Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[Cl:13][C:14]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]SC1SCC(=O)N=1>O1CCCC1>[Cl:13][C:14]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Reactant: Cc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(OCCCCCCCc2ccccn2)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, add 152 mg. 2-picoline and 1.5 ml. tetrahydrofuran (THF) and cool to -28° C. Add 104 mg. n-butyl lithium and stir about 30 minutes at -78° C. Add 20 mg. of the iodide prepared in Examples 2 and 3 in 1 ml. THF. Stir 1 hour at -78° C., let warm to room temperature and stir about 15 hours. Work up with water and methylene chloride then wash with water and brine then dry over sodium sulfate. Elute on a coarse silica column with methylene chloride then 50% ethylacetate/methylene chloride to obtain the title compound. Prepare the hydrochloride salt by reaction of the title compound with 0.1N HCl.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:5](=O)[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1.COC(=O)C(C1C=CC(F)=CC=1)C(=O)C1C=C[N:31]=CC=1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[C:3](=[O:22])[O:2][NH:31][C:5]=2[C:6]2[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C(C(=O)c1ccncc1)c1ccc(F)cc1
Reactant: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Product: CSc1nccc(-c2[nH]oc(=O)c2-c2ccc(F)cc2)n1

Procedure:
Using the procedure from Example 1l set forth above, substitute 2-(4-fluorophenyl)-3-oxo-3-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid methyl ester for 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-propionic acid methyl ester to produce the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccsc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)sc1C

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using 2,3-dirnethylthiophene (5.00 g, 44.6 mmol), 2.5M BuLi/hexanes (17.9 mL, 44.6 mmol) and benzyl bromide (5.30 mL, 44.6 mmol) in THF (44.6 mL). Purification on Biotage KP-Sil eluting with 1% EtOAc/pet ether gave 6.96 g (77%) of the tide compound as an oil. 1H NMR (DMSO-d6) δ2.01 (s, 3 H), 2.21 (s, 3 H), 3.98 (s, 2 H), 6.58 (s, 1 H), 7.18-7.37 (m, 5 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[CH:25]=[O:26])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCNC1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCN(c2ccccc2C=O)C1
Temperature: 130 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
3-[[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]methoxy]piperidine (59.1 mg, 0.183 mmol) and 2-fluorobenzaldehyde (0.0984 mL, 0.915 mmol) were dissolved in dimethylsulfoxide (2 mL). To this solution, cesium carbonate (119 mg, 0.366 mmol) was added and the mixture was stirred at 130° C. for 3 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate and the extracted washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 47.8 mg (61%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([CH2:17][O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:29])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)C(=O)c1c[nH]c2c(COC(=O)c3ccccc3)cccc2c1=O
Product: CC(C)C(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl

Procedure:
A solution of 3-isobutyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (11.81 g, 29.9 mmol) in phosphoryl chloride (100 ml) was heated at reflux for 2.5 hours, then the excess phosphoryl chloride evaporated. Water was added and the product extracted into a mixture of dichloromethane and isopropyl alcohol. Drying and evaporation of the organic layer gave crude 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (12.0 g), contaminated with isopropyl alcohol. This was used without further purification.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:32][CH3:33])=[C:11]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[C:18]1[C:17]([OH:24])=[C:16]([O:25][CH3:26])[C:15]([O:27][CH3:28])=[C:14]([O:29][CH3:30])[C:13]=1[N:12]2C)C1C=CC=CC=1.O1CCOCC1>C(O)C.[Pd]>[OH:24][C:17]1[C:18]2[C:19](=[O:23])[C:20]3[C:11](=[C:10]([O:32][CH3:33])[C:9]([OH:8])=[CH:22][CH:21]=3)[NH:12][C:13]=2[C:14]([O:29][CH3:30])=[C:15]([O:27][CH3:28])[C:16]=1[O:25][CH3:26]
Reactant: COc1c(OC)c(OC)c2c(c1O)c(=O)c1ccc(OCc3ccccc3)c(OC)c1n2C
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1c(OC)c(O)c2c(=O)c3ccc(O)c(OC)c3[nH]c2c1OC
Reaction time: 2.5 h

Procedure:
A mixture of 6-benzyloxy-1-hydroxy-10-methyl-2,3,4,5-tetramethoxy-9-acridone (344 mg, 0.76 mmol) in ethanol (80 ml) containing dioxane (20 ml) and 10% palladium on carbon (200 mg) was hydrogenated at 50 psi for 2.5 hours. The mixture was filtered through a pad of Celite and washed well with ethanol and chloroform. The combined filtrate and washings were evaporated in vacuo to dryness. The solid residue was recrystallized from a mixture of ethanol/hexane (2:3) to give 1,6-Dihydroxy-2,3,4,5-tetramethoxy-9-acridone, 222 mg (80.7%), mp 214-5 ° C. 1H-NMR (DMSO-d6): δ3.69, 3.75, 3.78, 3.80, and 4.02 (each 3H, s, 4×OMe, 1×NMe), 6.94 (1H, d, J=9.0 Hz, H-7), 7.84 (1H, d, J =9.0 Hz, H-8), 10.45 (1H, exchangeable, OH-6), 14.18 (lH, exchangeable, OH-1). Analyses: Calculated for C18H19NO7 : C, 59.83; H, 5.30; N, 3.88. Found C, 60.00, H, 5.38; N, 4.00.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[Cl:11][C:12]1[CH:13]=[CH:14][C:15](=[O:49])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]3[N:26]=[CH:27][N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:29]=3)=[CH:20][N:19]=2)[CH:17]=1>CC#N>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](=[O:49])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]3[N:26]([CH2:7][C:6]4[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH:27]=[N:28][CH:29]=3)=[CH:20][N:19]=2)[CH:17]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1
Temperature: 25 °C

Procedure:
4-Cyanobenzyl bromide (0.159 g, 0.813 mmol) and the imidazole from step 5 (0.430 g, 0.813 mmol) in CH3CN (4 mL) were heated at 60° C. for 18 hrs. The reaction was cooled to room temperature and the solvent evaporated in vacuo The residue was suspended in methanol (10 mL) and heated at reflux for 1 hr, cooled and the solvent evaporated in vacuo. The residue was partitioned between sat. NaHCO3 and CH2Cl2 and extracted with CH2Cl2. The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH2Cl2 3:97 to 4:96 gradient elution) to afford the free base which was converted to the hydrochloride salt to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]=1)[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>O1CCCC1>[CH2:35]([N:37]([CH2:38][CH3:39])[C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:8]=1)[CH3:36]
Reactant: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)O
Reactant: CCNCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)C(C)Cc1nc(-c2ccccc2)nc2ccccc12

Procedure:
The procedure is as in Example 85, starting with laevorotatory α-methyl-2-phenyl-4-quinazolinepropanoic acid (2 g) in tetrahydrofuran (20 cc), carbonyldiimidazole (1.65 g) and diethylamine (1.05 cc). After two recrystallizations in isopropyl ether, dextrorotatory N,N-diethyl-α-methyl-2-phenyl-4-quinazolinepropanamide (1.3 g), m.p. 93.8° C., is isolated.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:30][N:31]([CH3:45])[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:35]2([OH:38])[CH2:36][CH2:37][C:32]([N:31]([CH3:30])[CH3:45])([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:33][CH2:34]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
A solution of 1-benzenesulfonyl-1H-indol (600 mg, 2.33 mmol) in dry THF (30 ml) was cooled to −5° C. under a stream of argon. n-butyllithium (2.79 mmol, 1.75 ml of a 1.6 molar hexane solution) were added dropwise in such a way that a reaction temperature of 0° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2 hours at 0° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (493 mg, 2.33 mmol) in dry THF (5 ml) was added dropwise at 0° C. The mixture was stirred for 1 hour at 0° C. and then 3 days at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out by flash chromatography with cyclohexane/ethylacetate (V:V=1:1) over silica gel. 232 mg 1-(1-benzenesulfonyl-1H-indol-2-yl)-4-dimethylamino-4-phenylcyclohexanol with a melting point of 173–176° C. were obtained.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C:10]1[C:11]([F:27])=[CH:12][C:13]([Cl:26])=[C:14]([CH:25]=1)[O:15][CH2:16]/[C:17](/[O:23][CH3:24])=[CH:18]\[C:19]([O:21][CH3:22])=[O:20]>C(OCC)(=O)C>[Cl:26][C:13]1[CH:12]=[C:11]([F:27])[C:10]([N:9]=[C:2]=[O:3])=[CH:25][C:14]=1[O:15][CH2:16]/[C:17](/[O:23][CH3:24])=[CH:18]\[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)/C=C(\COc1cc(N)c(F)cc1Cl)OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)/C=C(\COc1cc(N=C=O)c(F)cc1Cl)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trichloromethyl chloroformate (1.37 g) is added dropwise to a solution of methyl (2E)-4-(5-amino-2-chloro-4-fluorophenoxy)-3-methoxybut-2-enoate (2.0 g) in ethyl acetate (30 ml). The mixture is stirred overnight at room temperature. It is concentrated under vacuum and the residue obtained (2.3 g) is used as such in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]1([C:27]2[CH:31]=[C:30]([NH2:32])[NH:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:32][C:30]2[NH:29][N:28]=[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:31]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Product: O=C(Nc1cc(-c2ccccc2)n[nH]1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-phenyl-1H-pyrazol-5-amine (16.0 mg, 0.12 mmol). The title compound was obtained as a solid (22.7 mg, 46.0% yield). MS m/z: 491.97, 493.97 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][N:39]=1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:44][C:42]2[CH:41]=[CH:40][N:39]=[C:38]([O:37][CH3:36])[CH:43]=2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: COc1cc(N)ccn1
Reactant: O=C(O)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2ccc(Cl)cc2F)ccn1
Yield: 38.6 %

Procedure:
A solution of 4-chloro-2-fluoro-benzoic acid (7.0 g, 40.10 mmol), HATU (15.25 g, 40.10 mmol), 2-methoxypyridin-4-amine (4.98 g, 40.10 mmol) and Et3N (22.4 mL, 160.4 mmol) in dichloromethane (63.0 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-50%) to yield 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (4.35 g, 39%), as a white solid. ESI-MS m/z calc. 280.04, found 281.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.09 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.66 (dd, J=10.1, 1.9 Hz, 1H), 7.46 (dd, J=8.3, 1.9 Hz, 1H), 7.21 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: S(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(C)(=O)=O.[C:45]1([SH:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11][C@H:7]2[CH2:6][S:51][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:33])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Sc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CSc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of (2S,4S)-2-mesyloxymethyl-N-(p-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine (9.6 g, 15.2 mmol) in THF (190 ml), thiophenol (2.34 ml, 22.8 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (3.4 ml, 22.8 mmol) were successively added dropwise in a nitrogen stream under cooling with ice. The reaction solution was stirred at room temperature for 15 minutes and the solvent was distilled off. To the residue, ethyl acetate was added. The organic layer was washed with 1N aqueous potassium hydrogensulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (Wakogel™ C-300 heptane-ethyl acetate 3:1) to give (2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-phenylthiomethyl-4-tritylthiopyrrolidine (9.24 mg, yield: 94%) as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[F:34][C:33]([F:35])([F:36])[C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=1)[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1cc(-c2ccc(CBr)cc2)cc(C(F)(F)F)c1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-3,5-bis(trifluoromethyl)biphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided a white solid. 1H NMR: δ 8.43 (br s, 1H), 7.91-7.99 (m, 4H), 7.85 (s, 1H), 7.53 (dd, J=6.5, 1.8 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.07 (dm, J=9.0 Hz, 2H), 4.00 (A of AB, J=13.7 Hz, 1H), 3.93 (s, 3H), 3.42 (B of AB), J=13.7 Hz, 1H). MS (m/e): 588.5 (M−H)−. Anal: Calc for C25H17F6NO5S2.C3H7NO: 50.75% C, 3.65% H, 4.23% N; Found: 50.70% C, 3.60% H, 4.01% N. MP: 122-125° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>CO>[N:13]1[CH:12]=[N:11][N:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=12
Reactant: COC(=O)c1ccn2ncnc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccn2ncnc2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 38 %

Procedure:
To a solution of methyl 2-aminoisonicotinate (28.8 g, 191 mmol) in DMF (97.5 mL) was added DMF-DMA (70.6 mL, 496 mmol) and the mixture heated to 130° C. for 12 hours. The mixture was then concentrated to give a residue. To the residue was added methanol (381 mL), followed by NH2OHSO4 (31.9 g, 248 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate in 18% yield, 6 g. To a solution of methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3 g, 16 mmol) in methanol was added 1M aq. LiOH (70 mL) and the resulting mixture stirred for 10 hours at room temperature. The pH was adjusted to 5-6 using aq. HCl and the whole mixture extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as white solid in 38% yield, 1.05 g 1H NMR (400 MHz, DMSO-d6): δ13.5-14.0 (s, 1H), 9.04-9.06 (m, 1H), 8.66 (m, 1H), 8.32 (m, 1H), 67.56-7.58 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:25]N(C)C=O.CI>O>[CH3:25][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:22])[O:19][CH2:20][CH3:21]
Reactant: CCOC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 1.5 g of [3-(3-methyl-1,2,4-triazolo[4,3-b]-pyridazin-6-yl)phenyl]carbamic acid, ethyl ester, 0.29 g of sodium hydride (50% in oil) and 150 ml of dimethylformamide was stirred under argon for 1 hour and then 0.38 ml methyl iodide was added. This mixture was stirred overnight then poured onto 500 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and concentrated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3). The fractions containing product were combined, the solvent evaporated in vacuo and the solid recrystalized from dichloromethane-hexane, to give 1.25 g of an off-white powder, mp 146°-149° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)=[O:19])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)=[O:19])[CH2:12][CH2:13]2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccc(C(=O)O)cc1
Yield: 146.7 %

Procedure:
A solution of 1-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}-3-(4-ethoxycarbonylphenyl)urea hydrochloride (2.59 g; 5.6 mmole) in methanol (75 ml) was refluxed for 8 hours with aqueous sodium hydroxide (1N; 10 ml). The reaction mixture was concentrated in vacuo, and the residue was dissolved in water. After filtration, the solution was acidified with hydrochloric acid, and the precipitated solid was collected and washed with methanol to provide the title compound (1.92 g; 80% yield) as colorless crystals, m.p. 244°-246° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH3:9])=[C:7]([C:10]#[CH:11])[N:6]=[C:5]2[CH3:12])[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[C:18](I)[CH:17]=[CH:16][N:15]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([C:11]#[C:10][C:7]2[N:6]=[C:5]([CH3:12])[N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[CH3:9])[CH:17]=[CH:16][N:15]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#Cc1nc(C)n(C2CC2)c1C
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1C1CC1

Procedure:
The title compound, MS: m/e=272.0 (M+H+), was prepared in accordance with the general method of example A, step 1 from 1-cyclopropyl-4-ethynyl-2,5-dimethyl-1H-imidazole and 2-chloro-4-iodo-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[I:11]NC(=O)CCC(N)=O>C(#N)C>[I:11][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: NC(=O)CCC(=O)NI
Reactant: Clc1ccn2ccnc2c1
Solvent: CC#N
Product: Clc1ccn2c(I)cnc2c1
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-imidazo[1,2,a]pyridine (6.10 g, 40 mmol) (Yamanaka, Motosuke et al., Chemical & Pharmaceutical Bulletin (1991), 39(6), 1556-67) in dry acetonitrile (100 mL), add N-iodosuccinamide. Stir for 30 minutes. Filter off the precipitate and then wash with acetonitrile. Recrystallize the precipitate from acetonitrile to give a white solid. Concentrate the filtrate, dilute with ethyl acetate, wash with 10% sodium hydrogensulfite (NaHSO3), saturated aqueous sodium bicarbonate, saturated aqueous NaCl, dry over MgSO4, filter and evaporate. Use the combined solid without further purification (8.0 g, 73%). 1H NMR (DMSO) δ 8.33 (d, 1H, J=7.3 Hz), 7.79 (d, 1H, J=2.0 Hz), 7.72 (s, 1H), 7.07 (dd, 1H, J=7.3 and 2.0 Hz).