Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CC([O-])=O.[Na+].[N:32]#[C:33]Br.O>CO>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][N:14]([C:33]#[N:32])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C#N)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 78.9 %

Procedure:
(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (0.16 g, 0.45 mmol) was dissolved in MeOH (4 mL) and cooled to 0° C. NaOAc (112 mg, 1.4 mmol) and CNBr (68 mg, 0.64 mmol) were added and the solution was slowly warmed to room temperature and stirred for 6 hours. H2O (15 mL) was added and the solution was extracted with CH2Cl2 (3×30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carbonitrile (134 mg, 79%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCCCC4)cc3c2)cc1

Procedure:
The product from Example 1C and piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, 1H), 3.65 (m, 2H), 3.55 (m, 2H), 3.33 (m, 2H), 3.05 (m, 2H), 2.0 (m, 2H), 1.5-1.9 (m, 4H); MS (DCI) m/z 331 (M+H)+;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][O:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: ClCc1ccccn1
Reactant: COC(=O)c1cc(O)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc(OCc2ccccn2)cs1

Procedure:
3.00 g (19.0 mmol) of methyl 4-hydroxy-2-thiophenecarboxylate, 3.11 g (19.0 mmol) of 2-chloromethylpyridine hydrochloride and 5.24 g (37.9 mmol) of potassium carbonate are heated under reflux in 60 ml of absolute 2-butanone for 10 hours under nitrogen. The mixture is then evaporated in vacuo and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The aqueous phase is extracted twice more with 100 ml of methylene chloride each time and the combined organic phases are dried over sodium sulfate/active charcoal, filtered and evaporated. The residue is digested with diisopropyl ether.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([OH:16])[C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[CH3:5][C:6]1[N:14]=[C:13]([CH3:15])[C:12]([N+:1]([O-:4])=[O:2])=[C:11]([OH:16])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1cc(O)c(C(=O)O)c(C)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc(C)c([N+](=O)[O-])c(O)c1C(=O)O
Temperature: 0 °C
Yield: 77 %

Procedure:
20 ml of 90% nitric acid is added to 100 ml of 98% sulphuric acid with stirring and cooling. To this solution is added portion-wise 6.9 g (41.1 mmol) of 2,6-dimethyl-4-hydroxy-nicotinic acid. The mixture is stirred at 80° C. for 1 hour, cooled down and added cautiously 300 g of crushed ice. The resulting suspension is filtered off. The cake is washed with water and dried. There is obtained 6.7 g (77%) of a white solid.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[OH:8].[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C>CO>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([OH:8])[CH2:6][NH:5][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[CH:24][CH:25]=2)=[CH:10][CH:11]=1
Reactant: NCC(O)c1ccc(F)cc1
Reactant: O=Cc1ccc(Oc2cnccn2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC(CNCc1ccc(Oc2cnccn2)cc1)c1ccc(F)cc1
Reaction time: 8 h
Yield: 35.1 %

Procedure:
Sodium cyanoborohydride (0.62 mL, 1 M in THF) was added to a solution of 2-amino-1-(4-fluoro-phenyl)-ethanol (80 mg, 0.52 mmol), 4-(Pyrazin-2-yloxy)-benzaldehyde (103 mg, 0.52 mmol) and glacial acetic acid (0.5 mL), in methanol (3 mL) at RT and the flask was stirred overnight. The reaction mixture was concentrated in vacuo; the residue was quenched with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane (3×4 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated again in vacuo to yield 1-(4-fluoro-phenyl)-2-[4(pyrazin-2-yloxy)-benzyl amino]-ethanol as a white solid 62 mg, 35%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30][CH2:31]C>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:29][CH2:30][CH3:31])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: CCCC=O
Product: CCCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 84 is treated with butyraldehyde according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: C1C(=O)N([O:8][C:9]([CH2:11][CH2:12][S:13][S:14][C:15]2[N:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)C(=O)C1.[NH3:21]>CO>[N:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:14][S:13][CH2:12][CH2:11][C:9]([NH2:21])=[O:8]
Reactant: N
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Solvent: CO
Product: NC(=O)CCSSc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-succinimidyl 3-(2-pyridyldithio)propionate (180 mg) was dissolved in methanol (4.5 ml), to which was added 1 ml of a methanol solution of ammonia (5% v/v). The mixture was stirred at 0° C. for 30 minutes, followed by concentration to 1 ml under reduced pressure. As a result, 3-(2-pyridyldithio)propanamide [disclosed in Japanese laid open Patent Application 57595/86 and CA105(19)173000q] was formed in the reaction solution. To this solution were added triethylamine (80 ml) and cysteamine hydrochloride (65 mg). The solution was stirred at room temperature for 10 minutes. Then, mitomycin A (50 mg) was added to the reaction solution, followed by stirring at room temperature for 2 hours. After addition of water (10 ml), the solution was extracted with chloroform (50 ml). The chloroform solution was dried with sodium sulfate, and the solvent was removed under reduced pressure. The material was chromatographed by the use of silica gel (10 ml; Wako-C200) and a solvent system of chloroform/methanol (9:1 v/v). The resultant blue fractions were collected combined, and concentrated. The concentrated fraction was dissolved in acetone and was dropwise added to cyclohexane to give precipitates. The precipitates were dryed under reduced pressure to obtain yellowish green powders of Compound 21 (15 mg) with a yield of 21%. The molar ratio of mitomycin-type substance contained in the produce was >99%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)#[N:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:28][CH2:27]1)#[N:19]
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-cyanophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 50° C. to yield 4-[4-(2-cyano-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M]+=408.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:15]([NH2:17])=[N:14][S:13](=[O:19])(=[O:18])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:15]([NH2:17])=[N:14][S:13](=[O:18])(=[O:19])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:28]
Reactant: CSCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)CCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Yield: 90 %

Procedure:
Prepared as in Example 245 from 5-(3-(methylthio)propoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide (Example 247) by the reaction with 1.0 equivalent of MCPBA as a white solid in 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.18-2.22 (m, 2H), 2.54 (s, 3H), 2.75-2.78 (m, 1H), 2.89-2.93 (m, 1H), 4.26 (t, J=6.4 Hz, 2H), 6.60-6.61 (d, J=8.4 Hz, 1H), 6.73-6.75 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.83 (s, 1H), 8.30 (s, 1H), 10.92 (s, 1H). MS 318 (MH+).
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2OC)=NC=1CC.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[N:40]=[C:41]([CH:58]=[CH2:59])[C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[OH:57])=[N:43][C:44]=1[O:45][CH3:46]>>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[N:40]=[C:41]([CH:58]=[CH2:59])[C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[O:57][CH2:2][CH3:3])=[N:43][C:44]=1[O:45][CH3:46]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Reactant: C=Cc1nc(-c2ccc(Cl)cc2Cl)c(OC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: C=Cc1nc(-c2ccc(Cl)cc2Cl)c(OC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxy-3-vinylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 1.11–1.14, 3.04–3.08, 3.37–3.44, 3.60–3.68, 3.84, 4.28–4.30, 5.34–5.37, 5.68–5.71, 5.90–5.99, 6.66–6.73, 7.14–7.26, 7.32–7.40; MS (ESI+) for C24H23Cl2N3O2 m/z 456 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][NH2:10].[CH2:11]([N:13]1[C:18](S(C)=O)=[C:17]([C:22]#[N:23])[C:16](=[O:24])[N:15]2[N:25]=[CH:26][CH:27]=[C:14]12)[CH3:12]>C(O)C>[NH2:23][C:22]1[N:9]([CH3:8])[N:10]=[C:18]2[C:17]=1[C:16](=[O:24])[N:15]1[N:25]=[CH:26][CH:27]=[C:14]1[N:13]2[CH2:11][CH3:12]
Reactant: CCn1c(S(C)=O)c(C#N)c(=O)n2nccc12
Reactant: CNN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c2nn(C)c(N)c2c(=O)n2nccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
Triethylamine (1.44 g) and methylhydrazine (1.44 g) were added to a solution of 3.25 g of 4-ethyl-5-methanesulfinyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile in 60 ml of ethanol. The mixture was stirred at room temperature for 10 minutes and then stirred at 100° C. for 20 minutes. The reaction mixture was ice-cooled and the crystals precipitated were collected by filtration and sequentially washed with ethanol, methanol and diethyl ether to provide 1.2 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][O:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[H][H]>[C].[Pd].O1CCCC1>[O:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[N:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(-c2cocn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(-c2cocn2)cc1

Procedure:
5% Palladium-carbon powder was added to a suspension of 4-(4-nitrophenyl)-1,3-oxazole in mixture of ethanol and tetrahydrofuran, and the reaction mixture was stirred under 1 atm of hydrogen at ambient temperature for 12 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography, to obtain [4-(1,3-oxazol-4-yl)phenyl]amine (pale yellow solid). Electron Impact-MS (M)+:160.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=5)=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:32][CH2:33][CH2:34][N:35]6[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]6)[CH:24]=5)=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: ClCCCN1CCCCC1
Reactant: Oc1cccc(-c2ccn3c(-c4ccnc(-c5ccc(F)cc5)c4)cnc3c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc(-c3cnc4cc(-c5cccc(OCCCN6CCCCC6)c5)ccn34)ccn2)cc1
Temperature: 60 °C

Procedure:
3-{3-[2-(4-Fluoro-phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridin-7-yl}-phenol (Ex. 1.102) (1 eq, 0.131 mmol, 50 mg), 1-(3-chloropropyl)piperidine monohydrochloride (2.0 eq, 0.262 mmol, 53.7 mg) and potassium carbonate (3.0 eq, 0.394 mmol, 54.4 mg) are dissolved in DMF (4 ml) and heated at 60° C. for 16 h. The reaction mixture is diluted with CH2Cl2 and washed with NaHCO3 and brine. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The reaction mixture is purified by flash chromatography on silica eluting with DCM/MeOH 7/3 to yield 3-[2-(4-fluoro-phenyl)-pyridin-4-yl]-7-[3-(3-piperidin-1-yl-propoxy)-phenyl]-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=507
Reaction SMILES: F[C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:14][C:13]([OH:16])([CH3:15])[CH2:12]1)=[N:7]2.C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:2]2[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:14][C:13]([OH:16])([CH3:15])[CH2:12]2)=[N:7]3)[CH2:36]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(C)(O)C3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(C)(O)C3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 10.9 %

Procedure:
7-Fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-193) (230 mg, 0.68 mmol) was dissolved in DMSO (5 ml), then triethylamine (195 μl, 1.36 mmol) and (3S)-3-(dimethylamino)pyrrolidine (181 μl, 1.43 mmol) were added, followed by stirring at 150° C. for 4 hours. After cooling, concentration under reduced pressure, dilution with ethyl acetate and washing with water, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (32 mg, 11%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCOCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:2]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(F)(F)F)ccc2N)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
A 4.5 L reactor was charged with 2-bromo-4-trifluoromethyl aniline (100 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (124 g, prepared as described in WO 2006/003494), 1,4-dioxane (2500 ml) and the solution was degassed for 30 minutes with argon. Dichloro-bis(triphenylphosphine)-palladium (5.6 g) was added and the resulting solution was stirred for 30 minutes at ambient temperature under an argon atmosphere. A degassed solution of sodium carbonate (127 g) in water (1200 ml) was added and the mixture was stirred at 60° C. for 3 hours. The mixture was cooled to ambient temperature and extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with water (3×400 ml), brine then dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in heptane (200 ml) and cooled to −70° C. and then allowed to warm to 0° C. The solid was collected by filtration and rinsed with cold heptane to afford 4-(2-amino-5-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (128 g) as a brown solid. MS (ES+) 214/215; 243/244 (MH+-BOC); 287/288; 343 (MH+); 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.4 (m, 2H), 3.65 (t, 2H), 4.05 (m, 2H), 5.8 (m, 1H), 6.7 (d, 1H), 7.2 (d, 1H), 7.3 (dd, 1H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]([NH2:25])[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].[O-:27][C:28]#[N:29].[K+]>C(O)(=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]([NH:25][C:28]([NH2:29])=[O:27])[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C(C)N)ccc2-3)n(C(C)C)n1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C(C)NC(N)=O)ccc2-3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 4.1 %

Procedure:
To a solution of 1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethylamine (0.120 g, 0.325 mmol) in acetic acid (0.0923 mL) and water (3.45 mL) was added a solution of potassium cyanate (0.132 g, 0.00162 mol) in Water (1.0 mL, 0.056 mol) dropwise. The reaction was stirred at 50° C. overnight, cooled down, filtered, and rinsed with cold water. The crude was precipitated in methanol/water and repurified by reverse-phase HPLC to give 542 as a beige solid (5.5 mg). MS(ESI+) 413.1. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=8.2 Hz, 1H), 7.12 (dd, J=8.3, 1.5 Hz, 1H), 6.98 (d, J=1.4 Hz, 1H), 6.47 (d, J=8.2 Hz, 1H), 5.83-5.68 (m, 1H), 5.47 (s, 2H), 4.70 (p, J=7.1 Hz, 1H), 4.44-4.25 (m, 2H), 3.42 (t, J=4.9 Hz, 2H), 2.32 (s, 3H), 1.52 (dd, J=6.5, 1.6 Hz, 6H), 1.32 (d, J=7.0 Hz, 3H)
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=O)[CH3:4].Cl.[CH3:16][C:17]([CH3:19])=[O:18]>C(O)C.O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:16][C:17](=[O:18])[CH3:19])[CH:11]=[CH:12][C:13]=1[OH:14])[CH3:4]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C=CC(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.4 %

Procedure:
10% sodium hydroxide aqueous solution (80 ml) was added under stirring to a solution of 3-ethoxy-4-hydroxybenzaldehyde (16.6 g, 100 mmol) in acetone (50 ml), 95% ethanol (50 ml) and water (400 ml). The reaction mixture was stirred for 24 hr at room temperature, after the reaction completed, the reaction mixture was neutralized with 6N hydrochloric acid to adjust pH=7.0, the precipitated yellow solid was collected by filtration, washed with water and ethanol successively, dried, and then recrystallized from 95% ethanol to give 14.5 g of a yellow crystal, mp: 98-100° C., yield 70.4%.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[S:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C>O1CCCC1>[CH2:17]([N:4]1[CH2:3][CH2:2][N:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:5]1=[S:6])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCN(CCc1ccccc1)C(=S)NCCCc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: S=C1N(CCCc2ccncc2)CCN1CCc1ccccc1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
Anhydrous tetrahydrofuran (2.5 ml) was added to a mixture of 1-(2-hydroxyethyl)-1-phenethyl-3-[3-(4-pyridyl)propyl]thiourea (Compound No. 7-2) (601 mg, 1.75 mmol) and triphenylphosphine (913 mg, 3.49 mmol), and the whole was stirred under ice/methanol-cooling. A solution of diisopropyl azodicarboxylate (710 mg, 3.49 mmol) in anhydrous tetrahydrofuran was added dropwise thereto, and after 10 minutes, ethyl acetate (100 ml) was added to the reaction mixture. The whole was washed with a saturated aqueous sodium hydrogencarbonate solution (40 ml) and saturated brine (40 ml) successively, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained solid was filtered off with hexane to give 107 mg (19%) of the titled compound as crystals.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[CH3:7][N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9](Cl)=[O:10]>CCOC(C)=O.CCCCCCC>[N:2]1([O:1][C:9](=[O:10])[N:8]([CH3:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: On1ccnn1
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)On1ccnn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-1,2,3-triazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (80%, oil). HPLC-MS m/z=219.1 (M+1), Rt: 2.50 min. Mp 105-106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Product: O=C(c1cccnc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.23 (m, 2H), 7.42-7.47 (m, 3H), 7.58-7.62 (m, 3H), 7.71 (dt, 1H, J=7.6 Hz, 2.0 Hz), 7.88 (s, 1H), 8.45 (b, 1H), 8.58 (bd, 1H, J=3.6 Hz), 9.67 (s, 1H). MS: m/z 458.1 (M++1)