Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH:9](OCC)(OCC)[O:10]CC.CC(O)C.[ClH:23]>O>[OH2:4].[OH2:10].[ClH:23].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 13 h

Procedure:
Under the nitrogen atmosphere, 10 g of 2-aminomalonamide and 35.4 mL of triethyl orthoformate were added to 200 mL of 2-propanol. After heating to 80° C., the reaction mixture was stirred for 13 hours at the same temperature. Color of the reaction liquid was pale blue when the reaction was completed. Subsequently, the reaction mixture was cooled to 58° C., then added with 10 mL of water followed by 8 mL of conc. hydrochloric acid. After cooling the reaction mixture to 5° C., the crystal was collected by filtration and then washed with 40 mL of acetone to give 16 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a green crystal.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([NH:17][CH:18]([CH2:22][CH2:23][CH3:24])[C:19]([OH:21])=O)=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[O:27][C:28]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])=[CH:29][N:30]=1.Cl.CN(C)C>C(Cl)Cl.C(Cl)CCl>[C:31]([C:28]1[O:27][C:26]([NH:25][C:19](=[O:21])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:22][CH2:23][CH3:24])=[N:30][CH:29]=1)(=[O:32])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCCC(NC(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)O
Reactant: Nc1ncc(C(=O)c2ccccc2)o1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCC(NC(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)Nc1ncc(C(=O)c2ccccc2)o1

Procedure:
A mixture of 2-[2-(3-phenoxy-phenyl)-acetylamino]-pentanoic acid (65 mg, 0.2 mmol), (2-Amino-oxazol-5-yl)-phenyl-methanone (38 mg, 0.2 mmol.), HBOT (32 mg, 0.24 mmol), EDC. HCl (58 mg, 0.3 mmol) and a trimethylamine (0.11 ml, 0.8 mmol) in methylene chloride was stirred at room temperature until disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound, LC-MS M+1=498.5.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][NH2:28]>CCN(CC)CC>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:28][CH3:27])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(F)c3)nc2N1C1CCCC1
Reactant: CN
Solvent: CCN(CC)CC
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(NC)c3)nc2N1C1CCCC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of (R)-8-cyclopentyl-7-ethyl-2-(2-fluoropyridin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 16, 200 mg, 0.56 mmol) in methylamine (5 mL of 2M in CH3OH), 1 mL of Et3N was added. The mixture was stirred at 110° C. in a sealed tube for 18 h, and then concentrated under reduced pressure, quenched with water and extracted with EtOAc. The combined organic phase was dried with Na2SO4, concentrated under reduced pressure, and chromatographed (CH2Cl2:CH3OH=10:1) to give the title compound as a white solid (150 mg, 70% yield). 1H NMR (CDCl3) δ: 9.76 (broad, 1H), 8.08 (s, 1H) 7.85 (d, 1H), 7.74 (s, 1H), 7.58 (d, 1H), 4.40 (m, 2H), 3.43 (s, 3H), 3.1 (s, 3H), 2.2-1.7 (m, 10H) and 0.89 ppm (t, 3H); LCMS: 367.2 m/z (M+H)+; ret. Time: 1.44 min (Analytical Method E).
Reaction SMILES: C([O:8][N:9]([CH2:12][C@@H:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]=[O:11])C1C=CC=CC=1.[H][H]>[Pd]>[OH:8][N:9]([CH2:12][C@@H:13]([C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:24][CH2:25]1)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]=[O:11]
Reactant: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(C=O)OCc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(O)C=O)CC2)cc1
Yield: 75 %

Procedure:
A solution of N-(benzyloxy)-N-((2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentyl)formamide (100 mg, 0.22 mmol) was hydrogenated under 1 atm of hydrogen in the presence of Pd/C (10%, 23 mg, 0.02 mmol, 0.1 eq.) for 2 h at room temperature. The mixture was filtered on a bed of cellite, evaporated to give the title product as an orange foam (60 mg, 75%). HPLC, Rt: 1.95 min (purity: 100%). M+ (LC-MS (ESI)): 364.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:64][CH2:65][C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH2:76][F:77])([CH2:74][F:75])[O:72][B:71]([OH:78])[C:70]=2[CH:79]=1>CN(C=O)C>[F:77][CH2:76][C:73]1([CH2:74][F:75])[O:72][B:71]([OH:78])[C:70]2[CH:79]=[C:66]([CH2:65][NH:64][C:23]([C:20]3[C:19]4[N:15]([CH:16]=[CH:17][CH:18]=4)[C:14]([C:11]4[CH2:10][C:9]([C:4]5[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=5)([C:26]([F:29])([F:27])[F:28])[O:13][N:12]=4)=[CH:22][CH:21]=3)=[O:25])[CH:67]=[CH:68][C:69]1=2
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2c(c1)B(O)OC2(CF)CF)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.24 mmol) and DIPEA (124 mg, 0.88 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (183 mg, 0.48 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (126 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by prep-TLC to provide the final title product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][NH2:11]>CO>[CH3:10][NH:11][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1cccc(O)c1
Reactant: CN
Solvent: CO
Product: CNCc1cccc(O)c1

Procedure:
10.0 g of 3-hydroxybenzaldehyde and 9.55 g of a 40% methanol solution of methylamine were mixed, and then the solvent was evaporated. The resulting Schiff base was dissolved in 50 ml of ethanol, and with stirring under ice cooling, 10.0 g of sodium borohydride was added. The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium chloride were added to extract it. The organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography Wakogel C-100, 100 g; eluting solvent: methylene chloride/methanol=10/1→5/1) to give 8.88 g (yield Λ%) of N-methyl-3-hydroxybenzylamine as pale yellow crystals, m.p. 138°-140° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1F)=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:19][NH:20][CH2:21][CH2:22][NH2:23]>N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:23][CH2:22][CH2:21][N:20]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CC(=O)c1ccccc1F)OCC
Reactant: CNCCN
Solvent: c1ccncc1
Product: CCOP(=O)(C=C1NCCN(C)c2ccccc21)OCC
Temperature: 95 °C
Yield: 26.6 %

Procedure:
A mixture of 10.45 g (38.1 mmol) of [2-(2-fluorophenyl)-2-oxoethyl]phosphonic acid diethyl ester and 14.1 g (190 mmol) N-methylethylenediamine in 100 ml of pyridine was heated at 95° C. for 18 hours. The solvent was evaporated and the residue was partitioned between 200 ml of water and 2×100 ml of dichloromethane. The combined organic portions were dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography eluting with 5% methanol/dichloromethane to give 3.14 g (26%) of (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester as a light brown oil; MS: m/e 311.0 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.CCCP(=O)=O.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][NH2:54])[CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([NH:54][CH2:53][CH2:52][CH2:51][N:48]5[CH2:49][CH2:50][O:45][CH2:46][CH2:47]5)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Reactant: NCCCN1CCOCC1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)NCCCN4CCOCC4)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.3 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (25 mg, 0.06 mmol), triethylamine (0.017 mL, 0.12 mmol), and catalytic DMAP in 1.1 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.043 mL, 0.072 mmol). After 5 min at rt, 3-morpholinopropylamine (0.011 mL, 0.072 mmol) was added and the reaction stirred at rt for 1.5 hours. The reaction was partitioned between EtOAc and brine/aqueous NaHCO3 solution, the EtOAc layer washed with brine/aqueous NaHCO3 solution, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/MeOH to give the title compound as an off-white solid (17 mg, 54%). 1H NMR (CDCl3) δ: 8.50 (s, 1H), 8.48 (s, 1H), 7.83-7.92 (m, 2H), 7.54 (d, J=4.7 Hz, 2H), 7.46 (d, J=8.2 Hz, 1H), 7.34-7.41 (m, 1H), 7.20-7.33 (m, 2H), 7.13 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.3 Hz, 1H), 4.50 (s, 2H), 3.52-3.63 (m, 8H), 3.23 (t, J=5.7 Hz, 2H), 2.87-2.98 (m, 1H), 2.56 (t, J=6.0 Hz, 2H), 2.47 (br. s., 4H), 1.75-1.85 (m, 2H), 1.27 (d, J=7.0 Hz, 6H)
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:18][C:19]1[C:24](F)=[CH:23][CH:22]=[C:21]([N+:26]([O-:28])=[O:27])[C:20]=1[O:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>C1COCC1>[F:18][C:19]1[C:20]([O:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1[CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Oc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cccc3ccccc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.4 %

Procedure:
Sodium hydride (60% oil dispersion) (4.07 g, 102 mmol) was added in portions to a solution of di-t-butyl malonate (11.01 g, 50.9 mmol) in THF (200 mL) at room temperature. After gas evolution ceased, 1-[(2,3-difluoro-6-nitrophenyl)oxy]naphthalene (13.94 g, 46.3 mmol), dissolved in THF (100 mL), was added. The reaction mixture was stirred at room temperature for 2 hrs and then poured on to ice and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated to give the title compound (26.59 g, 102%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.33-8.44 (m, 1H), 7.83-7.95 (m, 2H), 7.51-7.65 (m, 4H), 7.23-7.34 (m, 1H), 6.60 (d, 1H), 4.82 (s, 1H), 1.49 (s, 18H). ESMS: m/z 497.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[C:25]1([C@@:31]2(CO)[CH2:33][C@H:32]2[CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][CH2:20][C@:31]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:33][C@H:32]1[CH2:34][O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of polymer-bound triphenylphosphine (31.64 g, 67.08 mmol, 3 eq) and carbon tetrachloride (6.5 mL, 67.08 mmol, 3 eq) in 300 mL DCM was stirred at ambient temperature for 30 min. To this was added a solution of ((1R,2R)-1-phenyl-2{[(phenylmethyl)oxy]methyl)cyclopropyl)methanol (6.0 g, 22.36 mmol, 1 eq), accessed via the method of Preparation 20B, in 50 mL DCM and the entire reaction mixture was stirred at ambient temperature for 16 h. The mixture was then filtered and the resin washed with excess DCM. The organics were concentrated down to give the title compound (6.4 g, 22.36 mmol, 100%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.17 (m, 10H), 4.31-4.16 (m, 2H), 4.10-4.07 (m, 1H), 3.56-3.53 (m, 1H), 3.08-3.04 (m, 1H), 2.92-2.87 (m, 1H), 1.63-1.56 (m, 1H), 1.08-0.99 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][N:18]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]2[CH3:26])[CH:6]=[CH:5][N:4]=1.[SH:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C(O)(C)C>[CH3:9][C:8]1[C:3]([CH2:2][S:27][C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][N:18]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]1[CH3:26]
Reactant: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CC(C)O
Product: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
2.5 g (6 mmol) of 2-chloromethyl-3-methyl-4-{4-[2-(2-methyl-5-nitroimidazol-1-yl)ethylthio]butylthio}-pyridine and 0.9 g (6 mmol) of 2-mercaptobenzimidazole are heated to reflux for 1 h in 25 ml of isopropanol. The mixture is then cooled in an ice bath and the precipitated solid is filtered off with suction. The solid is taken up in water and treated with saturated sodium hydrogen carbonate solution. The mixture is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The title compound crystallizes and is washed with a little methanol with stirring. M.p. 160°-162° C.; yield 0.62 g (20% of theory).
Reaction SMILES: O([Si](C)(C)C)[Na].[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16](=[O:18])[CH3:17])=[C:10](F)[C:9]=1[N+:20]([O-:22])=[O:21].[O:23]1CCC[CH2:24]1>O1CCOCC1.CO>[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16](=[O:18])[CH3:17])=[C:10]([O:23][CH3:24])[C:9]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1F
Reactant: C1CCOC1
Agent: C[Si](C)(C)O[Na]
Solvent: C1COCCO1
Solvent: CO
Product: COc1c(NC(C)=O)c(F)cc(Cl)c1[N+](=O)[O-]
Yield: 63 %

Procedure:
A solution of 72.5 g (647 mmol) of NaOSi(CH3)3 in 25 ml of tetrahydrofuran was added dropwise at approximately 20° C. to a solution of 81 g (323 mmol) of N-(4-chloro-2,6-difluoro-3-nitro-phenyl)acetamide in 490 ml of dioxane and 50 ml of methanol. The mixture was subsequently heated for two hours at reflux temperature. After cooling and concentrating, the crude product (black oil) was stirred into ice-cold 10% strength hydrochloric acid. The resulting product of value was then extracted with ethyl acetate (3 times). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred once with water. The insoluble components were removed and washed three times with water. After drying, 52.1 g (63%) of the product of value were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH:21]=[CH:22][CH:23]=2)(O)[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH:21]=[CH:22][CH:23]=2)=[CH2:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1cccc(C(C)(O)c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(c1cccc(-c2ccccc2OC)c1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Yield: 40.1 %

Procedure:
A solution of crude 22 (2.66 mmol) in toluene (60 mL) was treated with para-toluenesulfonic acid (20 mg) and refluxed under a Dean-Stark trap for 1.5 hrs. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (100 mL) and water (100 mL). The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (40 g) with hexane (2 L) and 1% ethyl acetate in hexane (2 L) to afford pure 23 (0.12 g) and impure 23 (0.50 g).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[C:11]([NH:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:30]([O:34][C:35]([N:37]1[CH2:44][CH:43]2[O:45][CH:39]([CH2:40][NH:41][CH2:42]2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:30]([O:34][C:35]([N:37]1[CH2:38][CH:39]2[O:45][CH:43]([CH2:42][N:41]([CH2:16][CH2:15][N:10]([CH2:9][CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:29][CH:28]=3)[C:11]([NH:13][CH3:14])=[O:12])[CH2:40]2)[CH2:44]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: CNC(=O)N(CCOc1ccc(C#N)cc1)CCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2
Temperature: 45 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-{1-[2-(4-cyanophenoxy)ethyl]-3-methylureido}ethyl ester (1.35 g, 3.233 mmol; see Preparation I above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (1.48 g, 6.466 mmol; see WO 01/28992) and potassium carbonate (1.34 g, 9.7 mmol) in dry acetonitrile (15 mL) was stirred at 45° C. for 24 h. The reaction mixture was diluted with 20 mL water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel (using 2-2.5% methanol in dichloromethane) and further purification by preparative HPLC yielded 920 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@@H:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:47][C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH3:39])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 72 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and R-(+)-α-methylbenzylamine: yield 72%.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Cl:17])[C:15]=1[OH:16])[C:11]#[N:12].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2](=[CH2:6])[C:3]([O:16][C:15]1[C:14]([Cl:17])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[Cl:7])=[O:4]
Reactant: N#Cc1cc(Cl)c(O)c(Cl)c1
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(F)C(=O)Oc1c(Cl)cc(C#N)cc1Cl
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
10 g (0.092 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 5° C., with stirring and in the course of 20 minutes, to a solution of 16.7 g (0.089 mol) of 3,5-dichloro-4-hydroxybenzonitrile and 9 g (0.089 mol) of triethylamine in 200 ml of anhydrous methylene dichloride, and the reaction mixture was then stirred for a further 30 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous methylene dichloride. After 0.005 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and wash solution were removed by distillation, and the residue was recrystallized from boiling n-heptane. 18.7 g (81% of theory) of 2,6-dichloro-4-cyanophenyl α-fluoroacrylate were obtained, melting point 95° to 99° C.
Reaction SMILES: CO.C(OC([NH:10][C@@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:17]=2)[CH2:12]1)=O)(C)(C)C.[ClH:28]>C(O)C>[ClH:28].[NH2:10][C@@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:17]=2)[CH2:12]1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@H](NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)COc1ccc2c(c1)C[C@H](N)CC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.5 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline, EXAMPLE 3, in 35 ml of methylene chloride is cooled to 0° C. Then, there is added a solution of 7.7 ml of trifluoroacetic acid in 40 ml of methylene chloride and the mixture is left to stand under stirring at first 30 minutes at a temperature of 0°-5° C., then 4 hours at room temperature. After neutralization with a solution of sodium bicarbonate, the organic phase is separated, washed with water, dried and evaporated to dryness. The residue is taken up with 15 ml of ethyl acetate and made acid with a solution of hydrochloric acid in ethanol. The precipitated so obtained is filtered and washed with ether. Thus, 1.1 g of (R)-2-amino-7-carbethoxymethoxytetraline hydrochloride is obtained; m.p. 168°-171° C., /alpha/=+51.14° (methanol, c=1%). (b) To a solution of 5.8 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline, EXAMPLE 3, in 135 ml of absolute ethanol there is added at room temperature 82 ml of a 7.2. N solution of hydrogen chloride in ethanol. The mixture is left under stirring at room temperature for 150 minutes, then it is evaporated to dryness under reduced pressure. The residue is taken up with ethyl ether and filtered. Thus, 4.6 g of (R)-2-amino-7-carbethoxymethoxytetraline hydrochloride are obtained; m.p. 170°-171° C., /alpha/=+51° (methanol, c=1%). By crystallization from methanol, the melting point remains unchanged (170°-172° C.) and the /alpha/ rises to +51.6° (methanol, c=1%).