Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([O:6][CH3:20])=[O:5]
Reactant: N[C@H](CC(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cccc([N+](=O)[O-])c1

Procedure:
(R)-3-amino-3-(3-nitrophenyl)propionic acid is esterified in analogy to Example 2 by activation with thionyl chloride and reaction with methanol under standard conditions to give methyl 3-amino-3-(3-nitrophenyl)propionate, which is reacted with BOC-Gly-OH and 4-(4-methylpyridin-2-ylamino)butyric acid. Cleavage of the ester results in (R)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-nitrophenyl)propionic acid. Use of an excess of NaOH results in the sodium salt of (R)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-nitrophenyl)propionic acid. Preparative HPLC results in (R)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-nitrophenyl)propionic acid trifluoroacetate, RT* 16.89 min, FAB-MS (M+H)+ 444.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](Cl)=[O:11])=[CH:2]1.[N:13]12[CH2:20][CH2:19][C:16]([CH2:21][NH2:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2>C(Cl)Cl>[N:13]12[CH2:20][CH2:19][C:16]([CH2:21][NH:22][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:11])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: NCC12CCN(CC1)CC2
Solvent: ClCCl
Product: O=C(NCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
To a solution of 1H-indole-3-carbonyl chloride (112 mg, 0.625 mmol) in 3 mL of methylene chloride at 0° C. was added (quinuclidin-4-yl)methanamine (86 mg, 0.614 mmol) in 2 mL of methylene chloride. The mixture was stirred at room temperature overnight. The solvent was evaporated and water (20 mL) was added. The water layer was basified to pH 12 with 10% aqueous potassium hydroxide and extracted three times with 25 mL each of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield 26 mg of the desired product. 1HNMR: 11.6 (bs, 1H); 8.15 (m, 1H); 8.13 (bs, 1H); 7.65 (bs, 1H); 7.42 (d, 1H); 7.15 (m, 2H); 3.1 (m, 2H); 2.65 (m, 6H); 1.40 (m, 6H). MS (m/e): 284.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[N:12]1([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C)P(=O)(N(C)C)N(C)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][N:15]2[CH2:14][CH2:13][N:12]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[CH:29][CH:30]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCOC(=O)c1ccc(N2CCN(CC=Cc3ccc(Cl)cc3)CC2)cc1
Reaction time: 5 h
Yield: 48 %

Procedure:
A mixture of 9.4 g. (50 mmole) 4-chlorocinnamyl chloride and 13.1 g. (50 mmole) n-butyl 4-(piperazin-1-yl)-benzoate in 40 ml. hexamethylphosphoric acid triamide is heated for 10 hours to 60° C., 6.9 g. (50 mmole) potassium carbonate are added thereto and stirring continued for 5 hours at 60° C. After cooling, the reaction mixture is diluted with the tenfold amount of water, the organic components are taken up in ethyl acetate and the dried ethyl acetate solution is evaporated. The residue is recrystallised from methanol to give 10.0 g. (48%) of desired product; m.p. 115°-117° C. The hydrochloride melts at 166°-168° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.Cl.[OH:25][CH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[NH2:33]>>[OH:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[NH:33][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: N[C@@H]1CCCC[C@H]1CO
Agent: Cl
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCCCC3CO)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 85, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and trans-2-hydroxymethyl-1-cyclohexylamine hydrochloride (121 mg; 0.73 mmol; 5.0 eq.) as a white solid (32 mg, 50%). HPLC, Rt: 3.00 min. (purity 89.6%). LC/MS, M+(ESI): 435.1, M−(ESI): 433.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH:24]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu]Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][C:25]=3[O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[CH:14]=2)=[CH:8][C:7]=1[CH3:20]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1F
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3F)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
A solution of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.66 g, 2 mmol), 4-chloro-2-(2-fluoro-phenoxy)-phenol (0.3 g, 1.3 mmol), copper(I) chloride (0.06 g, 0.6 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.06 mL, 0.3 mmol), and cesium carbonate (0.82 g, 2.5 mmol) in NMP (10 mL) is heated to 120° C. The reaction is stirred overnight, and then is cooled to room temperature. The reaction is then quenched with 1N aqueous hydrochloric acid and extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent removed. The crude is purified by silica gel column chromatography using 9/1 hexanes/ethyl acetate to elute the pure product. The solvent is removed to afford about 0.072 g (11%) of the desired product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H24ClFO5 506, found 524 (M+NH4, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[OH:14])([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]=1[O:14][CH3:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c([N+](=O)[O-])cccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a suspension of compound 17A (1.4 g, 6.76 mmol) and K2CO3 (1.4 g, 10 mmol) in DMF (60 mL) was added iodomethane (0.46 mL, 7.44 mmol). After the addition, the mixture was stirred at 40° C. overnight, then cooled to rt, partitioned between ether and water. The separated ether layer was washed with water and brine, then dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 10% EtOAc/hexane to yield the title compound (1.38 g, 92% yield).
Reaction SMILES: Cl[Si](C)(C)[CH3:3].[C:6]1([C:12]2[N:13]([CH2:29][C:30]([OH:32])=[O:31])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH3:3][O:31][C:30](=[O:32])[CH2:29][N:13]1[C:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=[C:12]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cn1c(-c2ccccc2)ccc1-c1ccc(N2CCCCC2)cc1
Solvent: CO
Product: COC(=O)Cn1c(-c2ccccc2)ccc1-c1ccc(N2CCCCC2)cc1
Temperature: 65 °C

Procedure:
Chlorotrimethylsilane (275 mmol, 35 uL) is added dropwise to a cooled (0° C.) solution of [2-phenyl-5-(4-piperidin-1-yl-phenyl)-pyrrol-1-yl]-acetic acid (228 mmol) in methanol (anhydrous, 150 uL). The reaction is capped and allowed to heat/shake overnight at 65° C. The reaction is concentrated purified by flash chromatography over silica gel (3:1 methanol:methylene chloride). 64 mg of isolated product is confirmed by LCMS.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[N:10]=2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[N:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(NCCCO)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Yield: 74.4 %

Procedure:
A solution of 8.66 g (29.8 mmol) 3-[4-(4-Nitro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in a mixture of 173 ml THF and 173 ml methanol was hydrogenated over 3.46 g of 10% palladium on charcoal for 8 h. The catalyst was filtered off and the filtrate evaporated. The obtained oil was treated with a small amount of THF and the precipitate removed by filtration. Evaporation of the filtrate gave an oil that was purified by chromatography on silica (dichloromethane/ethanol 95:5) to give 5.77 g (74%) of 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol as colorless oil.
Reaction SMILES: C([N:8]1[C:12]([C:13]2([CH2:23][CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:22])[CH:19]=3)[CH2:14]2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH2:23]([C:13]1([C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:22])[CH:19]=2)[CH2:14]1)[CH3:24]
Reactant: CCC1(c2cncn2Cc2ccccc2)Cc2ccc(F)cc2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCC1(c2c[nH]cn2)Cc2ccc(F)cc2C1
Temperature: 25 °C

Procedure:
53 mg of 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole, 20 mg of Pd/C, 51 mg of ammonium formate and 2 ml of ethanol were added under nitrogen atmosphere into a round-bottomed flask equipped with a thermometer and a stirring bar. The reaction mixture was stirred at reflux temperature for 6 hours. The mixture was filtered and the filter (Celite™) was washed with ethanol. The reaction mixture was placed back into a round-bottomed flask and an additional 20 mg of Pd/C and 51 mg of ammonium formate were added under nitrogen atmosphere. The mixture was heated to reflux temperature and refluxed for 2 hours. Then the mixture was cooled to room temperature and filtered. The filter (Celite™) was washed with ethanol and after evaporation to dryness, whereby 4-(2-ethyl-5-fluoro-indan-2-yl)-1H-imidazole was obtained. The analytical sample was purified using TLC-plates. The purity was measured by HPLC: 60%. Normally the crude product was used in the following step.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[NH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].[BH4-].[Na+]>CO.CCOC(C)=O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([NH2:9])=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN1CCN(Cc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
To a stirred solution of 1-ethyl-piperazine (1.37 g, 12 mmol) in MeOH (30 mL) was added Ti(OiPr)4 (1.73 g, 6 mmol). Then the solution was stirred at room temperature for 15 min. Then 4-amino-3-nitro-benzaldehyde (Procedure 2F, steps a-b, 1.5 g, 9 mmol) in MeOH (10 mL) was added and the solution was stirred at room temperature overnight. Then NaBH4 (380 mg, 10 mmol) was added and the solution was stirred at room temperature for 1 hour. The solution was diluted with EtOAc and filtered. The filtrate was washed with water and brine, dried over anhydrous Na2SO4. Concentration gave product, which was purified by flash chromatography on silica to obtain the title compound (800 mg, yield: 34%). MS (ESI): 265 [M+H]+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=4)[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1.[C-:27]#[N:28].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][C:17]4[CH:18]=[C:19]([CH2:23][C:27]#[N:28])[CH:20]=[CH:21][CH:22]=4)[CH2:14][CH2:15]3)[S:9][C:5]=2[CH:4]=1
Reactant: ClCc1cccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCc1cccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
The mixture of 6-chloro[4-(3-chloromethylbenzyl)piperazine-1-yl]benzothiazole monohydrochloride (0.50 g; 1.27 mmol) and sodium cyanide (0.19 g; 3.82 mmol) in anhydrous N,N-dimethylformamide (5 ml) were stirred at 40° C. for 1.5 hours. After cooling, water and ethyl acetate were added to the reaction solution. The organic layer was separated and washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure and the percipitate was washed with diisopropyl ether to give {3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]phenyl}acetonitrile as pale blackish brown crystal (0.35 g; 72%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[ClH:20].[Cl:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ccn2)CC1
Agent: Cl
Product: Clc1ccnc(N2CCNCC2)c1
Reaction time: 3 h

Procedure:
Treat a room temperature solution of 4-(4-chloro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.6 g, 1.9 mmol) in CH2CL2 (4 mL) with HCl (4 N solution in dioxane, 1.5 mL, 5.9 mmol) resulting in a slight exotherm. Stir the mixture for 3 hours, add additional HCl (4 N solution in dioxane, 1.5 mL, 5.9 mmol), and stir overnight. Concentrate under reduced pressure to afford 1-(4-chloro-pyridin-2-yl)-piperazine hydrochloride, then titurate with Et2O (0.43 g). LCMS ES+(m/z) 198 [M+H]).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[CH:11]=[CH:10][CH2:9][C@H:8]([C:12]#[N:13])[O:7]1)(=[O:3])[CH3:2].C(OC[C@@H]1CC=C[C@H](C#N)O1)(=O)C>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]#[N:13])[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1C=CC[C@H](C#N)O1
Agent: [Pd]
Agent: CC(=O)OC[C@@H]1CC=C[C@H](C#N)O1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@H]1CCC[C@H](C#N)O1
Temperature: 23 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
To a dry THF (200 mL) solution containing ((2R,3S,6R)-3-acetoxy-6-cyano-3,6-dihydro-2H-pyran-2-yl)methyl acetate (5.5 g, 23 mmol), diphenylsilane (8.47, 46 mmol) and zinc chloride (7.52 g, 55.2 mmol) was added after N2 bubbling, Pd(PPh3)4 (2.66 g, 2.30 mmol). The reaction mixture was stirred at 23° C. for 4 h. (monitored by TLC). The reaction mixture was filtered through a short silica gel column using CH2Cl2 as solvent. The solvent was removed under reduced pressure and the crude material was purified by a silica gel column (Biotage flash chromatography system) using ethyl acetate:hexane (1:5) to (1:2) to afford 2.8 g (67% yield) mixture of ((2S,6R)-6-cyano-5,6-dihydro-2H-pyran-2-yl)methyl acetate and((2S,6R)-6-cyano-3,6-dihydro-2H-pyran-2-yl)methyl acetate. 1H NMR (400 MHz, CDCl3) δ ppm 6.06-6.15 (0.5 H, m, J=7.6, 5.3, 2.8, 2.8 Hz), 5.93-6.02 (0.5 H, m, J=10.4, 5.2, 2.6, 2.6 Hz), 5.69-5.79 (1 H, m), 4.54 (0.5 H, dd, J=9.9, 3.8 Hz), 4.48 (0.5 H, m), 4.11-4.23 (2 H, m), 3.89 (1 H, m), 2.59-2.69 (1 H, m), 2.33-2.42 (1 H, m,), 2.16-2.22 (1 H, m), 2.14 (3 H, s), 2.12 (3H, s). To the mixture of ((2S,6R)-6-cyano-5,6-dihydro-2H-pyran-2-yl)methyl acetate and ((2S,6R)-6-cyano-3,6-dihydro-2H-pyran-2-yl)methyl acetate. (2.6 g, 14.4 mmol) in ethyl acetate (200 mL) was added Pd/C (5%) (0.200 g). The reaction mixture was stirred at 23° C. for 6 h. under a hydrogen atmosphere (balloon). The Pd/C was then removed by filtration and the solvent evaporated in vacuo to afford 2.20 g (84% yield) of the target compound. 1H NMR (400 MHz, CDCl3) δ ppm 4.28 (1 H, dd, J=11.7, 2.7 Hz), 4.03-4.14 (2 H, m), 3.59-3.67 (1 H, m), 2.11 (3 H, s), 1.94-2.04 (2 H, m), 1.80-1.91 (1 H, m), 1.54-1.65 (2 H, m), 1.33-1.45 (1 H, m).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]([O:13][C:14]2[CH:31]=[CH:30][C:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22][C:16]=3[CH:15]=2)=[N:11][CH:12]=1)=[O:6].Cl.O>CC(C)=O>[CH3:29][C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][C:17]2[CH:30]=[CH:31][C:14]([O:13][C:10]3[N:11]=[CH:12][C:7]([C:5]([OH:6])=[O:4])=[N:8][CH:9]=3)=[CH:15][C:16]=2[CH2:22][CH2:21]1)=[O:24])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3cnc(C(=O)O)cn3)cc2CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 96.2 %

Procedure:
2M Sodium hydroxide solution (110 ml) was added to a solution of 1,1-dimethylethyl 7-({5-[(methyloxy)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D49, Step 1) (29.38 g, 73.6 mmol) in acetone (480 ml) and the resulting mixture was stirred at room temperature for 25 minutes. The mixture was acidified with 2M hydrochloric acid and then poured into water (2 L). The resulting white solid was collected by filtration, washed with water and dissolved in ethyl acetate (1 L). This solution was dried under sodium sulfate and evaporated in vacuo to give the title compound (27.3 g); MS (ES+) m/e 384 [M−H]+.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][CH:10]([O:16][CH3:17])[C:11]([CH3:15])([OH:14])[CH:12]=[CH2:13].[CH3:18][O-:19].[Na+].[CH3:21][OH:22]>>[CH3:8][O:9][CH:10]([O:16][CH3:17])[C:11]([CH3:15])([OH:14])[CH:12]=[CH2:13].[CH3:8][O:9][CH:10]([O:16][CH3:17])[C:11]([CH3:15])([O:14][C:18]([O:22][CH3:21])=[O:19])[CH:12]=[CH2:13]
Reactant: C[O-]
Reactant: CO
Agent: C=CC(C)(O)C(OC)OC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC(C)(OC(=O)OC)C(OC)OC
Reaction time: 8 h

Procedure:
1,000 parts of toluene and 292 parts of 1,1-dimethoxy-2-methyl-2-hydroxy-3-butene are taken, 437 parts of a 30 percent strength solution of sodium methylate in methanol are then added slowly at from 90° to 100° C. and at the same time the methanol is distilled off, until the internal temperature reaches 107° C. 236 parts of methyl chlorocarbonate are subsequently added at 30° C. and stirring is continued for 8 hours. The mixture is then stirred with 500 parts of water, after which the organic phase is separated from the aqueous phase. Working up the organic phase by distillation gives, in addition to unconverted 1,1-dimethoxy-2-methyl-2-hydroxy-3-butene, 348 parts of 1,1-dimethoxy-2-methyl-2-(methoxycarbonyloxy)-3-butene, of boiling point/20 mm Hg=107°-110° C. The yield is 85% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([OH:26])[CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:20]=2)(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: CO
Product: O=S(=O)(Nc1cccc(C(O)CN2CCOCC2)c1)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 1 M morpholine in methanol, a mixture of regioisomers was obtained. Reverse-phase HPLC was used to purify the mixture and the title compound was obtained as a pale orange powder. 1H NMR (300 MHz, CDCl3): δ 2.20-2.40 (3H, m), 2.50-2.70 (2H, m), 3.60-3.80 (4H, m), 4.66 (1H, m), 6.85-7.00 (2H, m), 7.03-7.19 (3H, m), 7.20-7.30 (1H, m), 7.30-7.40 (1H, m), 7.57 (2H, d, J=8 Hz) and 7.91 (2H, d, J=8 Hz). MS, m/z: Calcd, 474.142. Found, 474.56 (M).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][NH2:12]>>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][N:11]=[C:7]2[NH2:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: NN
Product: Nc1n[nH]c2ccc(Br)cc12
Temperature: 100 °C
Yield: 99.5 %

Procedure:
To a 250 mL round-bottom flask was added 5-bromo-2-fluorobenzonitrile (15.54 g, 77.7 mmol) and hydrazine (124 g, 3885 mmol). The reaction mixture was heated to 100° C. for 5 minutes. The hydrazine was then removed under reduced pressure to give 5-bromo-1H-indazol-3-amine (16.4 g, 99.5% yield). MS m/z: 213 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[CH:6][CH:7]([N:16]([CH3:33])[C:17](=[O:32])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)C.O.[OH-].[Li+].O.Cl>C1COCC1.CO.O>[CH3:33][N:16]([CH:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH:6]=[CH:5][C:4]([OH:34])=[O:3])[C:17](=[O:32])[C:18]1[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1
Reactant: CCOC(=O)C=CC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)Cc1ccc(Cl)cc1

Procedure:
A solution of 20 g of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pent-2-enoic acid ethyl ester and 15 g of lithium hydroxide monohydrate in 100 ml of THF/methanol/water 3:3:1 is stirred at room temperature for 4 hours, and then 200 ml of water and 1N hydrochloric acid are added (pH value approx. 2). The mixture is extracted twice with ethyl acetate. The combined organic phases are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. The title compound is obtained in the form of a colourless oil which can be used further without being further purified.