Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13](=O)[CH3:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]/[N:7]=[C:13](/[CH3:14])\[CH:12]([O:16][CH3:17])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COC(OC)C(C)=O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: COC(OC)/C(C)=N\Cc1ccc(Cl)cc1
Yield: 100 %

Procedure:
In a three-necked round bottomed flask equipped with a Dean Stark trap and reflux cooler, a solution of 4-chlorobenzylamine (97.3 g, 0.687 mol) and 1,1-dimethoxy-propan-2-one (89.5 g, 0.758 mol) in toluene (300 mL) was heated for 3 h at reflux. The reaction mixture was cooled down and the solvent removed in vacuo to yield the title compound as a pale yellow oil (166 g, 0.687 mol, 100%). MS (ES+): 242 (M(C12H1635ClNO2)+H)+. MS (ES+): 242 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:11]=[C:12]([NH:17][C@H:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH3:19])[CH:13]=[CH:14][C:15]=3[NH2:16])[CH:5]=2)[CH2:3][CH2:2]1.[C:27](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[CH:11]=[C:12]([NH:17][C@H:18]([C:20]5[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=5)[CH3:19])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:27]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ccc(N)c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ccc2ncn(-c3cc(C4CC4)[nH]n3)c2c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A mixture of (S)-N3-(5-cyclopropyl-1H-pyrazol-3-yl)-N1-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine (Method 62; 0.395 g, 1.12 mmol) and formamidine acetate (0.234 g, 2.25 mmol) in EtOH (5 ml) was heated at reflux for 2 hrs. After cooling to 25° C., the reaction mixture was treated with saturated sodium bicarbonate solution (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to give the title compound as an off-white solid (0.205 g, 50%). NMR (400 MHz) 12.65 (s, 1H), 8.17 (s, 1H), 7.43 (m, 2H), 7.33 (d, J=8.8 Hz, 1H), 7.10 (m, 2H), 6.90 (s, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.25 (d, J=6.4 Hz, 1H), 6.08 (s, 1H), 4.51 (m, 1H), 1.96 (m, 1H), 1.43 (d, J=6.8 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 361; Found: [M+H]+ 362.
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Cl)(Cl)([Cl:22])=O.[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:22][CH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(-c2ccccc2)oc(-c2ccccc2)[n+]1[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: ClCc1nc(-c2ccccc2)oc1-c1ccccc1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 4-methyl-2,5-diphenyloxazole 3-oxide (395 mg, 1.57 mmol) in chloroform (2 mL) was added dropwise a solution of phosphorus oxychloride (265 mg, 161 μL, 1.73 mmol) in chloroform (2.00 mL) over a period of 10 min. The reaction mixture was stirred at 65° C. for 4 h and cooled to 0-5° C. At that temperature, NH4OH (25% aqueous solution, 10 mL) was added dropwise and the mixture was extracted with dichloromethane (3×40 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and a dichloromethane/heptane gradient) as colorless solid (249 mg, 923 μmol, 58.7%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=1[F:32])[CH2:10][C:11]([N:13]1[CH2:19][C@@H:18]([CH3:20])[CH2:17][NH:16][C:15](=[O:21])[C@H:14]1[CH3:22])=[O:12])=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[NH2:8][C@H:9]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=1[F:32])[CH2:10][C:11]([N:13]1[CH2:19][C@@H:18]([CH3:20])[CH2:17][NH:16][C:15](=[O:21])[C@H:14]1[CH3:22])=[O:12]
Reactant: C[C@H]1CNC(=O)[C@@H](C)N(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CNC(=O)[C@@H](C)N(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)C1

Procedure:
(3R,6S)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3,6dimethyl-2H-1,4-diazepin-2-one (135 mg, 0.3 mmol) was treated with 4N hydrogen chloride in dioxane (2 mL) at room temperature for 2 hr. The solvent was removed under a stream of nitrogen, and the crude product was purified on preparative TLC plates (silica, 10% 2N ammonia/methanol in dichloromethane) to yield the title compound as white solid. MS (M+1): 358.2.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH3:20])([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:21].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C1(C)C=CC=CC=1>[O:32]=[S:31]1(=[O:33])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][C:3]([C:4]2[C:13](=[O:14])[C:12]([CH3:20])([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[C:11]3[C:6]([C:5]=2[OH:21])=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:34]1
Reactant: CSC(SC)=C1C(=O)c2ccccc2C(C)(CCC(C)C)C1=O
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A solution of Example 28F (0.087 g, 0.250 mmol) and 2-amino-benzenesulfonamide (0.045 g, 0.262 mmol) in toluene (7 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the desired product (0.105 g, 99%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:50])([F:49])[O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([O:40][C:39]([F:38])([F:49])[F:50])=[CH:42][CH:43]=2)[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: O=C1C(Cc2ccc(OC(F)(F)F)cc2)CCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 36-2, using 281 mg of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1, and using 4-trifluoromethoxybenzyl bromide in place of iodoethane, 383 mg (yield: 100%) of the captioned compound was obtained as a diastereomer mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][N:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:25]4[N:21]([CH3:20])[C:22](=[O:27])[NH:23][C:24]4=[O:26])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC(=O)NC1=O
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1C(=O)NC(=O)C1=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Temperature: 70 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (20 mg, 0.074 mmol) in 0.5 mL EtOH was added 1-methylimidazolidine-2,4-dione (8.4 mg, 0.074 mmol) and piperidine (7.5 μL, 0.074 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-1-methylimidazolidine-2,4-dione. LCMS (M+1=369)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cccc2ncc(O)cc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cnc2cccc([N+](=O)[O-])c2c1
Reaction time: 2 h

Procedure:
3-Hydroxy-5-nitroquinoline, as described above in Step D, (2.86 g, 15.04 mmol), tert-butyldimethylsilyl chloride (2.95 g, 19.55 mmol) and imidazole (3.07 g, 45.12 mmol) were dissolved in DMF (20 mL) and stirred for 2 hours. The reaction mixture was poured into H2O and extracted with Et2O (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C(N(CC)CC)C.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[C:18]([NH:22][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: Cc1ccnc(C(=O)O)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccnc(C(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
4-Methylpyridine-2-carboxylic acid (500 mg, 3.65 mmol), triethylamine (1.27 g, 12.5 mmol, 1.75 mL) and tert-butylamine (267 mg, 3.65 mmol) were combined and stirred in dichloromethane (1 mL). 1-Propanephosphonic acid cyclic anhydride (4.82 g, 7.5 mmol, 4.5 mL, 50% solution in ethyl acetate) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure and the resulting residue taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the title compound (376 mg). MS (ESI) m/z 193.4 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.ClCCCl.C([O:16][C:17]([C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22](=[O:29])[N:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]=1[CH3:36])=[O:18])(C)(C)C>>[CH3:36][C:20]1[N:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22](=[O:29])[CH:23]=[C:24]([C:25]([F:26])([F:28])[F:27])[C:19]=1[C:17]([OH:18])=[O:16]
Reactant: Cc1c(C(=O)OC(C)(C)C)c(C(F)(F)F)cc(=O)n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1c(C(=O)O)c(C(F)(F)F)cc(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (100 uL, 1 mmol) in 1,2-dichloroethane (200 uL, 2 mmol) was added to 2-methyl-6-oxo-1-phenyl-4-trifluoromethyl-1,6-dihydro-pyridine-3-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol). The obtained solution was stirred at r.t. overnight and evaporated. The residue was partitioned between 2M NaOH (4 mL) ethyl acetate (2×2 mL) to remove traces of the unreacted ester. The aqueous phase was acidified and the product extracted with ethyl acetate (2×3 mL). The combined organic solution was washed with brine, dried (MgSO4) and evaporated, yield 19.4 mg, 50%. LC-MS (m/z) 298.4 (MH+); tR=0.80 (method C).). 1H NMR (500 MHz, DMSO-d6): 1.99 (s, 3H, Me), 3.56 (br., CO2H+H2O), 6.86 (s, 1H, C5-H), 7.36 (d, J=7.3 Hz, 2H, two ortho-H of Ph), 7.50 (t, J=7.4 Hz, 1H, para-H of Ph), 7.56 (t, J=7.5 Hz, 2H, two meta-H of Ph).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][N:16]([CH2:29][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[CH2:32])[C:12]=2[N:13]=[CH:14][N:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C>[NH2:9][C:10]1[C:11]2[C:18]([C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:17]([Br:1])[N:16]([CH2:29][C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[CH2:32])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C[C@@H](Cn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C[C@@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
N-Bromosuccinimide (3.63 g) was added to a solution of (S)-tert-butyl (1-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (7.98 g) obtained in Step 3 in DMF (64 ml) at −15° C., and the mixture was stirred at −15° C. for 1 hour. A 10% aqueous sodium thiosulfate solution and ethyl acetate were added to the reaction mixture, and stirred at room temperature for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The resulting organic layer was washed with a saturated sodium chloride solution twice, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound (6.30 g) as a light-brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][NH:19][O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:31][CH:30]=2)[O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: Fc1ccc(CNOCCCN2CCOCC2)cc1
Product: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(F)cc2)OCCCN2CCOCC2)O1
Yield: 47.4 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (1.0 mmol) with N-(4-fluorobenzyl)-O-(3-morpholin-4-yl-propyl)-hydroxylamine (0.268 g, mmol) as described in the preparation of compound 44-C (acid wash was skipped in this case) gave 0.200 g (47% yield) of the title amide as a clear oil after chromatography on silica gel. 1HNMR 400 MHz (C6D6) δ (ppm): 1.10 (6H, s, CH3), 1.50 (2H, m, CH2), 2.19 (2H, t, J=6.6 Hz, NCH2), 2.20 (4H, m, NCH2), 3.70 (2H, t, J=6.2 Hz, OCH2), 3.71 (4H, m, OCH2), 4.73 (2H, s, NCH2), 6.85 (3H, m, CH and aromatics), 7.22 (2H, m, aromatics). HRMS (MAB N2) calculated for C21H27FN2O6 [M+]: 422.185315: found: 422.185246.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:31][CH2:32][CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[C:27]([F:30])([F:29])[F:28].[Li+].[OH-]>>[CH2:32]([O:31][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[C:27]([F:28])([F:29])[F:30])[C:3]([OH:34])=[O:2])[CH3:33]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C(F)(F)F)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C(F)(F)F)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl}-propionic acid as colorless liquid.
Reaction SMILES: C=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[C:9](=O)[CH2:8]3)[CH2:5][CH2:4]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[Na].O>O1CCOCC1.C(OC)(C)(C)C>[CH2:2]=[C:3]1[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([CH2:18][CH2:19][C@:20]12[CH3:21])[C@:15]1([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH:13]=[CH:14]1)[CH2:9][CH2:8]3
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: C=C1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 50.3 %

Procedure:
Refer to FIG. 190. A solution of 17-methylenandrost-4-en-3-one (9, 1.0001 g, 3.5160 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 2.43 g, 10.7 mmol) in dioxane (60 ml, freshly distilled after overnight reflux over sodium) was refluxed 6 h and then cooled with swirling in tap water. Methyl t-butyl ether (MTBE, 50 ml) was added and the suspension was filtered through diatomaceous earth. The residue was washed with two 50 ml portions of MTBE and the combined filtrates were concentrated under reduced pressure. Flash chromatography of the residue (20% ethyl acetate/hexanes on silica gel) followed by recrystallization from 95% ethanol gave off-white crystals (498.9 mg, 1.767 mmol, 50%), m.p. 155-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCCC=C(c1ccc(N)cc1)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=CCCCC(=O)O)c3cccnc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3 g of methyl 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoate, 1.9 g of 4-methylbenzene-sulphonic acid chloride and 5 ml of triethylamine in 100 ml of methylene chloride is stirred for one hour at ambient temperature. The organic phase is washed with water, evaporated down and the residue is purified pyer a silica gel column with ethyl acetate. The product fraction is evaporated down and heated in a mixture of 50 ml of ethanol and 3 ml of 10N sodium hydroxide solution to 50° C. for one hour. The reaction mixture is diluted with water and neutralised by the addition of citric acid. The agueous phase is extracted with ethyl acetate, dried and evaporated down. The residue is recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([Cl:43])[CH:37]=1>C1COCC1>[Cl:43][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][C:39]=1[F:42]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
Dissolved 336 mg (4.00 mmol) 2-butynoic acid in 20 ml of THF and chilled to 0° C. under N2. Added 520 μl (4.00 mmol) isobutyl chloroformate and 440 μl (4.00 mmol) N-methylmorpholine and stirred for 10 minutes. Added a solution of 500 mg (1.60 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile, stirred for minutes at 0° C. and then at 25° C. overnight. Stripped solvent, washed with water, collected and dried in vacuo. Recrystallized from ethyl acetate, giving 148 mg of a yellow solid: mass spectrum (electrospray m/e): M+H=379.1, 381.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13](OC)=[O:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][OH:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1
Reactant: COC(=O)c1cc(Br)cc2c1OC(C)(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(Br)cc(CO)c2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (668) (466 mg, 1.63 mmol) in tetrahydrofuran (16 mL) at 0° C. was added LAH (1 mL, 1.96 mmol). The reaction was stirred at 0° C. for 1 hour and quenched with 0.2 mL of water, 0.2 mL of 15% NaOH and 0.6 mL of water. The reaction was warmed to room temperature and diluted with diethyl ether. Magnesium sulfate was added and the solution was filtered, washed with diethyl ether, and the solvent removed in vacuo to provide (5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methanol (669).
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19]>>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[NH:20][C:18](=[O:19])[C:17]2[C:16](=[C:24]([Br:25])[CH:23]=[CH:22][CH:21]=2)[N:15]=1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: NC(=O)c1cccc(Br)c1N
Agent: [Na+]
Product: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Temperature: 115 °C
Yield: 27 %

Procedure:
Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (0.49 g, 2.3 mmol) and 2-amino-3-bromobenzamide (0.42 g, 1.9 mmol) were combined in trimethylsilylpolyphosphate (4.3 mL) at rt and the mixture was heated at 115° C. for 20 h with vigorous stirring. The mixture was allowed to cool to rt and then was partitioned between water (15 mL) and ethyl acetate (15 mL). The organic layer was separated and the aqueous layer (pH˜1) was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a 1:10 to 1:1 EtOAc/hexanes to afford 2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-3H-quinazolin-4-one as an off-white solid (0.19 g, 22%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:25][C:23]1[CH:22]=[C:4]([CH:3]=[C:2]([F:1])[CH:24]=1)[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1cc(F)cc(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3cc(F)cc(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
(2S,4R)-Methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.789 g, 2.24 mmol) (from example 130, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 17.65 mL, 100.77 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3,5-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (123 mg, 19%). 1H NMR (600 MHz, dmso) δ 1.07 (q, 1H), 1.33 (dq, 1H), 1.71-1.78 (m, 2H), 2.49-2.56 (m, 1H), 2.57-2.71 (m, 3H), 2.72-2.78 (m, 1H), 2.94-2.99 (m, 1H), 5.67 (s, 1H), 6.89-6.94 (m, 2H), 7.00 (tt, 1H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1248