Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]I)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][S:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[NH2:3])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCC(CCI)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H](CSCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.2 %

Procedure:
In a nitrogen gas flow, 562 mg of L-cysteine hydrochloride monohydrate is dissolved in an aqueous solution of 2N sodium hydroxide. To the resulting solution, 5 ml of a tetrohydrofuran solution containing 1.2 g of 2-(1-benzyloxycarbonyl-4-piperidyl)ethyl iodide is added, and stirred for 1.5 hours at room temperature. Then, 3 ml of ethanol is further added, and stirred for 2 hours. The reaction solvent is distilled off under reduced pressure. To the residue, water and ether are added, and the mixture is shaken. The water layer is separated and adjusted to pH 5 with 2N aqueous hydrochloric acid to precipitate crystals. The crystals are recrystallized from methanol to give 0.8 g of S-[2-(1-benzyloxycarbonyl-4-piperidyl)ethyl]-L-cysteine having a melting point of 185° to 188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12](OC)(=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14]>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: COC(=O)C(O)c1ccccc1
Solvent: CCOCC
Product: COc1ccc(CCNC(=O)C(O)c2ccccc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 20.0 g. (0.133 mol) of 4-methoxyphenylethylamine and 22.0 g. (0.133 mol) of methyl mandelate is heated at about 90° C. with stirring under nitrogen for 16 hours. The reaction mixture is taken up in ether and the product crystallized, giving N-[2-(4-methoxyphenyl)ethyl]mandelamide, m.p. 86°-88° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([N:14]1[C:18]2=[N:19][CH:20]=[CH:21][C:22](O)=[C:17]2[CH:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[CH2:7]([N:14]1[C:18]2=[N:19][CH:20]=[CH:21][C:22]([Cl:2])=[C:17]2[CH:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccnc2c1cnn2Cc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2c1cnn2Cc1ccccc1
Temperature: 0 °C
Yield: 57679.9 %

Procedure:
Phosphorus oxychloride (60 ml) and phosphorus pentachloride (20 mg) were added to 1-benzyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine (13.8 g) and the mixture was refluxed under heating for 2 hours. After completion of the reaction, phosphorus oxychloride was distilled away under reduced pressure and the residue obtained was poured into ice water. The mixture was neutralized with 2N aqueous solution of sodium hydroxide and the resultant crystals were collected by filtration. After drying, the crystals were recrystallized from ethyl acetate-hexane to give 13.5 g of 1-benzyl-4-chloro-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([C:6]1[N:7]([N:12]2C(=O)C3=CC=CC=C3C2=O)[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5].CN>C(O)C.O>[NH2:12][N:7]1[C:8]([CH3:11])=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)c2ccccc2F)n1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)c2ccccc2F)n1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
A rapidly stirred suspension of 2-(2-fluorobenzoyl)-5-methyl-1-phthalimidopyrrole (137 g, 0.39 mol) in 500 ml of 95% ethanol was treated with 230 ml of 40% w/w solution of methylamine and the mixture was further stirred at ambient temperature for 5 hours. The mixture was diluted with 300 ml of H2O and extracted with three 400 ml portions of dichloromethane. The combined extracts were dried (MgSO4), filtered, and evaporated to an oil which was purified by HPLC (silica gel, DCM) to give 71 g (83%) of an oil which solidified upon seeding. A three gram portion of this material was distilled at 120° (0.1 mmHg) to give 2.9 g of solid, m.p. 45°-48°.
Reaction SMILES: [Mg].Br[CH:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][C:9]=2[CH:18]=1)[CH3:4].[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10][C:9]3[CH:18]=[C:5]([CH:3]([CH3:4])[C:19]([OH:21])=[O:20])[CH:6]=[CH:7][C:8]=3[O:17][C:12]=12
Reactant: CC(Br)c1ccc2c(c1)Cc1cccnc1O2
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Reaction time: 8 h

Procedure:
A Grignard reagent is prepared from 0.31 g of metallic magnesium and 2.9 g of 7-(1-bromoethyl)-5H-[1]benzopyrano[2,3-b]pyridine in 10 ml of anhydrous tetrahydrofuran. To the Grignard reagent is added a large excess of dry ice. The mixture is allowed to stand overnight, and then poured into diluted hydrochloric acid. The precipitate is filtered off, and added to an aqueous sodium bicarbonate solution. An insoluble material is removed by filtration, and the filtrate is made acid with acetic acid. The resulting white crystals are collected and recrystallized from aqueous dioxane to give 2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid melting at 182.5°-183.5°C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.C(Cl)(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:16]=1
Reactant: OC1(c2cccnc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OC1(c2cccnc2)CCNCC1
Temperature: 68 °C

Procedure:
(Apparatus: 1 I three-necked flask with condenser) Palladium on charcoal (10%, catalytic amount) was added to a solution of 1-benzyl-4-(pyridin-3-yl)piperidin-4-ol (32 g) in methanol (220 ml), followed by ammonium formate solution (22.7 g in 50 ml of water). The reaction mixture was refluxed at 68° C. overnight. Thin layer chromatography control: 20% methanol in chloroform. The mixture was filtered over Celite and the filtrate was concentrated in vacuo. The residue was washed with acetone (100 ml) in order to obtain the desired compound in a pure form. Yield: 17.3 g (81%)
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O1CC[N:21]([CH:24]=[CH:25][CH2:26][CH3:27])CC1>>[CH2:26]([C:25]1[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:21][CH:24]=1)[CH3:27]
Reactant: CCC=CN1CCOCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Reaction time: 72 h
Yield: 56.9 %

Procedure:
Diethyl ethoxymethyleneoxalacetate (3.17 g, 0.013 mol) is added to a solution of 1-morpholinobutene (1.84 g, 0.013 mol) dissolved in CH2C12 (40 mL) at 0°. The solution is concentrated in vacuo, and ammonium acetate (50 g), ammonium hydroxide (10 mL), tetrahydrofuran (20 mL) and 95% ethanol (20 mL) are added. The solution is heated to reflux for 30 minutes, then held at 3° for 72 hours. The reaction solution is then partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give the product (1.85 g, 0.0074 mol, 57%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:7]12.[CH3:23][N:24](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[O:17]=[C:16]1[N:6]2[CH2:5][CH2:4][C:3]3[C:2]([C:23]#[N:24])=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]2=[CH:12][C:13]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[N:14][CH2:15]1
Reactant: O=C1CN=C(c2cccs2)C=C2c3cccc(Br)c3CCN12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cccc2c1CCN1C(=O)CN=C(c3cccs3)C=C21
Temperature: 170 °C
Reaction time: 0.27 h

Procedure:
A microwave flask was charged with 9-bromo-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 29) (145 mg, 0.39 mmol), Zn(CN)2 (191 mg, 1.63 mmol) and Pd(PPh3)4 (47 mg, 0.041 mmol) in DMF (4 mL) was heated to 170° C. for 18 h. The reaction was allowed to cool to RT, taken up in AcOEt and washed iwth H2O. The org. layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, hexane to hexan/AcOEt 1:1) and prep. HPLC (column: RP-C18 sunfire, 5 μm, 100×300 mm; solvent A: H2O+0.1% TFA; solvent B CH3CN; gradient (% B): 10-30% in 16 min; 50 mL/min). The product obtained was passed onto a SPE cartridge to release the free base, and the residue obtained was triturated in heptane/AcOEt to give the title compound (8 mg) as a yellow solid. UPLC-MS: MS 320.2 (M+H+); UPLC rt 0.87 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 3.07 (t, J=5.55 Hz, 2 H); 3.87 (br. s., 2 H); 4.29 (br. s., 2 H); 7.11 (t, J=4.14 Hz, 1 H); 7.51 (s, 1 H); 7.56 (t, J=7.87 Hz, 1 H); 7.66 (d, J=4.24 Hz, 2 H); 7.93 (d, J=7.47 Hz, 1 H); 8.42 (d, J=8.07 Hz, 1 H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)O1>C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc2ccc(-c3ccc(O)cc3)cc2c1
Temperature: 70 °C
Yield: 101.8 %

Procedure:
A solution of methyl 7-{[(trifluoromethyl)sulfonyl]oxy}-2-naphthalenecarboxylate (100 mg, 0.3 mmol), tetrakistriphenylphosphine palladium (14 mg, 0.012 mmol) and 4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl-) phenol (79 mg, 0.36 mmol) in a mixture of dimethoxyethane (1.6 mL) and 2 M aqueous Na2CO3 (1.3 mL) was heated in a 70° C. oil bath for one hour. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by chromatography on silica gel, (hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.085 g, 95.5% as 0.20 ethyl acetate). 1H NMR (DMSO-d6): δ 9.64 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.03-7.99 (m, 2H), 7.93-7.90 (m, 2H), 7.66 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 3.90 (s, 3H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([OH:12])[CH2:10][OH:11].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:1]([O:11][CH2:10][CH2:9][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilylchloride (100 g, 0.66M) in dry dichloromethane (70 ml) was added, drop-wise, to a stirred mixture of distilled ethylene glycol (205.6 g, 3.31M), dry dichloromethane (200 ml), triethylamine (120 ml, 0.86M) and 4-dimethylaminopyridine (8 g, 0.066M) at 0° C. under a nitrogen atmosphere. After the addition the mixture was allowed to warm to ambient temperature and was stirred for a further 3 hours. The mixture was then filtered and the filtrate washed with dilute sodium bicarbonate solution, brine, dried over magnesium sulphate, filtered and then evaporated in vacuo to give a pale yellow oil.
Reaction SMILES: [ClH:1].O1CCO[CH2:4][CH2:3]1.[NH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14].C(O)C>>[ClH:1].[NH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][CH2:3][CH3:4])=[O:14]
Reactant: C1COCCO1
Reactant: NCCOCC(=O)O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COCCN

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (4M, 32.7 ml, 131 mmol) was added to a solution of 2-(2-aminoethoxyl)acetic acid (1.56 g, 13.10 mmol) in ethanol (38.2 ml, 655 mmol) and heated for 2 h at a gentle reflux. The reaction mixture was evaporated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, br, 3H), 4.18 (s, 2H), 4.17-4.08 (m, 2H), 3.75-3.68 (m, 2H), 2.99-2.90 (m, 2H), 1.20 (t, 3H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[N:10]3[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[CH2:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1ncnn2c(Br)c(CCCN3CCCC3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cccc(-c2c(CCCN3CCCC3)cc3c(N)ncnn23)c1
Temperature: 90 °C
Yield: 66.4 %

Procedure:
To a solution of the compound (135 mg, 0.42 mmol) prepared in Example 13, 3-methoxyphenylboronic acid (96 mg, 0.63 mmol), potassium phosphate (2N, 1 mL 2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (11 mg, 0.01 mmol) in dioxane (3 mL) was deoxygenated by nitrogen gas for 5 minutes, and the reactor was sealed, heated at 90° C. for 20 hours. The mixture was concentrated, extracted with DCM and sodium hydroxide (1N). The organic layer was dried, concentrated, and the crude product was purified by prep TLC using 9% methanol in DCM (with 1% ammonium hydroxide) to obtain the title compound (98 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Br:15][C:16]1[C:17](Cl)=[C:18]([N+:23]([O-:25])=[O:24])[C:19]([NH2:22])=[N:20][CH:21]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:15][C:16]1[C:17]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[C:18]([N+:23]([O-:25])=[O:24])[C:19]([NH2:22])=[N:20][CH:21]=1
Reactant: Fc1ccc(CN2CCNCC2)cc1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(Cc3ccc(F)cc3)CC2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 17 h
Yield: 79.1 %

Procedure:
1-(4-Fluorobenzyl)piperazine (0.160 g, 0.81 mmol, 1.05 eq) was suspended in iPrOH (8 mL) and DIPEA (0.72 mL). To this solution, the 5-bromo-4-chloro-3-nitropyridin-2-amine (0.19 g, 0.77 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 60° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow solid (0.250 g, 75%); 1H-NMR (500 MHz, DMSO-d6): δ 2.43-2.55 (m, 4H, piperazine N(CH2)2), 3.05 (m, 4H, piperazine N(CH2)2), 3.51 (s, 2H, NCH2), 6.96 (br s, 2H, NH2), 7.14 (t, J=9.0 Hz, 2H, ArH), 7.35 (dd, J=8.5, 6.0 Hz, 2H, ArH), 8.15 (s, 1H, pyridine 6-H). LC (Method B)-MS (ESI, m/z): Rt=2.52 min—410/412 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8].[CH2:15](I)[CH3:16]>C(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:14][CH2:15][CH3:16])=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8]
Reactant: CCI
Reactant: CON(C)C(=O)c1cnc(O)c(Br)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCOc1ncc(C(=O)N(C)OC)cc1Br
Temperature: 25 °C
Reaction time: 40 h
Yield: 30 %

Procedure:
A mixture of 5-bromo-6-hydroxy-N-methoxy-N-methyl-nicotinamide (Preparation 239, 1.80 g, 6.90 mmol), ethyl iodide (2.8 mL, 34.5 mmol) and silver carbonate (3.8 g, 13.8 mmol) in DCM (10 mL) was stirred at room temperature for 40 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (2×30 mL), brine (20 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:petroleum ether 2:5) to afford the title compound as a yellow sticky solid in 30% yield, 600 mg.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH2:11]([NH2:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)CC>O>[CH2:11]([NH:23][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCN
Reactant: Clc1ncnc2nc[nH]c12
Solvent: O
Solvent: CCCO
Product: CCCCCCCCCCCCNc1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A mixture of 6-chloropurine (2.5 g, 0.016 mole) and n-dodecylamine (7.4 g, 0.04 mole) in 40 ml. of n-propanol was refluxed for 5 hours. The reaction mixture was stirred at room temperature for 1 hour and cooled with water (15° C.) for another hour. The product was collected by filtration, washed by two 5 ml. portions of n-propanol and dried in a vacuum oven overnight to give 4.5 g (92% yield) of 6-n-dodecylaminopurine, a colorless solid, m.p. 159°-160° C., λ max (H2O)=268 nm, ε=17.3×103.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([O:24]CC)=[O:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.O.[OH-].[Li+].Cl>O>[C:1]1([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([OH:24])=[O:23])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1[nH]c2cc(Cl)cc(Cl)c2c1NS(=O)(=O)c1ccccc1
Temperature: 65 °C
Yield: 0.1 %

Procedure:
Mix 3-[(phenylsulfonyl)amino]-2-carbethoxy-4,6-dichloroindole (0.35 g, 0,847 mmol), tetrahydrofuran (10 mL) and water (7 mL). Add lithium hydroxide monohydrate (0.11 g, 2.54 mmol) and stir at room temperature overnight. Warm at 65° C. for 5 hours, pour into water and acidify to pH 1 with 1N hydrochloric acid. Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the title compound (0.2 g, 61%); mp 229°-35° C. (dec).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)[CH:10]=[CH:9][N:8]=1)=[O:5])[CH3:2].[Br:20]NC(=O)CCC(N)=O>CN(C=O)C>[Br:20][C:10]1[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:8][CH:9]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCNC(=O)Nc1cc(-c2cncc(F)c2)ccn1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2cncc(F)c2)c(Br)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of N-ethyl-N′-(5-fluoro-3,4′-bipyridin-2′-yl)urea (Intermediate 29, 386 mg, 1.48 mmol) in DMF (7 mL), N-bromosuccinamide (396 mg, 2.22 mmol) was added. The resulting solution was heated to 80° C. and stirred at that temperature for 8 hours. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated and the organic layer was washed with 5% sodium thiosulfate solution, water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting solid was washed with acetonitrile and dried to give the title compound as an off-white solid (340 mg). MS (ESP): 340 (M+H+) for C13H12BrFN4O; NMR: 1.06 (t, 3H), 3.14 (q, 2H), 7.35 (t, 1H), 7.69 (s, 1H), 7.91-7.97 (m, 1H), 8.48 (s, 1H), 8.51 (t, 1H), 8.71 (d, 1H), 9.37 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11](C3SC=CC=3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O)(=O)=O.C[C:26]1(C)[O:30][CH:29]([CH2:31]O)CO1.O>CN(C)C=O>[NH:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:31][CH:29]2[O:30][CH2:26]2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Reactant: CC1(C)OCC(CO)O1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(p-hydroxyphenyl)-4-(2-thienyl)imidazole (19.5 g, 0.08 m) in dimethylformamide (65 ml) is added to a stirred suspension of sodium hydride (4.8 g, 0.10 m, 50% dispersion in mineral oil) in dimethylformamide (20 ml) at 80° C. After stirring at 80° C. for 0.5 hours, a solution of 2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane methanesulfonate, (I) (16.82 g, 0.08 m) in dimethylformamide (20 ml) is added rapidly and the mixture is stirred under nitrogen at 80° C. for 17 hours. The reaction mixture is poured into H2O (400 ml) and extracted with ether (3×350 ml). The combined extracts are washed with 5% NaOH solution (2×250 ml) and with H2O (3X), dried, and the solvent is evaporated under reduced pressure to yield crude (II) (14.22 g) which is used without further purification.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:38][C:39]([F:50])([F:49])[O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:46][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([O:40][C:39]([F:49])([F:50])[F:38])=[CH:42][CH:43]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(OC(F)(F)F)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-trifluoromethoxybenzylamine, m.p. 145-149° C. MS [(+)ESI, m/z]: 626 [M+H]+ Anal. Calcd for C36H30F3N3O4: C, 69.11; H, 4.83; N, 6.72. Found: C, 69.08; H, 4.95; N, 6.53.