s, 9H) 1.12-1.33 (m, 2H) 1.33-1.45 (m, 1H) 1.46-1.58 (m, 2H) 1.84-1.90 (m, 1H) 1.90 (s, 6H) 2.13-2.25 (m, 1H) 3.10-3.28 (m, 2H) 3.73-3.83 (m, 2H) 3.86 (t, J=5.3 Hz, 2H) 4.06 (t, J=5.3 Hz, 2H) 5.54 (dd, J=10.9, 4.3 Hz, 1H) 6.04 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.29-7.43 (m, 2H) 7.43-7.52 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.28 (d, J=2.7 Hz, 1H) 10.82 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:30]=1[N+:31]([O-])=O>C(O)C.[Ni]>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:30]=1[NH2:31]
Reactant: COC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: COC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1N

Procedure:
340 mg of 6-[(1,2-diphenyl-7-nitro-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was hydrogenated in ethanol with Raney nickel in an autoclave at 50° C. and at normal pressure. After hydrogen absorption ended, catalyst was filtered out and concentrated by evaporation in a vacuum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=2[CH:12]=[C:11]([CH2:20]O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1>[N:36]([CH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C:13]=2[CH:12]=1)=[N+:37]=[N-:38]
Reactant: CC1(C)Oc2cc(CO)cc(OCc3ccccc3)c2O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)Oc2cc(CN=[N+]=[N-])cc(OCc3ccccc3)c2O1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of (7-benzyloxy-2,2-dimethyl-benzo[1,3]dioxol-5-yl)-methanol (0.57 g, 2.0 mmol) and diphenylphosphoryl azide (0.52 mL, 2.4 mmol) in tetrahydrofuran (10 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.33 mL, 2.2 mmol). The mixture is allowed to warm to room temperature over the weekend and then quenched with the addition of water. The reaction mixture is extracted 3× with ethyl acetate, and the combined extracts were washed with 5% aqueous potassium hydrogen sulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to give 6-azidomethyl-4-benzyloxy-2,2-dimethyl-benzo[1,3]dioxole, which is used in the next step without purification.
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.NN.C(O)C.[OH-].[Na+]>O>[N:1]1([C:6]2[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCOc1ccc(-n2ccnc2)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCCCCCOc1ccc(-n2ccnc2)cc1

Procedure:
2-[5-[4-(1H-imidazol-1-yl)phenoxy]butyl]-1H-isoindole-1,3-(2H)-dione (Example 26) is cleaved by hydrazine in refluxing ethanol by the procedure of Example 2. The crude hydrochloride salt is dissolved in 20 parts of water, made basic with 10N NaOH, and the mixture then extracted with 30 parts of dichloromethane. After drying with Na2SO4, the dichloromethane is removed in vacuo to give the desired compound as a clear oil, with the correct molecular weight as determined by mass spectrometry.