Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:15])[CH2:9]OS(C)(=O)=O)=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:16][C:6]1[C:7]2[CH:8]([CH3:15])[CH2:9][N:24]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: CC(COS(C)(=O)=O)c1c(Cl)ncnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(CN2CC(C)c3c(Cl)ncnc32)cc1
Yield: 100.4 %

Procedure:
To a solution of methanesulfonic acid 2-(4,6-dichloro-pyrimidin-5-yl)-propyl ester (0.54 g, 1.89 mmol) in DCM (30 mL) and TEA (4 mL) was added 4-methoxybenzyl amine (0.80 g, 5.83 mmol). The mixture was refluxed overnight. After cooling, the solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to give 4-Chloro-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.55 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 8.24 (s, 1H), 7.17 (d, J=7.6 Hz, 2H), 6.86 (d, J=7.6 Hz, 2H), 4.55 (s, 2H), 3.80 (s, 3H), 3.66 (m, 1H), 3.37 (m, 1H), 3.07 (m, 1H), 1.31 (dd, J=7.2 Hz, J=1.2 Hz, 3H). MS (APCI+) [M+H]+291.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=4[Cl:26])[N:12]=[CH:11][C:10]=3[N:9]3[CH:27]=[N:28][N:29]=[C:8]3[C@H:7]2[CH2:30][CH3:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1NC=CN=1)([C:34]1[NH:35]C=CN=1)=O>CN(C=O)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21]([NH:35][CH3:34])=[O:22])=[CH:19][C:18]=4[Cl:26])[N:12]=[CH:11][C:10]=3[N:9]3[CH:27]=[N:28][N:29]=[C:8]3[C@H:7]2[CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Nc3ccc(C(=O)O)cc3Cl)nc2N1C1CCCC1
Solvent: CN(C)C=O
Product: CC[C@@H]1c2nncn2-c2cnc(Nc3ccc(C(=O)NC)cc3Cl)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
4-((R)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-ylamino)-3-chlorobenzoic acid (1-3) (27 mg) was dissolved in DMF (0.4 ml) and treated with carbonyl diimidazole (12 mg, 0.077 mmol) and the mixture stirred at RT for 90 min. The solution was cooled in an ice bath and methylamine gas bubbled in for 2 min. The mixture was stirred at RT for 2 hours, evaporated under reduced pressure and purified by chromatography to give 4-((R)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-ylamino)-3-chloro-N-methylbenzamide (15 mg) as a colourless solid.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.N(OCCCC)=O.CCOCC.[F:24][B-](F)(F)F.[H+]>C(O)C>[F:24][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: F[B-](F)(F)F
Agent: CCCCON=O
Agent: [H+]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)c1ccc(F)cn1
Temperature: -3 °C

Procedure:
The methyl 5-aminopicolinate (2.2 g) is dissolved in 5.5 ml 48% fluoroboric acid and 20 ml 95% ethanol. This mixture is cooled, with stirring, to -3° C. and then 1.81 g n-butyl nitrite added dropwise. After a further one-half hour at -3° C., 0.5 ml n-butyl nitrite is added slowly and stirring continued for one-half hour at 0° C. After adding 20 ml ether carefully, the mixture is rapidly filtered, and the solid washed twice with cold hexane. The solid is suspended in 100 ml heptane, and the suspension slowly heated with stirring. At about 60° C., a vigorous exothermic reaction occurs. Heating is then continued to 80° C. A red oil separates on the sides of the flask. The heptane solution is filtered, and the filtrate concentrated to give the desired product. The red oil is dissolved in water, excess sodium bicarbonate solution added, and the solution extracted with ethyl acetate. The ethyl acetate extract is washed with saturated brine, dried and concentrated. The residue is chromatographed on silica gel and the product, methyl 5-fluoropicolinate, eluted with 1:1-ether:hexane. This material is used directly for the preparation of the picolinic acid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].Cl.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aluminum chloride (1.23 g) was added to a solution of 7-bromoheptanoyl chloride (2 g) in benzene (20 ml) under ice-cooling, which was followed by stirring at room temperature for 1 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography to give 0.93 g of 7-bromo-1-phenyl-1-heptanone.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])=[N:4][C:5]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[N:6][C:7]=1[CH3:8].[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(CC)CC)C>C(#N)C.CN(C)C1C=CN=CC=1>[C:37]([O:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:18]=[CH:17][C:16]([N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][C:5]4[N:4]=[C:3]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[C:2]([OH:1])=[C:7]([CH3:8])[N:6]=4)[CH2:11][CH2:12]3)=[CH:21][CH:20]=2)=[CH:23][CH:24]=1)(=[O:39])[CH3:38]
Reactant: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)NCC(=O)O)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OCc1ccc(-c2ccc(N3CCC(Cc4nc(C)c(O)c(C(=O)NCC(=O)O)n4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.1 %

Procedure:
({[5-Hydroxy-2-{(1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid (0.13 g, 0.27 mmol) was dissolved in acetonitrile (8 mL), and acetic anhydride (0.063 mL, 0.67 mmol), triethylamine (0.092 mL, 0.66 mmol) and 4-dimethylaminopyridine (0.081 g, 0.66 mmol) were added, followed by stirring at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: dichloromethane/methanol), and a fraction corresponding to the Rf value=0.20 (dichloromethane/methanol=9/1) by thin layer chromatography was concentrated under reduced pressure. A mixed solvent of ethanol and water was added to the residue, whereby a solid was deposited. The resulting solid was collected by filtration, and dried under reduced pressure to afford the title compound (0.070 g, 0.13 mmol) as a pale yellowish white solid (yield 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[NH:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CC1C=CC(C(C)C)=CC=1.ClCCl.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2[nH]c3ccc(OC)cc3c2C1
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2[nH]c3ccc(OC)cc3c2c1
Temperature: 190 °C

Procedure:
A solution of 6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid ethyl ester (3.29 g, 12.1 mmol) in p-cymene (12 mL) was treated with palladium (10% on carbon, 2.25 g) and heated at 190° C. for 20 hours. The mixture was then cooled, diluted with dichloromethane and filtered over a pad of diatomaceous earth. The filtrate was concentrated in vacuo to a low volume and heptane (200 mL) was added to precipitate the title compound as a white solid (2.78 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:4]([O-])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].CS([Cl:21])(=O)=O.COCCOC>ClCCl>[Cl:21][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 15 °C

Procedure:
32.8 g (137 mmol) of 4,5-dimethyl-2-p-tolyloxazole 3-oxide hydrochloride were suspended in 165 ml of dichloromethane. 17.5 g (151 mmol) of methanesulfonyl chloride were added. The reaction was stirred at reflux up to full conversion (HPLC). Subsequently, 200 ml of ethylene glycol dimethyl ether were added, and the dichloromethane was distilled off under reduced pressure. The reaction mixture was cooled to 15° C. and 250 ml of water were added. The mixture was stirred at 15° C. for 1 hour. The precipitated product was isolated by filtration with suction, washed with water and dried at elevated temperature under reduced pressure.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>O>[N:40]1([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([O:20][C:21]4[C:22]([CH3:31])=[N:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:32][CH3:33])[CH:44]=[CH:43][N:42]=[CH:41]1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCn1ccnc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 57.4 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and imidazole (26 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 57%).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Na].[C:6]([C:8]1[CH:9]=[CH:10][C:11](I)=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])#[N:7]>[Cu]Br>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:4][CH:1]([CH3:3])[CH3:2])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])#[N:7]
Reactant: CC(C)O
Reactant: N#Cc1ccc(I)c(C(=O)O)c1
Agent: [Cu]Br
Agent: [Na]
Product: CC(C)Oc1ccc(C#N)cc1C(=O)O
Temperature: 120 °C
Yield: 55 %

Procedure:
To 198 mmol isopropanol was added 19.8 mmol sodium and the mixture was then heated at 100° C. until all the sodium was dissolved (30 min.). Susbsequently, 6.59 mmol 5-cyano-2-iodobenzoic acid [CAS: 219841-92-6; WO9901455] and 1.32 mmol copper (I) bromide were added and the reaction mixture heated at 120° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was suspended in 50 ml 1 M aq HCl and extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. Flash chromatography on silica gel (eluant: heptane/ethyl acetate) provided the title compound as a white solid (yield 55%). MS (m/e): 204.1 ([M−H]−, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][CH:12]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][N:13]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:12]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cc(F)ccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccccc2)CCc2c1[nH]c1cc(F)ccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 8-fluoro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and benzoyl chloride; 1H-NMR (CDCl3): δ 10.57 (1H, br s), 8.05 (1H, s), 7.55 (3H, m), 7.45 (3H, m), 7.05 (1H, dd), 6.87 (1H, m), 4.22 (4H, m), 3.24 (2H, t), 1.2 (3H, t); MS (ES): 379 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>O1CCCC1>[N:1]1([C:8](=[O:9])[CH2:7][C:6](=[O:10])[CH3:5])[CH2:4][CH2:3][CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: C1CNC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
A solution of 18.00 g (0.31 mol) azetidine in 50 ml tetrahydrofuran was added dropwise to a solution of 25.00 g of diketene (0.30 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 26.45 g (0.19 mol, 63% yield) of a white solid.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24]C(=O)C2C=CC=CC=2)=[N:9]3)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.Cl.CON>C(O)C>[NH2:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:9]=1
Reactant: N#Cc1ccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)s1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1ccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(N)=N3)s1
Temperature: 55 °C
Yield: 85.8 %

Procedure:
To N-[(4aR,7aR)-7a-(5-cyanothiophen-2-yl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (442 mg, 0.951 mmol) in ethanol (19 mL) is added pyridine (752.6 mg, 9.5 mmol) and O-methylhydroxylamine HCl (794.6 mg, 9.5 mmol). The mixture is heated to 55° C. under an atmosphere of nitrogen for 12 hours. The mixture is concentrated, dissolved in dichloromethane and concentrated again. The residue is dissolved in ethyl acetate and water and washed with saturated aqueous NaHCO3. The phases are separated and the aqueous phase extracted with ethyl acetate (30 mL). The organic phases are combined, dried over Na2SO4, filtered, and concentrated. The residue is purified with silica gel chromatography eluting with a 70:30 to 0:100 hexane/ethyl acetate gradient. The isolated product is repurified with silica gel chromatography eluting with 70:30 dichloromethane/ethyl acetate for 20 minutes and then a gradient to 0:100 to give the title product (294 mg, 86%). ES/MS (m/e): 361 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])[CH:2]([CH3:4])[CH3:3].NC(N)=[O:18].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:5][C:6]1[CH:7]=[N+:8]([O-:18])[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NC(N)=O
Reactant: COC(=O)c1cncc(OCC(C)C)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cc(OCC(C)C)c[n+]([O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 127.5 %

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 5-isobutoxynicotinate (5.13 g), urea-hydrogen peroxide adduct (4.84 g) and acetonitrile (82 mL) was added trifluoroacetic anhydride (8.25 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was filtered, and washed with acetonitrile. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound (7.04 g) as a white amorphous solid. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][CH2:13]O)=[CH:10][C:4]=2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:15])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc2c(c1)OC(F)(F)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC1(F)Oc2ccc(CCCBr)cc2O1
Yield: 89.7 %

Procedure:
Compound 87-2 (3.54 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (4.73 g) and N-bromosuccinimide (3.21 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (4.10 g) as a colorless oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]12[O:23][CH:15]1[CH2:16][C:17]1[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[OH:23][C@@H:15]1[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:14]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: c1ccc2c(c1)CC1OC21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN([C@@H]2c3ccccc3C[C@H]2O)CC1
Temperature: 60 °C

Procedure:
11.6 g of tert-butyl piperazine-1-carboxylate (62 mmol) and 8.2 g of indene oxide (62 mmol) are dissolved in 30 ml of acetonitrile. The reaction mixture is then heated at 60° C. overnight and evaporated to dryness. The residue obtained is purified by flash chromatography on 1 kg of silica (eluant: dichloromethane/ethanol 95/5) to yield tert-butyl trans-4-(2-hydroxy-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate in the form of a white meringue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.63 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.90 g, 4.8 mmol). The resulting free base was isolated as a white foam. Yield 1.04 g (55%). mp 95-100° C. FDMS m/e=405 (M+ of free base). α[D]589=5.91 (c=1.01, dimethylsulfoxide).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:56][C:49]([C:50]([NH:52][N:53]([CH3:55])[CH3:54])=[O:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:56][C:49]([C:50]([NH:52][N:53]([CH3:55])[CH3:54])=[O:51])=[CH:48][CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN(C)NC(=O)c1ccc(N)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)NN(C)C)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-amino-N′,N′-dimethylbenzohydrazide as the aniline component. (37%, MS=556.3 (M+H))
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=1.CN(C)C=O.C(Cl)(=O)C([Cl:26])=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([Cl:26])=[O:17])=[CH:11][CH:10]=1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1-c1ccc(C(=O)Cl)cc1

Procedure:
A stirred solution of 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid of Step A (0.790 g, 3.5 mmol) in dichloromethane (15 mL) was treated under nitrogen with a catalytic amount of N,N-dimethylformamide followed by dropwise addition of 2N oxalyl chloride in dichloromethane (2.8 mL). After the gas evolution ceased the mixture was refluxed for 4 hours, cooled, and evaporated. The residue was azeotroped twice with benzene and dried in vacuo to provide 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride. The crude 2′,6′-dimethyl-1,1′-biphenyl-4-carboxylic acid chloride (0.856 g, 3.5 mmol) was dissolved in dichloromethane (7 mL) and added dropwise to a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 12 (0.450 g, 1.41 mmol) in anhydrous tetrahydrofuran 10 mL) containing N,N-diisopropylethyl amine (0.860 mL). The mixture was stirred for 18 hours at room temperature and evaporated to dryness. The residue was dissolved in dichloromethane, the solution washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed over silica gel Merck-60 eluting with a gradient from 0 to 4% methanol in 1:1 hexane-ethyl acetate to provide the title compound (0.452 g) as a white solid after trituration with hexane, m.p. 216-218° C. (dec).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:25])[S:8]([N:11]1[CH:15]=[C:14]([CH2:16][C:17]([CH3:24])([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH2:19])[N:13]=[CH:12]1)(=[O:10])=[O:9].[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40](OC)=[O:41])=[CH:35][CH:34]=2)=[N:31][CH:32]=1>O1CCCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40]([C:12]3[N:11]([S:8]([N:7]([CH3:6])[CH3:25])(=[O:10])=[O:9])[CH:15]=[C:14]([CH2:16][C:17]([CH3:24])([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH2:19])[N:13]=3)=[O:41])=[CH:35][CH:34]=2)=[N:31][CH:32]=1
Reactant: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)cn1)C(F)(F)F
Reactant: COC(=O)Cc1ccc(-c2ccc(F)cn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Temperature: -10 °C
Reaction time: 3 h

Procedure:
n-Butyllithium (1.6 M in hexane) (4.19 mL, 6.7 mmol) was added to a −78° C. solution of N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide (Intermediate 4) (1.74 g, 5.59 mmol) in tetrahydrofuran (6 mL). After warming to −10° C. over 1 h, methyl [4-(5-fluoropyridin-2-yl)phenyl]acetate (1.14 g, 5.59 mmol) in tetrahydrofuran (6 mL) was added and the reaction allowed to warm to ambient temperature. After stirring at ambient temperature for 3 h, the reaction mixture was quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 2-{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide.