Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[C:16]([Br:19])([CH3:18])C.[C:20](=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:19][CH2:16][CH2:18][CH2:20][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:9]=1
Reactant: CC(C)(Br)Br
Reactant: O=C([O-])[O-]
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCC(O)c1cccc(OCCCBr)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
19.4 g. (0.1 mole) 3-(1-hydroxyhexyl)-phenol and 80.4 g. (0.4 mole) dibromopropane are dissolved in 150 ml. methyl ethyl ketone and heated to 80° C. 15.2 g. Potassium carbonate are added thereto in the course of 1 hour. The reaction mixture is then stirred for 8 hours at 80° C., the residue is filtered off and the solvent is evaporated, together with excess dibromopropane. The residue is taken up in ethyl acetate, extracted twice with aqueous sodium hydroxide solution, washed neutral, dried and evaporated. There are obtained 25.8 g. (82% of theory) of the title compound in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[C]=O.[C:12]1([N:18]=C=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C2C3NC(=CC=3)C(C3C=CC=CC=3)=C3N=C(C=C3)C(C3C=CC=CC=3)=C3NC(C=C3)=C(C3C=CC=CC=3)C3=NC=2C=C3)C=CC=CC=1.[Pd].ClC1C=CC=CC=1Cl>[N:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: [Pd]
Agent: C1=Cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Agent: [C]=O
Solvent: Clc1ccccc1Cl
Product: c1ccc(N=Nc2ccccc2)cc1
Temperature: 235 °C
Reaction time: 4 h

Procedure:
Into the autoclave previously described, 2 grams of palladium tetraphenylporphyrin and 30 grams of nitrobenzene are introduced and the total volume adjusted to 100 ml by means of orthodichlorobenzene. The reactor is closed and after scavenging with nitrogen, carbon monoxide is introduced until the pressure reaches 200 bars at 20° C. The autoclave is isolated and while maintaining an agitation is heated at 235° C. for 3 hours, then at 240° C. for 4 hours, 30 minutes. After cooling, the mixture is analyzed. The O.C.R. of the nitrobenzene is 94.7% and the selectivity for phenylisocyanate is 60.2%. No azobenzene is formed.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[CH2:29][C:28]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[O:27][N:26]=1)=O.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>O1CCOCC1>[F:11][C:8]([F:9])([F:10])[C:7]1[C:2]2[NH:1][C:23]([C:25]3[CH2:29][C:28]4([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[O:27][N:26]=3)=[N:22][C:3]=2[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])[CH:6]=1
Reactant: Nc1c(NC(=O)C2=NOC3(CCCCC3)C2)cc(-c2ccccc2C(F)(F)F)cc1C(F)(F)F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Product: FC(F)(F)c1ccccc1-c1cc(C(F)(F)F)c2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 91 %

Procedure:
1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (4-amino-5,2′-bis-trifluoromethyl-biphenyl-3-yl)-amide (9.22 g, 19.0 mmol, as prepared in the previous step) was placed in a 250 mL round-bottom flask equipped with a magnetic stir bar. Dry dioxane (200 mL) and CSA (883 mg, 3.80 mmol) were added. The flask was fitted with a reflux condenser, and the mixture was stirred at 100° C. for 7.5 h. The reaction was cooled to RT, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed twice with satd aq NaHCO3 (50 mL). The organic extract was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in a minimum amount of MeOH (50 mL) and placed in a freezer for 1 h. The resulting precipitate was isolated by filtration and washed with MeOH. The precipitate was purified by recrystallization from hot MeOH (30 mL), giving a pale yellow solid, which was dried under high vacuum. The filtrate was concentrated under reduced pressure and purified by column chromatography using an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min. The solid precipitate and column-purified material were combined, yielding 8.12 g (91%) of the title compound. 1H-NMR (400 MHz, CDCl3) 6: 1H-NMR (400 MHz, DMSO-d6) δ: 7.89 (d, J=7.6 Hz, 1H), 7.77 (t, J=7.3 Hz, 1H), 7.68 (t, J=7.6 Hz, 2H), 7.55 (d, J=7.6 Hz, 1H), 7.48 (s, 1H), 3.33 (s, 2H), 1.63-1.82 (m, 6H), 1.35-1.58 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12](=[O:15])([O-])[O-:13].[K+].[K+].O.[C:19](#N)[CH3:20]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([C:20]2[CH:19]=[CH:7][C:6]([C:12]([OH:13])=[O:15])=[CH:5][CH:4]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CC#N
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C(O)c1ccc(-c2ncccc2C(F)(F)F)cc1
Temperature: 160 °C
Yield: 81 %

Procedure:
4-Bis(hydroxyl)boron-1-methylbenzoate (2.8 mmol) was dissolved in acetonitrile (2 ml) and added to a 5 ml microwave vessel. To the solution was 3.5 mmol of 2-chloro-3-trifluoromethylpyridine (633 mg), 34 mg of tetrakis(triphenylphosphine)-palladium(0). After stirring until dissolution, 8.4 mmol of potassium carbonate (1.16 g) was added, followed by 1 ml of water. The mixture was then heated at 160° C. for 300 seconds. After reaction completion, the solvents were evaporated under vacuum. The residue was dissolved in 2N KOH and THF and heated for 10 min. After hydrolysis, the THF was evaporated and the basic layer was washed with EtOAC. The aqueous layer was then acidified and extracted 3 times with EtOAc. The organic layers were combined and washed with water and brine. After drying, filtration and evaporation, the residue was prufied by HPLC to give of the target compound as a white solid (602 mg; 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[NH:12][CH2:11][CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:12]1[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:13]1=[O:14])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)C(c2ccc(F)cc2)C1=O
Reaction time: 16 h

Procedure:
A solution of (±)-tert-butyl 2-(4-fluorophenyl)-3-oxopiperazine-1-carboxylate (50.0 mg, 0.170 mmol, described in Intermediate 48) and sodium hydride (8.15 mg, 0.204 mmol, 60% dispersion in mineral oil) in DMF (1 mL) was stirred at ambient temperature for 0.5 h. Ethyl bromoacetate (0.023 mL, 0.204 mmol) was added and stirring continued for 16 h. The reaction mixture was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were neutralized with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=381 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.O[N:33]1[C:37]2C=CC=CC=2N=N1.[Cl-].C[NH3+].C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][N:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH:33][CH3:37])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: C[NH3+]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
A mixture of [2-(7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (280 mg), N-ethyl-N′-(37-dimethylaminopropyl)carbodiimide hydrochloride (233 mg), 1-hydroxybenzotriazole (164 mg), methylammonium chloride (82 mg), triethylamine (0.2 mL) and N,N-dimethylformamide (12 mL) was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed successively with 1M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate/hexane=0/75/25 to 10/90/0, volume ratio) to give a pale yellow amorphous solid. The amorphous solid was crystallized from ethyl acetate-diethyl ether to give white crystals. The crystals were washed with methanol-acetone to give the title compound (178 mg, 62%) as colorless crystals. MS 475 (MH+). mp 207-209° C.
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19]CC)=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:39]>O1CCOCC1.O>[ClH:39].[NH2:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][CH2:34][C:35]([F:36])([F:38])[F:37])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:11]1
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NCC(F)(F)F
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (381a, 970 mg, 1.81 mmol) and LiOH monohydrate (381 mg, 9.09 mmol) in dioxane (8.0 mL) and water (4.00 mL) was heated at 110° C. for 5 h. It was concentrated to dryness and the remaining solid was treated with 4.0 M HCl solution in 1,4-dioxane (11.36 mL, 45.5 mmol) at RT and stirred for 30 min. The reaction mixture was concentrated to give 2-(1-aminocyclopropyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (381b) as a red-orange solid. It was used in the subsequent step without further purification assuming quantitative yield. m/z (ESI, +ve ion) 406.1 (M−35)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[BH4-].[Na+]>C1COCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:5][OH:6]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of 3,5-dichlorobenzoyl chloride (712 mg, 3.40 mmole) in THF (6 ml) at 0° C. is added dropwise a solution of sodium borohydride (227 mg, 6.0 mmole), in N-methyl pyrrolidinone (1.5 ml) maintaining the temperature at ≤18° C. The reaction mixture is stirred for 2 hours at ambient temperature and then partitioned with 0.5N aqueous HCl (60 ml) and EtOAc (60 ml). The layers are separated and the aqueous layer is washed with EtOAc (20 ml). The combined organic layer is washed with H2O (60 ml) and brine (40 ml), dried (Na2SO4), filtered, and concentrated to give crude product as a crystalline solid. One recrystallization from hot cyclohexane (7.5 ml) gives 2, i.e., 3,5-dichlorobenzyl alcohol (451 mg, 2.55 mmole, 75%, m.p. 77°-77.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:25][C:24](=[O:26])[CH2:23][N:22]=3)[C:9]=2[CH2:27][CH3:28])=[CH:4][CH:3]=1.[CH2:29](Br)[CH2:30][CH2:31][CH3:32]>>[CH2:29]([N:25]1[C:24](=[O:26])[CH2:23][N:22]=[C:21]1[C:10]1[C:9]([CH2:27][CH3:28])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCc1c(C2=NCC(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCCCBr
Product: CCCCN1C(=O)CN=C1c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1CC

Procedure:
Compound 30 was synthesized from 26 (102 mg, 0.23 mmol) and n-butyl bromide (500 mg, 3.65 mmol) as a white solid (55 mg, 49%) in a manner similar to that described in Example 59. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H), 7.30 (d, 2H), 7.25 (dd, 1H), 7.17 (d, 1H), 7.09 (d, 2H), 4.83 (s, 0.82H), 4.45 (s, 1.18H), 3.80 (s, 1.18H), 3.67 (s, 0.82H), 2.65 (q, 2H), 1.69 (br s, 2H), 1.42-1.25 (m, 2H), 1.13 (t, 3H), 0.97-0.86 (m, 3H); ESMS m/: 489.1 (M+1).
Reaction SMILES: [NH2:1][C@@H:2](/[CH:5]=[C:6](/[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)\[CH2:7][CH3:8])[CH2:3][OH:4]>C(O)C.[Pt]>[NH2:1][C@@H:2]([CH2:5][CH:6]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH2:7][CH3:8])[CH2:3][OH:4]
Reactant: CC/C(=C\[C@H](N)CO)c1ccc(Cl)cc1
Agent: [Pt]
Solvent: CCO
Product: CCC(C[C@H](N)CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (E)-(S)-2-amino-4-(4-chloro-phenyl)-hex-3-en-1-ol (0.52 g) at r.t. in ethanol (30 ml) under an argon atmosphere was added 5% Pt/C (180 mg). The mixture was stirred at r.t. under a hydrogen atmosphere for 16 hrs. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2-amino-4-(4-chloro-phenyl)-hexan-1-ol (mainly one epimer) (0.157 g, 30%) as colourless oil. MS (ISP): 230.3 ([{37Cl}M+H]+), 228.2 ([{35Cl}M+H]+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[S:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5].[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:17](Cl)=[O:18].[OH-].[Na+]>C(Cl)Cl>[CH3:11][C:8]1[S:7][C:6]([C:4](=[O:5])[CH2:3][NH:2][C:17](=[O:18])[C:16]2[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=[C:14]([C:13]([F:12])([F:27])[F:28])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)CN)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1
Yield: 83.1 %

Procedure:
In a manner similar to Example 1, the reaction of 2-amino-1-(5-methylthienyl)ethanone hydrochloride (2.6 g, 0.014 mole) in methylene chloride (75 ml) with 3,5-bis(trifluoromethyl)benzoyl chloride (3.8 g, 0.014 mole) and 2N sodium hydroxide solution (13.7 ml) yielded 4.6 g of N-[2-(5-methylthienyl)-2-oxoethyl]-3,5-bis(trifluoromethyl)benzamide as a solid.
Reaction SMILES: [I-].[K+].[CH2:3]([S:5][C:6]1[C:11]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)=[N:13][CH2:14][C:15]3[N:16]([C:17]([CH2:20]Cl)=[N:18][N:19]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:4].C[NH:30]C1CC1.O1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:3]([S:5][C:6]1[C:11]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)=[N:13][CH2:14][C:15]3[N:16]([C:17]([CH2:20][NH:30][CH2:35][CH:36]4[CH2:38][CH2:37]4)=[N:18][N:19]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:4]
Reactant: CNC1CC1
Reactant: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CCl)n1-2
Reactant: C1CCOC1
Agent: [I-]
Agent: [K+]
Product: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Example 2, potassium iodide and 7-(ethylthio)-1-(chloromethyl)-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with methylcyclopropylamine to give 7-(ethylthio)-1-[(cyclopropylmethylamino)methyl]-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[N:9]1([C:16]2[N:21]=[C:20]([NH2:22])[N:19]3[N:23]=[C:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:18]3[N:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(CC)CC>CC#N>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[C:24]1[N:25]=[C:18]2[N:17]=[C:16]([N:9]3[CH2:15][CH2:14][CH2:13][N:12]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:11][CH2:10]3)[N:21]=[C:20]([NH2:22])[N:19]2[N:23]=1
Reactant: Nc1nc(N2CCCNCC2)nc2nc(-c3ccco3)nn12
Reactant: ClCc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(N2CCCN(Cc3ccccn3)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloromethyl-pyridine (1.5 eq.) was directly added to a solution of 5-[1,4]diazepan-1-yl-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 8(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.9-7.1 (m, 4H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H); 3.8 (br s, 2H), 2.2-3.2 (m, 10 H). MS: m/z: 392 [M+H]+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:40])[C@H:6]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][CH2:23][C:24]2[C:32]3[O:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)=[C:17]([Cl:39])[CH:16]=1)[NH:7]C(=O)C(F)(F)F.Cl>O1CCCC1.O>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:39])[C:18]=1[O:22][CH2:23][C:24]1[C:32]2[O:31][C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)[CH2:14][C@@H:6]([C:5]([OH:40])=[O:4])[NH2:7]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(OCc2cccc3nc(-c4ccccc4)oc23)c(Cl)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](Cc1cc(Cl)c(OCc2cccc3nc(-c4ccccc4)oc23)c(Cl)c1)C(=O)O
Yield: 99.8 %

Procedure:
0.5 N Lithium hydroxide (4.5 ml, 2.25 mmol) was added to a solution of 3,5-dichloro-N-trifluoroacetyl-O-[(2-phenyl)-benzoxazol-7-yl]methyl-L-tyrosine methyl ester (246 mg, 0.434 mmol) in tetrahydrofuran (2 ml) at 5° C. and the mixture was reacted at 5° C. for 84 hrs. The reaction mixture was diluted with water, adjusted to pH 3-4 with 1N hydrochloric acid under ice cooling and allowed to stand at 5° C. The precipitates were collected by filtration, washed with water and then dried to give 3,5-dichloro-O-[(2-phenyl)-benzoxazol-7-yl]methyl-L-tyrosine (198 mg, 94%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:30])[CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:29])[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:20]3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].[OH2:41]>CN(C=O)C>[C:19]([OH:41])(=[O:20])/[CH:23]=[CH:36]\[C:37]([OH:39])=[O:38].[C:37]([CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:30])[CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:29])[CH:18]=[C:19]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:20]3)=[CH:15][CH:14]=2)=[CH:31][CH:32]=1)([O:39][CH3:40])=[O:38]
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CNCCc3ccc(O)cc3)ccc12
Reactant: O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(CCNCC(O)COc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1
Product: O=C(O)/C=C\C(=O)O
Temperature: -20 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
7-[3-[(4-Hydroxyphenethyl)amino]-2-hydroxypropoxy]flavone (10.8 g, 25.1 mmol), Example 13, was dissolved in 20 ml of warm DMF at 50°-60° C. and then cooled to -20° C. Sodium hydride (1.2 g, 0.0251 mmol) was added portionwise to the above cooled solution, stirred at -20° C. for 1 hour, and then cooled to -40° C. Methyl bromoacetate (3.8 g, 25.1 mmol) was added dropwise to the stirred solution and the reaction mixture was kept at this temperature for 2 hours and at RT overnight. The reaction was poured into 1.5 l of water, the water decanted, and the residue washed with two portions of water. The gummy material was then purified by flash column chromatography, eluting with CHCl3 --MeOH (20:1). The isolated material (2.7 g) was recrystallized from methanol, and the crystallized solid was treated with 30 ml of ethanol and maleic acid (0.3 g) to give the title compound as white crystals, mp 154°-156° C., 1.5 g (10% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([I:12])[CH:3]=1.O1CCCC1.[H][H]>C(O)CC>[Cl:1][C:2]1[CH:3]=[C:4]([I:12])[C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: [H][H]
Reactant: Nc1c(I)cc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCCO
Product: Nc1cc(Cl)cc(I)c1N
Temperature: 25 °C
Yield: 96.3 %

Procedure:
1.5 g of 4-chloro-2-iodo-6-nitroaniline together with 50 ml of tetrahydrofuran and 10 ml of 1-propanol are initially introduced into a stirred autoclave. 5 mg of FeCl2.4H2O and 0.3 g Pt/Pb-CaCO3 catalyst are added to the solution, and hydrogenation is carried out at 130° C. and 20 bar of hydrogen. After the hydrogenation has come to a standstill, the reaction mixture is cooled to room temperature, the reactor is rendered inert with nitrogen and the catalyst is filtered off. After filtration, the solvent is removed by distillation to give 1.3 g of 4-chloro-6-iodo-1,2-phenylenediamine as a crude product.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[Br:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[S:20])[N:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]2=[O:27].O>C1COCC1>[Br:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([S:20][CH3:3])[N:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]2=[O:27]
Reactant: O=C([O-])[O-]
Reactant: O=c1c2cccc(Br)c2[nH]c(=S)n1-c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc2c(Br)cccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of MeI (1.68 mL, 27.0 mmol), K2CO3 (2.49 g, 18.01 mmol), 8-bromo-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (402a; 3.00 g, 9.00 mmol) in 30 mL THF was fitted with a water cooled reflux condenser and heated to reflux (80° C. oil bath) overnight under N2. Additional 1.5 equiv MeI was added and heating continued. After 2 h, water was added, and the reaction was partitioned between water and EtOAc. The aqueous layer was washed 1× brine, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-(methylthio)-3-phenylquinazolin-4(3H)-one as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (1H, dd, J=7.8, 1.4 Hz), 8.07 (1H, dd, J=7.8, 1.4 Hz), 7.53-7.61 (3H, m), 7.44-7.51 (2H, m), 7.37 (1H, t, J=7.8 Hz), 2.56 (3H, s). m/z (ESI, +ve) 346.9/349.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C:6]([C:15]#[N:16])=[C:7](O)[CH:8]([CH2:11][S:12][CH3:13])[CH2:9][CH3:10])[CH2:2][CH3:3].O=P(Cl)(Cl)Cl.C([N:25](CC)CC)C>C(Cl)Cl>[NH2:25]/[C:7](/[CH:8]([CH2:11][S:12][CH3:13])[CH2:9][CH3:10])=[C:6](/[C:15]#[N:16])\[C:5]([O:4][CH2:1][CH2:2][CH3:3])=[O:17]
Reactant: CCCOC(=O)C(C#N)=C(O)C(CC)CSC
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCOC(=O)/C(C#N)=C(\N)C(CC)CSC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15 g (58.3 mmol) of n-propyl-2-cyano-3-hydroxy-4-[(methyl-sulfanyl)methyl]-2-hexenoate were dissolved in CH2Cl2, and 18 g (0.12 mmol) of POCl3 were added. At 0° C., 24 g (237 mmol) of triethylamine were then added dropwise, and the mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated and the residue was dissolved in acetonitrile. At 0° C., 50 ml (650 mmol) of 25% strength ammonia solution were then added dropwise to this solution, and the mixture was stirred for 1 h.