Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([C:22]([OH:24])=O)=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:22]([C:18]2[C:19]3[CH2:20][CH2:21][N:12]([CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=[CH:2][CH:3]=4)[CH2:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)=[O:24])=[CH:28][CH:27]=1
Reactant: O=C(O)c1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1)c1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
2-(Quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (80 mg, 0.251 mmol) was suspended in N,N-dimethylformamide (1.2 mL) then added 4-chloroaniline (45 mg, 0.351 mmol), 1-hydroxy-7-azabenzotriazole (34 mg, 0.251 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.376 mmol) and N,N-diisopropylethylamine (89 mg, 0.878 mmol). The reaction mixture was stirred at room temperature for two days then concentrated under vacuum. The crude material was purified by silica gel chromatography (50% to 67% ethyl acetate/hexane) to afford N-(4-chlorophenyl)-2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (92 mg) as a white solid. MS (ESI, pos. ion) m/z: 428.1 (M+1).
Reaction SMILES: C(OC([C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=2)=[N:17][CH:18]=[N:19]3)[CH2:9][C@@H:8]1[C:33]([O:35][CH3:36])=[O:34])=O)C=C.[NH2:37][C@@H]1CCN(CC2C=CC=C3C=2C(NC2C=CC=C(OC)C=2)=NC=N3)C[C@H]1C(NC)=O>CO>[NH2:37][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=2)=[N:17][CH:18]=[N:19]3)[CH2:9][C@H:8]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: C#Cc1cccc(Nc2ncnc3cccc(CN4CC[C@@H](C(=O)OCC=C)[C@@H](C(=O)OC)C4)c23)c1
Reactant: CNC(=O)[C@@H]1CN(Cc2cccc3ncnc(Nc4cccc(OC)c4)c23)CC[C@H]1N
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cccc(CN4CC[C@@H](N)[C@H](C(=O)OC)C4)c23)c1

Procedure:
Compound 18B was prepared from 18A in a similar way as 15F. It has an analytical HPLC retention time=1.546 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=416+.
Reaction SMILES: C1(CN(C)C2C=C(O)C(=O)NN=2)CC1.C([O:22][C:23]1[CH:24]=[C:25]([N:37]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH3:38])[N:26]=[N:27][C:28]=1[O:29]CC1C=CC=CC=1)C1C=CC=CC=1>>[CH:40]1([CH2:39][N:37]([CH3:38])[C:25]2[CH:24]=[C:23]([OH:22])[C:28](=[O:29])[NH:27][N:26]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CN(CC1CCCCC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: CN(CC1CC1)c1cc(O)c(=O)[nH]n1
Product: CN(CC1CCCCC1)c1cc(O)c(=O)[nH]n1
Yield: 26 %

Procedure:
Prepared according to the procedure for 6-((cyclopropylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one (Example 37) using 5,6-bis(benzyloxy)-N-(cyclohexylmethyl)-N-methylpyridazin-3-amine (Intermediate 47) but purified by reverse phase C18 chromatography, eluting with 5-100% acetonitrile/water with a 0.1% ammonia modifier in both the water and acetonitrile to give the title compound as a pale cream solid (45 mg, 26%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[CH2:5][O:6][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:9][NH2:10])[CH3:2].C(N(CC)CC)C.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>C(Cl)Cl>[CH2:24]([O:23][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][O:6][C:7]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][NH:10][C:36]([CH:33]1[CH2:35][CH2:34]1)=[O:37])[CH3:25]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(COC(CCN)(c1ccccc1)c1ccccc1)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(COC(CCNC(=O)C1CC1)(c1ccccc1)c1ccccc1)OCC
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows. The solution of 3.4 g of 2-(3-amino-1,1-diphenylpropoxy)-acetaldehye diethyl acetal, 1.5 g of triethylamine and 35 ml of methylene chloride is stirred and cooled in an ice bath during the dropwise addition of the solution of 1.05 g of cyclopropane carboxylic acid chloride in 15 ml of methylene chloride. Upon stirring subsequently for 1/2 hour at 0°-5° C, the solution is washed successively with 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated, to yield the 2-(3-cyclopropylcarbonylamino-1,1-diphenylpropoxy)-acetaldehyde diethyl acetal.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.[CH2:12]([C:18]1[CH:22]=[CH:21][S:20][C:19]=1B1OC(C)(C)C(C)(C)O1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:19]2[S:20][CH:21]=[CH:22][C:18]=2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCc1ccsc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(Br)c2nsnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCc1ccsc1-c1ccc(-c2sccc2CCCCCC)c2nsnc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
4,7-Dibromobenzo[c]-1,2,5-thiadiazole (1.00 g, 3.41 mmol) and 3-hexylthiophene-2-boronic acid pinacol ester (2.10 g, 7.14 mmol) were placed in a 100 mL 3-neck round bottom flask which was flushed with N2 gas for 5 minutes. Dimethoxyethane (20 mL) and water (30 mL) were added and the mixture was purged with N2 gas for 30 minutes. Sodium carbonate (4.23 g, 34.1 mmol) and catalyst Pd(PPh3)4 (0.430 g, 0.372 mmol) were added and the mixture was heated to 100° C. and stirred for 12 hours. The mixture was extracted into hexanes and passed through a silica column, by eluting first with hexanes (200 mL) and then eluting the product with a solution of 5% EtOAc in hexanes (200 mL). The procedure afforded 1.59 g of vibrant orange, 4,7-bis(3-hexylthiophen-2-yl)benzo[c][1,2,5]thiadiazole (Formula 2) in 99% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:5][N:6]=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>O1CCCC1>[C:40]([NH:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:25])=[CH:5][N:6]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4ccccc4)s3)CSC12

Procedure:
On treating 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.5 g) with benzoyl chloride (1.11 cc) in dry tetrahydrofuran (55 cc) in the presence of triethylamine (1.23 cc), using the working method of Example 1 (B), 3-(2-benzamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (1.8 g) is obtained in the form of cream-coloured crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[CH:4]=[N:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>CC1C=CC=CC=1C>[CH2:6]([N:5]1[CH:4]([C:3]2[C:2]([Cl:1])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:17])[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)O1
Reactant: Clc1cccc(Cl)c1C=NCc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(O)C1CC(=O)N(Cc2ccccc2)C1c1c(Cl)cccc1Cl
Reaction time: 5 h

Procedure:
2,6-Dichlorobenzilidene-benzylamine [100 gm. 0.39 mole] and succinic anhydride [39.0 gm. 0.39 mole] were refluxed with O-xylene [500 ml] for 12 hours. On cooling, the precipitate was filtered and washed with a little ethanol. The solid was recrystallized from ethanol to give white needles. After drying over boiling isobutyl methyl ketone and under vacuum for 5 hours, the title compound had a melting point of 179°-181° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2
Reactant: C1CCNC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 163) (200 mg, 0.44 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (99 mg, 44%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1.N1C=CC=CC=1>ClCCl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[S:34]([C:32]1[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=1)(=[O:36])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: c1ccc(CNc2ccc(CN3CCN(c4ccccc4)CC3)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N(Cc2ccccc2)c2ccc(CN3CCN(c4ccccc4)CC3)cc2)c1
Temperature: 25 °C

Procedure:
A solution of benzyl-[4-(4-phenyl-piperazin-1-yl methyl)-phenyl)-amine (30 mg, 0.08 mmol), 1-methylimidazole-4-sulfonyl chloride (51 mg, 0.27 mmol) and pyridine (24 μl, 0.30 mmol) in dry dichloromethane (2 ml) were heated to reflux for 15 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by column chromatography (5% methanol in dichloromethane) to afford the title compound as an off white solid (22 mg, 55%). HPLC retention time 7.04 min. Mass spectrum (ES+) m/z 502 (M+H). 1H-NMR (CDCl3) δH 2.54 (4H, m, 2×CH2), 3.16 (4H, m, 2×CH2), 3.45 (2H, br s, CH2), 3.71 (3H, s, CH3), 4.99 (2H, s, CH2), 6.84 (1H, t, J=7.3 Hz, ArH), 6.89 (2H, m, 2×ArH), 7.10 (2H, m, 2×ArH), 7.17-7.30 (10H, m, 10×ArH), 7.55 (1H, m, ArH).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:32][CH2:33][CH:34]([CH3:40])[C:35]([O:37]CC)=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=3)[N:22]=2)[CH:14]=1)(=[O:3])[CH3:2].[OH-].[Na+].CC(O)=O>CO.C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:32][CH2:33][CH:34]([CH3:40])[C:35]([OH:37])=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=3)[N:22]=2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)CSC(CCc1ccccc1C(C)=O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1CCC(SCC(C)C(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the ester of Step 7 (3.844 g, 6.67 mmol) and 1.0N NaOH (13 mL) in 55 mL of MeOH:THF 3:2 was stirred at r.t. for 24 h. 25% Aq NH4OAc was then added and the mixture was acidified with AcOH. The title acid was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with acetone:toluene:AcOH 5:95:1. Yield 3.491 g, 95%.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1)=[O:2].[CH3:13][C:14](=[N:18]O)[C:15](=O)[CH3:16].[ClH:20].C(OCC)(=O)C>>[Cl:20][CH2:13][C:14]1[N:18]=[C:1]([C:3]2[S:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=2)[O:2][C:15]=1[CH3:16]
Reactant: Cl
Reactant: CC(=O)C(C)=NO
Reactant: CCOC(=O)c1ccc(C=O)s1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2nc(CCl)c(C)o2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
A mixture of ethyl 5-formylthiophene-2-carboxylate (14.6 g), 2,3-butanedione-2-oxime (8.02 g) and 4N hydrogenchloride-ethyl acetate (300 mL) was stirred at room temperature for 15 hrs. The reaction mixture was concentrated, diethyl ether was added to the residue to allow precipitation of crystals, and crystals were collected by filtration. A mixture of the obtained crystal, tetrahydrofuran (500 mL) and thionyl chloride (14.16 g) was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:6, v/v) to give ethyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)thiophene-2-carboxylate as colorless crystals (5.41 g, yield 24%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 101-102° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([F:21])[CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:21])[CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1F
Agent: BrB(Br)Br
Product: Oc1ccc2cc(-c3ccc(O)c(F)c3)cc(F)c2c1

Procedure:
The title compound was prepared by reacting 8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (0.10 g, 0.35 mmol) with boron tribromide (0.7 mL of 1N solution, 0.7 mmol) according to method D to yield 0.020 g (21%) of a white solid: mp 218-220° C. d; 1H NMR (DMSO-d6): δ 7.01-7.07 (1H, m), 7.16-7.19 (2H, m), 7.46 (1H, dd, J=1.74 Hz, J=8.40 Hz), 7.56-7.65 (2H, m), 7.88 (1H, d, J=8.31 Hz), 7.93 (1H, bs), 10.04 (1H, s), 10.11 (1H, s); MS (ESI) m/z 271 (M−H)−.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][C:22](=[O:31])[C:23]4[C:28]([CH:29]=3)=[C:27]([CH3:30])[CH:26]=[CH:25][CH:24]=4)=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(C)(C)C.Cl>C(Cl)Cl>[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][C:22](=[O:31])[C:23]4[C:28]([CH:29]=3)=[C:27]([CH3:30])[CH:26]=[CH:25][CH:24]=4)=[CH:16][CH:15]=2)[CH2:9][CH2:8]1
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCC(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCC(O)CC4)cc3)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.8 %

Procedure:
To a stirred solution of 3-{4-[4-(tert-butyl-diphenyl-silanyloxy)-piperidin-1-ylmethyl]-phenyl}-5-methyl-2H-isoquinolin-1-one (213 mg, 0.36 mmol) in CH2Cl2 (2 mL) was added 1.25M methanolic HCl (1 mL) and the reaction stirred at RT for 48 h. The reaction mixture was concentrated in vacuo and the crude residue purified by reverse phase preparative HPLC-MS to afford 3-[4-(4-hydroxy-piperidin-1-ylmethyl)-phenyl]-5-methyl-2H-isoquinolin-1-one as a pale yellow solid (80 mg, 64%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[C:3]=1[O:31][CH2:32][CH3:33].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[C:3]=1[O:31][CH2:32][CH3:33]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(/C(C)=C(F)\C=C\C(C)=C\C(=O)O)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(4 bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6 fluoro-3-methyl-octa-2,4,6-trienoate (Compound A-158, 860 mg, 1.65 mmol) in ethanol was treated with a solution of 1 N NaOH to produce the title compound after purification by recrystallization from acetonitrile.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>>[Br:1][C:2]1[C:3]([Cl:9])=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(Cl)c(Br)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
5-Bromo-4-chloro-pyridin-2-ylamine (0.640 g, 3.0 mmol) was added in portions to conc. H2SO4 (6 ml) while the temperature kept at −10° C. The reaction mixture was then stirred at −10° C. for 15 min. The resulting solution was then heated at 55° C. and HNO3 (208 μL, 3.2 mmol) was added dropwise while the temperature was kept at 55° C.-60° C. maximum. The reaction mixture was stirred at 55° C. for 30 min then cooled to room temperature and poured slowly into ice (20 g). The pH was adjusted to 7 with 40% aqueous NaOH. The precipitated product was filtered, washed with water (20 ml) and dried in vacuo over P2O5 for 16 h to give the title compound as a yellow solid (0.580 g). 0.48 g was further purified by chromatography (hexane/ethyl acetate; v/v 7:3) to give the title compound as a yellow solid (0.287 g); 1H-NMR (250 MHz, CDCl3) 8.29 (s, 1H, 6-H).
Reaction SMILES: [C:1]([NH:4][N:5]=[C:6]([C:15]#[N:16])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])(=[NH:3])[NH2:2].C([OH:20])CC>CS(C)=O>[NH2:3][C:1]1[N:4]=[N:5][C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])=[C:15]([NH2:16])[N:2]=1.[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:6]([C:15]#[N:16])=[O:20]
Reactant: N#CC(=NNC(=N)N)c1ccc(Cl)cc1Cl
Reactant: CCCO
Solvent: CS(C)=O
Product: N#CC(=O)c1ccc(Cl)cc1Cl
Product: Nc1nnc(-c2ccc(Cl)cc2Cl)c(N)n1

Procedure:
The title compound was prepared as in Example 2(a) from 2,4-dichlorobenzoyl cyanide amidinohydrazone obtained in Example 3. The solvent for ring closure was a mixture of 1-propanol and dimethylsulfoxide (5:1). Total yield (from 2,4-dichlorobenzoyl cyanide): 55%; m.p. 220-222° C. (uncorrected).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH2:15][C@@H:16]([CH2:23][OH:24])[C:17]4[NH:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:25][NH:26][CH3:27]>C(#N)C>[CH3:25][N:26]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH2:15][C@@H:16]([CH2:23][OH:24])[C:17]4[NH:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:27]
Reactant: O=C1C=CC2=CN=C(c3ccc(CCl)cc3)N3C[C@@H](CO)C(=C23)N1
Reactant: CNC
Solvent: CC#N
Product: CN(C)Cc1ccc(C2=NC=C3C=CC(=O)NC4=C3N2C[C@H]4CO)cc1

Procedure:
This compound was prepared from intermediate 238c and dimethylamine using the procedure described in Example 171, except with acetonitrile as solvent. Received 85.1 mg (33%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Brc1cnc2ccc(NCc3ccccn3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-(aminomethyl)pyridine according to general procedure 1 providing the amino compound (97 mg, 25%) as a white solid; Rf=0.80 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.52-8.51 (m, 1H), 7.83-7.79 (m, 1H), 7.63 (d, J=9.7 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.41 (s, 1H), 7.33-7.31 (m, 1H), 6.84 (d, J=9.7 Hz, 1H), 4.70 (s, 2H); ES-MS: (M+H)=304, 306 m/z.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][CH2:17][CH:18]([O:26][C:27]1[C:35]2[CH:34]=[CH:33][S:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)C)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[S:32]1[CH:33]=[CH:34][C:35]2[C:27]([O:26][CH:18]([CH2:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:17][CH2:16][NH:14][CH3:13])=[CH:28][CH:29]=[CH:30][C:31]1=2
Reactant: CN(CCC(CC1CCCCC1)Oc1cccc2sccc12)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCC(CC1CCCCC1)Oc1cccc2sccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.7 %

Procedure:
Add trifluoroacetic acid (5.5 ml, 71 mmol) to a stirred solution of [3-(benzo[b]thiophen-4-yloxy)-4-cyclohexyl-butyl]-methyl-carbamic acid tert-butyl ester (1.49 g, 3.6 mmol) and dichloromethane (80 ml) at 0° C. under N2. Stir for 5 minutes at 0° C. and allow the reaction to reach room temperature. Stir for 90 minutes, add sodium bicarbonate. Partition between sodium bicarbonate and dichloromethane, wash the combined dichloromethane layers with brine, dry over sodium sulfate. Filter and concentrate to give the crude compound. Purify the compound by flash chromatography, eluting with 3% ethanol/0.3% ammonium hydroxide/chloroform to yield 0.511 g (45%) of the title compound: mass spectrum (ion spray) m/z=318 (M+1); HPLC (90/5/5 to 0/95/5 water/acetonitrile/5% formic acid) Xterra MS C18 2.1 mm×50 mm×3.5micron: Retention time 3.08 minutes, Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:5]([CH:7]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]1=O)=O.O.[NH2:21][NH2:22].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[CH2:14][C:10]4[S:11][CH:12]=[CH:13][C:9]=4[C:8]=3[NH:22][N:21]=2)[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C1Cc2sccc2C1=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Clc1cc(Cl)cc(-c2n[nH]c3c2Cc2sccc2-3)c1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
5-(3,5-Dichloro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.5 g, 4.8 mmol), hydrazine monohydrate (0.35 mL, 7.2 mmol), glacial acetic acid (0.8 mL) and ethanol (15 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(3,5-Dichloro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.33 g, 4.3 mmol) as yellow solid in 90% yield.