Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O.C(COC)OC>C(O)C>[Cl:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]2[N:3]([CH:14]=[C:12]([CH2:11][Cl:10])[N:1]=2)[CH:4]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: O=C(CCl)CCl
Solvent: CCO
Solvent: COCCOC
Product: ClCc1cn2cc(Cl)cc(Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 2-amino-3,5-dichloropyridine (Aldrich; 5.12 g), 1,3-dichloroacetone (Aldrich; 4.68 g), and dimethoxyethane (28 mL) is stirred overnight at room temperature. Ethanol (28 mL) is then added and the mixture is refluxed for 7.5 h and then stirred overnight at room temperature. The mixture is then refluxed for an additional 24 h and is then concentrated under reduced pressure and partitioned between saturated aq. sodium bicarbonate and dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is adsorbed to silica gel and chromatographed on silica gel using ethyl acetate/chloroform (10/90), followed by a second chromatography of the combined product fractions using methanol/dichlormethane (2/98), to give 2.22 g of 6,8-dichloro-2-(chloromethyl)imidazo[1,2-α]pyridine in three crops after crystallization from methanol/dichloromethane; mp 162-163° C.; MS m/z 234, 236, 238; IR (mineral oil) 994, 808, 861, 1522, 3056 cm-1 ; 1H NMR (CDCl3) δ4.79, 7.69, 8.10.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O.O>[CH2:3]([O:10][N:11]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=1)=[O:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCc1ccc(NC(=O)NOCc2ccccc2)cc1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCN(OCc1ccccc1)C(=O)Nc1ccc(CCCC)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Sodium hydride (0.14 g of 80% in mineral oil, 4.7 mmol) was added to a solution of 1-benzyloxy-3-(4-butylphenyl)urea (1.25 g, 4.2 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was heated briefly on a steam bath under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature then 1-bromopentane (0.63 g, 4.2 mmol) was added. The reaction mixture was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with water and then extracted with diethyl ether. The organic layer was washed with water, dried with magnesium sulfate and then concentrated to provide 1.47 g of crude product as a brown oil. This material was purified by flash chromatography (silica gel; 1:19 ethyl acetate:hexanes) to provide 0.96 g of 1-benzyloxy-3-(4-butylphenyl)-1-pentylurea as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[N:7]=[N:8][N:9]([C:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[N:10]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C(=O)N([Br:38])C(=O)C1>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([Br:38])[C:6]1[N:7]=[N:8][N:9]([C:11]([CH3:19])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[N:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nnn(C(C)(C)c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)c1nnn(C(C)(C)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
A solution of [2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-acetic acid ethyl ester (Norman, D. P. G. et al JOC 1999, 64, 9301-9306) (2.53 g, 9.23 mmol) in THF (50 mL) stirring at −78° C. under N2 is treated with a 1 M soluion of NaHMDS in THF (9.23 mL) followed by NBS (1.64 g, 9.23 mmol). After 15 min, the reaction mixture is quenched by the slow addition of water and diluted with EtOAc. The organic layer is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. The reaction mixture is purified by flash column chromatography eluted with 9:1 hexanes:EtOAc, then 2:1 hexanes:EtOAc, and finally flushed with EtOAc. The desired product, bromo-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-acetic acid ethyl ester, is recovered contaminated with 30% dibromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][CH:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:31]([CH:29]([CH3:30])[CH3:28])(=[O:33])=[O:32])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: CC(C)S(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 39 %

Procedure:
According to the procedure for compound 398 using 2-propanesulfonyl chloride (82 mg, 0.57 mmol) afforded 17.9 mg (39% yield) of 400, as a solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3].[C:14](N1C=CN=C1)(N1C=CN=C1)=O.CO>C1COCC1>[CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CS(=O)c1cccc(CC(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1cccc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
A solution of [3-(methylsulfinyl)phenyl]acetic acid (1.31 g, 6.60 mmol) and carbonyldiimidazole (1.18 g, 7.26 mmol) in 25.0 mL THF was stirred at room temperature for 15 minutes, then methanol (2.1 mL, 52.8 mmol) was added. After 10 minutes the reaction was briefly warmed to near reflux temperature, then allowed to cool to room temperature. After 20 minutes, the reaction was partitioned between EtOAc and NaHCO3/brine mixture. The EtOAc layer was washed with dilute brine, dilute HCl solution, brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as a yellow-orange oil (1.14 g, 82%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[S:18])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][O:22][CH3:23].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][S:18][C:10]1[NH:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COCCBr
Reactant: S=C1NN=C(c2ccccc2)C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCSc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 4 h
Yield: 73.2 %

Procedure:
To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.5 g, 1.981 mmol) in DMF (5 mL), were added 1-bromo-2-methoxyethane (0.275 g, 1.981 mmol) and K2CO3 (0.274 g, 1.981 mmol) at room temperature. After stirring for 4 h, the reaction was poured into water and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (0.45 g). LCMS m/z=311.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23 (s, 3H), 3.12-3.54 (m, 4H), 7.22-7.49 (m, 10H), 13.2 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH:5]([CH:14]1[CH2:16][CH2:15]1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[OH-].[K+].[CH2:20](O)C>>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([CH:14]1[CH2:15][CH2:16]1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:20])=[CH:11][CH:12]=1
Reactant: CN(C)CCC(Oc1ccc(O)cc1)C1CC1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(OC(CCN(C)C)C2CC2)cc1
Reaction time: 1 h

Procedure:
A mixture of 23.5 g of 1-dimethylamino-3-cyclopropyl-3-p-hydroxyphenoxy-propane, 100 ml of absolute ethanol and 200 ml of 0.5N ethanolic KOH is stirred for one hour at 20° and evaporated. The residue is dissolved in 250 ml of absolute DMF. 12.6 g of dimethyl sulphate is added in portions, with stirring. The mixture is boiled for two hours and evaporated; the residue is subjected to the customary working up; and 1-dimethylamino-3-cyclopropyl-3-p-methoxyphenoxy-propane is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[S:26][C:14]3[N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:21])[N:17]([CH3:20])[C:18](=[O:19])[C:13]=3[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[S:26][C:14]3[N:15]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:21])[N:17]([CH3:20])[C:18](=[O:19])[C:13]=3[CH:12]=2)=[CH:6][CH:5]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccc([N+](=O)[O-])cc3)sc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccc(N)cc3)sc21
Temperature: 90 °C
Yield: 7.9 %

Procedure:
To a solution of 6-(4-nitrophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H, 3H)-dione (275 mg) in ethanol (15 ml) and water (1 ml) was added iron powder (82 mg) and ammonium chloride (78 mg). The mixture was heated at 90° C. for 6 h. and then allowed to cool to room temperature. The reaction was filtered and then evaporated before being partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, and then evaporated. The resultant oil was purified by normal phase HPLC (isohexane:ethyl acetate 80-0:20-100) to give the title compound (20 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:14]=4[N:13]([CH3:20])[C:12]=3[C:21]([OH:23])=O)=[C:6]([F:24])[CH:5]=2)[CH2:3][CH2:2]1.[CH:25]([O:27][CH2:28][CH2:29][O:30][NH2:31])=[CH2:26].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>C1COCC1>[CH:25]([O:27][CH2:28][CH2:29][O:30][NH:31][C:21]([C:12]1[N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:24])=[O:23])=[CH2:26]
Reactant: C=COCCON
Reactant: Cn1c(C(=O)O)c(Nc2ccc(C3CC3)cc2F)c2cnccc21
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: C1CCOC1
Product: C=COCCONC(=O)c1c(Nc2ccc(C3CC3)cc2F)c2cnccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
A suspension of 3-(4-cyclopropyl-2-fluoro-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (88 mg, 0.25 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (028 mg, 0.28 mmol), HATU (114 mg, 0.30 mmol) and DIPEA (0.052 ml, 0.30 mmol) in THF (3 ml) was stirred at ambient temperature for 18 hours. On completion of the reaction, the mixture was concentrated in vacuo then re-dissolved in DCM. The solution was washed with saturated aqueous NaHCO3 and brine, dried over magnesium sulphate then concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM:MeOH, gradient 99:1 to 90:10) to give a yellow solid (34 mg, 33%). LCMS (method B): RT=2.46 min, M+H+=411. 1H NMR (CDCl3): 8.58 (1H, s), 8.41-8.36 (1H, m), 7.30 (1H, d, J=6.08 Hz), 7.26 (1H, d, J=1.99 Hz), 6.87 (1H, dd, J=8.33, 2.02 Hz), 6.47 (1H, dd, J=8.34, 3.82 Hz), 5.85 (1H, s), 4.11 (3H, s), 3.97-3.90 (2H, m), 3.71 (2H, dd, J=5.23, 3.41 Hz), 2.78 (1H, m), 1.22-1.13 (6H, m).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Cl[CH:15]([C:20]([CH3:22])=O)[C:16]([O:18][CH3:19])=[O:17].[OH-].[Na+]>O1CCCC1>[CH3:22][C:20]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[S:8][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 77.5 °C
Yield: 95.6 %

Procedure:
4-(Trifluoromethyl)thiobenzamide (20.5 g, 0.1 mol) was dissolved in tetrahydrofuran (300 ml) at room temperature, and then methyl 2-chloroacetoacetate (12.2 ml, 0.1 mol, 1.0 eq.) was added slowly for about 20 minutes therein while stirring. After completion of addition, the mixture was stirred again at room temperature for 30 minutes, and then the mixture was heated and refluxed at 75 to 80° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Subsequently, 50% aqueous solution of sodium hydroxide (150 ml) was added and stirred for 20 minutes. The resultant organic layer was separated by extraction with brine and ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to thereby yield 28.8 g of the title compound (yield: 95.6%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Mg].[Br:15][C:16]1[CH:17]=[C:18]([C:23]([C:25]2[CH:30]=[C:29]([Br:31])[CH:28]=[C:27]([Br:32])[CH:26]=2)=O)[CH:19]=[C:20]([Br:22])[CH:21]=1>O1CCCC1.C(COC)OC>[Br:15][C:16]1[CH:17]=[C:18]([C:23]2([C:25]3[CH:30]=[C:29]([Br:31])[CH:28]=[C:27]([Br:32])[CH:26]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]=[C:20]([Br:22])[CH:21]=1
Reactant: O=C(c1cc(Br)cc(Br)c1)c1cc(Br)cc(Br)c1
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Mg]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(C2(c3cc(Br)cc(Br)c3)c3ccccc3-c3ccccc32)c1

Procedure:
The corresponding Grignard compound is prepared from 144.5 g (620 mmol) of 2-bromobiphenyl and 15.3 g (580 mmol) of magnesium in a mixture of 500 ml of tetrahydrofuran and 250 ml of dimethoxyethane. A suspension of 224.0 g (450 mmol) of bis(3,5-dibromophenyl) ketone in 1000 ml of tetrahydrofuran is then added at room temperature, and the mixture is stirred for a further twelve hours. The solvent is removed in vacuo, 1000 ml of glacial acetic acid and 5 ml of hydrogen bromide are added to the residue, and the mixture is stirred for one hour. The suspension is heated under reflux for half an hour and stirred at room temperature for twelve hours. The solid is filtered off with suction, washed three times with 300 ml of ethanol and recrystallised twice from toluene. Yield: 183.2 g (289 mmol), 64.3%, purity about 99.8% (HPLC).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12](Cl)=[O:13])=[CH:8][CH:7]=1>O.CC(C)=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][C:12]([N:1]=[N+:2]=[N-:3])=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(Cl)C=Cc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Sodium azide (67 g, 1 mol) was suspended in a mixture of water and acetone (300 mL, 1:1). The mixture was cooled to 0° C., a solution of compound 3 (126.9 g, 0.52 mol) in dry acetone (400 mL) was added at 5° C. The resulting mixture was stirred at 0-5° C. for 4 h and then poured into water (1.5 L). The precipitate was filtered off, washed with water, dried. Additional drying in vacuo over P2O5 gave 4 (130.3 g, 100%)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[F:14].C[O:16][B:17]([O:20]C)[O:18]C.Cl>CCCCCC.O1CCCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:16][B:17]([OH:20])[OH:18])=[C:8]([F:14])[CH:9]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(Cl)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)Oc1ccc(Cl)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, n-butyllithium (1.6 mol/L-n-hexane, 18.8 mL) was added dropwise at −78° C. to a solution of n-hexane (11 mL) and tetrahydrofuran (30 mL). Then, a solution of 1-bromo-4-chloro-2-fluorobenzene (5.24 g) in n-hexane (15 mL) and tetrahydrofuran (15 mL) was added dropwise. The mixture was stirred at −78° C. for one hour, boric acid trimethyl ester (4.0 mL) in tetrahydrofuran (15 mL) was added dropwise. The mixture was raised to room temperature. After 2 hr, aqueous hydrochloric acid solution (3 mol/L, 120 mL) was added, and the mixture was extracted with diethyl ether (100 mL). The aqueous layer was extracted again with diethyl ether (100 mL), and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure, n-hexane was added to the residue, and the precipitated solid was collected by filtration to give the title compound (2.0 g) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7]Cl.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]>CN(C)C=O>[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]
Reactant: O=C1CCCCN1
Reactant: ClCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1CCCCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (3.87 g of 50% dispersion in oil, 0.0807 mole) was suspended and stirred in 80 ml of dry dimethylformamide. A solution of 1,4-dichlorobutane (44 ml, 0.404 mole) and 2-piperidone (8 g, 0.0807 mole) in 100 ml of dimethylformamide was added dropwise over 1 hour, maintaining the temperature at 25°-30° C. by use of a water bath. The reaction mixture was stirred for 16 hours at room temperature, then byproduct salt removed by filtration and the mother liquor evaporated in vacuo to one-tenth volume. The resulting concentrate was distributed between 100 ml of water and 100 ml of hexane. The lower, oily phase of three phases was separated, diluted with 50 ml of methylene chloride, dried over magnesium sulfate, filtered and evaporated to yield 1-(4-chloro-1-butyl)-2-piperidone as an oil [14.3 g; pnmr(CDCl3) delta 1.4-1.83 (4H, m), 3.03-3.72 (6H, m), 4.10-4.43 (2H, t, J=7)].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[C:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8]1)[CH:22]=[CH2:21]
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Yield: 19.4 %

Procedure:
Prepared according to Method D step B from 7-methyl-3-(4-methoxyphenyl)-1H-indazole (0.112 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and allylbromide (0.086 mL, 1.0 mmol) to give the title compound (0.027 g) as a white solid. Used as is without further characterization.
Reaction SMILES: [CH2:1]1[CH:11]2[C:5](=[N:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10]2=[O:12])[CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.CCCCCC>[CH2:17]([N:9]1[C:10](=[O:12])[CH:11]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]2=[N:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]1=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Nc2ccccc2N=C2CCCCC12
Reactant: BrCc1ccccc1
Solvent: CCO
Solvent: CCCCCC
Product: O=C1C2CCCCC2=Nc2ccccc2N1Cc1ccccc1
Yield: 66 %

Procedure:
Using 1,2,3,4,10,11a-hexahydro-11H-dibenzo [b,e][1,4]diazepin-11-one and benzyl bromide, the titled compound was synthesized in substantially the same procedure as in Working Example 4. Yield 66%. m.p. 123°-125° C. (ethanol-hexane).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[CH3:14][C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:17][N:16]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:14][C:15]1[CH:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:17]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[N:16]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)nn1-c1ccc2ccccc2c1
Reaction time: 48 h
Yield: 70 %

Procedure:
To the solution of 2-naphthylboronic acid (5.00 g, 29.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (4.48 g, 29.1 mmol) in 100 mL dry dichloromethane (DCM) were added pyridine (4.7 mL, 58.2 mmol) and anhydrous powder of copper(II) acetate (7.94 g, 43.7 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 2 days under argon. The mixture was diluted with DCM. It was filtered through a celite bed. The blue filtrate was washed with water (X2), dried over MgSO4, concentrated, purified by silica column to yield ethyl 3-methyl-1-(2-naphthyl)-1H-pyrazole-5-carboxylate and its regioisomer in a 1:1 ratio in 70% yield. Rf 0.59 (1:2 EtOAc: hexane), M+H 281; regioisomer, ethyl 5-methyl-1-(2-naphthyl)-1H-pyrazole-3-carboxylate, Rf 0.44 (1:2 EtOAc:hexane). ES-MS: (M+H)+281.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17](C)C)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.BrC1C=CC([C:25](OC)=[O:26])=C(CBr)C=1.Cl.NC(COC)C(OC)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@@H:12]([CH2:17][O:26][CH3:25])[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: COCC(N)C(=O)OC
Agent: Cl
Product: COC[C@@H](C(=O)OC)N1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 383 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and methyl 2-amino-3-methoxypropanoate hydrochloride.
Reaction SMILES: CCN(CC)CC.I[CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[SH:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[O:36]1[CH2:37][CH2:38][CH:33]([CH2:32][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([S:16][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:18][CH:19]=2)[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[CH2:34][CH2:35]1
Reactant: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S)cc1
Reactant: ICC1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(SCC2CCOCC2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-methoxymethylsulfanylphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 77, 1.29 g, 3.28 mmol) in THF (50 mL) was added to a stirred solution of AgNO3 (0.59 g, 3.28 mmol) in EtOH (85 mL) at 40° C. The mixture was protected from light and stirred at 40° C. for 21 h. The solvents were evaporated off under reduced pressure, then the remaining solid was triturated with i-PrOH (60 mL), THF (60 mL), and Et2O (60 mL). After air-drying, the solid was stirred vigorously with CH2Cl2 (200 mL) and 6M HCl (82 mL) for 4 h under Ar. The layers were separated, then the aqueous phase was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were filtered through Celite, washed with brine (100 mL) and dried (MgSO4). Filtration and solvent evaporation furnished 2-(4-mercaptophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=349.2 [M+H]+. NEt3 (0.14 mL, 1006 μmol) and a solution of 4-iodomethyltetrahydropyran (151 mg, 668 μmol) in anhydrous DMF (3 mL) were added to a stirred solution of this benzenethiol (197 mg, 565 μmol) in anhydrous DMF (7 mL) at 0° C. The mixture was warmed to 20° C., before being stirred for 16 h. The solvents were evaporated off under reduced pressure, then the residue was partitioned between CH2Cl2 (25 mL) and 2% aqueous citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL), then the combined organic layers were washed with H2O (10 mL), saturated aqueous Na2CO3 (10 mL), H2O (10 mL), and brine (10 mL). After drying (MgSO4), filtration and solvent evaporation gave a residue that was subjected to flash chromatography (IH-EtOAc, 3:1 to 0:1) to furnish the title compound: RTA=3.61 min; m/z (ES+)=447.3 [M+H]+.