Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:20][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]3)[NH:12][C:11](=[O:21])[C:10]=2[CH:22]=1.[OH-].[Na+]>O.O1CCOCC1>[CH3:19][N:15]1[CH2:16][CH2:17][CH2:18][C:13]2([NH:12][C:11](=[O:21])[C:10]3[CH:22]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:23])=[O:2])[CH:7]=[CH:8][C:9]=3[O:20]2)[CH2:14]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C)C1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Yield: 98.3 %

Procedure:
A solution of (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (220 mg, 0.70 mmol) in water (8 ml) and dioxane (16 ml) was treated with 1 M NaOH (0.90 ml) as described in Example 30, Step A to give (±)-(E)-3-{1′-methyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (208 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)[CH3:12].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([Cl:8])=[C:6]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([CH2:11][CH3:12])=[CH:14][CH:15]=2)=[O:18])[CH:7]=1
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(Cl)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of 1-bromo-4-chloro-2-methoxybenzene (5.1 g, 23 mmol) and 4-ethylbenzoyl chloride (4.1 g, 24 mmol) in 15 mL of anhydrous dichloromethane (DCM) was added aluminum trichloride (3.2 g, 24 mmol). The mixture was stirred at room temperature for 1 hour, followed by heating at reflux for 18 hours. The mixture was poured into 100 mL of ice-cold water and the organic layer was isolated. The aqueous solution was extracted with 25 mL DCM. The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and evaporated. Recrystallization from petroleum ether gave the intermediate (5-bromo-2-chloro-4-methoxyphenyl)(4-ethylphenyl)methanone 21 (5.6 g, 69%).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH3:32])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][N:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=[O:51].C(OCC)(=O)C>C(Cl)Cl>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH3:32])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]([OH:51])=[O:18])=[CH:12][N:13]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCO)cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC1CCCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
3-(2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propan-1-ol (140 mg) is dissolved in methylene chloride (2 ml), and thereto is added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (188 mg) at room temperature and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in the mixed solvent of tert-butanol (4 ml) and water (1 ml) and thereto are added 2-methyl-2-butene (128 μl), sodium dihydrogenphosphate dihydrate (44 mg) and sodium chlorite (73 mg) and the mixture is stirred at room temperature for 30 minutes. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:3) to give 3-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propionic acid (60 mg). The resulting carboxylic acid is dissolved in ethanol (0.5 ml), and thereto is added 1N-aqueous sodium hydroxide solution (85 μl) and the reaction solution is concentrated under reduced pressure to give 3-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexylmethyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-propionic acid sodium salt (60 mg). MS (m/z): 705 [M−Na]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1(Br)[CH:9]=[CH:8][CH:7]=[N:6][CH2:5]1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)C1(Br)C=CC=NC1
Solvent: C1COCCO1
Product: COC(=O)c1cncc(-c2ccsc2)c1
Temperature: 90 °C

Procedure:
Methyl-3-bromo-nicotinate and 3-thiophene boronic acid were dissolved in degassed dioxane (25 mL). To the homogeneous solution was added Pd((Ph3)4P)). The reaction was heated to 90° C. for 18 hours and then cooled to room temperature and concentrated. The residue was taken up into EtOAc and water. The layers were then separated and the organics washed with brine and dried (MgSO4). Flash LC (60% Hexanes/EtOAc) gave the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([OH:21])=O)=[CH:11][C:12]=3[C:13]3(OCCC[O:14]3)[C:5]2=[N:4][CH2:3]1.[O:24]([CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([N:33]4[CH2:34][CH2:35][CH2:36][C@H:32]4[CH2:31][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:21])=[CH:11][C:12]=3[C:13](=[O:14])[C:5]2=[N:4][CH2:3]1
Reactant: CC1(C)CN=C2N(C1)c1ccc(C(=O)O)cc1C21OCCCO1
Reactant: c1ccc(OC[C@@H]2CCCN2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CN=C2C(=O)c3cc(C(=O)N4CCC[C@H]4COc4ccccc4)ccc3N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]-8′-carboxylic acid (0.090 g, 0.284 mmol) in CH2Cl2 (7 mL) was added (2S)-2-(phenoxymethyl)pyrrolidine (0.75 g, 0.427 mmol), DCC (0.082 g, 0.039 mmol), HOBT (0.038 g, 0.281 mmol) and Et3N (0.045 mL, 0.277 mmol) and the solution stirred overnight at rt. The reaction was filtered through 1 cm of silica gel washing with EtOAc. The filtrate was dried over Na2SO4, filtered, concentrated and purified on silica gel eluting with acetone/hexane (30/70). The resulting white foam was dissolved in CH2Cl2 (1.5 mL) and methanesulfonic acid (1 mL) was added and the solution was stirred at rt overnight. The reaction was poured onto ice, basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (35/65) to give the title compound as a yellow foam (0.021 g, 20%). NMR (400 Mz, DMSO-d6): consistent. MS (ES+) m/z 418.3 [M+H].
Reaction SMILES: CCCCCCC.B(Br)(Br)Br.C([O:19][C@@H:20]1[C@@H:25]([O:26]CC2C=CC=CC=2)[C@H:24]([O:34]CC2C=CC=CC=2)[C@@H:23]([CH2:42][O:43]CC2C=CC=CC=2)[O:22][C@H:21]1[C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][C:58]2[C:67]3[C:61]([CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[C:60]([CH3:68])[CH:59]=2)[CH:52]=1)C1C=CC=CC=1.C(Cl)Cl.C1(C)C=CC=CC=1>C(Cl)Cl.CO>[CH3:68][C:60]1[CH:59]=[C:58]([CH2:57][C:53]2[CH:52]=[C:51]([C@@H:21]3[O:22][C@H:23]([CH2:42][OH:43])[C@@H:24]([OH:34])[C@H:25]([OH:26])[C@H:20]3[OH:19])[CH:56]=[CH:55][CH:54]=2)[C:67]2[C:61]=1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2
Reactant: Cc1cc(Cc2cccc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)c2cccccc1-2
Agent: BrB(Br)Br
Solvent: CO
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cc1cc(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)c2cccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
A 1 M n-heptane solution of boron tribromide (20 ml) was added dropwise to a solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-[(3-methylazulen-1-yl)methyl]phenyl]-D-glucitol (0.76 g) in methylene chloride (20 ml) at −78° C. and the mixture was stirred for 30 minutes. Methylene chloride-toluene (ratio: 2:1, 60 ml) was added to the reaction mixture and methanol (6 ml) was further added to the mixture. The reaction mixture was cooled to room temperature and concentrated to the half amount, followed by adding methanol (25 ml) to the mixture and concentrating. This operation was repeated three times. The residue prepared by the concentration was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[3-[(3-methylazulen-1-yl)methyl]phenyl]-D-glucitol (0.068 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:27])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C=CCCCNC(=O)C3CCCC3)c2CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCCCCNC(=O)C3CCCC3)c2CC1

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-[5-(cyclopentanecarbonyl-amino)-pent-1-enyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as obtained in the previous step in EtOAc (20 mL) and add 10% Pd/C (Degussa type, 200 mg). Then apply a pressure of 70 psi of hydrogen while shaken vigorously. Filter the crude mixture through a short pad of Celite® and concentrate in vacuo. Purify the resulting material by preparative HPLC to obtain the desired intermediate as a clear oil (311 mg, 87% for the two previous steps). MS (ES+) m/z=485.2 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10]([O:12]CC)=[CH2:11])[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19][C:20](=[O:22])[CH3:21].Cl.CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19][C:20](=[O:22])[CH3:21]
Reactant: C=C(OCC)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of crude 2-acetylamino-5-(1-ethoxy-vinyl)-4-trifluoromethyl-benzoic acid methyl ester from above in THF (100 mL) was treated with aqueous hydrochloric acid (1N, 50 mL), and the mixture was stirred at r.t. for 1 h under nitrogen. The mixture was then poured into EtOAc and washed once with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel 60, hexanes/EtOAc 2:1) to give 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (10.7 g, 35.1 mmol, 76% over two steps) as a white powder, m.p. 66-69° C., ESI-MS: m/z 326 [M+Na]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(#N)C>CCO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 81.9 %

Procedure:
In a 100 ml flask were placed fluvastatin methyl ester (2.42 g), EtOH (5 ml) and a solution of NaOH (0.23 g) in EtOH (7 ml). The mixture was stirred at reflux for 2.5 h and acetonitrile (50 ml) was added. The slurry was stirred at reflux for another 3 h then cooled to room temperature and stirred over night. The product was isolated by filtration under nitrogen and dried at 50EC in a vacuum oven for 24 h to obtain 2.02 g (83%) of fluvastatin sodium crystal Form XLVI.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1.C.[H][H]>CO.[Pt]=S>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: S=[Pt]
Solvent: CO
Product: COC(=O)C=Cc1cccc(N)c1
Reaction time: 2 h
Yield: 100.6 %

Procedure:
50 g of 3-nitrocinnamic acid methyl ester in 350 ml of methanol are hydrogenated in the presence of 1.5 g of the platinum sulphide catalyst described in Example 6 (5% strength on active charcoal) for 2 hours at 70° C and one half hour at 80° C under 130 bars hydrogen pressure in a stirred autoclave of 700 ml capacity. The pressure drop has ceased after 2 hours. The solution is freed from the catalyst and evaporated. 43 g of crystalline 3-aminocinnamic acid methyl ester of melting point 75° C are obtained.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH3:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:9][C:8]=1[O:14][CH3:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(O)ccc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OCC(=O)OC(C)(C)C)ccc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a suspension of 60% sodium hydride (96 mg, 2.4 mmol) in tetrahydrofuran (THF) (10 ml) was added 4-tert-butyl-3-methoxyphenol (360 mg, 2 mmol) at 0° C., followed by additional stirring for 30 minutes. Then, tert-butyl bromoacetate (468 mg, 2.4 mmol) was added and the mixture was refluxed at 80° C. for 1 hour. The reaction was then quenched with saturated aqueous solution of ammonium chloride and the crude product was extracted with ethylacetate. The organic layer was separated, washed with brine, dried over magnesium sulfate. Then, filtration, evaporation to remove the solvent under reduced pressure gave the residue, which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethylacetate (20/1 to 4/1) to furnish 466 mg (79% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.O.[NH2:16][NH2:17]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:16][NH2:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)c(Cl)nn1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(N2CCOCC2)c(Cl)nn1
Yield: 73.6 %

Procedure:
A mixture of 4-(3,6-dichloropyridazin-4-yl)morpholine (5 g, 21.3 mmol) and hydrazine hydrate (7.0 ml, 141 mmol) in 1,4-dioxan (100 ml) was stirred and heated at reflux for 20 hours. Upon cooling the 1,4-dioxan was removed in vacuo. The residue was then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous layer was further extracted with dichloromethane (x2). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol/aqueous ammonia (91:8:1) to give 6-chloro-5-(morpholin-4-yl)-pyridazine-3-ylhydrazine (3.6 g, 74%): 1H NMR (250 MHz, d6-DMSO) δ3.37-3.17 (4 H, m), 3.72-3.77 (4 H, m), 4.31 (2 H, br s), 6.58 (1 H, s), 7.97 (1 H, br s); MS (ES+) m/e 230, 232 [MH+].
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:20]/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24].[OH-].[Na+]>C(OCC)(=O)C.O>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: CCOC(=O)/C=C/CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
2-(Benzylamino)ethanol (19.05 ml, 132 mmol) and triethylamine (18.44 ml, 132 mmol) was added to water (150 ml) and the resulting mixture was heated to reflux temperature. (E)-Ethyl 4-bromobut-2-enoate (18.24 ml, 132 mmol) was added dropwise for 10 min The resulting mixture was further maintained at reflux temperature for 5 h. The reaction mixture was cooled to 25° C. and added NaOH (5.29 g, 132 mmol) after that the solvent was removed by distillation under reduced pressure to give orange oil. Ethyl acetate (150 mL) was added and the resulting solution was washed with water (2×50 mL). Ethyl acetate was distilled off under reduced pressure to give crude compound (15 g). This crude compound was purified by flash chromatography (Biotage) using eluent 20% ethyl acetate in hexane to yield 13 g of pure title compound as colorless viscous oil. m/z 264.08.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(=O)=O.C(Cl)(Cl)Cl.CS(C)=O.[C:18]([O:22][C:23]([N:25]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[N:34]=1)[CH:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][OH:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Br:39][C:35]1[N:34]=[C:33]([CH2:32][N:25]([CH:26]([CH:27]=[O:28])[CH:29]([CH3:30])[CH3:31])[C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)C(CO)N(Cc1cccc(Br)n1)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CC(C)C(C=O)N(Cc1cccc(Br)n1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a flame-dried flask was added oxalyl chloride (70 μL) followed by the addition of dry CH2Cl2 (2 mL). The resulting colorless solution was brought to −63° C. (dry ice/CHCl3) and a solution of DMSO (70 μL) in 0.5 mL dry CH2Cl2 was slowly added drop wise. The (tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-[2-hydroxy-1-(methylethyl)ethyl]carboxamide (0.19 g, 0.51 mmol), previously dissolved in dry CH2Cl2 (2 mL), was added slowly dropwise. The resulting mixture was kept at −63° C., and stirred for 30 min followed by the slowly addition of a solution of TEA (0.3 mL) in dry CH2Cl2 (1 mL). The mixture was stirred at −63° C. until all the starting material was consumed (checked by MS)(1.5 h). The mixture was brought to −20° C., quenched with a saturated solution of NH4Cl (15 mL) and diluted with EtOAc (35 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×30 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation without further purification to afford the title compound as a yellow-semi solid. EI-MS m/z 371 (M+H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][NH2:12])[CH2:2]1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][NH:12][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH2:2]1
Reactant: NCC1COc2ccccc2C1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCC3COc4ccccc4C3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using chroman-3-ylmethanamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 545 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[S:29]([C:25]1[CH:24]=[C:23]([NH:22][C:19]([C:18]2[CH:17]=[N:16][N:11]3[C:12]([CH2:14][CH3:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:20])[CH:28]=[CH:27][CH:26]=1)(=[O:30])(=[O:31])[NH2:32]
Reactant: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(N)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-ethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.26) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISN) 454.3 [(M−H)−]; mp 252-253° C.
Reaction SMILES: [CH3:1][NH2:2].Cl[S:4]([C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][CH:13]([CH3:15])[CH2:12][C:11]=2[CH:16]=1)(=[O:6])=[O:5].[OH-].[Na+]>O>[CH3:1][NH:2][S:4]([C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][CH:13]([CH3:15])[CH2:12][C:11]=2[CH:16]=1)(=[O:6])=[O:5]
Reactant: CN
Reactant: CC1Cc2cc(S(=O)(=O)Cl)cc(C(=O)O)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNS(=O)(=O)c1cc2c(c(C(=O)O)c1)OC(C)C2
Temperature: 5 °C

Procedure:
108 g of a 40% aqueous solution of methylamine and 108 ml of water were added into a 2-liter round-bottomed flask. The contents were cooled to 5° C. and 193 g of 5-chlorosulphonyl-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were then added in portions of 10 g, while cooling in an ice and salt bath so as to maintain the temperature at 5° C. After each addition of acid, 14.5 ml of a solution containing 140 ml of 30% sodium hydroxide in 140 ml of water were added.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O>[CH2:1]([N:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: OCCCCCCBr
Reactant: CCNc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCN(CCCCCCO)c1ccc(Br)cc1
Temperature: 110 °C
Yield: 100 %

Procedure:
36.8 g (184.1 mmols) of N-ethyl-4-bromoaniline, 48.1 ml (1.5-fold equivalent weight) of N,N-diisopropylethylamine and 28.9 ml (1.2 equivalent) of 6-bromohexanol were mixed, and the mixture obtained was heated at 110° C. for 14 hours in an atmosphere of argon. Water was added to the reaction solution obtained, which was then extracted with ethyl acetate. The organic layer obtained was dried with anhydrous magnesium sulfate and then concentrated. The residue thus obtained was heated under reduced pressure (160° C./0.3 torr), and the components distilled out were removed to obtain 55.6 g of crude N-ethyl-N-(6-hydroxyhexyl)-4-bromoaniline (yield: 100%; a dark-brown oily liquid).