Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[C:2]1=[O:12].FC(F)(F)S([O-])(=O)=O.[F:21][C:22]([I+]C1C=CC=CC=1)([F:27])[C:23]([F:26])([F:25])[F:24].CN(C)C=O>C(OCC)(=O)C>[F:21][C:22]([F:27])([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2](=[O:12])[NH:1]2)[C:23]([F:26])([F:25])[F:24]
Reactant: FC(F)(F)C(F)(F)[I+]c1ccccc1
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(C(F)(F)C(F)(F)F)cc2[nH]c1=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
A mixture of 0.5 g of 2(1H), 3(4H)-quinoxalinedione, 1.60 g of pentafluoroethylphenyliodonium trifluoromethanesulfonate and 10 ml of dimethylformamide was stirred overnight on an oil bath at 45° C. Ethyl acetate was then added to the reaction mixture and the unreacted 2(1H), 3(4H)-quinoxalinedione was removed by filtration (recovery of the starting material: 0.13 g). Water was added to the filtrate and, after rendering the mixture neutral, the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off. A small amount of methylene chloride was added to the residue and the precipitated crystals were collected by filtration to obtain 0.05 g of 6-pentafluoroethyl-2(1H), 3(4H)-quinoxalinedione as colorless crystals. Yield 6% (conversion yield, 8%). Melting Point (after recrystallized from acetonitrile): 317°-320° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH2:5][CH:4]([C:8](=O)[CH3:9])[CH2:3]1.[C:12](O)(=O)C.[CH:16]([NH2:18])=[NH:17]>C(O)CCC>[CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:12][N:18]=[CH:16][N:17]=2)[CH2:3]1
Reactant: N=CN
Reactant: CC(=O)C1CCCC(C)(C)C1
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC1(C)CCCC(c2ccncn2)C1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 1-(3,3-dimethyl-cyclohexyl)-ethanone (Herbac®) (10 g, 0.06 mol, commercially available at IFF), formamidine acetate (31 g, 0.3 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 4-(3,3-dimethyl-cyclohexyl)-pyrimidine (˜10 g) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[CH:19]([Mg]Br)=[CH2:20].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[C:6]2[C:7]=1[NH:8][CH:20]=[CH:19]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])c(Br)c1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)c2[nH]ccc2c1
Temperature: -45 °C
Reaction time: 0.75 h

Procedure:
Combine 3-bromo-4-nitro-1-tert-butyldimethylsilyloxybenzene and dry THF. Cool to about −45° C. and then treat with vinylmagnesium bromide (1.2 eq.) over a few minutes. After about 45 minutes, pour the reaction mixture into saturated aq. NH4Cl, extract with ether, combined the organic extracts and extract with water, dry over Na2SO4 and concentrate. Purify to give 7-bromo-5-(tert-butyldimethylsilanyloxy)-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>O1CCCC1>[OH2:19].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.64 g, 0.020 mole) and 1,1'-carbonyldiimidazole (3.18 g, 0.02 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2 hours with a stream of nitrogen bubbling through it. A solution of diethylamine (2.87 g, 0.04 mole) in tetrahydrofuran was added dropwise at room temperature to the stirred solution and the mixture was allowed to stir overnight. The tetrahydrofuran was evaporated and the solid residue was triturated with water. The solid was collected by filtration and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum at room temperature over the weekend to give 3.83 g (57%) mp 155°-56° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:17])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([F:16])=[C:12]([CH:15]=1)[C:13]#[N:14])([CH3:7])[CH3:6].CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[S:34])=[CH:28][C:27]=1[O:35][CH3:36]>C(Cl)Cl>[C:13]([C:12]1[CH:15]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4](=[O:17])[CH2:3][NH:2][C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:35][CH3:36])[CH:28]=2)=[S:34])[CH:9]=[CH:10][C:11]=1[F:16])#[N:14]
Reactant: CC(C)(C(=O)CN)c1ccc(F)c(C#N)c1
Reactant: COc1cc(N=C=S)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=S)NCC(=O)C(C)(C)c2ccc(F)c(C#N)c2)ccc1F
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a suspension of 5-(4-amino-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile hydrochloride (2.8 g, 10.9 mmol) in DCM (50 mL) were added Et3N (4.6 mL, 32.7 mmol, 3 eq) and 1-fluoro-4-isothiocyanato-2-methoxybenzene (2.2 g, 12 mmol, 1.1 eq). After stirring 2 h, the reation mixture was partitioned in DCM and water. The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (silica, Hex:EA=1:1) to give 1-(3-(3-cyano-4-fluorophenyl)-3-methyl-2-oxobutyl)-3-(4-fluoro-3-methoxyphenyl)thiourea (3.7 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.59 (bs, 1H), 7.53-7.49 (m, 2H), 7.26-7.18 (m, 2H), 6.89-6.79 (m, 2H), 6.70 (bs, 1H), 4.44 (d, J=4.4 Hz, 2H), 3.90 (s, 3H), 1.58 (s, 6H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:11])[CH2:8][CH2:9][OH:10].[CH:12]([CH:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13].C(OCC)(=O)C>O1CCCC1>[CH:12]([CH:14]([O:10][CH2:9][CH2:8][CH2:7][OH:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13]
Reactant: OCCCO
Reactant: C=CC(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(OCCCO)c1ccccc1
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
Potassium tert-butoxide (23.07 g, 0.206 mol) was added to a stirred solution of 1,3-propanediol (44.92 g, 0.591 mol) in dry tetrahydrofuran (400 ml) under an atmosphere of nitrogen. The reaction mixture was stirred for 15 min then a solution of vinylbenzylchloride (mixture of meta and para isomers) (30.00 g, 0.197 mol) in dry tetrahydrofuran (100 ml) was added dropwise over 30 min. The reaction was heated at reflux overnight then the tetrahydrofuran was removed in vacuo and the residue taken-up in water (400 ml) and diethyl ether (400 ml). The organic phase was washed with water, dried (magnesium sulfate) and concentrated in vacuo to give a liquid. The liquid was purified by column chromatography over silica gel (eluent 3:1:petrol ether/ethyl acetate, then ethyl acetate) to give the title compound (30.59 g, 0.159 mol, 81%) as a straw colored liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.Cl[C:19]([C:21]1[CH:22]=[C:23]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[N:24]2[C:28]=1[CH2:27][S:26][CH2:25]2)=[O:20].C>C(Cl)Cl.C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:19]([C:21]2[CH:22]=[C:23]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:24]3[C:28]=2[CH2:27][S:26][CH2:25]3)=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(Cl)c1cc(-c2cccnc2)n2c1CSC2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NC(=O)c2cc(-c3cccnc3)n3c2CSC3)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
A solution of 3-methoxyaniline (3.1 g) and of triethylamine (5.1 g) in methylene chloride (50 cc) is added over 15 minutes at a temperature of between 21° and 28° C. to a suspension of 7-chloroformyl-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (7.5 g) in methylene chloride (125 cc). The solution obtained is stirred at a temperature of about 20° C. for 16 hours. A product precipitates out. The crystals which have appeared are separated off by filtration, washed 3 times with methylene chloride (300 cc in total) and 3 times with distilled water (300 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. A crude product (5.1 g) melting at 220° C. is thus obtained. This product is dissolved in boiling 1-butanol (160 cc). The cloudy solution obtained is treated with decolourising charcoal (0.5 g) and filtered hot. The filtrate is cooled at a temperature of about 4° C. for 16 hours. The crystals which have appeared are separated off by filtration, washed twice with 1-butanol (30 cc in total) 3 times with ethanol (75 cc in total) and 3 times with diethyl ether (75 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-(3-Methoxyphenyl)-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.9 g) is thus obtained in the form of pale yellow crystals melting at 224° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Br[C:14]1[CH:19]=[N:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[CH3:21][O:20][C:17]1[N:18]=[CH:19][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=2)=[N:15][CH:16]=1
Reactant: COc1cnc(Br)cn1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(Oc2cc(C)c(C(C)=O)c(C)c2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 3.50 g, 21.3 mmol), 2-bromo-5-methoxypyrazine (6.04 g, 32.0 mmol), copper (271 mg, 4.26 mmol), and potassium carbonate (8.84 g, 64.0 mmol) in 35.5 mL of DMF was stirred at 100° C. overnight. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), concentrated under reduced pressure, and purified by column chromatography on silica gel (20% EtOAc in hexanes as eluant) to give 1-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (15-1, 2.90 g) as yellow oils: 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1 H), 7.87 (s, 1 H), 6.72 (s, 2 H), 3.96 (s, 3 H), 2.47 (s, 3 H), 2.24 (s, 6 H).
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:17]([CH:22]=2)[C:18]([O:20]C)=[O:19])(=[O:12])=[O:11])[CH2:6][CH2:5]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:17]([CH:22]=2)[C:18]([OH:20])=[O:19])(=[O:12])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Temperature: 50 °C

Procedure:
LiOH (15.39 mg, 0.64 mmol) was added to a stirred solution of methyl 5-[(4-methyl-1-piperazinyl) sulfonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 71; 260 mg, 0.64 mmol) in a mixture of tetrahydrofuran and water (3:1, 40 ml). The mixture was heated at 50° C. for 6 h and then diluted with ethyl acetate (50 nil). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a white solid. 120 mg.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH:9][CH3:10].C1COCC1>CO>[CH3:8][N:9]([CH3:10])[C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7]
Reactant: C1CCC2OC2C1
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCCC[C@H]1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of cyclohexene oxide (3.64 mL, 36.0 mmol) in 30 mL of dry methanol was added dropwise 2.0 M dimethylamine in THF (15.0 mL, 30.0 mmol). The reaction mixture was stirred at 0° C. for 4 h. The solution was then warmed to room temperature and stirred for 18 h. The reaction mixture was then concentrated under reduced pressure to afford 1.11 g (26% crude yield) of the crude product which was used in the following reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C:23]=3[N:24]2[CH3:27])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C:23]=5[N:24]4[CH3:27])=[CH:20][CH:19]=3)[C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 25.5 %

Procedure:
4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (259 mg, 1.09 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (400 mg, 1.1 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (145 mg, 25%) as a yellow solid: ESI MS m/z 521 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:28]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:25])[C@@H:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:12]=[O:28])(=[O:6])=[O:7]
Reactant: O=[O+][O-]
Reactant: C=C[C@H](OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Product: COc1ccc(CO[C@@H](C=O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 66 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enyl (3-chloropropyl)sulfonate (13a) (3.0 g, 7.7 mmol) dissolved in 100 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 2 mL (1.69 g, 27.2 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 2.0 g (66% yield) of the title compound (13b) as a colorless oil. Rf=0.49 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.08 (s, 6H), 2.27-2.33 (m, 2H), 3.24-3.28 (m, 2H), 3.53 (d, J=2.4 Hz, 1H), 3.65-3.68 (m, 2H), 3.82 (s, 3H), 4.00 (d, J=9.2 Hz, 1H), 4.13 (d, J=9.2 Hz, 1H), 4.44 (d, J=11.2 Hz, 1H), 4.60 (d, J=11.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 9.69 (d, J=2.4 Hz, 1H) ppm. MS (ESI) m/z 415.11 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN([C:27]([O:31][N:32]1N=NC2C=CC=C[C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNOC>C(Cl)Cl>[CH3:27][O:31][N:32]([CH3:33])[C:11]([C:9]1[CH:8]=[C:7]([CH3:14])[N:6]=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[N:10]=1)=[O:13]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc(C(=O)O)nc(NC(C)C)n1
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(C)nc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
To a solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid (2.0 g, 10.2 mmol) in DCM (45 mL), DIPEA (8.8 mL, 51.2 mmol) followed by TBTU (3.9 g, 12.3 mmol) is added. The mixture is stirred at rt for 30 min before N,O-dimethylhydroxylamine (1.20 g, 12.3 mmol) is added. The mixture is stirred at rt for 18 h before it is diluted with DCM, washed with sat. aq. NaHCO3, followed by water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:2 to give 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (2.39 g) as a yellow oil; LC-MS: tR=0.66 min, [M+H]+=239.03; 1H NMR (D6-DMSO): δ 1.14 (d, J=6.5 Hz, 6H), 2.28 (s, 3H), 3.23 (s, 3H), 3.67 (s, 3H), 4.05 (m, 1H), 6.50 (s br, 1H), 7.12 (s br, 1H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].O.[OH-].[Li+].C(OCC)(=O)C>C1COCC1.O>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)=[CH:19][CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)C(=O)O
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (51 mg, 0.108 mmol) in THF (3 mL) was treated with a solution of lithium hydroxide monohydrate (18 mg, 0.43 mmol) in water (1.0 mL). Additional THF was added to effect a clear solution and the reaction mixture was stirred 1 hr. TLC (ethyl acetate) indicated starting material was consumed. A few drops of acetic were added and the entire reaction mixture was applied to a 4×30 cm, C-18 reversed phase HPLC column and eluted with a linear gradient of acetonitrile in water of 5 to 95% over 35 min. The product containing fraction was lyophillyzed to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine (40 mg, 82%) as a white solid. LR-Electrospray: m/z positive ion, 481(M+Na), 459(M+H (2 Cl)); negative ion, 457 (M−H (2 Cl)).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.[CH2:28]([O:30][C:31](=[O:56])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([NH:43][C:44](OCC(Cl)(Cl)Cl)=[O:45])=[CH:41][C:40]([C:52]([CH3:55])([CH3:54])[CH3:53])=[N:39]2)[CH:33]=1)[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:28]([O:30][C:31](=[O:56])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([NH:43][C:44]([NH:27][C@@H:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C@H:17]([O:16][C:13]4[CH:14]=[CH:15][C:10]5[N:11]([C:7]([C@@H:3]6[CH2:4][CH2:5][CH2:6][N:2]6[CH3:1])=[N:8][N:9]=5)[CH:12]=4)[CH2:18][CH2:19]3)=[O:45])=[CH:41][C:40]([C:52]([CH3:55])([CH3:54])[CH3:53])=[N:39]2)[CH:33]=1)[CH3:29]
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of Intermediate 5c (163 mg, 0.45 mmol), Intermediate 30a (208 mg, 0.45 mmol) in 1,4-dioxane (3 mL) and DIPEA (119 μL, 0.68 mmol) was stirred at 90° C. for 3 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to give the product (291 mg, 96%). A 64 mg portion of this was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as a white powder after freeze-drying powder (38 mg). LCMS (Method 5): Rt 3.85 min, m/z 677.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26-1.33 (12H, m), 1.80-2.27 (11H, m), 2.30-2.39 (1H, m), 3.09-3.16 (1H, m), 3.99 (1H, br t, J 8.2), 4.32 (2H, q, J 7.1), 4.74-4.83 (1H, m), 5.36-5.41 (1H, m), 6.33 (1H, s), 7.11 (1H, d, J 8.6), 7.19-7.37 (5H, m), 7.66 (1H, t, J 7.9), 7.75 (1H, d, J 9.9), 7.80-7.84 (1H, m), 7.93-7.98 (1H, m), 8.07-8.09 (1H, m), 8.22-8.28 (2H, m).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:16][C@H:15]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CC(N(C)C)=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C@H:13]3[CH2:14][C@H:15]([CH2:17][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3ccc(CN4CCCC4)cc3)C2)cc1
Reactant: C1CCNC1
Solvent: CC(=O)N(C)C
Product: c1cc([C@H]2C[C@H](CN3CCCC3)C2)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of Example 48 (trans-toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester) (200 mg, 0.5 mmol) in DMA (1.5 mL) was added the appropriate amine, for example pyrollidine (84 uL, 1.0 mmol). The reaction was then heated to 110 □C (oil bath). After 12 hr the reaction was cooled to rt and concentrated under reduced pressure. This material was free based by stirring in solid K2CO3 and MeOH for 2 hours. After 2 hr of stirring silica gel was added to the vessel (dry pack) and the methanolic slurry was concentrated. Purfication of this material was accomplished by flash column chromatography using a 12 g ISCO column, eluting with a gradient of 5%–10% MeOH/CH2Cl2 with 0.2% NH4OH. The product containing fractions were collected and concentrated to give the title compound as a colorless oil. The HCl salt was made by taken the freebase up in EtOAc and then adding a solution of HCl (2 eq, 1 M HCl, THF) to give a colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=[C:17]=[S:18])[N:5]=1.[CH3:19]I.O>O1CCCC1>[CH3:3][C:4]1[N:5]=[C:6]2[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:17]([S:18][CH3:19])[N:7]2[N:8]=1
Reactant: CI
Reactant: Cc1nc(Cc2ccccc2N=C=S)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSC1=Nc2ccccc2Cc2nc(C)nn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.91 g of sodium hydride in 27 ml of tetrahydrofuran is added dropwise a solution of 8.74 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole in 60 ml of tetrahydrofuran over a period of 20 minutes. The mixture is stirred at room temperature for 2 hours. To the resulting suspension is added a solution of 5.4 g of methyl iodide in 35 ml of tetrahydrofuran dropwise at 0° over a period of 15 minutes. The mixture is stirred at room temperature for 1 hour, poured into water and extracted three times with methylene chloride. The organic extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to give 2-methyl-5-methylthio-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine.