Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)C.[N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[C:23]4=[N:24][C:25]([N:28]5[CH2:32][CH2:31][C:30](=[O:33])[CH2:29]5)=[CH:26][N:27]=[C:22]4[N:21]=[N:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[CH2:34]1COCC1>CS(C)=O>[O:33]1[C:30]2([CH2:31][CH2:32][N:28]([C:25]3[N:24]=[C:23]4[N:19]([CH2:18][C:14]5[CH:13]=[C:12]6[C:17](=[CH:16][CH:15]=5)[N:8]=[CH:9][CH:10]=[CH:11]6)[N:20]=[N:21][C:22]4=[N:27][CH:26]=3)[CH2:29]2)[CH2:34]1
Reactant: O=C1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Reactant: C1CCOC1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: c1cnc2ccc(Cn3nnc4ncc(N5CCC6(CO6)C5)nc43)cc2c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 63 %

Procedure:
To a flamed dry 3N round bottom flask fitted with a thermometer and condenser was added 95% NaH (69 mg, 2.69 mmol) and anhydrous DMSO (5.0 ml). After stirring for 2 min at R.T. and 70° C. for 45 mins, the reaction mixture was cooled to 3° C. and a solution of trimethylsulfonium iodide (504.1 mg, 2.47 mmol) in DMSO (3.6 ml) was added. After stirring for 30 mins at 3° C., to the reaction mixture, a suspension of 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-one (200 mg, 0.58 mmol) in 1:1 THF: DMSO (16 ml) was added dropwise. After stirring at 0° C. for 3 h, the reaction mixture was poured into an ice cold water (15 ml) and extracted with CH2Cl2 (4×60 ml). The organic layer was washed with brine and dried with MgSO4 and concentrated under reduced pressure. The resulting residue was purified via flash column chromatography eluted with 10% MeOH:CH2Cl2 to give the desired product (130 mg 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])=[CH:4][CH:3]=1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C(OCc1ccccc1)N1CCC(Sc2ccc(Cl)cc2)C(O)C1
Product: O=C(OCc1ccccc1)N1CCC(Sc2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 71(b), from benzyl (3RS,4RS)-4-(4-chloro-phenylsulphanyl)-3-hydroxy-piperidine-1-carboxylate by alkylation with 2-bromomethylnaphthalene there was obtained benzyl (3RS,4RS)-4-(4-chloro-phenylsulphanyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 518 (M+H)+.
Reaction SMILES: [Na+:1].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][S:13]([O-:16])(=[O:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O.CN(C=O)C>C1C=CC=CC=1>[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][S:13]([Cl:19])(=[O:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+:1].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][S:13]([O-:16])(=[O:14])=[O:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Agent: O=S(=O)([O-])CCCCOc1ccccc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCCCOc1ccccc1

Procedure:
4-Phenoxybutyl sulfonyl chloride (16) was synthesized as described in 12.1 using 15 (1.0 g, 4.37 mmol) and thionyl chloride (1.55 g, 13.0 mmol) in benzene (40 mL)/DMF (4 mL). Purification by flash column chromatography on silica gel afforded 15 (0.434 g, 40% yield) as a white solid (m p 65-67° C.).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][NH:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[CH:40][CH:41]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(OCCO)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)CO
Solvent: NCCO
Product: CC(C)(CO)NCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(2-hydroxyethoxy)phenyl]ethyl}benzofuran and 2-amino-2-methyl-1-propanol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F)([O-:3])=[O:2].CO[C:16]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19](OC)=[C:18]([CH3:26])[C:17]=1[OH:27]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[O:27][C:17]1[C:18]([CH3:26])=[CH:19][C:20]([CH3:23])=[C:21]([CH3:22])[CH:16]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(F)c1
Reactant: COc1c(C)c(C)c(OC)c(O)c1C
Product: Cc1cc(C)c(Oc2cc([N+](=O)[O-])ccc2[N+](=O)[O-])cc1C

Procedure:
The process was carried out as described in point 5.4 above, using 0.812 g (4.362 mmol) of 2,5-dinitrofluorobenzene and 0.856 g (4.362 mmol) of 2,5-dimethoxy-3,4,6-trimethylphenol. The title product was obtained in the form of a yellow solid (1.412 g, 89%) after column chromatography using, as eluent, a 75:25 mixture of light mineral spirit (60-80° C.):diethyl ether.
Reaction SMILES: C([NH:3][C:4](CC(C)=C)(C(OCC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.[CH:19]([NH:21][CH2:22][C:23]([NH:25][CH:26]([CH2:31][CH:32]=[CH2:33])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[O:20]>C(Cl)Cl.CO>[NH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:33][CH:32]=[CH:31][CH:26]([NH:25][C:23](=[O:24])[CH2:22][NH:21][CH:19]=[O:20])[C:27]([O:29][CH3:30])=[O:28]
Reactant: C=CCC(NC(=O)CNC=O)C(=O)OC
Reactant: C=C(C)CC(NC=O)(C(=O)OCC)C(=O)OCC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(N)CC=CC(NC(=O)CNC=O)C(=O)OC

Procedure:
Using the procedure of preparation B of Example 1, diethyl (formylamino)-(2-methyl-2-propenyl)-propanedioate in Step 2 was replaced by methyl 2-[(N-formylglycyl)-amino]-2-(2-propenyl)ethanoate to obtain the expected product with an Rf=0.2 in a methylene chloride/methanol (9:1) mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][C:3]=1[CH3:24].[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=4)=[CH:11][CH:10]=[C:9]3[CH3:23])=[CH:4][C:3]=2[CH3:24])=[CH:26]1
Reactant: OB(O)c1ccoc1
Reactant: Cc1cc(-n2c(C)ccc2-c2ccc(S(C)(=O)=O)cc2)ccc1Br
Product: Cc1cc(-n2c(C)ccc2-c2ccc(S(C)(=O)=O)cc2)ccc1-c1ccoc1

Procedure:
The title compound was prepared according to the procedure of Example 35 using 1-(4-bromo-3-methylphenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole instead of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole and 3-furanboronic acid instead of 2-furanboronic acid in step 4.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[CH:17]=[CH:18][CH:19]=1)[CH2:8]2.Cl>CO>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[CH:2]1[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=1)[CH2:4]2
Reactant: CC(C)(C)OC(=O)NCCc1cccc(OCCC2C3CC4CC(C3)CC2C4)c1
Agent: Cl
Solvent: CO
Product: NCCc1cccc(OCCC2C3CC4CC(C3)CC2C4)c1

Procedure:
Obtained from Intermediate 79 (1.25 g, 3.13 mmol) and hydrogen chloride 1.25 M in methanol (40 mL) by the same procedure described in Intermediate 17 (reaction time: overnight). The title compound was obtained as a yellow oil (0.71 g, 76%) and used in the next step without further purification. MS (M+): 300.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=O)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].O[NH:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1)=[NH:29].CC[O-].[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[O:22][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)[N:27]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: N=C(NO)c1cccc(O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCCc2nc(-c3cccc(O)c3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 180 °C

Procedure:
A mixture of ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (50 mg, 0.13 mmol), N,3-dihydroxybenzenecarboximidamide (25 mg, 0.16 mmol), 21% solution of NaOEt in EtOH (55 μl, 0.15 mmol) and EtOH (1.5 ml) was heated in the microwave at 180° C. for 10 min. Another aliquot of 21% solution of NaOEt in EtOH (55 μl, 0.21 mmol) was added and the mixture heated in the microwave at 175° C. for 30 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, concentrated and purified by the MDAP. The title compound was obtained as an off-white solid (20 mg, 32%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]2[S:22][C:21]([N:23]3[CH2:29][CH2:28][CH2:27][NH:26][C:25](=[O:30])[CH2:24]3)=[N:20][CH:19]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][C:15]1[CH:14]=[C:13]([C:18]2[S:22][C:21]([N:23]3[CH2:29][CH2:28][CH2:27][NH:26][C:25](=[O:30])[CH2:24]3)=[N:20][CH:19]=2)[CH:12]=[C:11]([NH:10][C:2]2[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=1
Reactant: CSc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CSc1ccnc(Nc2cc(C)cc(-c3cnc(N4CCCNC(=O)C4)s3)c2)n1
Temperature: 90 °C
Yield: 56.2 %

Procedure:
To an oven-dried vial was added 2-chloro-4-methylthiopyrimidine (0.885 g, 4.13 mmol), intermediate XX (1.25 g, 4.13 mmol), tris-(dibenzylideneacetone)dipalladium(0) (0.379 g, 0.413 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.985 g, 2.067 mmol), and potassium carbonate (1.143 g, 8.27 mmol). The vial was evacuated and backfilled with Ar (g) 3×. Degassed t-amyl alcohol (13.78 mL) was added, and the mixture was sealed and heated to 90° C. overnight. After cooling to room temperature, diluted with methanol, added 10 g silica, and concentrated in vacuo. Purified by CombiFlash (100:0 to 0:20 dichloromethane:methanol) to afford 4-[5-(3-methyl-5-{[4-(methylsulfanyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (0.990 g, 2.321 mmol, 56% yield) as a yellow solid. MS APCI: [M+H]+ m/z 427.1. rhSYK activity=+++.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1Br)NCc1ccccc1
Reaction time: 2 h

Procedure:
To a stirring solution of 2-bromophenylacetic acid in dichloromethane (0.2 M) was added benzylamine (1.2 eq), triethylamine (1.5 eq), and EDAC (1.5 eq). After 2 hrs, the solution was washed with water, 10% HCl, 10% sodium carbonate, and water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a colorless solid. EI-MS m/z 304/306 (M+H)+
Reaction SMILES: [CH:1]([C:3]1([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=O.NN.[OH-].[K+]>C(O)COCCO>[CH3:1][C:3]1([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][CH2:5][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]3[CH2:18][CH2:19][C@H:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22]3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CCCCCC1(C=O)CCC(c2ccc(CC[C@H]3CC[C@H](CCCCC)CC3)cc2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CCCCCC1(C)CCC(c2ccc(CC[C@H]3CC[C@H](CCCCC)CC3)cc2)CC1
Reaction time: 12 h

Procedure:
A mixture of 4.4 g (0.01 mole) of 1-[p-(4-formyl4-pentylcyclohexyl)-phenyl]-2-(trans-4-pentyl-cyclohexyl)ethane (Example 8), 40 ml of diethylene glycol, 15 ml of 90% hydrazine and 5.5 g of potassium hydroxide is heated and the hydrazine and water are distilled off until the temperature has risen to about 230° C. The reaction mixture is then boiled for 12 hours and, when cold, 200 ml of water are subsequently added. After customary working up, 1-[p-(4-methyl-4-pentylcyclohexyl)-phenyl]-2-(trans-4-pentylcyclohexyl)-ethane is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(-c2cncc(Br)c2)cc1
Temperature: 150 °C
Yield: 9.3 %

Procedure:
3,5-Dibromopyridine (4.4 mmol), 4-trifluoromethoxyphenyl boronic acid (5.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 mmol), 2 M potassium carbonate (8.44 mmol) and dioxane (21 mL) were combined in a vial and heated by microwave for 10 min at 150° C. The reaction mixture was taken up in ether and washed with brine. The ether layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. The crude mixture was purified by silica gel chromatography to yield 130 mg of 3-bromo-5-(4-trifluoromethoxy-phenyl)-pyridine as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (m, 2H), 8.00 (t, J=2.1 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H); EIMS 317 m/z (M+).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:2]1.[Li]CCCC.Cl[CH2:19][O:20][CH3:21]>C1COCC1>[CH:1]1([CH2:4][N:5]([CH2:19][O:20][CH3:21])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1CC1
Reactant: COCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCN(CC1CC1)C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 90.9 %

Procedure:
Tert-butyl cyclopropylmethylcarbamate (11.2 g, 65.4 mmol) was dissolved into THF (60 mL) and set to stir at −78° C. BuLi (2.5M, 28.8 mL) was then added portionwise over 10 minutes. The reaction was allowed to stir while warming to −20° C. for 10 minutes, and continued stirring at that temperature for another 10 minutes. The reaction was then recooled to −78° C. at which point chloro(methoxy)methane (5.79 g, 72.0 mmol) was added via syringe. The reaction was then allowed to stir overnight with warming. The reaction was then quenched with 1 N HCl and the organic layer separated. The aqueous layer was then extracted with DCM (2×), and the combined organic portions were dried with MgSO4, filtered and concentrated. The crude material was purified by passing through a silica plug eluting 10:1 Hex/EtOAc to give tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (12.8 g, 91%) as a clear liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:3]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=1[NH:1][C:7](=[O:8])[CH3:6])(=[O:4])[CH3:2]
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1CO
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(Cl)ccc1Oc1ccccc1COC(C)=O
Reaction time: 16 h

Procedure:
0.026 Part of 2-(2-amino-4-chlorophenoxy)benzyl alcohol is dissolved in 0.5 part pyridine and 0.5 part by volume acetic anhydride and allowed to stand at room temperature for 16 hours. The solvent is removed by evaporation under a nitrogen atmosphere and the resultant residue chromatographed on 0.6 part silicic acid. Elution with a 5:95 mixture of ethyl acetate-benzene and recrystallization from a mixture of ethyl acetate and benzene affords 2-(2-acetamido-4-chlorophenoxy)benzyl acetate. This compound melts at about 83° - 84° C. and is represented by the following structural formula. ##STR6## Elemental analysis shows C, 61.71%; H, 5.30%; Cl, 10.73%; N, 4.01%. The calculated values are C, 61.17%; H, 4.83%, Cl, 10.62%; and N, 4.20%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)[CH:23]=1.C(N(CC)CC)C>C(O)CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([CH2:27][N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=4)[CH2:14][CH2:13]3)[N:26]=2)[CH:23]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: FC(F)(F)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)nc1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A mixture of 1-(5-trifluoromethylpyridin-2-yl)piperazine (0.4803 g), 6-chloro-2-(chloromethyl) imidazo[1,2-a]pyridine (Example 4, Step 1; 0.4177 g), triethylamine (0.231 g), and ethylene glycol (1 mL) is stirred at 80° C. for 70 min. after which additional 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (0.072 g) is added; thirty minutes later another portion (0.0517 g) is added. After stirring for a total of 2 h, the mixture is cooled and partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. Chromatography on silica gel using methanol/dichloromethane (4/96) and crystallization from ethyl ether/hexane gives 0.549 g of the title compound; mp 81-82° C.; MS m/z 395; IR (mineral oil) 1617, 1332, 1328, 1112, 1082 cm-1. 1H NMR (CDCl3) δ2.68, 3.69, 3.77, 6.62, 7.14, 7.52, 7.55, 7.61, 8.14, 8.38.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:8]=[C:7]([Br:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:22])[CH:8]=[C:7]([Br:23])[CH:6]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cc(Br)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cc(Br)cc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-Bromo-5-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)[CH:17]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:12]4[N:11]([CH3:27])[N:10]=[N:9][C:8]=4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=[CH:15]3)=[N:19][CH:20]=2)[CH2:30][CH2:29]1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NC1CC1
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3CC3)cn2)cn1
Yield: 56 %

Procedure:
As described for example 22, 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (69 mg, 0.189 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (43 mg, 56%) which was obtained as a white foam. MS: m/e=404.4 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]2=[O:15])=[O:4].[N-:34]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CC(C)=O.CCOCC>[NH2:34][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:10]2=[O:15])=[O:4]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CN)c3C2=O)ccc1OC
Yield: 86.2 %

Procedure:
A mixture of 2-chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}acetamide (0.30 g, 0.61 mmol) and sodium azide (90 mg, 1.38 mmol) in acetone (10 mL) was heated to reflux for 8 hours. To the solution was added triphenylphosphine (0.30 g, 1.1 mmol) and water (0.4 mL). The solution was heated to reflux for 5 more h. The solvent was removed in vacuo to give an oil. The oil was stirred in ether (10 mL) and water (10 mL) overnight to give a suspension. The suspension was filtered and washed with ether and water to give 2-amino-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}acetamide as a yellow solid (250 mg, 86% yield); mp, 111-112° C.; 1H NMR (CDCl3) δ 1.48 (t, J=6.9 Hz, 3H, CH3), 1.74 (brs, 2H, NH2), 2.86 (s, 3H, CH3), 3.57 (s, 2H, CH2), 3.77 (dd, J=4.6, 14.5 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.11 (q, J=7.0 Hz, 2H, CH2), 4.56 (dd, J=10.2, 14.2 Hz, 1H, CHH), 5.89 (dd, J=4.6, 10.2 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.12-7.15 (m, 2H, Ar), 7.52 (d, J=7.2 Hz, 1H, Ar), 7.67 (t, J=7.5 Hz, 1H, Ar), 8.86 (d, J=8.3 Hz, 1H, Ar), 11.21 (s, 1H, NH); 13C NMR (CDCl3) δ 14.68, 41.51, 48.65, 54.69, 55.88, 64.49, 111.45, 112.50, 115.81, 118.24, 120.37, 124.94, 129.38, 131.29, 135.90, 136.88, 148.55, 149.68, 167.64, 168.83, 172.41; Anal Calcd for C22H25N3O7S: C, 55.57; H, 5.30; N, 8.84. Found: C, 55.46; H, 5.33; N, 8.35.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:5]=1)(=[O:3])[CH3:2].O1CCOCC1.C(OC)(C)(C)C.[Br:33]Br>O>[Br:33][CH2:2][C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:5]=1)=[O:3]
Reactant: BrBr
Reactant: CCOC(=O)c1cc(C(C)=O)nn1-c1ncccc1Cl
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C(=O)CBr)nn1-c1ncccc1Cl

Procedure:
1.20 g (4.40 mmol) of ethyl 3-acetyl-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate were initially charged in in each case 30 ml of dioxane and methyl tert-butyl ether and 776 mg (4.85 mmol) of bromine were added dropwise at RT. The mixture was then stirred under reflux for 6 h. The reaction mixture was added to water, and the organic phase was separated off, dried over sodium sulphate and concentrated. The residue was recrystallized from methyl tert-butyl ether.