Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:16]1[S:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:22][S:21][C:18]1[S:17][C:16]([C:2]([CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[O:1])=[CH:20][CH:19]=1
Reactant: CSc1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CSc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.3 %

Procedure:
1.41 g of t-butyl 4-[hydroxy-(5-methylsulfanylthiophen-2-yl)-methyl]-piperidine-1-carboxylate (compound in Production Example 389) was dissolved in 40 mL acetone, and 14 g manganese dioxide was added thereto and stirred at room temperature for 24 hours. The reaction mixture was filtered through Celite, then the solvent was removed to give 1.14 g t-butyl 4-(5-methylsulfanylthiophen-2-carbonyl)piperidine-1-carboxylate, 5 mL of 4 N hydrogen chloride in ethyl acetate was added thereto, and the mixture was left for 1 hour. The solvent was removed, and the precipitated crystals were washed with ethyl acetate/ether, to give 0.75 g of the title compound as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:9]2)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:9]2
Reactant: CCOC(=O)Cc1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc2c(N)cccc2cn1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
Ethyl 5-nitroisoquinoline-3-acetate (20 g) is dissolved in ethyl acetate (1 liter), and a catalyst consisting of palladium-on-carbon (3/97 by weight; 21 g) is added. The mixture is hydrogenated at atmospheric pressure, at a temperature of about 50° C., for 2 hours. It is filtered through diatomaceous silica and the filtrate is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. to yield ethyl 5-aminoisoquinoline-3-acetate (15.8 g) in the form of beige crystals, m.p.=90° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>>[N:9]1([C:14]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC1CCCCO1
Product: O=C(OCC1CCCCO1)n1ccnc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of (tetrahydro-2H-pyran-2-yl)methanol (369 mg, 3.18 mmol) and di(1H-imidazol-1-yl)methanone (1.0 g, 6.36 mmol) in 0.3 M CH3CI (10 mL) was stirred at 50° C. for 3 h. After allowing the reaction to cool to room temperature, the solvent was evaporated under reduced pressure giving (tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (412 mg) which was used without further purification. LC/MS: m/z 211.1 (M+H)+ at 0.94 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([O:5][P:6]([C:13]([F:48])([F:47])[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][C:19]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)([O:8]C(C)(C)C)=[O:7])(C)(C)C.[OH-].[Na+]>C1COCC1>[F:48][C:13]([F:47])([P:6]([OH:7])([OH:8])=[O:5])[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][C:19]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CC(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)(C(=O)c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC(Cc2ccc(C(F)(F)P(=O)(O)O)cc2)(C(=O)c2ccccc2)c2ccccc2)cc1
Reaction time: 18 h

Procedure:
To the compound of Step 1 (0.040 g, 0.059 mmol) was treated as described in Example 19 Step 6. To the crude mixture was added 2 mL of THF and 1 mL of 1N NaOH. After a period of 18 h at 60° C., the mixture was evaporated and purified by RP-HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2.[C:25](O)(=[O:27])[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:25](=[O:27])[CH3:26])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(CO)cn3)ccc21
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1

Procedure:
A solution of 3.195 g (10 mmol) of 2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-hydroxymethylpyridine, 600 mg (10 mmol) of glacial acetic acid, 2.06 g (10 mmol) of dicyclohexylcarbodiimide and 460 mg (3.765 mmol) of 4-dimethylaminopyridine in 150 ml methylene chloride is stirred at room temperature for 48 hours. The reaction mixture is then filtered and the residue washed with 50 ml of methylene chloride. The filtrate is then concentrated in vacuo and the residue is purified by chromatography followed by recrystallation to give the title compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[F:5][C:6]([F:12])([F:11])[S:7]([NH2:10])(=[O:9])=[O:8].[OH-].[Na+]>CC(C)=O.O>[CH3:1][NH:2][C:3]([NH:10][S:7]([C:6]([F:12])([F:11])[F:5])(=[O:9])=[O:8])=[S:4]
Reactant: CN=C=S
Reactant: NS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CNC(=S)NS(=O)(=O)C(F)(F)F
Reaction time: 18 h
Yield: 42.3 %

Procedure:
A solution of methylisothiocyanate (0.21 g.) in acetone (10 ml.) was added to a solution of trifluoromethanesulphonamide (0.45 g.) and sodium hydroxide (0.12 g.) in water (5 ml.), the mixture stirred at 60° for 18 hours and then evaporated to dryness. The residue was dissolved in water and the solution washed with ethyl acetate and then adjusted to pH 1 with concentrated hydrochloric acid. The mixture was treated with charcoal and filtered and the filtrate extracted with ethyl acetate. The combined ethyl acetate extracts were dried and evaporated to dryness and the residue recrystallised from petroleum ether (b.p. 60°-80°) to give 1-methyl-3-trifluoromethanesulphonylthiourea (0.27 g.), m.p. 88°-90°.
Reaction SMILES: C(Cl)(=O)C.[CH:5]([O:8][CH2:9][C@@H:10]1[CH2:14][O:13]C(C)(C)[O:11]1)([CH3:7])[CH3:6]>CO>[CH:5]([O:8][CH2:9][C@@H:10]([OH:11])[CH2:14][OH:13])([CH3:7])[CH3:6]
Reactant: CC(C)OC[C@@H]1COC(C)(C)O1
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(C)OC[C@@H](O)CO
Temperature: 25 °C

Procedure:
Acetyl chloride was added dropwise into a solution of MeOH (30 mL) at 0° C. with stirring for min. A solution of (4R)-4-(isopropoxymethyl)-2,2-dimethyl-1,3-dioxolane (1.7 g) (the product from step (i), in MeOH (30 mL), was added dropwise to the reaction mixture. The solution was then warmed to room temperature and stirred for 2 h. The reaction mixture was evaporated to give the subtitle compound as clear oil. Yield: 0.8 g
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH2:7]([O:9][C:10](=[O:22])[CH:11]([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[CH3:8]>>[CH2:7]([O:9][C:10]([C:11]1[C:12](=[O:13])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[C:3]2[C:17]=1[OH:18])=[O:22])[CH3:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: Nn1cccc1
Product: CCOC(=O)c1c(O)c2cccn2[nH]c1=O
Temperature: 170 °C
Yield: 8.1 %

Procedure:
A mixture of N-aminopyrrole (1.77 g, 20.56 mmol) and 2-ethoxycarbonyl-malonic acid diethyl ester (14.4 g, 61.68 mmol) was subjected microwave heating at 170° C. for 30 min; then cooled, the reaction mixture was directly purified with silica gel column to give the desired product (372 mg) as brown solid. ESI (m/z): 223 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:23])[CH:16](Cl)[C:17](=O)[CH:18]([F:20])[F:19])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:17]=1[CH:18]([F:20])[F:19])=[O:23])[CH3:13]
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)F
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C(F)F
Temperature: 50 °C
Yield: 42.6 %

Procedure:
8.84 g 4-Methoxythiobenzamide were dissolved in 100 ml ethanol and warmed to 50° C. Then 10.59 g 2-chloro-4,4-difluoro-3-oxo-butyric acid ethyl ester were added and the reaction mixture stirred under reflux for three hours. The cooled reaction mixture was evaporated in vacuo and the residue purified by chromatograph on silica gel with the eluent ethyl acetate/petroleum benzene=1:4 to obtain 7.04 g 4-difluoromethyl-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester as pale yellow solid.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:14]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:30])=[CH:28][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[OH:38]O>C(O)(=O)C.C([O-])(=O)C>[ClH:1].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][S:22](=[O:38])[CH2:21][CH2:20]3)[C:14]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:30])=[CH:28][C:13]=3[N:12]=2)=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: OO
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2CCCN1CCSCC1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(=N)N)cc1)n2CCCN1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.2 g of 2-(4-amidino-phenyl)-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-(3-thiomorpholino-propyl)-benzimidazole-hydrochloride are dissolved in 45 ml of glacial acetic acid and a solution of 0.39 ml of 30% hydrogen peroxide in 5 ml of glacial acetate acid is added thereto whilst cooling with ice water. The mixture is stirred for 4 hours whilst cooling with ice and for 16 hours at ambient temperature, the solvent is evaporated off in vacuo and the residue is purified by column chromatography (silica gel; methylene chloride/methanol/water=1:1:0 to 1:1:0.1). Yield: 0.6 g (26% of theory), Rf value: 0.46 (silica gel; methylene chloride/methanol/conc. ammonia=1:1:0.1)
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6])#[N:2].[K+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1>[C:1]([C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:6])#[N:2]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ncccc1C(=O)[O-]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)c1cccnc1C#N
Yield: 100.3 %

Procedure:
Toluene (40 cc) containing compound 3 (4.1 g; 0.022 mol), ethyl bromoacetate (3.35 g; 0.02 mol) and TDA-1 (0.3 cc) is heated under reflux for 4 hours. The toluene is then evaporated off and the residue taken up with water and then extracted with dichloromethane. After drying, evaporating and crystallization in pentane, (ethoxycarbonyl)-methyl 2-cyanonicotinate (4.7 g; m.p. 74° C.) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:7]([CH2:19][CH2:20][CH2:21][CH2:22]O)[C:6]=2[C:5]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:4][CH:3]=1.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>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)[CH2:22][CH2:21][CH2:20][CH2:19][N:7]3[C:6]=2[C:5]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3)n(CCCCO)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.2 %

Procedure:
To a solution of 4-[4-chloro-2-[(4-chlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 36; 200 mg, 0.48 mmol) and triphenylphosphine (186 mg, 0.71 mmol) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (0.140 mL, 0.71 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 24 hours followed by concentration in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/isopropyl ether to give the title compound (105 mg, 0.26 mmol, 54%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:20](OCC)=[O:21])[CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([CH2:20][OH:21])[CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 7 h
Yield: 76.7 %

Procedure:
To a cooled solution, −78° C., under nitrogen, of ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate (Example 3, 172 mg, 0.50 mmol) in THF (8.0 mL) was added LiAlH4 (2.4 M in THF, 2.0 mL, 4.8 mmol). The reaction mixture was stirred for 7 h before being quenched with a 1 N NaOH (aq.) solution. The crude reaction mixture was filtered through CELITE® and the aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated onto silica. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a yellow solid (115 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J=2.3 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H), 7.94 (d, J=9.0 Hz, 1H), 7.64 (s, 1H), 7.57-7.43 (m, 4H), 7.37 (dd, J=2.7, 9.0 Hz, 1H), 5.43 (t, J=5.7 Hz, 1H), 5.34 (s, 2H), 4.71 (d, J=5.5 Hz, 2H). [M+H]=300.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[OH:20][CH:21]([CH2:29][O:30][CH3:31])[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH:21]([OH:20])[CH2:29][O:30][CH3:31])[CH2:28][CH2:27]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Reactant: COCC(O)CN1CCNCC1
Solvent: c1ccncc1
Product: COCC(O)CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3CCS2)CC1

Procedure:
A mixture of 500 mg (1.67 mmol) of 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylic acid and 1.45 grams (8.3 mmol) of N-(2-hydroxy-3-methoxy-1-propyl)-piperazine was suspended in 20 ml of pyridine and the mixture was heated to reflux for thirty six hours. When the reaction was completed, pyridine was evaporated therefrom under reduced pressure and ethanol was added to the residue. Insoluble matters were filtered, washed with ether, and recrystallized from acetonitrile to give the title compound as flaky crystals. Yield 397.8 mg (54.5 percent). Melting point 224° C. Elementary analysis calculated as C20H24FN3O5S: C 54.91, H 5.53, N 9.60; Found: C 54.94, H 5.55, N 9.60.
Reaction SMILES: [N:1]1([CH:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[Li+].[OH-].Cl>C1COCC1.O>[N:1]1([CH:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(-c2ccc(C(CC)n3ccnc3)nc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(c1ccc(-c2ccc(C(=O)O)cc2)cn1)n1ccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl 4-(6-(1-(1H-imidazol-1-yl)propyl)pyridin-3-yl)benzoate (25 mg, 0.07 mmol; prepared as described in Example 5) in THF (2 mL) and water (1 mL) was added LiOH (6 mg, 0.14 mmol) at rt and the reaction was stirred at rt for about 4 h. The reaction mixture was neutralized with 1N HCl (pH=6) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by prep TLC using 5% methanol in DCM to provide 4-(6-(1-(1H-imidazol-1-yl)propyl)pyridin-3-yl)benzoic acid as an off white solid (12 mg, 54.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.14 (dd, 1H), 8.01 (d, 2H), 7.83 (d, 3H), 7.40 (d, 1H), 7.31 (s, 1H), 6.90 (s, 1H), 5.39 (s, 1H), 2.34-2.19 (m, 2H), 0.81 (t, 3H), LC-MS m/z calcd for [M+H]+ 308.13. found 308.1.
Reaction SMILES: C(=O)C(C)C.[CH2:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])=[CH:12][CH:13]=2)[CH2:8][NH:7]1.N1C[CH:31]=[C:30]([C:33]2C=CC(NC(N3CC4C(=CC=CC=4)C3)=O)=CC=2)[CH2:29][CH2:28]1>>[CH3:31][CH:30]([CH3:33])[CH2:29][CH2:28][N:7]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])[CH:10]=2)[CH2:6]1
Reactant: O=C(Nc1ccc2c(c1)CNC2)N1Cc2ccccc2C1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Agent: CC(C)C=O
Product: CC(C)CCN1Cc2ccc(NC(=O)N3Cc4ccccc4C3)cc2C1

Procedure:
The title compound was prepared as described in Example 429, substituting 3-methylbutanal for isobutyraldehyde and N-(isoindolin-5-yl)isoindoline-2-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.47 (s, 1H), 7.29-7.37 (m, 5H), 7.09 (d, J=8.1 Hz, 1H), 4.75 (s, 4H), 3.77-3.79 (m, 2H), 3.74-3.76 (m, 2H), 2.64 (t, J=7.5 Hz, 2H), 1.60-1.71 (m, 1H), 1.37-1.43 (m, 2H), 0.91 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 350 (M+H)+.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=1)(=O)C.C[O-].[Na+]>CO.Cl>[NH2:13][C:11]1[N:12]=[C:7]([CH2:6][CH2:5][SH:4])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)SCCc1cccc(N)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1cccc(CCS)n1

Procedure:
6-(2-Acetylthioethyl)-2-pyridylamine (0.56 g) was dissolved in methanol (10 ml). To the solution was added, at 0° C., sodium methylate (a 4.9N methanol solution, 0.58 ml), and the mixture was stirred for 30 minutes. To the reaction mixture was added iN hydrochloric acid (2.85 ml), followed by concentration under reduced pressure. To the concentrate was added ethyl acetate (10 ml), which was subjected to extraction. The extract solution was dried over anhydrous magnesium sulfate, followed by concentration to leave the title compound as an oily product (0.43 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: CCc1cnc(N2CCC(=O)CC2)cn1
Reactant: NC1CC1
Product: CCc1cnc(N2CCC(NC3CC3)CC2)cn1

Procedure:
The title compound is prepared from 1-(5-ethyl-pyrazin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 4. LC (method 7): tR=0.65 min; Mass spectrum (ESI+): m/z=247 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:11]=1[C:12]([OH:14])=O.N>CS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[S:9][C:10]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:11]=1[C:12]2=[O:14]
Reactant: COc1ccccc1Sc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: CS(=O)(=O)O
Agent: N
Product: COc1cccc2c(=O)c3cc([N+](=O)[O-])ccc3sc12
Temperature: 100 °C

Procedure:
2-(2-Methoxy-phenylsulfanyl)-5-nitro-benzoic acid (13.00 g, 42.58 mmol) was suspended in methanesulphonic acid (100 ml) and heated at 100° C. The crude mixture was slowly poured onto ice with vigorous stirring then neutralized with conc. ammonia solution. The precipitate was filtered and washed with water. The yellow/lime colored solid was dried under vacuum at 50° C. to give the crude title compound which was used without any further purification (12 g, 98%). m/z (LC-MS, ESP), RT=4.89 min, (M++1)=288.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH:14]([N:13]([C@H:11]1[CH2:10][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:28]4[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:12]1)[CH3:17])([CH3:18])[CH3:15]
Reactant: COc1ncccc1B(O)O
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncccc1-c1ccc2nc([C@H]3C[C@H](N(C)C(C)C)C3)sc2c1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 52A for the product of Example 1E and substituting 2-methoxypyridine-3-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (dd, J=4.99, 1.87 Hz, 1H) 7.97-8.05 (m, 2H) 7.66 (dd, J=7.18, 1.87 Hz, 1H) 7.63 (dd, J=8.42, 1.87 Hz, 1H) 7.00 (dd, J=7.49, 4.99 Hz, 1H) 3.99 (s, 3H) 3.78-3.85 (m, 1H) 3.53-3.63 (m, 1H) 2.92-3.09 (m, 1H) 2.63-2.73 (m, 2H) 2.52-2.61 (m, 3H) 2.14 (d, J=5.93 Hz, 3H) 0.96-1.08 (m, 6H). MS: (M+H)+=368.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26]>>[F:12][C:11]([F:14])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:26]#[C:25][C:27]3[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=3)=[CH:3][N:4]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3n2)cc1
Product: Nc1ncc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nn23)cn1

Procedure:
The title compound was prepared from 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazine (example C.26 step 11) (457 mg, 1 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (155 mg, 1.3 mmol) according to general procedure II. Obtained as a light yellow solid (50 mg, 11%). MS (ISP) 449.2 [(M+H)+]; mp 220-221° C.