Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]([C:17](=O)[CH3:18])=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[CH:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:27]OC(OC)N(C)C.[NH2:35][C:36]([NH2:38])=[NH:37].Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:16]([C:17]3[CH:18]=[CH:27][N:35]=[C:36]([NH2:38])[N:37]=3)=[C:15]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[N:14]=[CH:13]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: N=C(N)N
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2C(C)=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(N)n2)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of the ketoimidazole prepared in Example 2 above (2.6 g, 7.24 mmol) in 15 mL of DMF was added N,N-dimethylformamide dimethyl acetal (1.92 mL, 1.72 g, 14.5 mmol) and the solution was heated at 120° C. for 2 h. At this time, TLC and HPLC indicated no starting material and the solution was cooled to 95° C. and ethanol (30 mL), guanidine•HCl (2.77 g, 28.95 mmol) and K2CO3 (4.0 g, 28.9 mmol) were added. After 16 hours, HPLC indicated that the reaction was complete and the solution was cooled to room temperature. The solution was diluted with 100 mL of EtOAc and washed with 2×150 mL of 3 N HCl. The aqueous layers were combined and basified with excess solid K2CO3 until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2×150 mL of EtOAc. The combined organics were dried over Na2SO4 and activated charcoal, filtered through Celite, and concentrated in vacuo. The residue was recrystallized from EtOAc/MeOH/Hexanes to yield the imidazole product (0.9 g, 30%) as a beige solid; mp=228-230° C.; IR (KBr) 3321, 3157, 1712, 1658, 1568, 1507, 1470, 1437 cm−1; 1H NMR (CDCl3) δ 8.17 (1H, d, J=5.3 Hz), 7.71 (1H, s), 7.43 (2H, m), 7.00 (2H, t, J=8.7 Hz), 6.50 (1H, d, J=5.3 Hz), 5.16 (2H, br s), 4.74 (1H, tt, J=3.7, 12.0 Hz), 4.35 (2H, m), 4.15 (2H, q, J=7.1 Hz), 2.82 (2H, t, J=12.5 Hz), 2.15 (2H, d, J=12.5 Hz), 1.85 (2H, m), 1.28 (3H, t, J=7.1 Hz); 13C NMR (DMSO-d6) δ 163.61, 162.76, 159.54, 158.66, 158.01, 154.35, 138.88, 136.25, 131.00, 129.16, 129.05, 124.98, 115.08, 114.80, 110.84, 60.64, 53.06, 42.70, 32.48, 14.43; Anal. Calcd for C21H23N6O2F; C, 61.4; H, 5.7; N, 20.5; Found C, 61.0, H, 5.5; N, 20.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](SC)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[C:32]1([CH2:38][CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.Cl.[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH2:48][NH2:49]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:49][CH2:48][C:44]3[NH:43][CH:47]=[CH:46][N:45]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCc1ccccc1
Reactant: NCc1ncc[nH]1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: Cl
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound is prepared from 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid by following the procedures in Example 19 using 2-phenylethanamine for the amide formation and (1H-imidazol-2-ylmethyl)amine dihydrochloride for the displacement reaction: LC-MS m/z 592 (M+H)+, 1.77 min (ret time).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20]C)=[O:19])=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([OH:20])=[O:19])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)c1sccc1NC(=O)Cc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Nc2ccsc2C(=O)O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Methyl 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate (5.7 g, 18.7 mmol) was dissolved in THF/H2O (40 mL, 4/1, v/v). Sodium hydroxide (2.24 g, 56.1 mmol) was added and the reaction mixture was stirred at 60° C. for 8 h. The resulting solution was acidified with 10% aqueous HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylic acid. Retention time (min)=1.678, method [1], MS (ESI) 292.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:29]=[C:30](Cl)[O:31][C:32](Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]3[N:10]([C:9]=2[C:30]([O:31][CH3:32])=[O:29])[CH2:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(-c2ccc(F)cc2)c(-c2ccccc2)c2n1CCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 176.2 %

Procedure:
A solution of 6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (prepared according to Laufer et al., 1.11 g, 4 mmol) in CHCl3 (20 ml) is cooled to 0° C. in an ice bath, treated with triethylamine (0.44 g, 4.4 mmol), and diphosgene (0.43 g, 2.2 mmol), dissolved in CHCl3 (5 ml) is added dropwise. After addition is complete, the mixture is stirred at RT for a further 4 h in the cold. After addition of MeOH (4 ml), it is additionally stirred at RT for 16 h. The reaction solution is washed with water, and then with Na2CO3 solution (10%) until acid-free and finally washed again with water. The separated CHCl3 phase is dried using Na2SO4 sicc. and concentrated. As a residue, 1.3 g (100%) of methyl 2-(4-fluorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate are obtained (GC. 93%). The substance is used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[CH3:25].[C:26](#[N:30])[CH2:27][C:28]#[N:29].N1CCCCC1>C(O)C>[NH2:30][C:26]1[O:15][C:16]2[C:24]([CH:6]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=3)[C:27]=1[C:28]#[N:29])=[CH:23][CH:22]=[C:21]1[N:20]([CH3:25])[CH:19]=[CH:18][C:17]=21
Reactant: N#CCC#N
Reactant: Cn1ccc2c(O)cccc21
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a mixture of 3,4,5-trimethoxybenzaldehyde (53 mg, 0.27 mmol), 4-hydroxy-1-methylindole (40 mg, 0.27 mmol) and malononitrile (18 mg, 0.27 mmol) in 1.5 mL of ethanol was added piperidine (0.01 ml, 0.1 mmol). The solution was stirred at room temperature overnight and precipitates were observed. The precipitates were collected by filtration and dried to yield 70 mg (66%) of title compound as white solids. 1H NMR (CDCl3): 7.06-7.02 (m, 2H), 6.80 (d, J=8.1 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.42 (s, 2H), 4.79 (s, 1H), 4.66 (s, 2H), 3.81-3.78 (m, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[C:34]([CH3:35])=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=4)[CH2:22][C@H:21]3[CH3:36])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:37]O>OS(O)(=O)=O>[CH3:37][O:31][C:30](=[O:32])[C:29]1[CH:33]=[C:34]([CH3:35])[C:26]([N:23]2[CH2:24][CH2:25][N:20]([C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:13]=[C:12]([N:14]4[CH2:18][CH2:17][CH2:16][CH:15]4[CH3:19])[N:11]=3)[C@H:21]([CH3:36])[CH2:22]2)=[N:27][CH:28]=1
Reactant: CO
Reactant: Cc1cc(C(=O)O)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCCC3C)n2)[C@H](C)C1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)[C@H](C)C2)c(C)c1
Temperature: 25 °C

Procedure:
Reflux a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid (120 mg, 0.245 mmol) and 2 drops of concentrated H2SO4 in MeOH for 4 h. Cool to room temperature, concentrate, and partition between saturated NaHCO3 and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc-Hexanes (1:4) to afford the title ester as an oil.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]2[C:11]([NH:16][C:17]3[CH:18]=[C:19]([NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[N:12][N:13]([CH3:15])[CH:14]=2)[CH:5]=1)=O.[N:37]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.CS(C)=O>CC(O)C>[CH3:23][C:22]1[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:18][C:17]=1[NH:16][C:11]1[C:10]([C:6]2[CH:5]=[C:4]([NH:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:9]=[CH:8][N:7]=2)=[CH:14][N:13]([CH3:15])[N:12]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nn(C)cc1-c1cc(S(C)=O)ncn1
Reactant: NCCN1CCOCC1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nn(C)cc1-c1cc(NCCN2CCOCC2)ncn1
Temperature: 80 °C

Procedure:
The mixture of N-{3-[4-(6-Methanesulfinyl-pyrimidin-4-yl)-1-methyl-1H-pyrazol-3-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (30 mg, 0.058 mmol) and 2-Morpholin-4-yl-ethylamine (100 uL) in 2-propanol is heated to 80° C. for 3 hours. The reaction mixture is cooled to room temperature and condensed. The crude product is then treated with 1 mL DMSO and purified by LC/MS to afford N-(4-Methyl-3-{1-methyl-4-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-pyrazol-3-ylamino}-phenyl)-3-trifluoromethyl-benzamide.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:11]([CH:28]=[O:29])=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:30]1[O:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>CO.ClCCl>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:11]([CH2:28][OH:29])=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:30]1[O:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncc(-c2cn(C3CCNCC3)nc2CO)cc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Sodium tetrahydroborate (42.6 mg) and tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (550 mg) in methanol (10 ml) were stirred at room temperature for 1 hour. The reaction was incomplete and further sodium tetrahydroborate (42.6 mg) was added at room temperature and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100 ml) and washed with water (2×20 ml), dried over magnesium sulfate and concentrated to dryness. The residue was dissolved in dichloromethane (2 ml) and the solution was cooled to 0° C. and treated with trifluoroacetic acid (3 ml). The resulting solution was allowed to stir at room temperature for 1 hour and then concentrated to dryness. The residue was re-dissolved in methanolic ammonia (7N, 5 ml) and absorbed onto silica and purified by flash chromatography on silica gel eluting with 0 to 15% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanol (440 mg) as a solid. The tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate used as starting material was prepared as follows: 4-bromo-2H-pyrazole-3-carbaldehyde (3 g), potassium carbonate (3.32 g) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (6.23 g) in acetonitrile (150 ml) were stirred at reflux overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to yield tert-butyl 4-(4-bromo-3-formyl-pyrazol-1-yl)piperidine-1-carboxylate (4.10 g) as a clear colourless oil which crystallised on standing. NMR Spectrum: (CDCl3) 1.48 (s, 9H), 1.92 (dd, 1H), 1.96 (dd, 1H), 2.10-2.18 (m, 2H), 2.81-2.97 (m, 2H), 4.27 (bs, 2H), 4.28-4.38 (m, 1H), 7.543 (s, 1H), 9.96 (s, 1H); Mass spectrum: M+H+ 360.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14][CH3:15])[CH:12]=[CH:13][C:7]=2[NH:6][S:5]1(=[O:17])=[O:16])[CH3:3].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:3][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14][CH3:15])[CH:12]=[CH:13][C:7]=2[N:6]([CH2:22][CH:21]=[CH2:20])[S:5]1(=[O:17])=[O:16])[CH3:1]
Reactant: C=CCBr
Reactant: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN1c2ccc(SC)cc2CN(C(C)C)S1(=O)=O

Procedure:
3,4-Dihydro-3-(1-methylethyl)-6-methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide (10 g, 0.0367 mol) was added to a suspension of sodium hydride (1.61 g, 60% dispersion) in dry dimethylformamide (200 ml) at room temperature under a nitrogen atmosphere. The pale grey suspension was stirred for ten mins, and then allyl bromide (3.49 ml, 0.0404 mol) was added in one portion. The reaction mixture was stirred at 80° C. for 3 hr. The mixture was then concentrated in vacuo to yield a brown residue. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was then dried (MgSO4) and concentrated in vacuo to afford 3,4-dihydro-3-(1-methylethyl)-6-methylthio-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. δ(1H NMR, DMSO, ppm): 1.1 (6H, d), 2.5 (3H, s), 4.1 (1H, m), 4.5 (2H, d), 4.7 (2H, s), 5.3 (1H, dd), 5.4 (1H, dd), 6.0 (1H, m), 7.0 (1H, d), 7.3 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([NH:36][NH2:37])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH:37][NH:36][C:34]([C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)=[O:35])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Reactant: NNC(=O)c1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)NNC(=O)c4cccs4)s3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and thiophene-2-carboxylic acid hydrazide (14.2 mg, 0.1 mmol, Aldrich) in N,N-dimethylformamide (1 ml) was added HATU (38 mg, 0.1 mmol) and diisopropylethylamine (26 μl, 0.15 mmol). The mixture was stirred at ambient temperature overnight. The solvent was reduced in vacuo and water (3 ml) was added. After sonication, the crude was filtered and sent directly for purification with prep-HPLC to afford thiophene-2-carboxylic acid N′-[4-(3-chloro-phenyl)-2-(5,6-dimethoxy benzoimidazol-1-yl)-thiazole-5-carbonyl]-hydrazide (37.9 mg, 70.2%) as a white solid. MS m/z 540 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(C1C=C(C=C(C)C=1O)[C:15]#[N:16])C>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9])[C:15]#[N:16]
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: Cc1cccc(Cl)c1O
Product: Cc1cc(C#N)cc(Cl)c1O

Procedure:
The title compound is prepared from commercially available 2-chloro-6-methyl-phenol in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile). LC-MS: tR=0.85 min. 1H NMR (CDCl3): δ2.33 (s, 3H), 6.10 (s, 1H), 7.38 (s, 1H), 7.53 (d, J=1.8 Hz, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([N:15]1[CH2:19][CH:18]([CH2:20][O:21][C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[O:17][C:16]1=[O:29])([CH3:14])[CH3:13]>ClCCl>[CH:12]([N:15]1[CH2:19][CH:18]([CH2:20][O:21][C:22]2[CH:23]=[N+:24]([O-:9])[C:25]([CH3:28])=[CH:26][CH:27]=2)[O:17][C:16]1=[O:29])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)cn1
Solvent: ClCCl
Product: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)c[n+]1[O-]
Reaction time: 8 h

Procedure:
A solution of 4.1 g of m-chloroperbenzoic acid in 30 ml of dichloromethane is added over the course of 10 minutes to a solution of 4.8 g of 3-isopropyl-5-[(6-methylpyridin-3-yloxy)methyl]-oxazolidin-2-one in 50 ml of dichloromethane, whilst stirring, and the mixture is left to stand overnight at room temperature. After dilution with 50 ml of dichloromethane the reaction mixture is extracted with 30 ml of saturated potassium bicarbonate solution at a time, dried over sodium sulphate and evaporated in vacuo. The crystalline residue is recrystallised from dichloromethane - ether. 3-[(3-Isopropyl-oxazolidin-2-on-5-yl)methoxy]-6-methyl-pyridine-1-oxide, thus obtained, melts at 137°-139° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH:9]([C:13]2[S:17][C:16]([C:18]([OH:20])=O)=[CH:15][CH:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:21])[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.Cl.[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:18]([C:16]1[S:17][C:13]([CH:9]([S:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=3)=[C:4]([CH3:21])[CH:5]=2)[CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=1)=[O:20]
Reactant: COC(=O)CCN
Reactant: Cc1cc(SC(c2ccc(C(=O)O)s2)C(C)C)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(C(Sc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)C(C)C)s1
Yield: 69.8 %

Procedure:
To a mixture of (±)-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carboxylic acid (0.420 g, 0.905 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.148 g, 1.06 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.151 g, 1.12 mmol) in DMF (9.0 mL) is added N, N-diisopropylethylamine (0.49 mL, 2.81 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.0.228 g, 1.19 mmol) and stirred overnight. The reaction mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate, gradient from 0% to 75% to provide (±)-3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.347 g, 70%) as a white foam. MS (ES): 548.1 [M−H]−. The racemic material is separated by chiral HPLC (column: Chiralpak AD-H 4.6×150 mm; eluent: 10:90 3A alcohol/Heptane; flow rate: 0.6 mL/min; UV absorbance wavelength: 280 nm) to provide Isomer 1 (0.126 g, >99% ee) and Isomer 2 (0.119 g, 94.5% ee).
Reaction SMILES: [I:1][C:2]1[C:20]([C:21]([O:23]CC)=[O:22])=[C:5]2[CH2:6][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:8]3[CH2:12][O:11][CH2:10][C@@H:9]3[N:4]2[N:3]=1.[OH-].[Na+]>C1COCC1.O>[C:16]([O:15][C:13]([N:7]1[C@@H:8]2[CH2:12][O:11][CH2:10][C@@H:9]2[N:4]2[N:3]=[C:2]([I:1])[C:20]([C:21]([OH:23])=[O:22])=[C:5]2[CH2:6]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)OC(C)(C)C)[C@@H]1COC[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2[C@H]2COC[C@H]21
Temperature: 70 °C
Yield: 60.1 %

Procedure:
To a stirred solution of Intermediate 352D (0.85 g, 1.835 mmol) in THF (5 mL) was added a solution of NaOH (0.220 g, 5.50 mmol) in water (4 mL) and the reaction mixture was heated to 70° C. for 16 h. The reaction mixture was concentrated and the pH of the residue was adjusted to 4-5 using an aqueous solution of citric acid. The formed precipitate was filtered, washed with n-hexanes and dried to afford Intermediate 352E (0.48 g, 51%) as an off-white solid. MS(ES): −m/z=434 [M−H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 12.80-12.67 (m, 1H), 5.30 (d, J=18.5 Hz, 2H), 4.87 (dd, J=3.4, 6.8 Hz, 1H), 4.46-4.32 (m, 1H), 4.12-4.04 (m, 1H), 3.98-3.90 (m, 1H), 3.89-3.82 (m, 1H), 3.80-3.69 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](Cl)[C:5]2=[CH:9][CH:10]=[CH:11][N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:4]2=[N:3]1.[C:21]1([CH3:31])[CH:26]=CC(S(O)(=O)=O)=CC=1>C(NCCC)CC>[CH3:1][N:2]1[CH:7]=[C:6]([N:2]([CH2:26][CH2:21][CH3:31])[CH2:7][CH2:6][CH3:5])[C:5]2=[CH:9][CH:10]=[CH:11][N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:4]2=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN1C=C(Cl)C2=CC=CN(c3ccc(Cl)c(Cl)c3)C2=N1
Solvent: CCCNCCC
Product: CCCN(CCC)C1=CN(C)N=C2C1=CC=CN2c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Heat a mixture of 2-methyl-4-chloro-8-(3,4-dichlorophenyl)pyrido[2,3-c]pyridazine (4) (1.0 g, 3.1 mmol) and p-toluenesulfonic acid (1.6 g) in 5 mL of di-n-propylamine in a sealed tube at 180° C. for 48 hours. Cool the reaction mixture to ambient temperature and partition between ethyl acetate and water. Wash the organic layer with water and dry over MgSO4. Evaporate the dried solution and purify the desired product 5 by flash chromatography.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(Cl)Cl>O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) mixture of 10.5 g. (0.054 mol.) of 2-phenylbenzofuran and 11.5 g (0.058 mol.) of 3,5-dimethyl-4-methoxybenzoyl chloride in 100 ml. of methylene chloride is added dropwise 28.7 g. (0.11 mol.) of stannic chloride. The reaction mixture is allowed to warm to ambient temperature, then stirred for two hours. Water is slowly added to the mixture and it is stirred an additional 30 minutes. The layers are separated and the organic phase is washed with water until the washings are neutral, dried (MgSO4) and concentrated to give 3-(3,5-dimethyl-4-methoxybenzoyl)-2-phenylbenzofuran.