Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]COCC.C[Si](C=[N+]=[N-])(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([C:42]([OH:44])=[O:43])[C:17]2[C:18]([CH:41]=1)=[N:19][N:20]([CH2:22][C:23]([C:39]#[N:40])([NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[O:27])[CH3:24])[N:21]=2>C1COCC1.CO>[Cl:13][C:14]1[CH:15]=[C:16]([C:42]([O:44][CH3:1])=[O:43])[C:17]2[C:18]([CH:41]=1)=[N:19][N:20]([CH2:22][C:23]([C:39]#[N:40])([NH:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=1)=[O:27])[CH3:24])[N:21]=2
Reactant: CC(C#N)(Cn1nc2cc(Cl)cc(C(=O)O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Cl)cc2nn(CC(C)(C#N)NC(=O)c3ccc(OC(F)(F)F)cc3)nc12
Reaction time: 8 h
Yield: 40 %

Procedure:
A 2 molar ether solution of trimethylsilyldiazomethane was added to 6-chloro-2-[2-cyano-2-({[4-(trifluoromethoxy)phenyl]carbonyl}amino)-propyl]-2H-benzotriazole-4-carboxylic acid (100 mg) dissolved in a ten to 1 one mixture of THF and methanol (2 mL). After overnight at room temperature, the mixture was concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (42 mg, 40%). MS (ES): M/Z [M+H]=482. 1H NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 3.78 (s, 3H), 5.44 (d, J=13.3 Hz, 1H), 5.58 (d, J=13.3 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.8 Hz, 2H), 8.02 (d, J=1.9 Hz, 1H), 8.52 (d, J=1.9 Hz, 1H) and 8.87 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.O(C1C=CC(N)=CC=1)C1C=CC=CC=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)[NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:60][CH:59]=2)C)=CC=1)C(O)=O)C>>[CH3:21][O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([CH3:15])([C:17](=[O:19])[NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:60][CH:59]=2)[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:22]
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: Nc1ccc(Oc2ccccc2)cc1
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 4-phenoxy-phenylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C28H31NO6 [M+H]+: 478.
Reaction SMILES: [C:1](=[O:9])([O:5][CH:6]([CH3:8])[CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([F:48])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH2:42][C@@H:43]([OH:47])[C:44]([OH:46])=[O:45])[NH:27][C:28]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])[CH:31]=3)=[O:29])=[CH:21][CH:20]=2)[CH:18]=1.CCN(CC)CC>CC(C)=O>[CH:6]([O:5][C:1]([O:2][CH2:3][O:46][C:44](=[O:45])[C@H:43]([OH:47])[CH2:42][N:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=2[F:48])=[CH:20][CH:21]=1)[NH:27][C:28]([C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])[CH:31]=1)=[O:29])=[O:9])([CH3:8])[CH3:7]
Reactant: CC(C)OC(=O)OCCl
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 60 °C
Reaction time: 5 h
Yield: 7.4 %

Procedure:
Chloromethyl isopropyl carbonate (17.3 mg, 114 μmol) and NaI 17.0 mg, 114 μmol) were combined in acetone (1.0 mL, 14 mmol) and heated at 60° C. for 1 hour. The mixture was then cooled to room temperature. A mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (20.0 mg, 38 μmol) dissolved in acetone (1.0 mL) and treated with Et3N (10.6 μL, 76 μmol) was added and the resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated and the residue was dissolved in AcOH (2.0 mL), filtered and purified by reverse phase preparative HPLC. The product was freeze dried and purified by reverse phase preparative HPLC to yield the title compound (1.8 mg, purity 100%). MS m/z [M+H]+ calc'd for C31H28ClF2N3O8, 644.15. found 644.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]1([CH:27]=[CH:26][C:2]2[CH:7]=[CH:6][C:5]3[CH2:8][C:9]4[C:21]5[NH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:13]=5[C:12]5[C:22](=[O:25])[NH:23][CH2:24][C:11]=5[C:10]=4[C:4]=3[CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(C=Cc2ccccc2)cc1-3
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), styrene (30 mg, 0.29 mmol) and triethylamine (0.5 mL) in DMF (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (25 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 48 hours. The mixture was cooled to ambient temperature, filtered through a pad of Celite®, then the solvent was concentrated at reduced pressure. The product was triturated with MeOH to give 85 mg (80%) of a brown solid. Recrystallization from DMF-Et2O gave the product, Compound I-24, as a tan solid. The melting point was greater than 300° C. The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): δ4.2 (s, 2H), 5.02 (s, 2H), 7.25-7.5 (m, 7H), 7.6-7.75 (m,4H), 7.8 (d, 1H, J=8Hz), 8.2 (s, 1H), 8.6 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.8 (s, 1H). MS(FAB): m/e 413 (m+1)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:25]1[C:30]([OH:31])=[CH:29][CH:28]=[C:27]([CH3:32])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:5]2[N:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH:7]=[C:3]([CH2:2][O:31][C:30]3[CH:25]=[CH:26][C:27]([CH3:32])=[CH:28][CH:29]=3)[N:4]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2cn(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(Cl)cc3)n2)cc1
Reaction time: 6 h
Yield: 81.4 %

Procedure:
A mixture of 122 mg (0.32 mmole) of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Step 1), p-cresol (69 mg, 0.64 mmole), and potassium carbonate (110 mg, 0.8 mmole) in 5 ml of dimethylformamide was stirred at 85–90° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and aqueous sodium chloride, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane gave 2-(4-chlorophenyl)-4-[(4-methylphenoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole as a pure white solid (118 mg): m.p. (DSC) 193° C. Anal. Calc'd. for C24H21ClN2O3S (Mw 452.96): C, 63.64; H, 4.67; N, 6.18. Found: C, 63.42; H, 4.64; N, 5.79.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][CH:25]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3c[nH]c4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=476.3.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[C:10]([CH2:11]O)=[C:9]([CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3=[N:25][N:26]=[C:27]([C:28]4[CH:32]=[C:31]([CH3:33])[O:30][N:29]=4)[N:17]3[N:16]=2)[N:8]=[N:7]1.ClCC1N=NNC=1.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH3:33][C:31]1[O:30][N:29]=[C:28]([C:27]2[N:17]3[N:16]=[C:15]([O:14][CH2:13][C:9]4[N:8]=[N:7][N:6]([CH3:5])[C:10]=4[CH2:11][N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)[C:24]4[C:19]([C:18]3=[N:25][N:26]=2)=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:32]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CO)nn23)no1
Reactant: C1CCNCC1
Agent: ClCc1c[nH]nn1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CN4CCCCC4)nn23)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
Thionyl chloride (625 μl, 8.6 mmol) was added to a stirred suspension of [1-methyl-4-({[3-(5-methylisoxazol-3-yl)[1,2,4]triazolo[3,4-α]phthalazine-6-yl]oxy}methyl)-1H-[1,2,3]triazol-5-yl]methanol (672 mg, 1.71 mmol) in CH2Cl2 (50 ml) and the mixture was stirred at room temperature for 1 h under N2, during which period the solid dissolved and then precipitated. The reaction mixture was concentrated under reduced pressure and then azeotroped with toluene (2×50 ml) and used without further purification. A portion of the crude chloromethyltriazole (125 mg, 0.30 mmol) and piperidine (0.30 ml, 3.0 mmol) in CH2Cl2 (6ml) were stirred at room temperature for 48 h under N2. The mixture was then concentrated under reduced pressure while dry loading onto silica and purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 solution as eluent to yield the desired phthalazine (126 mg, 90%), which was then recrystallised CH2Cl2/iso-hexanes. 1H NMR (360 MHz, CDCl3) δ 8.67 (1H, d, J=8.0 Hz), 8.14 (1H, d, J=8.0 Hz), 7.93 (1H, t, J=8.0 Hz), 7.75 (1H, d, J=8.0 Hz), 6.94 (1H, s), 5.77 (2H, s), 4.12 (3H, broad s), 3.70-3.60 (2H, m), 2.59 (3H, s), 2.40-2.30 (4H, m), 1.75-1.33 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][O:27][C:28]1[CH:48]=[CH:47][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[N:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=3)[CH2:35][CH2:34]2)=[CH:30][CH:29]=1>C(Cl)Cl.CO>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[N:45]=[CH:44][C:43]([NH:46][C:23]([C:20]4[CH:21]=[CH:22][C:13]([C:3]5[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=5[Cl:1])=[C:14]5[C:19]=4[N:18]=[CH:17][CH:16]=[CH:15]5)=[O:24])=[CH:42][CH:41]=3)[CH2:35][CH2:34]2)=[CH:47][CH:48]=1
Reactant: COc1ccc(CN2CCN(Cc3ccc(N)cn3)CC2)cc1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 6-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-3-ylamine (Step 111.1) and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 672.1 [M+H]+; TLC: Rf=0.45 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 3-(6-chloro-3-pyridyl)-3-oxopropionate (9.0 g, 39.5 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.58 g, 39.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (9.45 g, 39.5 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=1:1) to give ethyl 3-(6-chloro-3-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (14.2 g, 93%) as a colorless oil.
Reaction SMILES: [CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])([O-:9])=[O:8].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([S:3]([NH:6][C:13]([C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)=[O:14])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Yield: 84.5 %

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 1, using ethyl sulphonamide (3 g, 27.5 mmol), 3-nitrobenzoic acid (4.6 g, 27.5 mmol), 4-dimethylaminopyridine (3.36 g, 27.5 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (5.28 g, 27.5 mmol) and anhydrous dichloromethane (200 ml). The title compound (6 g, 84%) was afforded as a colourless solid. mp 178°-181° C. 1H NMR (360 MHz, D6 -DMSO) δ 1.28 (3H, t, J=7.4 Hz), 3.54 (2H, q, J=7.4 Hz), 7.83 (1H, dd, J=8.0 and 8.0 Hz), 8.33-8.38 (1H, m), 8.47-8.50 (1H, m), 8.75-8.90 (1H, m), 12.40 (1H, brs).
Reaction SMILES: C[O-].[K+].[CH3:4][O:5]CCOCCN(CCOCCOC)CCOCCOC.[CH2:26]([CH:28]([C:31]1[C:32]2[N:33]([C:38]([C:42]3[S:46][C:45]4[CH:47]=[CH:48][C:49](F)=[CH:50][C:44]=4[C:43]=3[CH3:52])=[C:39]([CH3:41])[N:40]=2)[N:34]=[C:35]([CH3:37])[CH:36]=1)[CH2:29][CH3:30])[CH3:27]>ClCCl.O>[CH2:26]([CH:28]([C:31]1[C:32]2[N:33]([C:38]([C:42]3[S:46][C:45]4[CH:47]=[CH:48][C:49]([O:5][CH3:4])=[CH:50][C:44]=4[C:43]=3[CH3:52])=[C:39]([CH3:41])[N:40]=2)[N:34]=[C:35]([CH3:37])[CH:36]=1)[CH2:29][CH3:30])[CH3:27]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(OC)cc4c3C)c(C)nc12
Reaction time: 0.08 h
Yield: 293.2 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 0.014 g (0.197 mmol) of potassium methoxide and 0.005 mL (0.013 mmol) of tris[2-(2-methoxyethoxy)ethyl]amine are heated at 150° C. and stirred vigorously for 5 minutes. 0.050 g (0.131 mmol) of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-imidazo[1,2-b]pyridazine is added and the reaction is followed by TLC (2:1 Hexanes/Ethyl Acetate) and MS. After 4 h, the reaction mixture is diluted with 20 mL dichloromethane and 20 mL of water. The layers are separated and the aqueous is extracted 3×50 mL of dichloromethane, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using hexanes:ethyl acetate as a solvent system. Combined fractions to obtain 0.015 g of the title compound, 29% yield. MS, ES+=394.2 (M+1); H1NMR (DMSO-d6) δ 7.863-7.842 (d, J=8.368, 1H); 7.327-7.321 (m, 1H); 7.076-7.049 (m, 1H); 6.991 (s, 1H); 3.857 (s, 3H); 3.094 (m, 1H); 2.477 (s, 3H); 2.350 (s, 3H); 2.180 (s, 3H); 1.853-1.760 (m, 4H); 0.793-0.757 (m, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1C1=CCOCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cnc1C1=CCOCC1
Temperature: 65 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of as 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-nitropyridine (0.19 g, 0.69 mmol) in EtOAc (10 mL) was added tin(II) chloride dihydrate (0.78 g, 3.48 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 65° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH (20 mL), water (20 mL), and brine (20 mL). After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as mostly 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridinamine.
Reaction SMILES: C(O[C:5]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:20]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:19][CH:18]=1)=[C:6](C1C=CN=CC=1)[C:7]([O:9][CH3:10])=[O:8])(=O)C.C1(C)C=CC=CC=1.N12C[CH2:50][CH2:49][N:48]=[C:47]1[CH2:46][CH2:45][CH2:44]CC2>CCOCC>[CH2:30]([C:20]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:17](/[CH:5]=[C:6](\[CH2:44][C:45]2[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=2)/[C:7]([O:9][CH3:10])=[O:8])=[CH:18][N:19]=1)[CH2:31][CH2:32][CH3:33]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCc1ncc(C(OC(C)=O)=C(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCc1ncc(/C=C(\Cc2ccncc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 90 °C

Procedure:
A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(4-pyridyl)propenoate (7.5 mmol), toluene (50 mL) and 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) (3.4 mL, 22.5 mmol) was heated at 90° C. for 18 hours under argon. The cooled mixture was diluted with ether, and washed with brine, dried and concentrated to 3.1 g (97%) of the title compound. NMR showed that the trans or E isomer was the primary product.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].P(Br)(Br)[Br:31].CN(C=O)C>C(Cl)Cl>[Br:31][CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Yield: 49.6 %

Procedure:
The title compound was made in a similar way as that of the intermediate C6, using 3-(1-hydroxyethyl)-4-(3-(morpholinosulfonyl)phenyl)-1H-isochromen-1-one (intermediate B9, 163 mg, 0.392 mmol), 1M PBr3 (0.68 ml, 0.667 mmol) in DCM (3.2 ml) at RT. The crude was tritured with DMF to give the title compound (93 mg, 49%). The solution was purified via reverse phase chromatography with a Biotage C18 SNAP 30 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%); Phase B ACN 99.9%, formic acid 0.1%) to give further compound (68 mg, 36.2%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])=O.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=O)[CH2:26]Br)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([CH2:25][C:26]2[O:18][C:5]3[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:9][C:4]=3[C:2]=2[CH3:1])=[CH:23][CH:22]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Cc2oc3ccc(OCc4ccccc4)cc3c2C)cc1
Yield: 93.2 %

Procedure:
A mixture of 2-hydroxy-5-benzyloxyacetophenone (93 g, 380 mmoles), p-methoxyphenacyl bromide (88 g, 384 mmoles) and potassium carbonate (106 g, 768 mmoles) in acetone (1.5 L) was refluxed for 46 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using 10% ethylacetate in hexane as eluent to yield (127 g, 89%) of 2-(p-methoxybenzyl)-3-methyl-5-benzyloxybenzofuran, E48.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C@@H:5]([N:13]1[C:17]2=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=[C:16]2[N:15]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=3[CH3:34])[N:27]([CH3:36])[CH:26]=2)[C:14]1=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.O.[OH-].[Li+].C(O)(=[O:44])C>O1CCOCC1.O>[C:22]([C:19]1[N:18]=[C:17]2[N:13]([C@@H:5]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:4][C:3]([OH:2])=[O:38])[C:14](=[O:37])[N:15]([CH2:24][C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=4[CH3:34])[N:27]([CH3:36])[CH:26]=3)[C:16]2=[CH:21][CH:20]=1)(=[O:44])[NH2:23]
Reactant: CC(=O)O
Reactant: COC(=O)C[C@H](c1ccc(F)cc1)n1c(=O)n(Cc2cn(C)c3cc(C)cc(C)c23)c2ccc(C#N)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c2c(Cn3c(=O)n([C@H](CC(=O)O)c4ccc(F)cc4)c4nc(C(N)=O)ccc43)cn(C)c2c1
Reaction time: 24 h
Yield: 13 %

Procedure:
To a stirred solution of (R)-3-[5-cyano-2-oxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl]-3-(4-fluoro-phenyl)-propionic acid methyl ester (0.17 g, 0.33 mmol) in dioxane (10 ml) and water (3 ml) was added lithium hydroxide monohydrate (70 mg, 1.66 mmol). The reaction was stirred for 24 hours after which time it was diluted with water and acidified using acetic acid. The resulting precipitate was collected via filtration and washed with water. The remaining solid was purified via preparative TLC (2×1 mm silica gel plates, 5% MeOH/Dichloromethane) to afford 22 mg (13%) of the title compound. LCMS, M++1, m/z: 516.20.