Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:29]=[C:30]2[CH:36]=[C:35]([C:37](O)=[O:38])[NH:34][C:31]2=[CH:32][N:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:5]=[C:4]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1)[C@@H:3]([NH:2][C:37]([C:35]1[NH:34][C:31]2=[CH:32][N:33]=[C:28]([Cl:27])[CH:29]=[C:30]2[CH:36]=1)=[O:38])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: N[C@@H](Cc1cccnc1)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)N1CCCC1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-amino-3-pyridin-3-yl-1-pyrrolidin-1-ylpropan-1-one hydrochloride (Preparation 54, 239 mg, 0.94 mmol) in DMF (5 mL) was added DIPEA (0.60 mL, 3.28 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 184 mg, 0.94 mmol) and TBTU (330 mg, 1.03 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and sodium hydroxide solution (2×100 mL, 1N). The organic phase was dried (MgSO4) and evaporated to dryness give the title compound as a brown solid. δH (CD3OD): 1.74-1.94 (4H, m), 3.12-3.39 (4H, m), 3.41-3.48 (1H, m), 3.69-3.75 (1H, m), 5.07-5.12 (1H, m), 7.16 (1H, s), 7.34-7.39 (1H, m), 7.67 (1H, s), 7.79-7.83 (1H, m), 8.37-8.42 (1H, m), 8.45-8.51 (1H, m), 8.56 (1H, s); m/z (ES+)=398 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C[C@H](C)N1
Yield: 59.7 %

Procedure:
2,6-cis-Dimethylpiperazine (40.3 mmol, 4.6 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (40.3 mmol, 13.58 g) and potassium carbonate (81 mmol, 11.13 g) were combined and stirred overnight at room temperature in acetonitrile (25 mL). The reaction mixture was diluted with ethyl acetate and filtered through dicalite. The filtrate was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 90/10/1 dichloromethane/methanol/ammonia) to afford the title compound (8.91 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([NH:22]C(=O)OC(C)(C)C)[CH:20]=5)[NH:15][C:14]4=[O:30])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:30])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:43][CH:42]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1(CC1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(-c3n[nH]c4cc([C@@H]5C[C@@]56C(=O)Nc5ccc(N)cc56)ccc34)cc2)CC1
Reaction time: 1 h
Yield: 5.1 %

Procedure:
The Suzuki coupling was executed according to the method in Example A45, except substituting tert-butyl 2-(3-iodo-1H-indazol-6-yl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-ylcarbamate (70 mg, 0.136 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (57 mg, 0.190 mmol). The resulting product was was dissolved into CH2Cl2 (1.0 mL) and TFA (50 uL) was added. After 1 h the reaction was complete, the solvent was removed and the residue purified by prep-HPLC to give a white powder (3.2 mg, 15%); 1H NMR (400 MHz, CD3OD) δ 7.94 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.53 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.05-7.02 (m, 3H), 6.04 (s, 1H), 4.01-3.97 (bs, 2H), 3.75-3.65 (bs, 2H), 3.46 (t, J=8.4 Hz, 1H), 3.32-3.28 (bs, 2H), 3.18-3.08 (bs, 2H), 3.00 (s, 3H), 2.35-2.31 (m, 1H), 2.29-2.25 (m, 1H); MS ESI [M+H]+ 465.1, calcd for [C28H28N6O+H]+ 465.24.
Reaction SMILES: C1(C)C=CC=CC=1.I[C:9]1[O:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=1.[CH2:20]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[C:21]1([CH2:20][N:27]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:9]2[O:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1oc(I)nc1C
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1oc(N(Cc2ccccc2)Cc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A reaction vessel fitted with a calcium sulfate drying tube was charged with 5 ml of toluene, 0.56 g (2 mmol) of ethyl 2-iodo-4-methyl-5-oxazolecarboxylate and 2 ml (10 mmol) of dibenzylamine. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then heated at reflux for 4 hours, cooled, and then diluted with ethyl ether. The mixture was washed with water, then with 5% hydrochloric acid, and then with water. The ether solution was dried with sodium sulfate and then concentrated under reduced pressure to yield 0.4 g of a yellow glass. This glass was dissolved in hot hexane and then with the vessel cooling in a dry ice bath, a white solid material was deposited. The solid material was filtered off giving 0.35 g of product (m.p.=75°-77° C.) identified in Table I.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([NH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:38])([F:37])[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][C@@H:34]([NH2:36])[CH3:35])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([S:8][CH2:9][C@H:10]([NH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[C:11](=[O:13])[NH:36][C@@H:34]([CH3:35])[CH2:33][NH:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:37])[F:38])=[CH:31][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](CSCc1ccccc1)NC(=O)N1CCOCC1
Reactant: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CSCc1ccccc1)NC(=O)N1CCOCC1
Yield: 6.4 %

Procedure:
3-Benzylsulfanyl-2-(R)-[(morpholine-4-carbonyl)-amino]-propionic acid (182 mg, 0.56 mmol, 1.2 eq.), N1-(4-Trifluoromethoxy-phenyl)-(S)-propane-1,2-diamine from Scheme 1a (110 mg, 0.47 mmol, 1.0 eq.), and HATU (185 mg, 0.56 mmol, 1.2 eq.) were dissolved in CH2Cl2 (2 mL) at room temperature. DIPEA (245 μL, 1.41 mmol, 3.0 eq.) was added via syringe and the resulting mixture was monitored by LC/MS to completion. After the reaction was complete, the solvent was evaporated and directly purified by mass-directed HPLC and provided 22 mg (0.03 mmol, 5%) of a off-white solid (mono-TFA salt): HPLC-MS calcd. for C25H31F3N4O4S (M+H+) 541.2. found 541.3.
Reaction SMILES: Br[C:2]1[C:11](Br)=[C:10]([N+:13]([O-])=O)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:16]([OH:18])=[O:17].[H][H]>[Pd].O>[NH2:13][C:10]1[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]([C:16]([OH:18])=[O:17])=[CH:2][CH:11]=1
Reactant: [H][H]
Reactant: O=C(O)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Agent: [Pd]
Solvent: O
Product: Nc1ccc(C(=O)O)c2c1OCCO2
Temperature: 50 °C
Yield: 83.7 %

Procedure:
400 ml of water, 98.5 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid, 100 ml of soda and 10 g of Pd/c were introduced into an autoclave and then hydrogen under a pressure of 40 kg/cm2 was introduced while heating to 50° C. The mixture was filtered and then treated with 95 ml of hydrochloric acid. The precipitate was dried off, washed and dried. 42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 186° C.; yield: 83.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:17]C)(OC)[CH2:13][OH:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:19]I.[OH-].[K+].S(=O)(=O)(O)O>O.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=[O:17])[CH2:13][O:14][CH3:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(CO)(OC)C1(c2ccc(Cl)cc2)CCC1
Reactant: CI
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 0.08 h

Procedure:
2-[1-(4-Chlorophenyl)cyclobutyl]-2,2-dimethoxyethanol (1.48 g) and then methyl iodide (1.86 g) were added to a mixture of powdered potassium hydroxide (1.23 g) and dry dimethylsulphoxide (10 ml) which had been stirred for 5 minutes. The mixture was stirred for 30 minutes and was then poured into water (100 ml). The resulting mixture was acidified with concentrated sulphuric acid and extracted with dichloromethane. The extract was washed with water and dried and then evaporated to give 1-[1-(4-chlorophenyl)cyclobutyl]-2methoxyethanone as an oil.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:15])=[O:14]
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Product: CS(=O)(=O)c1ccccc1-c1cccn2nc(N)nc12

Procedure:
8-(2-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.50 g, 2.3 mmol) and 2-(methylsulfonyl)phenylboronic acid (0.56 g, 2.8 mmol) in a manner analogous to Step 2c. The reaction product was isolated as a pale yellow solid (0.249 g, 37%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.56 (d, J=6.6 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.36 (d, J=7.1 Hz, 1H), 6.93 (d, J=6.9 Hz, 1H), 5.99 (s, 2H), 3.16 (s, 3H). MS=289 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccc(Cl)cc3)ccc2c1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
7-(4-Chloro-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.22 mmol) and CuCN (39 mg, 0.44 mmol) were suspended in DMF (1.0 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/CH2Cl2) to give the title compound in 65 mg. MS: (−) m/z 353.25 (M−1).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)C.[OH-].[K+].C(O)C>O>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:7]1[N:6]([CH2:5][C:4]([OH:21])=[O:3])[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=1
Reactant: CCOC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccccn2)nc2cccnc21
Yield: 95.3 %

Procedure:
A solution of 2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (18.0 g, 0.064 mole), potassium hydroxide pellets (5.6 g, 0.100 mole), 95% ethanol (250 ml) and water (10 ml) was refluxed for 11/2 hr. The solution was evaporated to 1/3 volume and then diluted with water (50 ml) and acidified with glacial acetic acid. Water (200 ml) was added and the mixture filtered after precipitation was complete, giving 15.5 g (96%) of a granular solid. Recrystallization of a 2.0-g portion twice from ethanol-water gave 1.5 g of an off-white granular solid, mp 224°-225° C. with decomposition.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])[C@@H:9]([NH2:14])[CH2:10][CH:11]([CH3:13])[CH3:12].CN1C=CC(NC(=O)[C@@H](N2[CH2:33][C:32]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])[CH:36]=3)=[CH:31][C:30]2=[O:46])CC(C)C)=N1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])[C@@H:9]([N:14]1[CH2:33][C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][C:42]([OH:45])([CH3:43])[CH3:44])[CH:36]=2)=[CH:31][C:30]1=[O:46])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Reactant: CC(C)C[C@H](N)C(=O)Nc1cnccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)C[C@@H](C(=O)Nc1cnccn1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 100 °C
Yield: 22.5 %

Procedure:
A mixture of (S)-2-amino-4-methyl-pentanoic acid pyrazin-2-ylamide (prepared as in Example 245, 0.400 g, 1.92 mmol), (E)-4-bromo-3-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (prepared as in Example 235, 0.462 g, 1.29 mmol) and N,N-diisopropylethylamine (0.734 g, 5.69 mmol) in acetonitrile (16.6 mL) were sealed in a tube and heated at 100° C. for 12 h. The mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL) and the phases separated. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), sealed in an Emry Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 5% to 35% ethyl acetate/hexanes) to afford (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (127 mg, 22%) as a tan solid: HR-ES-MS m/z calculated for C24H30N4O4 [M+H]+ 439.234, observed 439.2341; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.9 Hz, 3H), 0.93 (d, J=6.9 Hz, 3H), 1.04 (s, 6H), 1.39-1.70 (m, 2H), 1.72-1.87 (m, 1H), 2.66 (s, 2H), 4.21 (d, J=18.4 Hz, 1H), 4.36 (s, 1H), 4.55 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.02 (dd, J=10.9, 4.5 Hz, 1H), 6.94-7.19 (m, 3H), 7.34 (t, J=7.5 Hz, 1H), 8.36 (d, J=2.7 Hz, 1H), 8.41 (d, J=1.5 Hz, 1H), 9.26 (s, 1H), 11.16 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:23][N:22]=[C:21]([O:24][C:25]3[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][C:26]=3[Cl:36])[CH:20]=2)=[CH:15][CH:14]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:23]1[C:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:20][C:21]([O:24][C:25]2[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][C:26]=2[Cl:36])=[N:22]1)=[O:11])[CH3:8]
Reactant: FC(F)(F)c1cc(Cl)c(Oc2cc(-c3ccc(Cl)cc3)[nH]n2)c(Cl)c1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
Potassium carbonate (0.25 g, 1.8 mmol) and ethyl isocyanate (0.11 g, 1.5 mmol) were added to a solution of 5-(4-chlorophenyl)-3-(2,6-dichloro-4-trifluoromethylphenyloxy)pyrazole (0.61 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a white solid of N-ethyl-5-(4-chlorophenyl)-3-(2,6-dichloro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.39 g, yield: 54.3%). mp: 88-89° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.17 (t, J=7.3 Hz, 3H), 3.30 (dq, J=6.1 and 7.3 Hz, 2H), 5.96 (s, 1H), 6.65-6.85 (m, 1H), 7.30-7.50 (m, 4H), 7.70 (s, 2H).
Reaction SMILES: Cl.[CH3:2][C@@:3]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1>C(O)CCC>[CH2:2]([O:9][C:8]([C@:3]1([CH3:2])[CH2:7][CH2:6][CH2:5][NH:4]1)=[O:10])[CH2:3][CH2:7][CH3:6]
Reactant: C[C@@]1(C(=O)O)CCCN1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)[C@]1(C)CCCN1
Temperature: 60 °C

Procedure:
Concentrated HCl (2 ml) was added to a suspension of (S)-2-methyl-pyrrolidine-2-carboxylic acid (2 g) in butan-1-ol (50 ml) which was heated at 60° C. for 18 h then at reflux for 4 days. The RM was evaporated, partitioned between saturated aqueous NaHCO3 and DCM, extracted 3× with DCM, dried over Na2SO4 and evaporated. The isolated oil was then kugelrohr distilled at 10 mbar to give the title compound as a clear colorless oil from the fraction distilling at an oven temperature of 100-120° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH2:31][C:32]1[CH:36]=[CH:35][NH:34][N:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:31][C:32]2[CH:36]=[CH:35][NH:34][N:33]=2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: Nc1cc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2cc[nH]n2)cc1)Cc1nc2ccccc2[nH]1
Yield: 22.4 %

Procedure:
Using General Procedure B: To a stirred solution of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (199 mg, 0.50 mmol) and 3-aminopyrazole (60 mg, 0.72 mmol) in THF (5 mL) and acetic acid (0.2 mL) was added NaBH(OAc)3 (166 mg, 0.78 mmol) and the resultant mixture stirred at room temperature for 2.5 days. Purification of the crude material by radial chromatography on silica gel gel (2 mm plate, CH2Cl2/MeOH/NH4OH, 100:1:1 then 50:1:1) afforded the desired amine (52 mg, 23%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].NC(N)=[O:13].OO.C(=O)([O-])[O-].[K+].[K+]>C(=O)([O-])[O-].[K+].[K+].CC(C)=O.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: NC(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
The procedure of R. Balicki and L. Kaczmarek, Syn. Comm., 23, 3149 (1993)was used. Into a 1 L round bottom flask equipped with a magnetic stirrer was added acetone (60 mL), water (60 mL) , 2-chloro-6-fluorobenzonitrile (14.5 g, 93.5 mmol), urea (22.5 g, 374 mmol), 30% hydrogen peroxide (42.4 g, 374 mmol), and potassium carbonate (1.3 g, 9.0 mmol). The resulting slurry was stirred at room temperature overnight. Additional portions of urea (11.2 g, 30% hydrogen peroxide (41 g), acetone (30 mL) and potassium carbonate (0.63 g) were added and the mixture was allowed to stir for an additional 2 hr. Additional portions of urea (11.2 g, 30% hydrogen peroxide (41 g), acetone (30 mL) and potassium carbonate (0.63 g) were again added and the mixture was allowed to stir overnight. The acetone was removed in vacuo, the residue extracted with methylene chloride, the organics were combined, washed with brine, dried (MgSO4) and the solvent removed in vacuo to give 15.8 g (97.5% yield) of 2-chloro-6-fluorobenzamide (97% pure by GC): mp140-141° C.; 1H NMR (CDCl3) d 7.2-7.4 (m, 2H), 7.0 (m, 1H), 6.3 (s, b, 1H), 5.9 (s, b, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[CH2:23](Br)[C:24]#[CH:25].[OH-].[K+]>C(O)C.O>[CH2:25]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1)[C:24]#[CH:23]
Reactant: C#CCBr
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCN1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (300 mg) in ethanol were added propargyl bromide (2.0 g) and potassium hydroxide (570 mg) in water at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. After ethanol was distilled off, water was added to the residue, and the resultant mixture was extracted with chloroform. The chloroform extract was dried, evaporated and chromatographed to afford 5-(4-propargylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as crystalline material. M.P., 124°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][C:36]=1[F:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:34]2[CH:33]=[CH:32][C:31]([F:30])=[C:36]([F:37])[CH:35]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(F)c(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)c(F)c3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,4-difluorophenol: ESMS m/e: 526.8 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(CC)CC>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (4.18 g, 20.0 mmol), morpholine (2.09 g, 24.0 mmol), Et3N (6.07 g, 60.0 mmol) and EtOAc (30 mL) was stirred at rt for 5 h. The mixture was then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (5.0 g, 91%).