Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:16])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH3:15])C=C.C(OC([CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29](=[O:44])[CH:30]([NH:32][C:33](=[O:43])[C:34]1[CH:39]=[C:38]([Cl:40])[C:37]([NH2:41])=[C:36]([Cl:42])[CH:35]=1)[CH3:31])=O)(C)(C)C.O=C1OC(OCCC2C=CC=CC=2)C(NC(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)C1>>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:29](=[O:44])[CH:30]([NH:32][C:33](=[O:43])[C:34]2[CH:39]=[C:38]([Cl:40])[C:37]([NH2:41])=[C:36]([Cl:42])[CH:35]=2)[CH3:31])=[O:16])[CH2:11][C:10](=[O:12])[O:9]1)[CH3:15]
Reactant: CC(NC(=O)c1cc(Cl)c(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCC
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1cc(Cl)c(N)c(Cl)c1
Yield: 54 %

Procedure:
Prepared from (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 1-[2-(4-amino-3,5-dichloro-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester according to the method used for 98a to afford 158 mg of title compound (54% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.08-1.30 (m, 3H), 1.32-1.52 (m, 3H), 1.72-2.44 (m, 4H), 2.40-3.05 (m, 2H), 3.50-3.97 (m, 4H), 4.25-4.70 (m, 3H), 4.70-4.86 (m, 1H), 5.33 (s, 0.4H), 5.47 (s, 0.1H), 5.56 (d, 0.4H), 5.62 (d, 0.1H), 7.50 (s, 1H), 7.80 (s, 1H). Analytical HPLC: 10.84 min. LC-MS (ES+): m/e=501.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O:16][C@@H:17]([CH3:21])[C:18](O)=[O:19])(=O)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.CC#N.O.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18](=[O:19])[C@@H:17]([OH:16])[CH3:21])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)O[C@@H](C)C(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](O)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reaction time: 1 h
Yield: 8.7 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.350 g, 1.52 mmol; Example 1, Step H), (S)-2-acetoxypropanoic acid (0.422 g, 3.20 mmol), BOP—Cl (0.813 g, 3.20 mmol), and triethylamine (1.06 mL, 7.61 mmol) were placed in DCM (5 mL) and stirred for 1 hour. 3M aqueous LiOH (3 mL) was then added, and the reaction was stirred for 1 hour and then poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-60% CH3CN/water) to give (S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamide (0.040 g, 9% yield).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CS(C)=O.Cl[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH2:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][C:23]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)=[CH:22]4)=[N:16][N:17]=2)[N:14]=1>O>[CH3:1][N:2]([CH3:3])[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH2:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][C:23]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)=[CH:22]4)=[N:16][N:17]=2)[N:14]=1
Reactant: CNC
Reactant: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(Cl)nn45)cc3c2)cn1
Solvent: CS(C)=O
Solvent: O
Product: CN(C)c1ccc2nnc(Cc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Temperature: 130 °C
Yield: 30 %

Procedure:
To a 5 ml microwave vial 1 ml of dimethylamine 40% in water was added followed by 300μ of DMSO to dissolve 25 mg (0.067 mmol) 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoline. The reaction heated in a microwave for 2000 seconds at 130° C. The reaction mixture was filtered then purified via preparatory HPLC to return the title compound (7.7 mg, 30% yield). Analytical data is presented in Table 2.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1.F[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].[NH4+].[Cl-]>C1COCC1>[F:26][C:24]1[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([NH:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:25]=1
Reactant: Nc1ncccc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ncccc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
LiHMDS (1.0M in THF, 4.0 mL, 4.0 mmol) was added dropwise to a stirred solution of 2-amino-3-fluoropyridine (224 mg, 2.0 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere at −78° C. After 15 min stirring at −78° C., a solution of 2,4-difluoro-1-nitrobenzene (0.22 mL, 2.0 mmol) in THF (5 mL) was added and stirring at −78° C. was continued for 1 h. The mixture was slowly warmed to 0° C. and stirring continued for 1 h. The crude solution was poured into a saturated aqueous solution of NH4Cl (50 mL). The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions were washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound as an orange solid (93 mg, 19%). LCMS (Method C): RT 3.97 min [M+H]+ 252.10.
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:18])[CH2:13][NH:14][CH:15]2[CH2:17][CH2:16]2)=[CH:8][C:7]=1[F:19])(=O)C>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:18])[CH2:13][NH:14][CH:15]2[CH2:17][CH2:16]2)=[CH:8][C:7]=1[F:19]
Reactant: CC(=O)Nc1ccc(C(O)CNC2CC2)cc1F
Agent: Cl
Product: Nc1ccc(C(O)CNC2CC2)cc1F

Procedure:
m.p. of the hydrochloride: 157°-158° C. (decomp.), was prepared from 1-(4'-acetylamino-3'-fluoro-phenyl)-2-cyclopropylamino-ethanol analogous to Example 4.
Reaction SMILES: [OH-].[Na+].C([O:6][CH:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=1)[CH2:8][O:9]C(=O)C)(=O)C>O>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:7]([OH:6])[CH2:8][OH:9])=[N:14][CH:15]=1)[CH3:20]
Reactant: CCc1ccc(C(COC(C)=O)OC(C)=O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C(O)CO)nc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
19.91 g (0.497 mol) Sodium hydroxide was added to a solution of 71 g (0.226 mol) acetic acid 2-acetoxy-2-(5-ethyl-pyridin-2-yl)-ethyl ester in 355 mL water. Reaction mixture was stirred at 40° C. for 2 hr. After completion of reaction on TLC, reaction mixture was neutralized with con. HCl and precipitated solid was filtered off and dried to get 1-(5-ethyl-pyridin-2-yl)-ethan-1,2-diol. Yield of the product was 32.1 g (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])=[CH:26][N:27]=1>>[Cl:34][C:30]1[C:29]([F:35])=[C:28]([C:25]2[S:24][C:23]([CH2:22][N:11]3[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:12]3)=[N:27][CH:26]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Fc1c(Cl)cccc1-c1cnc(CBr)s1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2ncc(-c3cccc(Cl)c3F)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
70 mg (0.23 mmol) of the compound from Example 5A were reacted with 70 mg (0.23 mmol) of the compound from Example 90A analogously to the preparation of the compound in Example 77. This gave 90 mg (72% of theory) of the title compound.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:5]=1[C:6]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C(=O)C)=[C:20]([CH2:28][CH2:29][CH3:30])[CH:19]=2)=[CH:14][CH:13]=1)[CH2:10]Cl)=[O:7].N>O.CN(C)C=O>[F:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:4]([F:3])[C:5]=1[C:6]1[O:7][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:28][CH2:29][CH3:30])[CH:19]=3)=[CH:14][CH:13]=2)[N:8]=1
Reactant: CCCc1cc(-c2ccc(C(CCl)NC(=O)c3c(F)cccc3F)cc2)ccc1OC(C)=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)ccc1O
Reaction time: 8 h

Procedure:
At −10° C., a solution of 3.7 g (92 mmol) of sodium hydroxide in 10 ml of water is added dropwise with stirring to a solution of 27 g (57 mmol) of 2,6-difluoro-N-[2-chloro-1-(4-(4-acetoxy-3-n-propylphenyl)phenyl)ethyl]-benzamide in 150 ml of dimethylformamide. The mixture is stirred overnight, 43 ml of a 25% strength solution of ammonia are added and the mixture is stirred overnight. The reaction mixture is then poured onto ice-water and extracted repeatedly with ethyl acetate. The combined ethyl acetate extracts are dried over MgSO4 and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][C@H:13]1[CH2:18][O:17][CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][C@@H:13]2[CH3:12])[N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Temperature: 80 °C
Reaction time: 17 h
Yield: 75.9 %

Procedure:
A mixture of 2,6-dichloro-9H-purine (5.2 g, 27.51 mmol), (S)-3-methylmorpholine (3.30 g, 32.62 mmol) and DIPEA (5.0 mL, 28.71 mmol) in IMS (130 mL) were heated at 80° C. for 3 h then stirred at r.t. for 17 h. The resulting white precipitate was collected by filtration and the filtrate concentrated in vacuo to a reduced volume and the resulting precipitate also collected by filtration. Both batches of solid were combined in DCM and the organic phase washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo affording the title compound as a white powder (5.3 g, 76%). LCMS (method H): RT 2.54 min [M+H]+ 254.1
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>CC(O)(C)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:21]([C:3]([S:4][C:5]3[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)=[C:2]([CH3:15])[NH:24]2)=[CH:22][CH:23]=1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Temperature: 70 °C

Procedure:
[3-(2-Oxo-propylsulfanyl)-phenyl]-acetic acid (3.69 g, 16.5 mmol) was dissolved in t-BuOH (100 mL) then 3-chlorophenylhydrazine hydrochloride (3.25 g, 18.15 mmol) was added. The reaction was heated to 70° C. for 2 hour then cooled and submitted to aqueous workup to afford a mixture of regioisomers which included the title compound. The crude material was brought forward to the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:9][CH2:8][C:4]1[N:3]=[C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OCC
Reactant: OCc1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc(CO)n1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
2-Bromopyridine-6-methanol (2 g) was dissolved in 10 mL of dry DMF, and 1.73 mL of ethyl acrylate, 2.95 g of tetra(n-butyl)ammonium chloride, 1.78 g of sodium bicarbonate and 2 g of Molecular Sieves (Molecular Sieves 3A ( 1/16)) to the above solution, additionally under argon atmosphere 119 mg of palladium(II) acetate was added thereto, and then the mixture was stirred at 80° C. for 5 hours. After being cooled, the insoluble portion was filtrated off, and water was added thereto and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=2:1) to give 1.39 g of ethyl 3-(6-hydroxymethylpyridin-2-yl)-trans-acrylate as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)#[CH:2].Br[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.CN(C=O)C.CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:20][CH:19]=4)=[C:3]([C:1]#[C:2][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of compound 17a (0.23 g, 0.57 mmol) and 2-bromoquinoline (1.0 g, 4.8 mmol) in a vial was evacuated and back flushed with Argon. Dry DMF (5 mL) and DIEA (0.99 mL, 5.7 mmol) were added via syringe and the mixture was deoxygenated by bubbling Argon gas through the stirred solution for 5 min. To the mixture were added CuI (5.4 mg, 0.028 mmol) and dichlorobis(triphenylphosphine)palladium(II) (40 mg, 0.057 mmol). The resulting mixture was stirred at rt for 1 h, and was poured into water (50 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (20 mL) and brine (2×20 mL). The organic layer was concentrated, and the resulting residue was purified by flash column chromatography on silica gel (20-60% EtOAc/heptane) to give tert-butyl 4-(8-morpholino-2-(quinolin-2-ylethynyl)imidazo[1,2-b]pyridazin-3-yl)benzoate as a yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[CH2:16]Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]1[O:25][CH:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>[OH-].[Na+]>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[CH2:16][N:22]2[CH2:21][CH:20]([CH3:19])[O:25][CH:24]([CH3:26])[CH2:23]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CNCC(C)O1
Reactant: CC(=Cc1cccc(Oc2ccccc2)c1)CBr
Agent: [Na+]
Agent: [OH-]
Product: CC(=Cc1cccc(Oc2ccccc2)c1)CN1CC(C)OC(C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
3-(m-Phenoxyphenyl)-2-methyl-2-propenyl bromide (1.0 g) was added to 2,6-dimethylmorpholine (2.0 g) at 0° C. while stirring, followed by aging at the same temperature for 3 hours. Ice water (100 ml) and 15% aqueous sodium hydroxide solution (30 ml) were added to the resultant mixture to make basic, followed by extraction with ethyl acetate (50 ml×3). The extracts were combined together, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-[3-(m-phenoxyphenyl)-2-methyl-2-propenyl]-2,6-dimethylmorpholine (cis-isomer, 0.3 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[C:6]([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2[O:26][CH3:27])=[CH:5]1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2[O:26][CH3:27])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc(N)cc12
Reaction time: 24 h
Yield: 96.4 %

Procedure:
Palladium-on-carbon (10% w/w, 0.1 g.) was added to a solution of 4-(1-acetyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid (0.35 g.) in a mixture of 1:1 v/v methanol:tetrahydrofuran (50 ml.), which solution had been deoxygenated by passing a stream of nitrogen gas through it, and the mixture hydrogenated at an initial pressure of 50 psi. After 24 hours, the catalyst was removed by filtration through diatomaceous earth, and the filtrate evaporated to give 4-(1-acetyl-5-aminoindol-3-ylmethyl)-3-methoxybenzoic acid (Z) (0.31 g., 91%); partial NMR (250 MHz, CD3OD): 2.53(s,3H, NCOCH3); 3.94(s,3H, OMe); 4.00(s,2H, ArCH2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=4[Cl:29])[C:22]([O:24]C)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.O[Li].O.Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=4[Cl:29])[C:22]([OH:24])=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: COC(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a suspension of methyl 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate (31 g, 61 mmol) in THF (200 mL) and H2O (100 mL) was added LiOH.H2O (6.42 g, 153 mmol). The reaction mixture was stirred at room temperature overnight. Then it was acidified with 2N HCl to pH 2-3, and concentrated to remove most of solvent. The resulting precipitate was washed by water, dried to give the carboxylic acid, 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (27.3 g, 91%). LC-MS: (ESI, m/z)=494 [M+1]+
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].C[N+](C)(C)[CH2:31][C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.[OH-].[Na+]>C(OCCOCCOCC)C>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: C[N+](C)(C)Cc1ccco1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCCOCCOCC
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccco2)c1Oc1ccccc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 3-mercapto-4-phenoxy-5-sulfamylbenzoic acid (1.6 g) in diethylene glycol diethyl ether (15 ml), anhydrous potassium carbonate (0.5 g) and trimethylfurfurylammonium iodide (2 g) were added. The resulting mixture is stirred at 110°C. for 4 hours, cooled and poured into 0.3 N sodium hydroxide (75 ml). After extraction twice with diethyl ether, the aqueous layer is adjusted to pH 3 by addition of acetic acid. The reaction product is extracted with ethyl acetate, and the resulting organic solution is evaporated in vacuo. The residue is triturated with aqueous acetone giving rise to crystallisation. The 3-(2-furylmethylthio)-4-phenoxy-5-sulfamylbenzoic acid thus obtained is recrystallized from aqueous ethanol and dried. The compound is obtained with a melting point of 214°-216°C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1)C1C=CC=CC=1.[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:43][CH2:42]1>>[CH2:28]([N:27]1[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:53]4[CH2:52][CH2:51][N:50]([CH2:49][CH2:48][CH2:47][N:44]5[CH2:43][CH2:42][O:41][CH2:46][CH2:45]5)[CH2:55][CH2:54]4)=[O:39])[CH:33]=3)[CH:11]=2)=[N:24][N:25]=[N:26]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C(CN1CCNCC1)CN1CCOCC1
Product: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCN(CCCN4CCOCC4)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid and 1-(3-morpholinopropyl)-piperazine as described in general procedure D. LCMS: 550 [M+H].
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]1[CH:16]=[C:17]([C:22]2([OH:32])[CH2:26][CH2:25][N:24]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:23]2)[CH:18]=[C:19](F)[CH:20]=1>>[F:14][C:15]1[CH:20]=[C:19]([S:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]3)[CH:18]=[C:17]([C:22]2([OH:32])[CH2:26][CH2:25][N:24]([CH2:27][C:28]([F:29])([F:30])[F:31])[CH2:23]2)[CH:16]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCN(CC(F)(F)F)C1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Product: CN1C(=O)CCc2cc(Sc3cc(F)cc(C4(O)CCN(CC(F)(F)F)C4)c3)ccc21
Yield: 30 %

Procedure:
Using an analogous procedure to that described in Example 6, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 3-(3,5-difluorophenyl)-3-hydroxy-1-(2,2,2-trifluoroethyl)pyrrolidine to give 3-[5-fluoro-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-3-hydroxy-1-(2,2,2-trifluoroethyl)pyrrolidine as a gum in 30% yield.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3[C:26]([CH2:41][O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[C:27]([C:38](O)=[O:39])[CH:28]=[C:29]4[C:37]=3[C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=[CH:30]4)=[CH:24][C:19]=2[O:18][CH2:17]1.[CH2:50]([O:57][CH2:58][CH2:59][CH2:60][NH2:61])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:50]([O:57][CH2:58][CH2:59][CH2:60][NH:61][C:38]([C:27]1[CH:28]=[C:29]2[C:37](=[C:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)[C:26]=1[CH2:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:33]1[O:34][CH2:35][O:36][C:32]=1[CH:31]=[CH:30]2)=[O:39])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: NCCCOCc1ccccc1
Reactant: O=C(O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCCCOCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A 60% sodium hydride dispersion in mineral oil (4 g, 0.1 mol) in a small portion at room temperature was added to a stirred solution of 3-amino-1-propanol (7.51 g, 0.1 mol) in THF (150 mL). The mixture was stirred for 30 min under nitrogen, and benzyl bromide (11.9 mL, 0.1 mol) was added. The mixture was stirred for 10 h at room temperature, and concentrated in vacuo. The residue was partitioned between 1 N aqueous HCl solution and CH2Cl2. The aqueous layer was adjusted to pH 10 with 10% aqueous NaOH solution, and extracted with CH2Cl2 (3×100 mL). The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2/MeOH (3:1 to 2:1, v/v) to give 3-(benzyloxy)propylamine (1.37 g, 8.3%) as a yellow oil. 1,3-Dicyclohexylcarbodiimide (14.4 mg, 0.07 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise to a mixture of 5 (32 mg, 0.07 mmol) and 3-(benzyloxy)propylamine (11.6 mg, 0.07 mmol), and 1-hydroxybenzotriazole hydrate (9.5 mg, 0.07 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 18 h at room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2/MeOH (30:1, v/v) to afford 8 (36 mg, 85%) as a pale yellow liquid. 1H NMR (CDCl3) δ 8.05 (s, 1H, H4), 7.44 (d, 1H, H5, J=8.7 Hz), 7.19-7.28 (m, 11H, H6+2×OCH2Ph), 6.78-6.82 (m, 3H, H2′+H5′+H6′), 6.06 (AB, 2H, 3′,4′-OCH2O—, Δδ=6.9 Hz, J=1.5 Hz), 5.84 (AB, 2H, 7,8-OCH2O—, Δδ=4.2 Hz, J=1.5 Hz), 4.45 (s, 4H, 2×OCH2Pb), 4.38 (s, 2H, 2-CH2OBn), 3.55 (m, 4H, 3-CONHCH2CH2CH2OBn), 1.87 (quintet, 2H, 3-CONHCH2CH2CH2OBn. J=6.3 Hz); MS (FAB, positive) m/z 604 [M+H]+.