Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][O:46][CH:47]1[CH2:50][NH:49][CH2:48]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13]([N:49]2[CH2:50][CH:47]([O:46][CH3:45])[CH2:48]2)=[O:15])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: COC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CN(C(=O)c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)C1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (116 mg, 0.38 mmol), HATU (218 mg, 0.46 mmol), 3-methoxy-azetidine (57 mg, 0.57 mmol) and DIPEA (0.27 mL, 1.5 mmol) in DMF (2 mL). MS (LC-MS): 373.0 [M]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][O:44][CH2:45][C:46]([O:48]C)=[O:47])[CH:5]=[CH:6][CH:7]=1.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][O:44][CH2:45][C:46]([OH:48])=[O:47])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1

Procedure:
The title compound was prepared as a white foam (0.172 g, 47%) from {2-[3,3″-Dichloro-5′-(8-indol-1-yl-octylcarbamoyl)-[1,1′;3′,1″]terphenyl-2′-yloxy]-ethoxy}acetic acid, methyl ester using a procedure similar to Step 4 of example 165; dec.>50° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.32 (m, 8H), 1.44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 3.17-3.42 (m, 6H), 3.61 (s, 2H), 4.12 (t, J=7 Hz, 2H), 6.37 (d, J=3.1 Hz, 1H), 6.95-6.99 (m, 2H), 7.06-7.10 (m, 2H), 7.32 (m, 1H), 7.41-7.55 (m, 6H), 7.57-7.60 (m, 2H), 7.68-7.77 (m, 2H), 7.87 (s, 2H), 8.54 (t, J=5.5 Hz, 1H), 12.50 (broad s, 1H); IR (KBr) 3410, 2940, 1625, 1560, 1540, 1460, 1220, 1130 cm−1; mass spectrum [(+)APCI], m/z 687 (M+H)+; Anal. Calcd. for C39H40Cl2N2O5.0.5H2O: C, 67.24; H, 5.93; N, 4.02, Found: C, 67.26; H, 6.02; N, 3.96.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1ccc(-c2cc(C(Cl)C3CCCCC3)c(C)o2)nn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)nn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A mixture of 3-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-6-methylpyridazine (107 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (175 mg), sodium carbonate (74 mg) and sodium iodide (210 mg) in N,N-dimethylacetamide (5 mL) was stirred at 80° C. for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (30% ethyl acetate/hexane to 100% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.3 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (56 mg, 33%).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15]>O.[OH-].[Na+]>[C:3]([CH2:2][NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[C:12]([OH:21])=[O:20])([OH:5])=[O:4]
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNc1ccccc1C(=O)O
Temperature: 42.5 °C
Reaction time: 96 h

Procedure:
To a solution of chloroacetic acid (347 g, 3.67 mol) in water (500 mL), sodium carbonate (200 g, 4.72 mol) was carefully added at room temperature under stirring. The formed solution was heated to 40-45° C. and quickly added to a mixture prepared from a suspension of anthranilic acid (500 g, 3.65 mol) in water (340 mL) and 35% aqueous sodium hydroxide solution (320 mL) and heated to 40-45° C. The reaction mixture was kept at 40° C. for 4 days and the solid reaction mixture was treated with a solution of sodium hydroxide (150 g, 3.75 mol) in water (4 L). The mixture was heated to 60° C. and filtered off while hot. The solid residue was washed on the filter with 20% aqueous sodium hydroxide until the solid residue was dissolved, and the combined filtrates were acidified with 37% aqueous hydrochloric acid to pH 3. The precipitate was filtered off; an additional amount of the product precipitated overnight from the filtrate and was collected. The product was dried at 100° C. to give total 567 g (80%), m.p. 220° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[C:24]([C:29](Cl)=[O:30])=[N:25][CH:26]=[CH:27][CH:28]=1.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH:12][C:29]([C:24]3[C:23]([C:22]([F:33])([F:21])[F:32])=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:30])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ncccc1C(F)(F)F
Reactant: NCC1(c2ncc(Br)cc2Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.3 %

Procedure:
350 mg of C-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropyl]-methylamine (step 3 of PREPARATION EXAMPLE 3) was dissolved in 7 ml of dichloromethane and 0.37 ml of triethylamine was added at ambient temperature. Then a solution of 308 mg 3-(trifluoromethyl)pyridine-2-carbonyl chloride (1.10 eq, 1.47 mmol, 0.) in 3 ml of dichloromethane was added dropwise. The reaction mixture was stirred at ambient temperature for 14 hours, then water was added, the phases were separated and the water phase was extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. Crude material was obtained as a brown sticky solid, which was purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (2:1) as a solvent. Thus, 560 mg of N-[[1-(5-bromo-3-chloro-2-pyridyl)cyclopropyl]methyl]-3-(trifluoromethyl)pyridine-2-carboxamide was obtained as a sticky solid. 1H-NMR (CDCl3): 8.70 ppm (d, 1H), 8.45 ppm (d, 1H), 8.12 ppm (d, 1H), 7.90 ppm (s, 1H, broad), 7.83 ppm (d, 1H), 7.52 ppm (m, 1H), 3.73 ppm (d, 2H), 1.10 ppm (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccn2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of 5-bromoisatin (10.0 g, 44.4 mmol) in anhydrous N,N-dimethylformamide (100 mL) at 0° C. was added slowly sodium hydride (60% w/w dispersion in mineral oil, 3.90 g, 97.7 mmol). The solution was stirred for 30 min and 2-(bromomethyl)pyridine hydrobromide (11.2 g, 44.4 mmol) was added. The solution was stirred at ambient temperature for 16 h and poured into ice water (1.3 L) with vigourous stirring, causing a precipitate to be deposited. The solid was collected by filtration to afford 5-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione (4.93 g, 35%) as a orange solid: 1H NMR (300 MHz, CDCl3) 8.55-8.50 (m, 1H), 7.72-7.56 (m, 1H), 7.34-7.28 (m, 1H), 7.25-7.18 (m, 1H), 6.93-6.88 (m, 1H), 5.03-4.99 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3)ccc2n1C
Temperature: 25 °C
Yield: 52.4 %

Procedure:
In 20 ml of pyridine was dissolved 0.80 g (3.67 mmol) of ethyl 5-amino-1-methyl-2-indolecarboxylate. While stirring at room temperature, 0.57 g (4.03 mmol) of benzoyl chloride was added to the solution. After stirring for 2 hours at 70° C., the reaction mixture was cooled to room temperature and then poured onto ice water. The mixture was then extracted three times with ethyl acetate. The combined extracts were washed with 1N hydrochloric acid and then with saturated sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 0.62 g (52.5%) of ethyl 5-benzamido-1-methyl-2-indolecarboxylate.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][C:17]([OH:25])([CH2:18]3)[CH2:16]1)[CH2:22]2>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:14][C:15]23[CH2:24][C@H:19]4[CH2:20][C@H:21]([CH2:23][C:17]([OH:25])([CH2:18]4)[CH2:16]2)[CH2:22]3)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC12C[C@@H]3C[C@@H](CC(O)(C3)C1)C2
Reaction time: 48 h

Procedure:
To a stirred solution of Example 8D (0.06 g, 0.305 mmol ) in acetonitrile (3 mL ) at room temperature under nitrogen, was added 3-amino-1-adamantanol (0.1 g, 0.61 mmol ). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 5-7% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 328 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.5-2 (14H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:29])=[C:22]([CH2:24][C:25]([O:27]C)=[O:26])[CH:23]=1.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:29])=[C:22]([C:24]2[C:25](=[O:26])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]3[C:5]([CH:8]=2)=[CH:6][N:7]=[C:2]([CH3:30])[CH:3]=3)[CH:23]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:29])=[C:22]([C:24]2[C:25](=[O:27])[N:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4]3[C:5]([CH:8]=2)=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=3)[CH:23]=1
Reactant: O=Cc1cnc(Cl)cc1Nc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1cc(N)ccc1C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2-c1ccccc1
Product: Cc1ccc(N)cc1-c1cc2cnc(Cl)cc2n(-c2ccccc2)c1=O
Temperature: 100 °C

Procedure:
6-Chloro-4-phenylamino-pyridine-3-carbaldehyde 18 (21 mg, 0.09 mmol) is mixed with 2-(5-amino-2-methyl-phenyl)acetic acid methyl ester 7 (18 mg, 0.1 mmol) and potassium carbonate (37 mg, 0.27 mmol) in DMF (2 mL). The mixture is heated to 100° C. for 16 h. After cooling to rt and removing solvent in vacuo, the crude product is purified using flash chromatography (hexane:ethyl acetate=1:1). The title compound 3-(5-amino-2-methyl-phenyl)-7-chloro-1-phenyl-1H-[1,6]naphthyridin-2-one 19 is obtained as a pale solid. 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.68 (s, 1H), 7.53-7.57 (m, 2H), 7.47-7.51 (dt 1H), 7.20-7.23 (m, 2H), 6.96 (d, 1H), 6.59 (dd, 1H), 6.58 (s, 1H), 6.52 (s, 1H), 2.05 (s, 3H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][N:12]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([CH3:27])[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:28])[N:15]=2)[C:11](=[O:29])[CH2:10]1)(C(C)(C)C)(C)C>C1COCC1.O>[OH:8][C@@H:9]1[CH2:13][N:12]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([CH3:27])[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:28])[N:15]=2)[C:11](=[O:29])[CH2:10]1
Reactant: Cc1nc(C(=O)Nc2cn(C)nc2N2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)co1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2cn(C)nc2N2C[C@@H](O)CC2=O)co1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.9 %

Procedure:
To a solution of N-(3-((4S)-4-((tert-butyl(dimethyl)silyl)oxy)-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-methyl-1,3-oxazole-4-carboxamide (32 mg) in THF (2.0 mL) was added 1M tetra-n-butylammonium fluoride THF solution (0.15 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (10 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:6][CH:5]=1.[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:27]=1[S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:27]=1[S:34]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)(=[O:35])=[O:36]
Reactant: COC(=O)CCCC=C(c1ccc(CCN)cc1)c1cccnc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)NCCc2ccc(C(=CCCCC(=O)O)c3cccnc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.24 g of methyl 6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hex-5-enoate, 2.2 g of 2,4,6-trimethylbenzenesulphonic acid chloride and 100 ml of triethylamine in 50 ml of dichloromethane is stirred for 30 minutes at ambient temperature. Then the reaction mixture is washed twice with water, dried and evaporated down. The residue is purified over a silica gel column using ethyl acetate. The crude product obtain is heated in a mixture of 32 ml of ethanol and 5 ml of 4N sodium hydroxide solution for 30 minutes to 50° to 60° C. The reaction mixture is evaporated down, the residue is taken up in 50 ml of water and washed with ethyl acetate. The aqueous phase is adjusted to pH 5 by the addition of citric acid and extracted twice with ethyl acetate. The organic phase is dried, evaporated down and the residue is chromatographed over a silica gel column using ethyl acetate. The crude product is then recrystallised from ethyl acetate/diisopropyl ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH2:12]O)[CH2:6][C:5]1([CH3:15])[CH3:14].[C:16]([O:35]C)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[Li+].[OH-]>CO>[C:16]([OH:35])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:16]([O:1][CH2:2][CH2:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH3:12])[CH2:6][C:5]1([CH3:15])[CH3:14])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Reactant: CC1(C)CC(CO)CC(C)(C)N1CCO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)OCCN1C(C)(C)CC(C)CC1(C)C
Temperature: 140 °C

Procedure:
9.8 g of 1-(2-hydroxyethyl)-2,2,6,6-tetramethyl-4-hydroxymethyl piperidine as obtained in Example 2 (0.045 mole) were admixed to 28.7 g of methyl stearate (0.09 mole) in the presence of 0.5 g of LiOH. The mixture was heated to 140° C. in a nitrogen atmosphere and was maintained under stirring until complete evolvement of the reaction methyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH:12]([CH2:17][O:18][CH3:19])[CH2:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4]([CH3:20])[N:3]=1.C(O)(=O)C>CO.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:20])=[CH:5][C:6]=1[NH:11][C@H:12]([CH2:17][O:18][CH3:19])[CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCC(COC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: COCC[C@@H](COC)Nc1cc(C)nc(Cl)c1N

Procedure:
2—Chloro-6-methyl-3-nitro-N-(1-methoxymethyl-3-methoxypropyl)pyridin-4-amine (˜16.82 mmol) was heated at reflux with Fe powder (10 g) in methanol (120 mL) in the presence of glacial acetic acid (10 mL) for 2 h. Then the iron was filtered through celite, the celite was washed with methanol(80 mL) and the filtrate was stripped in vacuo. The residue was dissolved in 10% HCl (120 mL) and EtOAc was added (160 mL). The mixture was neutralized with solid NaHCO3 and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4) and stripped in vacuo (4.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=O.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[O:9][C:15]([C:14]3[C:13]([F:12])=[CH:21][CH:20]=[CH:19][C:18]=3[F:22])=[N:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1oc(-c2c(F)cccc2F)nc2cccc(Cl)c12

Procedure:
6-Chloroanthranilic acid (0.566 g), 2,6-difluorobenzoyl chloride (0.93 mL) and triethyl amine/toluene (1/1) (18 mL) were reacted as described under (10). Reaction time 2 days. Extraction between ethyl acetate (100 mL) and HCl (2N, 100 mL), followed by separation of the organic layer, drylng over MgSO4, filtering and evaporation gave a crude product which was dissolved in warm THF (20 mL) and precipitated with hexane. The resulting mixture was further purified on a silicagel column using dichloromethane as eluent. The isolated fraction was dissolved in warm THF (20 mL) and precipitated with hexane, ylelding 5-chloro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (0.65 g) mp. 176 C, MS m/e: 293/295 M+.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([C:25]2[CH:29]=[C:28]([C:30]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[NH:31])[S:27][C:26]=2[S:40][CH3:41])(=[O:24])=[O:23])[CH:17]=1)C.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:36]([O:35][C:33]([NH:32][C:30](=[NH:31])[C:28]1[S:27][C:26]([S:40][CH3:41])=[C:25]([S:22]([C:18]2[CH:17]=[C:16]([C:10]3[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7][CH2:6][CH2:5][C:4]([OH:42])=[O:3])[CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])[CH:29]=1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CCOC(=O)CCOCc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2COCCC(=O)O)c1
Yield: 76.7 %

Procedure:
To a solution of 3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}-propionic acid ethyl ester (7.0 mg, 11 μmol) in THF (0.5 mL) and MeOH (0.25 mL) was added a solution of lithium hydroxide monohydrate (0.56 mg, 13 μmol) in H2O (50 mL). The mixture was microwaved at 80° C. for 150 seconds, acidified with 0.25 N HCl to ˜pH 3, extracted with EtOAc/DCM (1:1, 3×). The extracts were combined, washed with H2O, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with MeOH/DCM (2 to 4%) to give the title compound (5.1 mg, 76% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:7][CH2:6][C:5]2C=CC=C[C:4]=2O1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH:2]([NH:7][C:6]1[CH:5]=[CH:4][CH:21]=[CH:20][C:19]=1[CH2:23][OH:22])([CH3:12])[CH3:1]
Reactant: CC1(C)NCc2ccccc2O1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)Nc1ccccc1CO
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 2,2-dimethyl-1,4-dihydro-2H-benzo[1,3]oxazine (125 g, 0.77 mol) in THF (1 L) was filtered through a scintillation funnel and then added dropwise via an addition funnel, over a period of 2.5 h, to a stirred solution of 1.0 M LiAlH4 in THF (800 mL) at 0° C. The reaction was quenched by slow portionwise addition of Na2SO4.10H2O (110 g), over a period of 1.5 h, at 0° C. The reaction mixture was stirred overnight, filtered and the solid salts were washed thoroughly with THF. The filtrate was concentrated under reduced pressure to yield 2-isopropylaminophenylmethanol (120 g, 95%) as a yellow oil. 1H NMR (CDCl3; 300 MHz): 1.24 (d, 6H, CH(CH3)2), 3.15 (bs, 1H, OH), 3.61 (sept, 1H, CH(CH3)2), 4.57 (s, 2H, CH2), 6.59 (t, 1H, ArH), 6.65 (d, 1H, ArH), 6.99 (d, 1H, ArH), 7.15 (t, 1H, ArH).