Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[CH3:11]O>>[CH3:11][O:9][C:8](=[O:10])[CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: CO
Product: COC(=O)Cc1cc(C)no1

Procedure:
A solution of 3-methyl-5-isoxazole acetic acid (10.2 g, 72.6 mmol) in methanol (100 mL) was treated with p-toluene-4-sulfonic acid monohydrate (1.0 g, cat.) and the resulting mixture was then heated under reflux for 4 h. After cooling, the mixture was then evaporated and the brownish residue stirred with saturated sodium bicarbonate solution and diethylether. The organic phase was dried over sodium sulfate and concentrated to afford (3-methyl-isoxazol-5-yl)-acetic acid methyl ester (9.62 g) as a light yellow oil. This was then dissolved in butanol and reacted with hydrazine hydrate As described for example 112a. The resulting mixture was then heated under reflux for 16 h and after cooling and evaporation, the residue was crystallized from n-butanol/toluene to afford the title compound as a white solid (5.30 g). Concentration of the mother liquor provided another crop of solid material (2.95 g, overall yield: 73%). 1H-NMR (300 MHz, DMSO): δ=2.19 (s, 3H), 3.25 (s, 2H), 4.29 (s, 2H), 6.17 (s, 1H), 9.29 (s, 1H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:16]=O.[C:25](#[N:29])[CH2:26][C:27]#[N:28].N1CCCCC1>C(O)C.O>[NH2:29][C:25]1[O:11][C:1]2[C:2]([CH:16]([C:15]3[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:13]([Br:12])[CH:14]=3)[C:26]=1[C:27]#[N:28])=[CH:3][CH:4]=[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=21
Reactant: Oc1cccc2ccccc12
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Temperature: 80 °C

Procedure:
1-Naphthol (170 mg, 1.2 mmol), 3-bromo-4,5-dimethoxybenzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μl) and then stirred at 80° C. under LC-MS (Liquid chromatography-mass spectrometry) control till the reaction was complete. The reaction mixture was cooled down to room temperature and diluted with water to about 15 ml drop wise addition. The mixture was stirred at room temperature for about 1 h. Thus formed precipitates were collected by filtration, washed well with 60% aqueous ethanol and dried under high vacuum to get 394 mg (0.90 mmol, 90%) of the pure solids of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[CH:16][C:15]=2[C:28]#[N:29])=[CH:11][C:10]=1[F:32])=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[C:28]#[N:29])=[CH:11][C:10]=1[F:32])=[O:8]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3Cl)c(F)c2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2Cl)c(F)c1
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To a stirred solution of tert-butyl 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)-3-fluorophenoxy)-3-cyanophenyl)acetate (15 mg, 0.0276 mmol) in dichloromethane was added TFA. The reaction was stirred for 2 hours and then concentrated. The crude material was purified by preparative TLC (10% methanol/0.5% AcOH/dichloromethane). The appropriate section was collected and then purified a second time by preparative TLC to provide 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)-3-fluorophenoxy)-3-cyanophenyl)acetic acid (0.0042 g). 1H NMR (400 MHz, CD3OD) δ 7.70-7.74 (m, 2H), 7.61 (d, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 6.88-6.94 (m, 2H), 3.52-3.65 (m, 4H), 3.05 (t, J=7.0 Hz, 2H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[N-:22]=[N+:23]=[N-:24].[Li+]>CN1CCCC1=O.O>[N:22]([CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1)=[N+:23]=[N-:24]
Reactant: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)Cn1c(CN=[N+]=[N-])nc2c(N)nc3ccccc3c21

Procedure:
2-Chloromethyl-l(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (2.5 g; 0.0077 mol, Example 10) was suspended in N-methylpyrrolidone (15 mL). A solution of lithium azide (2.3 g) in water (45 mL) was added to the suspension. The resulting mixture was heated on the steam bath for 2 hr and then diluted with water (about 45 mL). The tan solid was washed with water and dried to yield 1.4 g (60.9%) of crude product. The solid was recrystallized from ethanol to give a pure product m.p. 174°-178° C. Analysis: C, 61.0; H, 5.8; N, 33.2. Found: C, 60.9; H, 5.6; N, 32.6.
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=[O:9])OC.[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19]#[N:20])[CH:14]=[C:15]([Cl:17])[CH:16]=1.[C:21](O)(=O)C>C1(C)C=CC=CC=1.O.CO>[CH3:21][C:12]1[C:11]([Cl:10])=[CH:16][C:15]([Cl:17])=[CH:14][C:13]=1[CH:18]([C:19]#[N:20])[C:6]([OH:5])=[O:9]
Reactant: CC(=O)O
Reactant: N#CCc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1c(Cl)cc(Cl)cc1C(C#N)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
A mixture of sodium methoxide (25% in methanol, 225.9 g, 1.045 mol) and toluene (996 mL) was boiled to remove the methanol/toluene azeotrope. Toluene was added as necessary in portions during the course of the distillation. When the head temperature reached 110° C. the distillation was continued for 20 min. The mixture was allowed to cool to room temperature and toluene was added so that the volume was the same as it was prior to distillation. Methanol (74 mL) and dimethylcarbonate (118.4 g, 1.31 mol) were added to the reaction mixture. The mixture was warmed to 50° C. and 3,5-dichlorophenylacetonitrile (148.2 g, 0.796 mol) in toluene (140 mL) was added over 3.5 h. The resulting mixture was allowed to cool to room temperature overnight, then warmed to 50° C. for a further 2 h. The mixture was allowed to cool to room temperature and acetic acid (80 g, 1.33 mol) was added drop-wise. Water (350 mL) was added to the reaction mixture and the organic phase separated and the solvent removed under reduced pressure. Crystallisation of the resulting residue from methanol (171 mL) gave the product as a white solid (148 g, 76%) melting at 97-99° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH:19]CC4C=CC(OC)=CC=4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH2:19])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][C:3]=1[C:29]([F:30])([F:31])[F:32]
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(F)c(C(F)(F)F)c4)ncnc3cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: Nc1cc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc2cn1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A stirred solution of compound 166 (1.0 g, 2.26 mmol) in TFA (20 mL) was treated with anisole (490 μL, 4.51 mmol) at room temperature. The mixture was stirred overnight, then diluted with ethyl acetate and the solvents were removed under reduced pressure. The residue was triturated with hexane and then treated with aqueous ammonia (5N, 100 mL) with stirring for 30 min. The resulting solid was collected by filtration, washed with water and dried under vacuum to give N4-(4-fluoro-3-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4,6-diamine (168) (720 mg, 99%) as a yellow solid, m.p. 252-255° C. 1H NMR [(CD3)2SO] δ 9.90 (s, 1H), 8.72 (s, 1H), 8.38 (s, 1H), 8.34 (dd, J=6.5, 2.6 Hz, 1H), 8.24-8.28 (m, 1H), 7.54 (t, J=9.7 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 2H). Anal. Calcd for C14H9F4N5.0.55EtOAc: C, 52.35; H, 3.63; N, 18.84%. found: C, 51.96; H, 3.70; N, 18.46%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]([O:26]C(=O)C)([CH3:25])[CH3:24])=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>CO.O.C1COCC1>[CH2:35]([O:34][C:32]1[CH:31]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:33]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]([OH:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1)=[O:13])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(O)C(=O)Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.2 %

Procedure:
To a stirred suspension of N-{6-[(3,5-dibenzyloxybenzoyl)amino]-pyridin-3-yl}-2-acetoxy-2-methyl-propionamide (158 mg) in methanol (10 ml) was added a solution of LiOH.H2O (30 mg) in water (1 ml) and THF (3 ml). The mixture was stirred at ambient temperature for 20 hours. Volatile material was removed by evaporation. To the residue was added water (10 ml). Made acidic with 2M hydrochloric acid. Precipitate filtered off, washed with ethyl acetate, and dried under high vacuum to give the title compound (120 mg) as a solid, 1H NMR δ d6-DMSO): 1.35 (s, 6H), 5.18 (s, 4H), 6.88 (s, 1H), 7.28 to 7.48 (m, 12H), 8.08 (d, 1H), 8.22 (d, 1H), 8.82 (s, 1H), 9.90 (s, 1H), 10.96 (s, 1H). MS ES+ 512.16 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:24])[C:3]=1[OH:25].O[C@@H:27]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([O-:30])=[O:29].BrBr>C(Cl)(Cl)Cl>[Br:24][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:25][C@H:27]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([OH:30])=[O:29]
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Reactant: O=C([O-])[C@@H](O)CCc1ccccc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](CCc4ccccc4)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 9) and (S)-2-hydroxy-4-phenyl-butyrate, ethyl ester (Example 27) according to the procedure of Example 30. White solid: [a]25/D =−12.187° (9.929 mg/mL, CHCl3); NMR (DMSO-d6); δ 13.24 (s, 1H), 8.21 (d, J=8 Hz, 1H), 7.73 (s, 2H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.52-7.45 (m, 2H), 7.32-7.28 (m, 2H), 7.24-7.20 (m, 3H) 5.02 (d, J=6Hz, 1H), 2.99-2.86 (m, 1H), 2.75-2.65 (m, 1H), 2.45 (s, 3H), 2.30-2.20 (m, 2H), 1.61 (s, 3H); MS (+FAB): [M+], 3 bromine isotope pattern, 700 (30%), 702 (100%), 704 (90%), 706 (55%); Anal. Calc. for C30H23Br3O3S: C, 51.23, H, 3.30, N, 0.00. Found: C, 51.33, H, 3.33, N, 0.29.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](C=CC(OC)=O)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:35][CH2:34]C1.OS([O-])=O.[Na+]>CC(C)=O.CCCCCC.O=[Os](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][C:17]([CH:34]=[O:35])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:30])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)c(C(F)(F)F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C[C@@H]1CN(c2ncc(C=O)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of (2R)-4-[5-(2-methoxycarbonyl-vinyl)-3-trifluoromethyl-pyridin-2-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester from step (d) above (6.02 g, 14 mmol), OsO4 (4.43 mL, 0.7 mmol, 4% in H2O, Aldrich) and N-methylmorpholine N-oxide (1.96 g, 16.8 mmol, Aldrich) in acetone (16 mL) was stirred at room temperature for 5 h. To the mixture was added saturated aqueous solution of NaHSO3 (910 mL) and the mixture was extracted with EtOAc (2×40 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was dissolved in dichloromethane (20 mL). To the solution was added Pb(OAc)4 (7.44 g, 16.8 mmol, Aldrich) in one portion and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with hexane (10 mL), filtered through a Celite® pad and the filter cake was washed with 50% EtOAc/hexane. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 30% EtOAc/hexane to give the title compound as a gum. MS (ESI, pos. ion) m/e: 374 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH3:12][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO>[NH2:2][C:3]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC1(C(=O)O)CCOCC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1(N)CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 99 %

Procedure:
To a solution of 4-amino-4-carboxy-tetrahydropyrane hydrochloride (2 g) in methanol was added dropwise a solution of 2M trimethylsilyldiazomethane-diethylether (33 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo, and the resultant crude product was dissolved in hexane-diethylether (1 mL/1 mL), and thereto was added an aqueous 4N hydrochloric acid. The precipitates were collected by filtration to give 4-amino-4-methoxycarbonyl-tetrahydropyrane (2.13 g, yield: 99%) as white crystals.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5]C(=O)C(F)(F)F)=O.[OH:14][C@:15]1([C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[C:16](=[O:18])[CH3:17].C1(C)C=CC=CC=1.[ClH:45]>CO>[Cl:45][CH2:2][C:3]([O:14][C@:15]1([C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[C:16](=[O:18])[CH3:17])=[O:5]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)[C@@]1(OC(=O)CCl)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-/N,N-bis(2-chloroethyl)amino/-4-methylbenzoic acid (27.6 g) and trifluoroacetic anhydride (21.0 g) is heated under stirring at 60° C. for 15 min. To the mixture 17α-hydroxypregn-4-ene-3,20-dione (16.5 g) is added and the mixture is heated under stirring at 80° C. for 5 h. Toluene (150 ml) is added, the solution is filtered, and to the filtrate chloroform (200 ml) is added. After washing with H2O and aq. NaHCO3, drying, and evaporation an oil is obtained, to which a mixture of methanol (300 ml) and conc. HCl (3 ml) is added. After 16 h at room temperature the solution is evaporated and the residue chromatographed on a silica gel column using toluene/ethyl acetate (2:1) as eluent. The eluate fraction having Rf =0.40 gives 17α-/3-(N,N-bis(2-chloroethyl)amino)-4-methylbenzoyloxy/pregn-4-ene-3,20-dione (1, 6.8 g, m.p. 170°-1° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Reactant: CC(=O)OC(C)=O
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(C)=O)cc3CO1)CO2
Yield: 88.2 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (100 mg, 0.321 mmol) and acetic anhydride (60.7 ul, 0.642 mmol) according to the procedure described for Example 48. Obtained the title compound as a white solid (100 mg, 88%), MS (ISP) m/e=354.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:62][C@@H:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([C:55]6[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=6)=[CH:51][CH:50]=5)[C:46]([OH:45])=[O:63])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C)cc2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (19 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) and (S)-2-amino-3-(4′-methyl-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 842.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1)C.O.[NH2:17][NH2:18]>C(O)C>[NH:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[CH2:5][C:4]([NH:17][NH2:18])=[O:3]
Reactant: NN
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1nc2ccccc2[nH]1
Yield: 76 %

Procedure:
15 g 1H-benzo[d]imidazole-2-acetic acid ethyl ester (0.074 mol), 100 mL anhydrous ethyl alcohol and 37 mL of 80% hydrazine hydrate were added to a three-necked bottle and reacted under reflux for 4 hours. A white solid was isolated. After sucking filtration, the filter cake was washed with ethanol. After drying, 10.7 g white solid was obtained. Yield: 76%, MS: 191(M+1).
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.CCCCCC.Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[F:28])[N:24]([CH3:29])[N:23]=[CH:22]2.CN([CH:33]=[O:34])C>C1COCC1.C1(C)C=CC=CC=1>[F:28][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][N:24]2[CH3:29])=[CH:20][C:19]=1[CH:33]=[O:34]
Reactant: Cn1ncc2cc(Br)c(F)cc21
Reactant: CN(C)C=O
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1ncc2cc(C=O)c(F)cc21
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A 2 M solution of n-butyl magnesium chloride in THF (4.8 mL, 9.57 mmol) was added to toluene (34 mL) under nitrogen and cooled to −10° C. To this was added a 1.3 M solution of n-butyl lithium in hexane (12.2 mL, 19.5 mmol) and after 1 h, the RM was cooled to −30° C. To the RM was then added a solution of 5-bromo-6-fluoro-1-methyl-1H-indazole (vii) (4 g, 17.73 mmol) in THF (17 mL) and the reaction was warmed up to −10° C. After 1 h, DMF (8.23 mL, 106 mmol) was added and the RM was stirred at −10° C. for another 1 h. The reaction was quenched using 2 N HCl and was allowed to warm up to room temperature. After 30 min, the RM was basified with saturated aqueous NaHCO3 solution and then extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated under vacuo. The residue was triturated with Et2O. The precipitate formed was filtered off to give a yellow solid identified as the desired aldehyde (tR 0.79 min (conditions 2), MH+=179).
Reaction SMILES: N[CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:33]([O:37][C:38]([NH:40][C:41](=[N:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])SC)=[O:39])([CH3:36])([CH3:35])[CH3:34].C([N:55](CC)C(C)C)(C)C.ClCCl>CN(C)C=O.[Hg](Cl)Cl>[C:33]([O:37][C:38]([N:40]([CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:16][CH2:17]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:41]([NH2:55])=[N:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)nc1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65 %

Procedure:
To a solution of N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide (synthesized in Example 3F-5) (104 mg) and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (85 mg) in N,N-dimethylformamide (5 mL) were added N,N-diisopropylethylamine (0.12 g) and then mercury (II) chloride (113 mg) at room temperature. The solution was stirred at room temperature for 3 days. Dichloromethane was added to the solution and insolubles were filtered off with Celite. The solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography [silica gel, dichloromethane-methanol-aqueous ammonia (97:3:0.2)] to give the title compound (0.1049 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C1COCC1.Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2>C(O)(=O)C>[C:1]1([CH2:7][CH2:8][O:9][C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[NH:19][CH:20]=[N:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: OCCc1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(CCOc2ncnc3nc[nH]c23)cc1
Temperature: 60 °C
Yield: 62 %

Procedure:
2-Phenylethanol (13 ml) was stirred under nitrogen and sodium (0.75 g, 32.36 mmol) was added. The reaction was heated to 60° C. When no sodium remained, anhydrous THF (18 ml) and 6-chloropurine (1.0 g, 6.47 mmol) were added. After refluxing under nitrogen for 5 h, the reaction mixture was allowed cool to room temperature and neutralised with glacial acetic acid. The THF was removed and the remaining alcohol was removed in vacuo. The product was recrystallised from ethanol and isolated as a white crystalline solid (962 mg, 62%), m.p. 209-210° C.; (Found: C, 64.57; H, 5.12; N, 23.54. Calc. for C13H12N4O: C, 64.99; H, 5.03; N, 23.34%); νmax (cm−1) 3135,3063, 3031, 2948, 2897, 2797, 2672, 2583 (NH, C—H); δH (200 MHz, d6-DMSO) 8.483 (1H, s, C(2)H or C(8)H), 8.365 (1H, s, C(2)H or C(8)H), 7.366-7.194 (5H, m, Ph), 4.741 (2H, t, J=7.0 Hz, OCH2), 3.134 (2H, t, J=7.0 Hz, CH2Ph); m/z 240 (M+, 11%), 149 ([M—Bn]+, 11%), 136 ([M—CH2CH2Ph]+, 87%), 119 ([M—OCH2CH2Ph]+, 40%), 104 ([CH2CH2Ph]+, 100%), 91 (BN+, 37%), 77 (Ph+, 55%), 69 (48), 65 (15), 51 (26).