Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>CCO.Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Reaction time: 22 h
Yield: 66.8 %

Procedure:
To a suspension of Example 272A (0.13 g, 0.34 mmnol) in EtOH (3.5 mL), a solution of tin(II) chloride dihydrate (0.31 g, 1.36 mmol) in conc. HCl (0.68 mL) was slowly added. The reaction was stirred for 22 hours and partitioned between dichloromethane (75 mL) and 1 N NaOH (75 mL). The organic layer was washed with 1 N NaOH (1×50 mL), brine (1×50 mL), partially dried (Na2SO4), and concentrated to a colored solid (0.13 g). The desired product was crystallized from acetonitrile to yield colored crystals (0.08 g, 68%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N:9]2[C:33](=[O:34])[C:12]3=[CH:13][N:14]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH:32]=[CH:31][CH:30]=[N:29]5)=[CH:24][CH:23]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)[N:4]=[CH:3]1.C([BH3-])#N.[Na+]>O1CCCC1.ClCCl>[OH:8][CH2:7][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[N:9]1[C:33](=[O:34])[C:12]2=[CH:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1
Reactant: Cn1cnc(-n2nc3c4ccccc4n(Cc4ccc(-n5cccn5)cc4)cc-3c2=O)c1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cnc(-n2nc3c4ccccc4n(Cc4ccc(-n5cccn5)cc4)cc-3c2=O)c1CO
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1-Methyl-4-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)-1H-imidazole-5-carbaldehyde (Example 555, 50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL) and dichloromethane (15 mL), cooled to 0° C. and treated with sodium cyanoborohydride (0.033 mL, 1 M tetrahydrofuran solution, 0.033 mmol, 0.3 equiv). After stirring for 5 minutes at 0° C., the mixture was warmed to ambient temperature and stirred for 1 hour. Additional sodium cyanoborohydride (0.033 mL, 1 M tetrahydrofuran solution, 0.033 mmol, 0.3 equiv) was added and after 1 hour, the mixture was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (85:15 to 40:60; water containing 0.5% trifluoroacetic acid:acetonitrile containing 0.5% trifluoroacetic acid). The appropriate fractions were concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.04 (1H, br s), 8.37 (1H, br d, J=4.7 Hz), 8.20 (1H, m), 7.85 (1H, d, J=8.8 Hz), 7.77 (2H, d, J=8.3 Hz), 7.74-7.65 (4H, m), 7.61 (1H, br t, J=6.7 Hz), 7.44 (2H, d, J=7.6 Hz), 6.51 (1H, m), 5.82 (2H, s), 4.00 (2H, s) 2.65 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 452.1842 [(M+H)+; calculated for C25H22N7O2: 452.1829].
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[S:14](Cl)(=[O:16])=[O:15]>[NH4+].[Cl-]>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[S:14]([NH2:2])(=[O:16])=[O:15]
Reactant: [NH4+]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Agent: [Cl-]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])ccc1S(N)(=O)=O
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a concentrated solution of ammonium hydroxide (28%, 2.5 mL, 20 mmol) was added cautiously 2-methoxy-4-nitrobenzenesulfonyl chloride (0.25 g, 1.0 mmol). After stirring 24 h the reaction mixture was added to satd NH4Cl (50 mL) and extracted with DCM (2×50 mL). The combined extracts were washed with brine, dried (anhyd Na2SO4) and concentrated under reduced pressure. The crude residue was chromatographed (silica, MeOH/DCM, 0:100 to 10:90) to yield 2-methoxy-4-nitrobenzenesulfonamide (0.16 g, 68%) as a pale brown solid. 1H-NMR (DMSO-d6) δ 7.99 (1H, d), 7.90-7.95 (2H, m), 7.47 (2H, br s), 4.04 (3H, s). The title compound was prepared from 2-methoxy-4-nitrobenzenesulfonamide in a manner similar to that described for Example 3A. 1H-NMR (DMSO-d6) δ 9.69 (1H, s), 8.01 (1H, d, J=8.1), 7.92 (1H, app t, J=7.6), 7.81 (1H, app t, J=7.6), 7.74 (1H, d, J=1.8), 7.63 (1H, d, J=8.6), 7.50 (1H, d, J=7.6), 7.47 (1H, dd, J=1.8, 8.6), 6.93 (2H, s), 6.66 (1H, s), 3.88 (3H, s), 2.14 (3H, s), 1.89 (3H, s); MS (ESI): 468 (MH+). B. In a similar manner as that described for Example 6A, the following was prepared by replacing ammonium hydroxide with dimethylamine:
Reaction SMILES: [CH2:1]([PH:8](=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:23]([O:30][C:31]([CH:33]([CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[CH2:34]P(C)(=O)OCC1C=CC=CC=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:1]([P:8]([CH2:34][CH:33]([C:31]([O:30][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:32])[CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])(=[O:9])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CP(=O)(CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=[PH](O)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
Benzylphosphinic acid (2.3 g, 15 mmol) in 150 mL of dry dichloromethane was cooled to 0° C. under a nitrogen atmosphere. Triethylamine (6.5 g, 65 mmol) was added followed by trimethylsilyl chloride (5.8 g, 54 mmol) while the reaction temperature was maintained at 0° C. After 30 minutes dibenzyl 2-methylenepentanediote (2) in 20 mL of dichloromethane was added over 5 minutes. The reaction mixture was left to warm to room temperature and stirred overnight. The clear solution was cooled to 0° C. and quenched with 5% hydrochloric acid and with brine, dried (MgSO4) and evaporated to give a clear yellow liquid. Purification by flash chromatography and elution with 1:1 hexane/ethyl acetate containing 10% acetic acid yielded 2.0 g (28%) of benzyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3, R=CH2Ph, R1+H) as a clear light yellow oil. Rf 0.37 (1:1 Hex./EtOAc, 10%AcOH).
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26](OC)[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.[N:35]1([CH2:40][CH2:41]O)[CH:39]=[N:38][CH:37]=[N:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2([O:4][CH3:3])[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:41][CH2:40][N:35]4[CH:39]=[N:38][CH:37]=[N:36]4)=[CH:26][CH:27]=3)[N:22]=[CH:21][NH:20]2)=[C:16]([F:34])[CH:15]=1
Reactant: OCCn1cncn1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1(Nc2ccc(Cl)cc2F)NC=Nc2cc(OCCn3cncn3)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.93 mmol), (prepared as described for the starting material in Example 24), 2-(1,2,4-triazol-1-yl)ethanol (159 mg, 1.4 mmol), (Ann. Pharm. Fr. 1977, 35, 503-508), and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (10 ml). The mixture was stirred for 2 hours at ambient temperature and further triphenylphosphine (246 mg, 0.9 mmol) and diethyl azodicarboxylate (147 μl, 0.9 mmol) were added. The mixture was stirred for 1 hour at ambient temperature and the resulting precipitate was collected by filtration, washed with methylene chloride and ether and dried under vacuum. This solid was suspended in methylene chloride/methanol and a 5M solution of hydrogen chloride in isopropanol (1.0 ml) was added. The volatiles were removed by evaporation, the residue was triturated with ether. The resulting solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)4-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline hydrochloride (219 mg, 52%). m.p. 169-174° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C1C=CN=C(C2C=CC=CN=2)C=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:9]2[CH2:11][CH2:10]2)[C:4](=[O:8])[CH:3]=1
Reactant: OB(O)C1CC1
Reactant: Oc1cc(Br)ccn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccn2)nc1
Product: O=c1cc(Br)ccn1C1CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 4-bromopyridin-2-ol (100 mg, 0.58 mmol), cyclopropylboronic acid (100 mg, 1.3 mmol), Cu(OAc)2 (245 mg, 1.2 mmol), and bipyridine (100 mg, 0.64 mmol) in Cl(CH2)2C1 (5.0 mL) was stirred for 24 h at 70° C. The crude mixture was filtered. The filtrate was collected and concentrated to afford the crude product, which was purified by silica gel column chromatography on silica gel with PE/EA (5:1) to afford tittle compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 1 H), 6.79 (d, 1 H), 6.31 (dd, 1 H), 3.34-3.23 (m, 1 H), 1.14 (d, 2 H), 0.86 (d, 2 H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCCC)=[N:18][C:17]3=[O:25])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][O:37][C:38](=[O:49])[CH2:39][NH:40][C:41]([CH:43]1[O:48][CH2:47][CH2:46][NH:45][CH2:44]1)=[O:42]>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:45]4[CH2:46][CH2:47][O:48][C@H:43]([C:41]([NH:40][CH2:39][C:38]([O:37][CH3:36])=[O:49])=[O:42])[CH2:44]4)=[N:18][C:17]3=[O:25])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: COC(=O)CNC(=O)C1CNCCO1
Product: COC(=O)CNC(=O)[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
Methyl N—({(2S)-4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholin-2-yl}carbonyl)glycinate was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and [(Morpholine-2-carbonyl)-amino]-acetic acid methyl ester following General Procedure B.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:31])[NH:10][CH:11]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[C:12](=[O:23])[NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]([NH:10][CH:11]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[C:12]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)=[O:23])=[O:31]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC(C(=O)Nc1ccc2[nH]ncc2c1)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NC(C(=O)Nc1ccc2[nH]ncc2c1)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of ({[(3-chloro-phenyl)-(1H-indazol-5-ylcarbamoyl)-methyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester (0.09 mmol) in dichloromethane (2.5 mL) at 0° C. was added trifluoroacetic acid (2.5 mL) and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo to afford compound the title compound (9 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ 3.8(2H, m), 5.8(1H, m), 7.4–7.7(5H, m), 7.9–8.2(4H, m), 9.3–9.4(1H, m), 10.6 (1H, s), 13.0(1H, br s); MS (ES+): m/e=358.3(40%), 134.3(100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[C:7]([CH3:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:21]([O:25][C:26](=[O:43])[CH2:27][C:28]1[C:29]([CH3:42])=[N:30][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[C:32]=1[CH3:33])([CH3:24])([CH3:23])[CH3:22].C1(C)C(S([O-])(=O)=O)=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[C:21]([O:25][C:26](=[O:43])[CH2:27][C:28]1[C:29]([CH3:42])=[N:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:11]([C:8]3[O:9][C:10]4[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=4[C:7]=3[CH3:14])=[O:13])=[CH:39][CH:40]=2)[C:32]=1[CH3:33])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1nn(Cc2ccc(N)cc2)c(C)c1CC(=O)OC(C)(C)C
Reactant: Cc1c(C(=O)O)oc2c(Cl)cccc12
Agent: CN(C)c1ccncc1
Agent: Cc1ccccc1S(=O)(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nn(Cc2ccc(NC(=O)c3oc4c(Cl)cccc4c3C)cc2)c(C)c1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 7-chloro-3-methylbenzofuran-2-carboxylic acid (185 mg, 0.88 mmol) in 6 mL dichloromethane is added oxalyl chloride (0.123 mL, 1.14 mmol) and a drop of dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid tert-butyl ester (428 mg, 1 mmol) in form of the toluene sulfonate salt and diisopropylethylamine (0.39 mL, 2.27 mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (11 mg, 0.09 mmol) the solution is stirred at room temperature for 12 hours. The solution is extracted twice with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated in vacuo to yield 426 mg of (1-(4-[(7-chloro-3-methyl-benzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=508; Retention time HPLC: 1.60 min (method H)). b) To a solution of (1-(4-[(7-chloro-3-methyl-benzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (426 mg, 0.84 mmol) in dichloromethane (10 mL) is added trifluoroacetic acid (400 mL, 5.2 mmol) and the mixture is stirred at room temperature for 3 days. The solvent is evaporated in vacuo, and the residue is suspended in water and treated with diethyl ether and the precipitating product is filtered off to yield 174 mg of the title compound (ESI mass spectrum: [M+H]+=452; Retention time HPLC: 1.39 min (method J)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.C(N(CCCC)CCCC)CCC.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([NH2:42])=[NH:41].[OH-].[Na+]>O.C(O)C>[OH:13][C:11]1[C:10]([C:3]2[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[C:16]([OH:18])[N:42]=[C:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)[N:41]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: N=C(N)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Solvent: CCO
Product: Oc1nc(-c2ccccn2)nc(O)c1-c1c(F)cc(F)cc1F
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
332 g (1.16 mol) of diethyl 2-(2,4,6-trifluorophenyl)malonate and 192 g (1.04 mol) of tributylamine were heated at 180° C. for eight hours together with 182 g (1.17 mol) of pyridine-2-carboxamidine. In the course of this, the ethanol produced was distilled off. The reaction mixture was then allowed to cool to 60-70° C. and was mixed with a solution of 116 g (2.89 mol) of sodium hydroxide in 1200 ml of water. After stirring for 30 min and cooling to approximately 20-25° C., the mixture was extracted with methyl tert-butyl ether (MTBE) and, after phase separation, the aqueous phase was acidified with 6N hydrochloric acid. After filtering off and drying, 180 g of the title compound were obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][CH2:23][C:24](=O)[C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[C@@H:18]([C:38]([O:40][CH3:41])=[O:39])[CH2:17]1>N1C=CC=CC=1>[F:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][CH2:23][C:24](=[N:2][OH:3])[C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[C@@H:18]([C:38]([O:40][CH3:41])=[O:39])[CH2:17]1
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=NO)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
0.834 g of hydroxylamine hydrochloride is added, with stirring and under an inert atmosphere, to a mixture of 3.5 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 35 cm3 of pyridine at a temperature in the region of 20° C. The mixture is stirred for 5 hours at a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue is taken up in 300 cm3 of ethyl acetate and 100 cm3 of water. After standing for 16 hours, the mixture is extracted with 3 times 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 3 times 100 cm3 of water, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. 3.35 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-hydroxyimino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate are obtained.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:46][OH:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:46][OH:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(CO)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CO)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.39 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.62 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 26%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:23]#[N:24])([CH3:22])[CH3:21])[CH:15]=2)[CH:8]=[CH:9][C:10]=1[CH3:11])=[O:4].CCN(C(C)C)C(C)C.[C:35]1([C:41]([SH:54])([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[C:23]([C:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:5]([C:3](=[O:4])[CH2:2][S:54][C:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:6]=1)=[O:25])([CH3:22])[CH3:21])#[N:24]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CBr
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 70.9 %

Procedure:
A solution of N-(3-(2-bromoacetyl)-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 113 (1.127 mmol, 450 mg), DIPEA (1.352 mmol, 0.224 mL) and triphenylmethyl mercaptan (1.240 mmol, 343 mg) in DMF (5 ml) was stirred overnight at room temperature. Evaporated to dryness. Purification by chromatography (0-10% ethyl acetate in Toluene) gave 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(tritylthio)acetyl)phenyl)benzamide 114 (475 mg, 70.9%). NMR (400 MHz, CDCl3) 1.80 (s, 6H), 2.38 (s, 3H), 3.55 (s, 2H), 7.31-7.15 (m, 10H), 7.39 (d, J=2.3 Hz, 1H), 7.42 (m, 3H), 7.44 (m, 3H), 7.56 (t, J=7.8 Hz, 1H), 7.72 (m, 2H), 7.74 (m, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.99 (t, J=1.9 Hz, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]([S:17]([CH3:20])(=[O:19])=[O:18])[C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)#[N:2].[Br:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1.C(N(CC)CC)C>C(O)C.Cl.C(#N)C.[Pt](=O)=O>[Br:21][C:22]1[C:23]([NH:2][CH2:1][CH2:3][CH2:4][CH2:5][N:6]([S:17]([CH3:20])(=[O:19])=[O:18])[C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=2)=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(=O)Nc1cccc(N(CCCC#N)S(C)(=O)=O)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(N(CCCCNc2nc(Cl)ncc2Br)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
460 mg (1.56 mmol) of N-{3-[(3-cyano-propyl)-methanesulfonyl-amino]-phenyl}-acetamide in 25 ml of ethanol and 0.5 ml of concentrated HCl are hydrogenated with use of 60 mg (0.26 mmol) of platinum(IV)oxide for 5 hours at room temperature under normal pressure. The batch is filtered and concentrated by evaporation. The residue that is obtained is mixed with a solution of 355 mg (1.56 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 15 ml of acetonitrile. 0.45 ml of triethylamine is added drop by drop, and it is stirred for 16 hours at room temperature. The batch is concentrated by evaporation, and the residue that is obtained is purified by chromatography (DCM/EtOH 95:5). 330 mg (0.67 mmol, corresponding to 43% of theory) of the product is obtained.