Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])[CH3:25]
Reactant: CCN
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Product: CCNC(=O)c1cnc(/C=C/c2c(-c3ccc(F)cn3)noc2C)s1
Yield: 78 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using ethylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (70 mg, 78%) which was obtained as a yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=359.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:26]1C(C)=NC=CC=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[C:19]([CH3:26])=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Br
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2C)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (example 5) in accordance with the general method of example 20 using 3-Bromo-2-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=334.1 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:11][N:9]1[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5][CH:4]([CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:10]1
Reactant: C1COCCN1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Product: CN1CC(CCN2CCOCC2)Oc2ncccc2C1=S
Reaction time: 6 h

Procedure:
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-thione, 4.5 g (0.018 mole) was dissolved in morpholine (30 ml). The solution was heated with stirring to 50°-60° C. for 6 hr. The morpholine was then removed by rotary evaporation (90° C., vacuum pump). The residue was taken up in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (2×30 ml). The organic layer was concentrated by rotary evaporation (60° C., water aspirator). The residue was recrystallized from ethanol giving 3.26 g (60%) of light yellow crystals, m.p. 152°-153° C.
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCCNC4)n3)ccc21
Reactant: CC(=O)OCCCCCCl
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCCN(CCCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out starting from 3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrobromide and 5-chloropentyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:10]([OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:10]([O:22][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2CCN(Cc3ccccc3)CC2O)cc1
Reactant: BrCc1ccc2ccccc2c1
Product: COc1ccc(C2CCN(Cc3ccccc3)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 12(b), by alkylating (3RS,4RS)-1-benzyl-4-(4-methoxy-phenyl)-piperidin-3-ol [Example 44 (c)] with 2-bromomethylnaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(4-methoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a beige coloured solid; MS: 437 (M)+. Subsequent reaction with 2,2,2-trichloroethyl chloroformate gave 2,2,2-trichloro-ethyl (3RS,4RS)-4-(4-methoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellowish oil; MS: 539, 541 (M+NH4)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:23])[C:11]([F:22])=[C:12]([F:21])[C:13]=2[NH:17]C(=O)C)[N:8]([CH:24]2[CH2:26][CH2:25]2)[CH:7]=1)=[O:5])C.C(OC(=O)CC(=O)C1C(F)=C(F)C(F)=C(F)C=1NC(=O)C)C.C(OC(OCC)OCC)C.C(OC(=O)C)(=O)C>>[CH:24]1([N:8]2[C:9]3[C:14](=[C:13]([NH2:17])[C:12]([F:21])=[C:11]([F:22])[C:10]=3[F:23])[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NC(C)=O)c2c1=O
Agent: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1NC(C)=O
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
This product can be converted to 5-acetylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester by a three step reaction. The 2-acetylamino-3,4,5,6-tetrafluoro-β-oxobenzene-propanoic acid ethylester is first treated with triethylorthoformate and acetic anhydride. After removal of the solvent the residue is treated with a solution of cyclopropylamine in t-butanol. After the reaction is complete a solution of potassium t-butoxide in t-butanol is added. The resulting product is 5-acetylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester. The ester is hydrolyzed to form 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([F:10])[CH:9]=2)[CH2:3][CH2:2]1.Cl[C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:21]3[CH:22]=[C:23]([CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])[N:24]=[N:25][CH:26]=3)[CH:7]=[C:8]([F:10])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2cc(F)cc(C3CC3)c2)OC1(C)C
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2cc(F)cc(C3CC3)c2)cnn1

Procedure:
The title compound was prepared from 2-(3-cyclopropyl-5-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine. (1H-NMR (300 MHz, CDCl3) δ=9.38 (s, 1H), 6.80-7.55 (m, 6H), 5.50 (s, 2H), 2.41 (s, 3H), 1.92-2.02 (m, 1H), 1.02-1.14 (m, 2H), 0.68-0.78 (m, 2H))
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:7]=1[CH:18]=[CH:19][CH2:20][C:21]([O:23]C)=[O:22])[CH3:5]>CO.O>[CH3:5][CH:4]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[CH:9]=[C:8]([CH:15]([CH3:16])[CH3:17])[C:7]=1[CH:18]=[CH:19][CH2:20][C:21]([OH:23])=[O:22])[CH3:3]
Reactant: COC(=O)CC=Cc1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1cc(C(C)C)c(C=CCC(=O)O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.7 %

Procedure:
Sodium hydroxide (0.23 g, 5.7 mmol) was added to a solution of 3-[2,4,6-tris (1-methylethyl)phenyl]-2-propenyl carboxylic acid, methyl ester (1.5 g, 5.2 mmol) in 100 mL methanol and 10 mL water. Stirred at room temperature for 48 hours and concentrated to dryness. Partitioned the residue between water and diethyl ether. The aqueous layer was acidified with concentrated HCl and extracted with dichloromethane. The organic extract was dried over MgSO4, filtered, and concentrated to give 1.33 g of 3-[2,4,6-tris-(1-methylethyl)phenyl]-2-propenyl carboxylic acid as a white solid, mp 201°-203° C.
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[N:13]([O-:15])=[O:14].[Na+].N(O)=O.C(=O)([O-])[O-].[Ca+2]>S(=O)(=O)(O)O.O>[Cl:12][C:11]1[C:2]([N+:13]([O-:15])=[O:14])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: Nc1ccc2ccncc2c1Cl
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: O=NO
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2ccncc2c1Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
7-Amino-8-chloroisoquinoline (0.05 mole) in dilute aqueous sulfuric acid at 3° C. is treated with sodium nitrite (0.05 mole). After 30 minutes, the reaction mixture is tested for nitrous acid with starch/iodide paper as described in Example 15. When a positive reaction is obtained, the mixture is neutralized with aqueous calcium carbonate solution and added with stirring to a hot solution (50° C.) of 50 g. of sodium nitrite, 5 g. of cupric sulfate pentahydrate and 50 ml. of water containing 3 g. of cuprous oxide in suspension. The reaction mixture is heated to 70° C. for 10 minutes and then extracted with ether. The extract is evaporated to give 8-chloro-7-nitroisoquinoline. The product is purified by chromatography on silica gel, eluting with ether followed by recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Cl.ClC1C2C(=CC(OCCCl)=C(OC)C=2)N=CN=1>CC(N(C)C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:23][CH2:22][Br:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: ClCCBr
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: COc1cc2c(Cl)ncnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Cl)ncnc2cc1OCCBr
Temperature: 90 °C
Yield: 62.6 %

Procedure:
A mixture of 4-chloro-6-methoxyquinazolin-7-ol (5.0 g, 24 mmol), potassium carbonate (9.94 g, 72 mmol) and 1-bromo-2-chloroethane (7.98 ml, 96 mmol) in dimethyl acetamide (50 ml) was heated at 90° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and then filtered. The filtrate was purified directly by silica gel chromatography eluting with a 20 to 80% mixture of ethyl acetate in iso-hexane. The obtained product was triturated with diethyl ether to give a 3:1 mixture of 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline: 4-chloro-7-(2-bromoethoxy)-6-methoxyquinazoline (4.77 g, 73% yield) as a white solid:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1([F:35])[CH2:14][N:13]([C:15]([C:17]2[S:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[O:16])[CH2:12][C:11]2([CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[O:10]1.C1(C)C=CC=CC=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:35][C:9]1([F:8])[CH2:14][N:13]([C:15]([C:17]2[S:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[O:16])[CH2:12][C:11]2([CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[O:10]1
Reactant: Cc1ccc(C(=O)N2CC(F)(F)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CC(F)(F)OC3(CCNCC3)C2)s1
Reaction time: 0.42 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 2,2-difluoro-4-(5-methylthiophene-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step d) (0.4 g) in dichloromethane (20 mL) at 20° C. The solution was allowed to stand at 20° C. for 25 minutes. Toluene (40 mL) was added and the solvents were removed under reduced pressure. The residue was evaporated down twice with acetonitrile. The resultant gum was triturated with ether to afford the subtitled compound. Yield 0.39 g.
Reaction SMILES: Br.[NH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:5].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([O:32][C:33]([NH:2][CH2:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:5])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(CN)c1ccc(O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CNC(=O)OCc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of 4.64 g of (±)-4-(2-amino-1-methylethyl)phenol hydrobromide, 100 ml of ethyl acetate, 6.92 g of potassium carbonate, 40 ml of water and 3.75 g of benzyloxycarbonyl chloride is stirred at room temperature overnight. After the reaction, the ethyl acetate layer is separated therefrom, washed, dried, and then evaporated under reduced pressure to remove the solvent. 4.82 g of (±)-4-(2-benzyloxycarbonylamino-1-methylethyl)phenol are obtained as pale yellow oil.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:29])[CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][C@H:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@H:8]([CH2:25][CH:26]=[CH2:27])[C:7]1=[O:28]>[Pd]>[ClH:1].[CH3:29][N:3]([CH3:2])[CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][C@H:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@H:8]([CH2:25][CH2:26][CH3:27])[C:7]1=[O:28]
Reactant: C=CC[C@@H]1C(=O)N(CCN(C)C)c2ccccc2C[C@@H]1c1ccc(OC)cc1
Agent: [Pd]
Agent: Cl
Product: CCC[C@@H]1C(=O)N(CCN(C)C)c2ccccc2C[C@@H]1c1ccc(OC)cc1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A solution of (cis)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-(2-propenyl)-2H-1-benzazepin-2-one, monohydrochloride (1.5 g, 3.62 mmol; see Example 16) containing a 10% palladium on charcoal suspension (0.15 g, 10% b/w) was hydrogenated overnight at 1 atmosphere. The suspension was filtered through a Celite pad and evaporated in vacuo to yield 1.47 g of a white solid, melting point 178°-180° C., dec.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[C:6]2[C:14]=1[CH2:13][C@H:12]1[C@@H:7]2[CH2:8][NH:9][CH2:10][CH2:11]1.CCN(CC)CC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl>[CH2:32]([O:31][C:29]([N:9]1[CH2:8][C@H:7]2[C@H:12]([CH2:13][C:14]3[C:6]2=[CH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:2]=3[CH3:1])[CH2:11][CH2:10]1)=[O:30])[CH3:33]
Reactant: Cc1cc(-c2ccccc2)cc2c1C[C@@H]1CCNC[C@H]21
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(-c4ccccc4)cc3[C@H]2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of cis-8-methyl-6-phenyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (22 mg, 0.084) in CH2Cl2 was added Et3N (43 mg, 0.42 mmol) followed by ethyl chloroformate (18 mg, 0.17 mmol). The reaction mixture was stirred at 20° C. for 2 h and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give cis-8-methyl-6-phenyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (20 mg, 0.060 mmol).
Reaction SMILES: C(O[CH:4]1[CH2:12][C:11]2[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2O1)C.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:13])[C:11]=2[CH:12]=[CH:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC1CC2=C(CCCC2=O)O1
Reactant: NCc1ccccc1
Product: O=C1CCCc2c1ccn2Cc1ccccc1
Temperature: 110 °C
Yield: 56 %

Procedure:
A mixture of 182 mg of 2-ethoxy-4-oxo-2,3,4,5,6,7-hexahydrocoumarone and 1 ml of benzylamine was heated in a glass tube at 110° C. for 12 hours. The reaction mixture was purified by column chromatography on silica gel using a solvent mixture of ethyl acetate and n-hexane (1:1) to give 126 mg of N-benzyl-4-oxo-4,5,6,7-tetrahydroindole as white crystals (yield 56%). ##STR21##
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:11][C:4]1[CH:3]=[C:2]([I:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(I)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
4-Iodo-2-nitro-benzoic acid (20 g, 68 mmol, 1.0 equiv.) was dissolved in 200 mL of EtOAc and then SnCl2.2H2O (46 g, 204 mmol, 3.0 equiv.) was added in three portions. The reaction mixture was stirred at rt for 16 h. Satd. aq. NaHCO3 was carefully added to adjust the mixture to pH=9. The precipitated solid was removed by filtration through diatomaceous earth, washing with water. The aqueous layer in the filtrate was separated and acidified with conc. HCl to pH=2. The precipitated solid was collected by filtration and dried to afford the title compound as white solid (19 g, 68 mmol, 100%). 1H NMR (400 MHz, CD3OD): 1H NMR (500 MHz, CDCl3): 7.56 (d, J=8.5, 1H), 7.08 (s, 1H), 6.99 (d, J=8.5, 1H), 5.71 (br s, 2H).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([C:73]2[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:77]([C:76]3[CH:75]=[CH:74][C:73]([N:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)=[CH:80][CH:79]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 36.7 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-morpholin-4-yl-benzaldehyde (1.1 eq, 0.056 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 37%) as an off-white solid; δH (500 MHz, DMSO-d6) 2.61 (s, br, 4H, piperazine N(CH2)2), 3.24 (t, J=4.9 Hz, 4H, morpholine N(CH2)2), 3.62 (s, 2H, CH2), 3.64 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 3.76 (t, J=4.7 Hz, 4H, morpholine O(CH2)2), 7.06 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.79 (dt, J=7.7, 1.7 Hz, 1H, pyridine H-4), 8.04 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.6 Hz, 1H, pyridine H-6), 8.56 (d, J=1.5 Hz, 1H, pyridine H-2), 13.22 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH:10]([C:11]([OH:13])=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:23]1[CH:27]=[CH:26][NH:25][C:24]=1[CH2:28]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([S:7][CH:8]2[CH:10]([C:11]([O:13][CH2:28][C:24]3[NH:25][CH:26]=[CH:27][C:23]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:12])[C:9]2([CH3:15])[CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)C(Sc2ccccc2)C1C(=O)O
Reactant: OCc1[nH]ccc1Cc1ccccc1
Product: CC1(C)C(Sc2ccccc2)C1C(=O)OCc1[nH]ccc1Cc1ccccc1

Procedure:
Using the method of Example 1, 3-phenylthio-2,2-dimethylcyclopropanecarboxylic acid is reacted with 3-benzylpyrrolylmethyl alcohol to yield 3-benzylpyrrolylmethyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:19]2=[S:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=NC1CCCCC1
Reactant: O=C(O)CNc1ccccc1
Solvent: CCO
Product: O=C1CN(c2ccccc2)C(=S)N1C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A mixture of N-phenyl glycine (15.1 g, 0.1M) and cyclohexylisothiocyanate (21.2 g, 0.15M) was heated at 100° C. for 8 hours and then allowed to stand at room temperature overnight. The reaction mixture was placed in about 50 ml of ethanol, collected by filtration and recrystallized from ethanol to produce 11 grams (0.047M) of the above-identified product having a melting point of 156° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:18][N:6]1[CH2:7][C@@H:2]([CH3:1])[N:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][C@H:5]1[CH3:8]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@H](C)CN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@H](C)CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of (2R,5R)-2,5-dimethyl-1-(phenylmethyl)piperazine (prepared according to J. Med. Chem. 2006, 49, 716-726, utilizing N-Boc-D-alanine in place of N-Boc-L-alanine) (667 mg, 3.26 mmol) in dichloromethane (25 mL) at 0° C. was added formaldehyde (0.367 mL, 37% water solution, 4.89 mmol) followed by sodium triacetoxyborohydride (900 mg, 4.24 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield (2R,5R)-1,2,5-trimethyl-4-(phenylmethyl)piperazine (680 mg, 96%). LCMS: (M+H)+: 219.1.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:13][CH2:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:3]1=[O:28].CCN(C(C)C)C(C)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][N:13]([CH2:14][CH:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:44]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:45])[C:3]1=[O:28]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cn1c(=O)c(CNCC(c2ccccc2)C2CCOCC2)cc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)c(CN(CC(c2ccccc2)C2CCOCC2)C(=O)C2CCCCC2)cc2ccccc21
Reaction time: 1 h

Procedure:
To 1-methyl-3-({[2-phenyl-2-(tetrahydro-2H-pyran-4-yl)ethyl]amino}methyl)quinolin-2(1H)-one (46.5 mg, 0.124 mmol) in CH2Cl2 (3 ml) and added DIEA (0.043 ml, 0.247 mmol) then cyclohexanecarbonyl chloride (0.018 ml, 0.136 mmol). The reaction was stirred for 1 hour and then concentrated in vacuo. Purified by reversed-phase chromatography (15-75% ACN in water (with 0.5 ml/l NH4OH), 20×100 mm Phenomenex Gemini C18 column). Desired fractions were concentrated in vacuo. HRMS [M+H]1+ 487.2962. 400 MHz 1H NMR (CDCl3) δ 7.59-7.47 (m, 2 H), 7.37 (d, J=8.52 Hz, 1 H), 7.33-7.13 (m, 7 H), 4.26 (d, J=18.4, 1 H), 4.17-3.95 (m, 2 H), 3.88-3.76 (m, 2 H), 3.74 (s, 3 H), 3.44-3.23 (m, 3 H), 2.97-2.91 (m, 0.8 H, rotational isomer A), 2.67-2.62 (m, 0.2 H, rotational isomer B), 2.42-2.19 (m, 0.2 H, rotational isomer B), 2.15-2.08 (m, 0.8 H, rotational isomer A), 1.95-0.95 (m, 15 H). 29.4 mg, 49%.