Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>>[CH3:20][C:21]1[CH:22]=[C:23]([CH3:24])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:4]=2)[N:2]=1
Reactant: Cn1cnc2c(Nc3ccncc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2nc(Nc3ccncc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (2-hydrazino-9-methyl-9H-purin-6-yl)-pyridin-4-yl-amine and 2,4-pentanedione.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](C(Cl)=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([O:12][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 41.6 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)-3-(pyridin-2-yl)propanoic acid (1.00 g, 3.76 mmol) in DCM (10 mL) was added TEA (0.974 mL, 7.52 mmol) and DMAP (23 mg, 0.188 mmol) and the reaction mixture was cooled to 0° C. and BnCOCl (635 mL, 4.51 mmol) was added via an addition funnel over 20 min. The mixture was allowed to warm to ambient temperature overnight at which time it was quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-50% ethyl acetate/hexanes+1% TEA) provided (S)-benzyl 2-((tert-butoxycarbonyl)amino)-3-(pyridin-2-yl)propanoate (0.558 g, 42%) as a light brown solid. MS (EI) for C20H24N2O4, found 257.2 [M-Boc]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[NH2:8][C:9]1[N:14]=[C:13](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:12]([CH2:28][C:29]2[CH:30]=[C:31]([CH2:37][C:38]([O:40]C)=[O:39])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])=[C:11]([CH3:42])[N:10]=1.[OH-].[K+]>C(O)CCC>[NH2:8][C:9]1[N:14]=[C:13]([NH:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4])[C:12]([CH2:28][C:29]2[CH:30]=[C:31]([CH2:37][C:38]([OH:40])=[O:39])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])=[C:11]([CH3:42])[N:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c1
Reactant: CCC[C@H](N)CO
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Temperature: 160 °C

Procedure:
(S)-(+)-2-Amino-1-pentanol (100 mg) was added to a suspension of the product from step (v) (243 mg) in butan-1-ol (2 mL). The reaction was heated in a microwave at 160° C. for 2 h. 5M KOH (0.5 mL) was added and the mixture heated in a microwave at 100° C. for 1 h. The solvent was evaporated under reduced pressure and the residue purified by RPHPLC to give the subtitle compound as a white solid, 60 mg.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2]([C:1]([OH:14])=[O:13])=[CH:3][C:4]=1[O:5][CH3:6])(=[O:17])[CH3:16]
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C(=O)O)cc(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
In a 100 ml flask, under a nitrogen atmosphere, 1.50 g (7.57 mmoles) of syringic acid is dissolved in 15 ml of dry pyridine. 0.86 ml (9.08 mmoles) of acetic anhydride is added dropwise and the mixture is agitated at ambient temperature for 18 hours. The pyridine is evaporated off under reduced pressure, the residue is taken up in 25 ml of dichloromethane and washed with 10 ml of a molar solution of HCl then with 2×10 ml of water. The organic phase is dried over sodium sulphate, filtered and evaporated under vacuum. 1.72 g (95%) of a beige powder is obtained. Melting point: 181-183° C.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([CH2:53][OH:54])[CH:49]=[C:50]([NH2:52])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:51]=[C:50]([NH:52][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:7])[CH:49]=[C:48]([CH2:53][OH:54])[CH:47]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C(=O)O
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 69.5 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,5-dimethylphenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: [CH3:1][O:2]C1C=CC(C)=CC=1.[C-]#N.[Na+].[CH3:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[CH3:13][O:14][CH:15]([O:2][CH3:1])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(C)cc1
Reactant: COCc1ccc(OC)cc1
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccc(C(OC)OC)cc1
Yield: 15 %

Procedure:
In the article "Nuclear Cyanation of Methylanisoles" by k. Yoshida, M. Shigi and T. Fueno in J. Org. Chem., 1975, Vol. 40, No. 1, pp. 63-66, the reaction of 4-methoxytoluene (Ic) in a methanolic solution of NaCN or Na acetate is described. In this reaction, 4-(methoxymethyl)-anisole and, in a material (current) yield of 15% (24%) of the theoretical, anisaldehyde-dimethylacetal (IIc) are also formed, in addition to the respective ring-substitution products.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH3:17])=[C:6]([N+:18]([O-])=O)[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH3:17])=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(NC2CCCCC2C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(NC2CCCCC2C)c(N)c1
Reaction time: 4 h
Yield: 99 %

Procedure:
13.50 g 4-(2-Methyl-cyclohexylamino)-3-nitro-benzoic acid methyl ester were dissolved in 60 ml methanol, 0.49 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 4 h. The catalyst was removed by filtration over celite, the filtrate was concentrated to obtain 12.00 g (99%) of 3-Amino-4-(2-methyl-cyclohexylamino)-benzoic acid methyl ester.
Reaction SMILES: CO[CH2:3][C:4]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[N:14]1.[BrH:20].C(O)(=O)C>C(O)(=O)C>[Br:20][CH2:3][C:4]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[N:14]1
Reactant: Br
Reactant: COCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Solvent: CC(=O)O
Product: Cn1nnn(-c2cccc(C3CC3)c2CBr)c1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2-methoxymethyl-3-cyclopropylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 7) 26.0 g, acetic acid 40 ml and 25% hydrogen bromide-acetic acid solution 40 ml was stirred at 65° C. for two hours. To the reaction mixture was added saturated saline, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give 1-(2-bromomethyl-3-cyclopropylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 30.8 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]([F:18])([F:17])[CH2:14]2)[CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]2([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][C:15]([F:18])([F:17])[CH2:16]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(F)(F)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C2CCN(Cc3ccccc3)C2)CC(F)(F)C1
Temperature: 0 °C
Yield: 62.1 %

Procedure:
Under an atmosphere of nitrogen, 825 mg (2.17 mmol) of 1-benzyl-4-[3-(tert-butoxycarbonylamino)-1,1-difluorocyclobutan-3-yl]-2-pyrrolidone (Isomer F2) was dissolved in 20 ml of tetrahydrofuran to which, while cooling in an ice bath with stirring, was subsequently added 6.51 ml of 1 N borane-tetrahydrofuran complex tetrahydrofuran solution. Ten minutes thereafter, the ice bath was detached and the reaction mixture was stirred at room temperature for 18 hours. After evaporation of the solvent under a reduced pressure, the thus obtained residue was mixed with 30 ml of 80% ethanol and 3 ml of triethylamine and heated under reflux for 2 hours. After evaporation of the solvent under a reduced pressure, the thus obtained residue was mixed with ethyl acetate and saturated sodium bicarbonate aqueous solution to effect separation of layers. The organic layer was washed with saturated brine, the aqueous layer was extracted with ethyl acetate and then the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 494 mg (62.2%) of the title compound. 1H-NMR data of the thus obtained compound coincided with the aforementioned data of its enantiomer Isomer F1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19](S(C2C=CC=CC=2)(=O)=O)[CH:18]=[C:17]3[C:32]#[N:33])[CH:10]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[C:32]#[N:33])[CH:10]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)c(C#N)cn3S(=O)(=O)c2ccccc2)C(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]cc(C#N)c3c2)C(Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a suspension of 4-(1-benzenesulfonyl-3-cyano-1H-indol-5-yl)-3-benzyl-piperazine-1-carboxylic acid tert-butyl ester (0.37 g, 0.7 mmol) in 10 mL MeOH was added K2CO3 (0.27 g, 2.0 mmol) in 2 mL H2O. The reaction mixture was stirred for 30 minutes and then solution was concentrated under reduced pressure and extracted with EtOAc. The combine organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification via flash chromatography (25% EtOAc in hexane) afforded 3-benzyl-4-(3-cyano-1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 85%) as a white foam; MS (M+H)=417.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][CH2:16][CH:17]([N:20]1[CH2:23][CH:22]([NH2:24])[CH2:21]1)[CH2:18][F:19].C(NC(C)C)(C)C>O1CCOCC1>[F:15][CH2:16][CH:17]([N:20]1[CH2:23][CH:22]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:21]1)[CH2:18][F:19]
Reactant: NC1CN(C(CF)CF)C1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: NS(=O)(=O)c1ccc(NC2CN(C(CF)CF)C2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-3-nitrobenzenesulfonamide (0.225 g) and 1-(1,3-difluoropropan-2-yl)azetidin-3-amine (0.193 g) in dioxane (5 mL) was added diisopropylamine (0.832 mL). The reaction was sonicated and then heated to 100° C. After stirring overnight, the reaction was concentrated and loaded onto silica gel (GraceResolv 12 g) and eluted with a gradient of 0.5% to 3.5% methanol/dichloromethane to give the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([Cl:22])=[CH:7][C:8]([Cl:21])=[C:9]([N:11]2[C:19](=[O:20])[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12]2)[CH:10]=1)(=[O:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:6]([Cl:22])=[CH:7][C:8]([Cl:21])=[C:9]([N:11]2[C:19](=[O:20])[N:14]3[CH2:15][CH2:16][CH2:17][CH:18]([Br:23])[C:13]3=[N:12]2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(-n2nc3n(c2=O)CCCC3Br)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a solution of 3.55 g (10.4 mmol) of 5,6,7,8-tetrahydro-2-(5-acetyloxy-2,4-dichlorophenyl)-1,2,4-triazolo[4,3-α]pyridin-3(2H)-one in 100 mL of carbon tetrachloride was added 2.03 g (11.4 mmol) of N-bromosuccinimide at room temperature. The mixture was warmed under reflux by irradiating with a sun lamp for 3h. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel, eluting with a 1:1 v:v mixture of ethyl acetate and n-hexane to give 4.10 g of the title product of Step 1 as a white solid, m.p.: 75°-83° C.; 1H NMR (CDCl3, 300 MHz) δ 7.6 (s,1H), 7.35 (s,1H), 5.25 (m,1H), 4.0 (m,1H), 3.6 (m,1H), 2.75 (s,3H), 2.5-1.9 (m,4H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>C(=S)=S.C(Cl)(Cl)Cl>[C:19]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[OH:14])(=[O:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(C(C)(C)C)cc(C(=O)O)c1O
Temperature: 0 °C
Reaction time: 20 h
Yield: 48.7 %

Procedure:
A vigorously stirred solution of 5-tert-butyl-salicyclic acid (3.88 g) in carbon disulphide (80 ml) was treated portionwise with anhydrous aluminium chloride (8.8 g). The mixture was brought cautiously to the reflux temperature and treated with acetyl chloride (3.45 g) dropwise during 15 minutes. The mixture was heated at reflux with vigorous stirring for 20 hours and then the mixture was added to a mixture of chloroform (80 ml), ice (100 g) and concentrated hydrochloric acid (20 ml), and stirred for a further one hour. The organic layer was then separated, washed with water (3 × 20 ml), and dried over anhydrous sodium sulphate, and the solvent was removed in vacuo. The resulting solid was recrystallized from ethyl acetate, to give 3-acetyl-5-tert-butylsalicylic acid (2.3 g), m.p. 159°-161° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2c(c1)OCO2
Yield: 100.5 %

Procedure:
A solution of alcohol (a) (1.90 g, 11 mmol) in dichloromethane (25 ml) was treated at 0° C. with triethylamine (1.9 ml, 13.7 mmol) and methanesulfonyl chloride (1.1 ml, 13.7 mmol). After 1.5 hours at room temperature the mixture was partitioned between dichloromethane and water. The organic extract was dried and evaporated to give a yellow oil (2.7 g, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][O:10][N:11]1[C:15](=[O:16])[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]1=[O:21])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOC(=O)CCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of 4-bromo-n-butyric acid ethyl ester (1.2 g, 6.13 mmol) in dimethylformamide (9 ml) were added N-hydroxyphthalimide (1.5 g, 9.19 mmol) and Hunig base (N,N-diisopropylethylamine, 2.13 mL) at room temperature, and the mixture was stirred at 80° C. over night. The reaction mixture was poured into saturated aqueous ammonium chloride, and the resultant mixture was extracted with ethyl acetate (3×40 ml). The combined organic layers were washed with saturated brine (2×30 ml), dried over Na2SO4, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (100 g, n-hexane/ethyl acetate (2:1)) to give 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-butyric acid ethyl ester (1.47 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([O:21][CH3:22])[CH:15]=[CH:14]2.Cl.[N:24]([O-])=O.[Na+].O>C(O)(=O)C>[CH3:22][O:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18]([CH:17]=1)=[CH:19][CH:20]=[C:11]1[C:12]=2[N:24]=[N:1][C:2]2[CH:7]=[C:6]3[O:8][CH2:9][O:10][C:5]3=[CH:4][C:3]1=2
Reactant: COc1ccc2cc(-c3cc4c(cc3N)OCO4)ccc2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(ccc3c4cc5c(cc4nnc23)OCO5)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.3 %

Procedure:
6-(2-Amino-4,5-methylenedioxyphenyl)-2-methoxynaphthalene 46 (170 mg, 0.58 mmol) was dissolved in acetic acid (4.5 mL) and concentrated hydrochloric acid (0.9 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.36 g in 3.6 mL water). The resulting diazonium solution was allowed to warm slowly to room temperature and left for 1 day. To the resulting red solution containing some precipitate was added 50 mL water and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 50:50 hexanes:ethyl acetate to give the pure 43 (20 mg) in 11% yield; mp 258-260° C.; IR (KBr) 2922, 1611, 1497, 1465, 1414, 1370, 1272, 1201 cm−1; UV (MeOH) 286, 228 nm (log ε=4.72, 4.41); 1H NMR (CDCl3) δ4.01 (3H, s), 6.23 (2H, s), 7.30 (1H, J=2.6), 7.48 (1H, dd, J1=9.1, J2=2.6), 7.75 (1H, s), 7.95 (1H, s), 8.00 (1H, d, J=9.2), 8.19 (1H, d, J=9.1), 9.62 (1H, d, J=9.2); 13C NMR δ56.01, 97.95, 102.88, 107.48, 108.31, 119.09, 119.61, 119.71, 120.57, 125.89, 126.56, 132.26, 134.59, 142.52, 145.88, 150.21, 152.14, 160.16; HRMS (EI) calcd for C18H12N2O3 m/z: 304.0848; found: 304.0843.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[OH-].[Na+].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10]#[N:11]
Reactant: BrCC1CCCCC1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#CC(CC1CCCCC1)c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
A mixture of 18.5 parts of 2,4-dichlorobenzeneacetonitrile and 180 parts of N,N-dimethylformamide is stirred and cooled in an ice-bath while nitrogen gas is introduced. 3.2 Parts of a sodium hydroxide solution 78% are added portionwise and the whole is stirred for one hour. Then there are added dropwise, during a one hour-period, 17.8 parts of (bromomethyl)cyclohexane while still cooling and while nitrogen gas is still introduced. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is poured onto water. The precipitated product is filtered off and triturated in a mixture of methanol and water. The product is filtered off and dried, yielding 25.5 parts of 2,4-dichloro-α-(cyclohexylmethyl)benzeneacetonitrile; mp. 58.8° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[I:10]I>C(O)C.CCOC(C)=O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:1][C:2]1[CH:7]=[C:6]([I:10])[C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1
Reactant: II
Reactant: Nc1ccc(Br)cc1F
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c(F)cc(Br)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
(4-bromo-2-fluorophenyl)amine (6 g) was dissolved in ethanol (200 mL), silver sulfate (10.8 g) was added and then iodine (8.8 g) was added in small portions. After the addition was complete, the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and evaporated to leave a dark oil which was taken up in EtOAc, washed with saturated sodium thiosulphate (100 mL×2), sodium carbonate solution (100 mL×2) and water. The organic layer dried over anhydrous Na2SO4 and evaporated. The crude product was purified by column chromatography to give (4-bromo-2-fluoro-6-iodophenyl)amine (D159) (8.6 g) as a yellow solid. MS (ES): C6H4BrFIN requires 315; found 315.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:24](OC)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:18][C:17]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cncs2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cnc(C(=O)c3ccccc3)s2)CC1
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
To 30 mg of 1-t-butyloxycarbonyl-4-(thiazol-5-yl)piperidine (prepared by method of example 291) in 3 ml THF at −78° C. was added 0.123 mmol of n-BuLi. The reaction was stirred for 20 min, then 18 mg of methyl benzoate was added. The reaction was stirred for 1 hr at −78° C. The solvent was evaporated under reduced pressure. The residue was dissolved in 1:1 MeOH:Et2O then purified by prep TLC with 1:1 hexane:EtOAc to give 11 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:8]=[C:7]([Br:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:22])[CH:8]=[C:7]([Br:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cc(Br)cc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-Bromo-5-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.