Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:17][C:18]#[N:19])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C=O)C>C(O)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:16][CH2:17][C:18]3[NH:28][N:27]=[N:26][N:19]=3)[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1ccc(-c2csc(N(CCC#N)Cc3cccs3)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)c1ccc(-c2csc(N(CCc3nnn[nH]3)Cc3cccs3)n2)cc1

Procedure:
[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-[2-(1H-tetrazol-5-yl)-ethyl]-thiophen-2-ylmethyl-amine was prepared following general procedure H using 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionitrile (278 mg, 0.756 mmol), sodium azide (657 mg, 99%, 10 mmol), ammonium chloride (535 mg, 10 mmol) and DMF (3 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:1, with 0.5% v/v acetic acid) gave the product compound (110 g, 0.268 mmol).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[C:24]([F:30])[CH:23]=1>>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[Cl:19])[C:7]2=[O:20])=[C:24]([F:30])[CH:23]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)[nH]1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(Br)cc1F
Yield: 79 %

Procedure:
By the procedure of Example 76, Step D, 5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 59, Step A) was alkylated with 4-bromo-2-fluorobenzyl bromide to give a 79% yield of the title compound as an off-white foam, homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (FAB) m/e 483, 485 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C.Br[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[ClH:2].[Cl:2][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1ccc(N2CCN(CCCc3ccccc3)CC2)nn1
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of 3.6 parts of 3-chloro-6-(1-piperazinyl)pyridazine monohydrochloride, 5.3 parts of sodium carbonate and 90 parts of N,N-dimethylacetamide was stirred for a while at 60° C. Then there were added 3 parts of (3-bromopropyl)benzene and the whole was stirred overnight at 60° C. The reaction mixture was poured into water. The product was filtered off and converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 3.2 parts (60%) of 3-chloro-6-[4-(3-phenylpropyl)-1-piperazinyl]pyridazine monohydrochloride; mp. 207.3° C. (compound 226) In a similar manner there were also prepared:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:25][C:23]1[O:22][N:21]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][CH:18]=2)[N:24]=1
Reactant: Cc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)no1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(N3CCNCC3)cc2)no1
Reaction time: 2 h

Procedure:
1 mmol of 4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was stirred in 3 ml of 1,4-dioxane saturated with gaseous HCl. After 2 h at room temperature, the reaction mixture was evaporated to dryness to yield the tide compound as a colorless solid. MS (m/e): 245.1 (MH+, 100%)
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9]2([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl>O>[CH3:20][N:19]([CH3:21])[C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CN(C)C1(c2cccc(F)c2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
[8-(3-Fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-dimethyl-amine hydrochloride (7.2 g, 22.75 mmol) was dissolved in water (9.6 ml), concentrated hydrochloric acid (14 ml, 455 mmol) was added and the mixture was stirred at room temperature for 4 d. When the hydrolysis had ended, the reaction mixture was extracted with diethyl ether (2×50 ml) and the aqueous phase was rendered alkaline with 5 N sodium hydroxide solution, while cooling with ice, during which the product precipitated out. It was possible to isolate the ketone Ket-13 as a yellow solid with a melting point of 83-88° C. and a yield of 50% (6.05 g).
Reaction SMILES: CS([O:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]2)[CH2:8][CH2:7]1)(=O)=O.[CH2:20]([N:27]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][C:32]([O:39][CH3:40])=[C:33](O)[CH:34]=2)[N:29]=[CH:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH2:20]([N:27]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][C:32]([O:39][CH3:40])=[C:33]([O:5][C@H:6]3[CH2:11][CH2:10][C@H:9]([N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[CH2:13]4)[CH2:8][CH2:7]3)[CH:34]=2)[N:29]=[CH:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O
Reactant: CN1CCN([C@H]2CC[C@@H](OS(C)(=O)=O)CC2)CC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O[C@H]1CC[C@H](N2CCN(C)C(=O)C2)CC1

Procedure:
650 mg (cis)-1-methanesulphonyloxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane in 3 ml N-methyl-2-pyrrolidinone are added dropwise at 120° C. over two hours to 632 mg 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline and 1.09 g caesium carbonate in 4 ml N-methyl-2-pyrrolidinone. The product is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14][CH2:15]C)=[O:13])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N+:20]([O-:33])=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1sc(-c2cc[n+]([O-])cc2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a solution of ethyl 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylate (430 mg, 1.20 mmol) in DMF (6.0 mL) was added mCPBA (322 mg, 1.44 mmol) and the mixture was stirred at room temperature overnight. To the reaction was added DCM (30 mL) and saturated sodium bicarbonate (25 mL). The layers were separated and the aqueous layer extracted with DCM (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=50/50→100/0) to give 449 mg of the title compound as a white solid (100% yield). LC/MS (FA) ES+ 375. 1H NMR (300 MHz, CDCl3) δ: 8.23-8.20 (m, 2H), 7.84-7.81 (m, 2H), 7.33-7.23 (m, 4H), 4.51 (s, 2H), 4.38 (q, 2H, J=7.2 Hz), 1.39 (t, 3H, J=7.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2]>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:10]2[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCC(O)c2ncccc21
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(CN2CCCC(O)c3ncccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.5 g of 5-(4-nitrobenzoyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine, O-acetate in 10 ml of methanol-water (8:2) is added KHCO3 and the mixture stirred at room temperature overnight. The mixture is concentrated under vacuum, diluted with 10 ml of water and extracted with ethyl acetate. The extract is dried (Na2SO4) and the solvent removed to give the product as a solid. Chromatography on silica gel with ethyl acetate as solvent gives crystals, m.p. 182°-185° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].Br[CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Si:26]([O:25][CH2:24][CH2:23][CH2:22][N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:9]2[CH:8]=[CH:7][C:6]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:12][CH2:13]1)([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27]
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCN1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 70 °C

Procedure:
A mixture of EXAMPLE 157B (300 mg), (3-bromopropoxy)(tert-butyl)dimethylsilane (304 mg) and cesium carbonate (967 mg) was suspended in anhydrous N,N-dimethylformamide (5 mL). The reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified using flash column purification with 3-10% methanol/dichloromethane to afford the title compound.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:35][O:36][C:37](=[O:48])[C:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=1)=O>O1CCCC1>[CH3:35][O:36][C:37](=[O:48])[C:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=1)=[CH:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=CC(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A suspension of isobutyl triphenylphosphonium bromide (2.02 g, 4.96 mmol) in dry tetrahydrofuran (5.4 mL) was cooled to 0° C. and then treated dropwise with a 1.0M solution of sodium bis(trimethylsilyl)amide (5 mL, 4.96 mmol). The bright orange reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then treated with a solution of (3,4-dichloro-phenyl)-oxo-acetic acid methyl ester (0.77 g, 3.30 mmol) in tetrahydrofuran (3 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (10 mL) and then concentrated in vacuo to remove tetrahydroftiran. The residue was further diluted with water (50 mL) and then extracted with ethyl acetate (2×75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 97/3 hexanes/ethyl acetate) afforded the 2-(3,4-dichloro-phenyl)-4-methyl-pent-2-enoic acid methyl ester (749 mg, 83%) as a yellow viscous oil containing a 3.5:1 mixture of (E):(Z) isomers. The isomeric mixture was used without further separation and characterization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(OC(C)(C)C)=O)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1>[Pd].C(O)C.C1COCC1>[NH2:21][C:17]1([C:14]2[CH:15]=[CH:16][C:11]([C:9]3[N:10]=[C:5]4[C:4]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:3][CH:2]=[N:7][N:6]4[C:8]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)/C=C/c1cc(Br)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)CCc1ccnn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Reaction time: 1 h
Yield: 1 %

Procedure:
To a mixture of methyl (2E)-3-[6-bromo-2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl]acrylate that was prepared in a manner analgous to that described for Example 72, Step 1 (0.50 g, 0.83 mmol) and 10% palladium on carbon (0.26 g) in a mixture of ethanol (14 mL) and THF (5 mL) was placed under a hydrogen atmosphere at room temperature for 1 h. The resulting mixture was treated with additional 10% palladium on carbon (0.26 g) and placed under a hydrogen atmosphere for 1 h. Solids were removed by filtration and washed with ethanol (20 mL). The combined organic solutions were treated with 10% palladium on carbon (0.26 g) and placed under a hydrogen atmosphere for 1 h. Solids were removed by filtration and washed with ethanol (20 mL). The combined organic solutions were concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.5 min, gradient to 74% hexane/26% EtOAc 2.5 min, gradient to 70% hexane/30% EtOAc 2.0 min, gradient to 50% hexane/50% EtOAc 3.0 min, 50% hexane/50% EtOAc 6.4 min, gradient to 25% hexane/75% EtOAc 3.5 min, 25% hexane/75% EtOAc 5.3 min gradient to 100% EtOAc 5.3 min, 100% EtOAc 21.2 min). The resulting material was further purified using preparative HPLC (Agilent Prep 1200 equipped with 2× Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5 μm 100×30 mm column; gradient from 100% water with 0.1% HCO2H to 70% water with 0.1% HCO2H/30% MeOH over 1.0 min, gradient to 30% water with 0.1% HCO2H/70% MeOH over 7.0 min, gradient to 100% MeOH over 0.1 min, 100% MeOH 1.9 min) to give methyl 3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-yl}propanoate (0.003 g, 1%):
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:22])[C:4]([C:6]1(O)[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7]1)=O.Cl.[N-:24]=[C:25]=[O:26].[K+]>C(O)C>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[NH:24][C:25](=[O:26])[NH:2][C:3]=2[CH3:22])[CH:11]=[C:10]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:9]=1[OH:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: [N-]=C=O
Reactant: CC(N)C(=O)C1(O)C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1[nH]c(=O)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 48 %

Procedure:
By following the same procedure as in Example 6 using 1.6 g of 4-(2-aminopropionyl)-2,6-di-tert-butyl-4-hydroxyphenol hydrochloride, 20 ml of ethanol, 0.5 ml of concentrated hydrochloric acid, 0.8 g of potassium isocyanate, a reaction product thus obtained was recrystallized from aqueous isopropanol to provide 0.7 g of 4-(3.5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[CH:10][N:11]([CH3:34])[C:12]=1[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[C:22]([N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])=[O:7])[CH2:2][CH2:3][CH3:4].Cl[C:40]1[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]2[C:41]=1[CH:42]=[CH:43][C:44]([S:51]([NH2:54])(=[O:53])=[O:52])=[CH:45]2>>[CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[CH:10][N:11]([CH3:34])[C:12]=1[C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:54][S:51]([C:44]2[CH:43]=[CH:42][C:41]3[C:46](=[C:47]([Cl:50])[CH:48]=[CH:49][CH:40]=3)[CH:45]=2)(=[O:53])=[O:52])=[CH:15][C:14]=1[C:22]([N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)c1ncn(C)c1-c1ccc(C(=O)O)cc1C(=O)N1CCc2ccccc2C1
Reactant: NS(=O)(=O)c1ccc2c(Cl)ccc(Cl)c2c1
Product: CCCCN(CCCC)C(=O)c1ncn(C)c1-c1ccc(C(=O)NS(=O)(=O)c2ccc3cccc(Cl)c3c2)cc1C(=O)N1CCc2ccccc2C1
Yield: 12.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 265, 4-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid (150 mg, 0.29 mmol) and 8-chloronaphthalene-2-sulfonamide (Intermediate 5, 140 mg, 0.58 mmol) were converted to the title compound (26 mg, 12%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.99 (s, 1H), 8.18-8.09 (m, 3H), 8.05 (dd, J=8.4, 2.0 Hz, 1H), 7.94-7.91 (m, 1H), 7.72 (dd, J=7.2, 1.2 Hz, 1H), 7.69 (s, 0.5H), 7.62-7.55 (m, 1.5H), 7.42 (dd, J=8.0, 4.8 Hz, 1H), 7.21-7.13 (m, 3.5H), 6.93 (d, J=8.0 Hz, 0.5H), 4.78 (br s, 0.5H), 4.62-4.49 (m, 1.5H), 3.90 (br s, 0.5H), 3.60 (br s, 0.5H), 3.50 (s, 3H), 3.49-3.39 (m, 2H), 3.24 (t, J=6.4 Hz, 0.5H), 3.18-3.13 (m, 1.5H), 2.90 (br s, 1.5H), 2.85-2.65 (m, 2.5H), 1.50-1.09 (m, 8H), 0.89-0.79 (m, 6H); MS(ESI+) m/z 742.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.O.[Br:16]Br.S([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[Br:16][C:2]1[C:1](=[O:14])[C:13]2[C:5](=[CH:4][CH:3]=1)[C:6]1[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=2
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: BrBr
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C(Br)=CC=C2C1=Cc1ccccc12
Reaction time: 12 h
Yield: 92.9 %

Procedure:
In a three-liter flask having four openings equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser, respectively, 256 g (1.4 mol) of fluorenone, 1 L of water, three drops of a surfactant, and five drops of sulfuric acid were placed and stirred to mix. By adding 250 g (1.6 mol) of bromine into the mixture, a reaction was started. After the reaction had been conducted at 50° C. for 12 hours, unreacted bromine was decomposed with an aqueous solution of sodium hydrogen sulfite. The reaction product, which was a dark yellow solid, was filtered and thus 365 g of a crude product was obtained. The crude product was dissolved in toluene and was subsequently washed with water and a sodium hydrogencarbonate aqueous solution. The resulting organic liquid was dried using anhydrous magnesium sulfate. After filtration, the liquid was concentrated and then allowed to stand at 0° C., so that a yellow solid was precipitated. The precipitate was filtered and subsequently washed with toluene, followed by drying. Thus, 339 g (1.3 mol, yield of 92%) of a yellow solid product was obtained. This product was subjected to gas chromatography and the purity of the product was 99.4%.
Reaction SMILES: Cl.C[NH:3][C@H:4]([C:23]([OH:25])=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[O:14])=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C>[ClH:21].[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@@H:4]([C:23]([OH:25])=[O:24])[NH2:3])=[CH:7][CH:8]=1)=[O:14]
Reactant: CN[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Temperature: 42.5 °C
Yield: 200.2 %

Procedure:
To a solution of methyl 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine hydrochloride salt (30 mmol, 12.1 g) in ethanol (300 mL) was added 1 N sodium hydroxide (90 mL). The mixture was heated to 40-45° C. for 1 h at which point TLC analysis of the reaction mixture indicated the absence of starting material and it was cooled to room temperature. The solvent was removed under vacuum and the residue was extracted with ether (2×100 mL) to remove neutral impurities. Then, the basic aqueous layer was acidified with 1 N hydrochloric acid to pH 2 to give a clear solution. The solution was lyopholized under high vacuum to afford 11.7 g (100%) of the title compound as a white amorphous solid. HR MS (C16H15Cl3N2O3): Obs. mass, 354.2014. Calcd. mass, 354.2053 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[NH:6]1[CH:10]=[CH:9][N:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][CH2:4][N:6]1[CH:10]=[CH:9][N:8]=[N:7]1)[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCn1ccnn1
Temperature: 25 °C

Procedure:
Chloromethyl ethyl ether (125 g, 1.32 mole) was added dropwise over 1.5 hours to an ice-cooled, stirred suspension of 1,2,3-triazole (91.4 g, 1.32 mole) and anhydrous potassium carbonate (183 g, 1.32 mole) in acetone (1.5 l). The mixture was then allowed to warm to room temperature and stirred for a further 18 hours. The solvent was evaporated under reduced pressure, the residue dissolved in water (1 l) and the aqueous solution extracted with dichloromethane (3×300 ml). The combined extracts were washed with saturated brine (3×300 ml), dried (Na2SO4) and evaporated under reduced pressure to furnish a pale yellow oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]([Cl:23])([Cl:22])[CH:8](Cl)[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[Cl:6][C:7]([Cl:23])([Cl:22])[CH:8]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)C(C(Cl)C(Cl)(Cl)Cl)n1cncn1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Reaction time: 3 h

Procedure:
14.6 g (0.2 mol) of diethylamine were slowly added dropwise to 33.4 g (0.1 mol) of 1,1,1,2-tetrachloro-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one (Example 3) in 150 ml of tetrahydrofuran at room temperature. The mixture was then subsequently stirred at 50°-60° C. for 3 hours. The diethylamine hydrochloride which had precipitated was filtered off and the filtrate was concentrated in vacuo. According to thin layer chromatography of the residue over silica gel 60 (Merck, particle size 0.063-0.200 mm) and with ether/hexane in the ratio 1:1 as the running agent, 1,1,1-trichloro-2-diethylamino-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one was obtained as the pure diastereomer of the A* form, as a yellow oil, in a yield of 8.9 g (24.1% of theory), and as the pure diastereomer of the B* form, of melting point 103°-110° C., in a yield of 6.4 g (19.4% of theory).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH2:35]O.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:35][CH2:34][CH2:33][C:32]#[C:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=1
Reactant: OCCCC#CCOCCCc1ccccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCC#CCOCCCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Triphenylphosphine (2.89 g) in dichloromethane (20 ml) was added dropwise to a solution of 6-[3-(2-pyridinyl)propoxy]-4-hexyn-1-ol (2.33 g) and carbon tetrabromide (3.65 g) in dichloromethane (30 ml) cooled in an ice-bath. The reaction mixture was stirred at room temperature for 1 h, the solvent was evaporated and the residue was purified by FCC eluting with hexane-ether (1:1) to give the title compound as an orange oil (2.0 g), t.l.c. (hexane-ether 1:1) Rf 0.2.