Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.CC(C)([O-])C.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[O:71]1[C@@H:73]([CH:74]([CH3:76])[CH3:75])[CH2:72]1.[Si](O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC=C2[C@@H](OC[C@@H](O)C(C)C)C)C[C@@H](O[Si](C(C)(C)C)(C)C)C1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C(OCC)C.O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:72][C@@H:73]([OH:71])[CH:74]([CH3:76])[CH3:75])[CH3:22])[CH2:12][C@@H:11]([OH:31])[CH2:10]1
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)[C@H]1CO1
Agent: CC(C)(C)[O-]
Agent: CC(C)[C@H](O)CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@H](O)CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 106 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (97.9 mg, 0.175 mmol), potassium t-butoxide (230 mg, 2.05 mmol) and dibenzo-18-crown-6 (45.0 mg, 0.125 mmol) in toluene (6 ml) was added (S)-(+)-1,2-epoxy-3-methylbutane (0.18 ml, 1.72 mmol) at room temperature and the mixted solution was stirred at 106° C. for one hour. The reaction solution was diluted with diethyl ether and washed with brine, and then the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was separated by preparative thin layer chromatography (0.5 mm×4, hexane:dichloromethane:ethyl acetate=45:5:2, developed three times) to give a fraction containing 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{2(S)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene (67.5 mg). An aliquot of 52.6 mg was dissolved in tetrahydrofuran (1.5 ml) and stirred with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.5 ml) under the condition of an outer temperature of 71° C. for 10 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine successively, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by preparative thin layer chromatography (0.25 mm×2, dichloromethane:ethanol=15:1, developed twice) to give the title compound as a colorless oil (20.6 mg, 36%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[NH2:27]>>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19][NH:27][C:23]3[NH:22][CH:26]=[CH:25][N:24]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Reactant: Nc1ncc[nH]1
Agent: Cl
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CNc2ncc[nH]2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1H-imidazol-2-amine. m/e+ 372 for C18H16Cl2N5 [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.27 (m, 4H), 6.92 (d, J=6.6 Hz, 2H), 6.76 (s, 2H), 4.67 (s, 2H), 4.50 (bs, 1H), 2.31 (s, 3H) ppm.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1([N:29]=[C:30]=[S:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:19][NH:18][C:16](=[S:17])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[S:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: S=C=NC1CCCCC1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Product: S=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=S)NC1CCCCC1

Procedure:
The compound is prepared by a method analogous to that of Example 5 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydrazine carbothioamide and cyclohexylisothiocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(C)c2ccc(Cl)cc2)CC1

Procedure:
Example 100 was prepared from 2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H, J=2.0 Hz), 7.34–7.28 (m, 5H), 7.21 (dd, 1H, J=2.0. 8.0 Hz), 7.09 (d, 1H, J=8.0 Hz), 6.98 (br s, 1H), 3.55 (q, 1H, J=7.2 Hz), 3.34 (m, 2H), 3.02 (d, 1H, J=11.6 Hz), 2.93 (d, 1H, J=11.6 Hz), 2.68 (m, 1H), 2.51 (m, 1H), 2.39 (dt, 2H, J=6.8, 2.0 Hz), 2.29 (s, 3H), 2.04–1.97 (m, 2H), 1.80–1.60 (m, 6H), 1.52 (d, 3H, J=7.2 Hz), 1.24 (dd, 6H, J=1.6, 6.8 Hz); ESMS m/e: 484.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[CH:7]=1)=[O:4].[OH:19][S:20]([Cl:23])(=O)=[O:21]>C(Cl)Cl>[O:16]=[C:14]([CH3:15])[CH2:13][CH2:12][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:17])([F:18])[F:1])[CH:11]=[CH:10][C:9]=1[S:20]([Cl:23])(=[O:21])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)CCc1cccc(NC(=O)C(F)(F)F)c1
Solvent: ClCCl
Product: CC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
To 2,2,2-trifluoro-N-(3-(3-oxobutyl)phenyl)acetamide (2 g, 8 mmol) was added HOSO2Cl (9 g, 77 mmol) dropwise at 0° C. The mixture was stirred at r.t. for 3 hrs. The reaction mixture was diluted with DCM and washed with water, the organics was dried over Na2SO4 and concentrated to give 2-(3-oxobutyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (1.5 g, yield 54%). 1H NMR: (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.76 (d, 1H), 7.70 (t, 1H), 7.63 (d, 1H), 3.31 (t, 2H), 2.82 (t, 2H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@@H:21]([OH:23])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].S(OC)(O[CH3:47])(=O)=O.[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@@H:21]([O:23][CH3:47])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](OC)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 52.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (114 mg, 0.185 mmol) prepared in Example 120c, dimethyl sulfate (17.9 μL, 0.189 mmol), sodium hydride (63%; 10.5 mg, 0.276 mmol) and THF (2.0 mL), to yield the title compound (60.0 mg, 51%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][C:36](=[O:38])[CH3:37])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared using General Procedure 7: To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (15 mg, 0.03 mmol) in anhydrous DCM (1 mL) was added triethylamine (11 mg, 0.1 mmol) followed by acetyl chloride (4.2 mg, 0.05 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude mixture purified by preparative HPLC to afford (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)acetamide 14. LCMS-ESI (m/z) calculated for: C23H22N4O2S: 418.2; found 419.3 [M+H]+, tR=3.34 min. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=8.9, 2.3 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 5.83 (d, J=8.4 Hz, 1H), 5.57 (q, J=7.9 Hz, 1H), 4.76 (dt, J=12.2, 6.1 Hz, 1H), 3.46 (ddd, J=17.1, 8.8, 3.8 Hz, 1H), 3.28-3.15 (m, 1H), 2.75-2.62 (m, 1H), 2.07 (s, 3H), 1.98-1.80 (m, 1H), 1.46 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 170.36, 167.43, 166.14, 162.16, 145.92, 142.83, 133.89, 133.77, 129.44, 128.23, 127.18, 126.95, 123.21, 116.05, 114.36, 104.23, 73.03, 55.00, 34.03, 31.95, 23.92, 22.24.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=1)[C:7](=O)[CH3:8]>C(O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C:6]2[S:3][C:2]([NH2:4])=[N:1][C:7]=2[CH3:8])[CH:15]=[CH:14][N:13]=1
Reactant: CC(=O)C(Br)c1ccnc(Cl)c1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccnc(Cl)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Thiourea (1.8 g, 29.4 mmol) is added to a stirred solution of 1-bromo-1-(2-chloro-pyridin-4-yl)-propan-2-one (7.3 g, 29.4 mmol) in ethanol (150 ml). The mixture is heated at 60° C. for 3 hours then allowed to cool to room temperature and stand for 18 h. The hydrobromide salt of the titled compound precipitates during this time and is removed by filtration and washed with diethyl ether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:11]=[C:9]([CH3:10])[CH2:8][C:4]1[CH:3]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OC
Reactant: CC(=O)Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cccc(CC(C)=O)c1
Temperature: 25 °C
Yield: 105.9 %

Procedure:
A solution of 3-bromophenylacetone (50.0 g, 235 mmol), methyl acrylate (40.4 g, 469 mmol), palladium(II)acetate (7.9 g, 35.2 mmol), tri-ortho-tolylphosphine (21.4 g, 70.4 mmol) and triethylamine (82 ml) in acetonitrile (900 ml) was heated at reflux under a nitrogen atmosphere for a period of 16 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. Purification by flash column chromatography eluting with pentane:ethyl acetate (90:10 changing to 70:30 by volume) gave the title compound as an orange oil (54.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:9](Br)[CH2:10][CH:11]([CH3:13])[CH3:12]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)CCBr
Solvent: CC#N
Product: CC(C)CCn1cc(Br)ccc1=O
Yield: 62300 %

Procedure:
According to Scheme 1 Step 2: The title compound was prepared from 5-bromopyridin-2(1H)-one (1 eq, 0.01 mol, 1.73 g) and 1-isopentylbromide (1 eq, 0.01 mmol, 1.51 g) according to the procedure described for Example 1 Step 2. Reaction conditions: 3 hours under reflux in acetonitrile. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column SiO2) using CH2Cl2/AcOEt (80/20) as the eluent to afford 5-bromo-1-isopentylpyridin-2(1H)-one (6.23 mmol, 1.52 g, 62%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:46])([CH:43]([F:45])[F:44])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[N:40][NH:39][C:38]4=[O:42])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:39]1[C:38](=[O:42])[N:37]([C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:46])[CH:43]([F:44])[F:45])=[CH:24][CH:23]=4)[CH2:30][CH2:29]3)=[CH:36][CH:35]=2)[CH:41]=[N:40]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(N2CCN(c3ccc(OCC(F)(F)C(F)F)cc3)CC2)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(N3CCN(c4ccc(OCC(F)(F)C(F)F)cc4)CC3)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 21.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.31 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.50 g of 4-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-3(2H,4H)-1,2,4-triazolone, 0.15 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)- 2,3-epoxy-1-methylpropyl]-4-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH:9]=[N+:10]2[O-:31])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc3ccc(OC)cc3[n+]([O-])c2)cc1
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A mixture of methyl 4-(7-methoxyquinolin-3-yl)benzoate (632 mg, 2.16 mmol), m-CPBA (742 mg, 4.31 mmol) and DCM (10 mL) was stirred overnight. Saturated Na2CO3 solution was added and adjusted the pH>7, the organic layer was washed with water (50 mL×2), dried over NaSO4 and evaporated in vacuo to give the crude product as a yellow solid (540 mg, 81.0%).
Reaction SMILES: [CH3:1][C:2]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17](=[O:25])OC2C=CC=CC=2)[CH:12]=1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C([N:29](CC)C(C)C)(C)C.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(C=CC=1)N>C1COCC1>[CH3:1][C:2]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17](=[O:25])[NH2:29])[CH:12]=1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(CN1CCOCC1)c1cc(NC(=O)Oc2ccccc2)no1
Agent: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Product: CC(C)(CN1CCOCC1)c1cc(NC(N)=O)no1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A stirred solution of phenyl 5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-ylcarbamate (22 mg), N,N-diisopropylethylamine (12 mg, 0.093 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (15 mg, 0.051 mmol) in THF (0.5 mL) was heated at 60° C. for 15 h. The reaction mixture was cooled to rt and partitioned between saturated aqueous sodium carbonate and dichloromethane. The organic layer was separated and concentrated under reduced pressure to give the crude product. Purification via preparative TLC afforded 14346,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-yl)urea (5 mg, 1% over three steps) as a solid. 1H NMR (400 MHz, CDCl3) 89.35 (brs, 1H), 8.65 (brs, 2H), 7.66 (s, 1H), 7.57 (s, 1H), 7.29-7.41 (m, 3H), 7.01 (m, 1H), 6.10 (s, 1H), 4.09 (s, 6H), 3.63-3.66 (m, 4H), 2.40-2.70 (m, 6H), 1.32 (s, 6H); LC-MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([O:8][CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:18]>N1C=CC=CC=1>[NH2:1][C:2]([O:8][CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4](=[S:18])[NH2:5]
Reactant: S
Reactant: CCOC(N)=C(C#N)C#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(N)=C(C#N)C(N)=S
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
A mixture of 51.2 g of 3-amino-3-ethoxy-2-cyano-2-propenenitrile (above) and 37.8 g of triethylamine in 200 ml of pyridine was continuously stirred and heated to 70° while 60 g of gaseous hydrogen sulfide was bubbled in during 1.5 hours. Heating was continued at 65°-70° for 0.5 hour. Thin-layer chromatographic analysis indicated that no reaction had occurred. The mixture was heated overnight at 55° but still no reaction had occurred. An additional 150 ml of pyridine was added and the mixture was heated to 75°-80° while 17 g of hydrogen sulfide was bubbled in during 0.5 hour. Thin-layer chromatographic analysis indicated that a reaction had occurred, but was incomplete. An additional 18 g of hydrogen sulfide was added during 1 hour at 75°-80°; thin-layer chromatography indicated that the reaction was completed. The reaction mixture was evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol to give a first crop of 28 g of 3-amino-2-cyano-3-ethoxypropenethioamide; m.p. 170°-171°. A second crop of 15 g of this product (m.p. 169°-171°) was obtained by diluting the mother liquor with ice-water. A small sample of crop I was recrystallized again from ethanol (charcoal) to give an analytical sample; m.p. 180°-181°. A total of 43.0 g of 3-amino-2-cyano-3-ethoxypropenethioamide was obtained. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([NH:22][CH2:23][CH3:24])[N:15]=1.Cl>O.C(O)C>[CH2:7]([O:6][C:4]([C:3]1[C:2](=[O:10])[N:22]([CH2:23][CH3:24])[C:16]2[C:17]([C:18]=1[NH2:19])=[CH:20][CH:21]=[C:14]([Cl:13])[N:15]=2)=[O:5])[CH3:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCNc1nc(Cl)ccc1C#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(N)c2ccc(Cl)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2.07 g. (0.09 g. atom) of sodium in 75 ml. of ethanol is added 14.4 g. (0.09 mole) of diethyl malonate. The solution is stirred at room temperature for 5 minutes and then 5.4 g. (0.03 mole) of 6-chloro-2-ethylaminonicotinonitrile is added. The mixture is heated under reflux for about 6 hours. The mixture is cooled and diluted with 75 ml. of water and acidified with conc. hydrochloric acid. The precipitate which forms is collected and air dried to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:21]=[C:20]([Cl:19])[CH:25]=[C:24]([Cl:26])[CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(Cl)cc(Cl)c3)cccc2c1N
Yield: 52.5 %

Procedure:
Using method B, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3,5-dichlorophenyl boronic acid (252 mg, 1.32 mmol) were reacted to afford the title compound (65 mg, 52.5% yield) as a pale-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.26 (br, 1H), 8.48 (d, J=8.2 Hz, 1H), 7.95 (d, J=7.2 Hz, 2H), 7.74-7.85 (m, 3H), 7.67 (t, J=2.0 Hz, 1H), 3.31 (m, overlapped with H2O), 1.60 (m, J=7.3 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H). MS APCI, m/z=375/377 (M+H). HPLC 2.52 min.
Reaction SMILES: ClC1C=CC(CN2CCC(NC3C=CC(C#N)=CC=3)CC2)=CC=1OCC.C(OC([N:34]1[CH2:39][CH2:38][CH:37]([N:40](C(OC(C)(C)C)=O)[C:41]2[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][N:42]=2)[CH2:36][CH2:35]1)=O)(C)(C)C.Cl>O1CCOCC1.C(O)C>[NH:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41]2[N:42]=[CH:43][C:44]([O:47][S:48]([CH3:51])(=[O:49])=[O:50])=[CH:45][CH:46]=2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OS(C)(=O)=O)cn2)CC1
Agent: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CS(=O)(=O)Oc1ccc(NC2CCNCC2)nc1

Procedure:
The title compound was prepared in analogy to the procedure described for (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediate B16/step 2) from 4-[tert-butoxycarbonyl-(5-methanesulfonyloxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester by cleavage of the BOC group with 4 M HCl in dioxane and ethanol at 70° C. MS (ISP): 272.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[C:10]([CH3:24])[CH:9]=1)=[O:6].CC(C)([O-])C.[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:24][C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:13]=[CH:12][C:11]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCl)cc2C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2C)cc1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Methyl 4'-((4-chlorobutanoyl)amino)-2'-methylbiphenyl-4-carboxylate (D28) (1.65 g, 4.8 mmol) was stirred in dry dimethylformamide (DMF) (20 ml) as potassium t-butoxide (0.70 g, 5.7 mmol) was added. The mixture was stirred for 30 min, diluted with ethyl acetate (200 ml), washed successively with brine, water and brine, dried (Na2SO4) and evaporated to give a light brown gum. Chromatography on silica gel, eluting with 0-50% ether/dichloromethane, gave the title compound (1.15 g, 71%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]#[N:21])=[N:14]2)[CH:7]=1)[CH3:2].[Cl-].C([NH2+]CC)C.O.[S-2:30].[Na+].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20](=[S:30])[NH2:21])=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: [S-2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(C#N)ccc2=O)c1
Agent: CC[NH2+]CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Nc1cccc(Cn2nc(C(N)=S)ccc2=O)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
200 mg (0.67 mmol) of ethyl[3-(3-cyano-6-oxo-6H-pyridazin-1-ylmethyl)-phenyl]carbamate are dissolved in 1 ml of DMF, and 219 mg (2 mmol) of diethylammonium chloride and 165 mg (2 mmol) of sodium sulfide hydrate are added. The yellow suspension is stirred at 55° C. for 2 hours. 10 ml of water are added to the reaction mixture. The precipitate is filtered off with suction, washed with water and dried in vacuo. The substance is reacted further without further purification.