Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O.O>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([O:12][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2=O
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To a solution of 3,4-dihydro-5-hydroxy-1(2H)-naphthalenone (8.20 g, 50.6 mmol) in N,N-dimethylformamide (80 mL) was added sodium hydride (60% dispersion in liquid paraffin, 2.22 g, 55.6 mmol) at 0° C. and the mixture was stirred at that temperature for 10 minutes. Then, ethyl bromoacetate (9.29 g, 55.6 mmol) was added and the mixture was further stirred at room temperature for 30 minutes. This reaction mixture was poured in water (80 mL) and extracted with 2 portions of ethyl acetate. The organic layers were pooled, washed with water, dried over anhydrous magnesium sulfate (MgSO4), and filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from hexane-diisopropyl ether to provide 8.40 g of the title compound. Yield 67%.
Reaction SMILES: C[O-].[Na+].[C:4]([OH:8])(=[O:7])[CH2:5][SH:6].Cl[CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CO>[C:4]([OH:8])(=[O:7])[CH2:5][S:6][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCC#CCC#CCCl
Reactant: O=C(O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCC#CCC#CCSCC(=O)O
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
2.02 ml of a 30% solution of sodium methoxide in methanol were added dropwise to a solution of 372 μl of thioglycolic acid in 5 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then a solution of 1.2 g of 1-chloro-2,5-tetradecadiyne in 6 ml of methanol was added under an inert atmosphere. The mixture was maintained under stirring for 20 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4) filtered and concentrated under vacuum in a rotary evaporator. The oily residue obtained crystallized on cooling. 3-Thia-5,8-heptadecadiynoic acid was recrystallized from heptane and then from hexane and finally from diisopropyl ether. The acid was thus isolated in the form of beige crystals with a yield of 49.4%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH:11]([Br:13])[Br:12].CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:22])=[O:7])=[CH:4][C:3]=1[CH:11]([Br:13])[Br:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)c(C(Br)Br)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)c(C(Br)Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 250 mL round bottom flask was charged with the 4-Bromo-3-(dibromomethyl)benzoic acid prepared as described above (114.6 g, 307 mmol) in anhydrous toluene (1.14 L) and anhydrous DMF (6.3 mL). The resulting suspension was stirred at RT under an argon atmosphere. Oxalyl chloride (29.5 mL, 338 mmol) was added dropwise. The reaction mixture became a clear yellow solution at the end of the reaction. HPLC indicated the reaction was complete in 2 hours. The solution was decanted away from a gummy oil deposited at the bottom of the reaction flask and the solution was concentrated on a rotary evaporator and then on a high vacuum pump overnight to dryness. The 4-Bromo-3-(dibromomethyl)benzoyl chloride was obtained as a light brown solid 115.02 g, 95.7% yield and area percent=93.5%. The 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH:23]1([NH:26][C:27](=[O:45])[C:28]2[CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[C:31]([CH3:43])=[C:30]([F:44])[CH:29]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.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>[CH:23]1([NH:26][C:27](=[O:45])[C:28]2[CH:33]=[C:32]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:7][N:8]4[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=3)[C:31]([CH3:43])=[C:30]([F:44])[CH:29]=2)[CH2:24][CH2:25]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)CCOCn1nc(S(C)(=O)=O)c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(S(C)(=O)=O)nn(COCC[Si](C)(C)C)c2c1
Yield: 66.1 %

Procedure:
A mixture of 6-bromo-3-(methylsulfonyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazole (Intermediate 76) (0.18 g) N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 62) (0.14 g) aqueous sodium carbonate (1M, 1.32 ml) and tetrakis(triphenylphosphine)palladium(0) (0.01 g) in isopropanol (2 ml) was stirred at reflux under nitrogen for 18 h. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (2:1) to give the title compound (0.15 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:37][CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:22]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].C1C=C(Cl)C=C(C(OO)=[O:48])C=1>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:37]([CH3:38])=[O:48])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:22]([NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: CSc1nc(-c2cc(C(=O)NCCc3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(2-phenylethyl)benzamide (200 mg, 0.369 mmol) in dichloromethane (7 mL) was added m-CPBA (86.1 mg, 0.553 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then the reaction mixture was applied to flash chromatography to afford the titled compound 157 mg (76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].Br.CS(C)=O.C(OCC)(=O)C>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCOCC2)cc1NC(N)=S
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COc1ccc(C2CCOCC2)c2sc(N)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a stirred solution of 1.90 g (7.13 mmol) [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea in 20 ml acetic acid heated to 80° C. was added dropwise 1.45 ml (8.27 mmol) hydrobromic acid (5.7 M solution in acetic acid) and stirring continued for 30 min at 80° C.0.56 ml (7.85 mmol) DMSO was then added dropwise and the reaction mixture stirred for a further 30 min at 80° C. The mixture was then cooled to room temperature, poured slowly onto sodium bicarbonate solution, and ethyl acetate added. The mixture was stirred for 10 minutes at room temperature and the resulting crystals collected by filtration, washing with ethyl acetate. The mother liquor phases were separated and the organic phase concentrated in vacuo to 5 ml. The resulting second crop of crystals was collected by filtration and combined with the first crop to afford 920 mg (49%) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine as a white solid. ES-MS m/e (%): 265 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[N:3]=1.[F-].[Cs+].[CH2:19]([N:26]1[CH2:33][CH2:32][CH:31]2[CH:27]1[CH2:28][NH:29][CH2:30]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([N:26]1[CH2:33][CH2:32][CH:31]2[CH2:30][N:29]([C:2]3[CH:7]=[C:6]([NH2:8])[N:5]4[N:9]=[C:10]([C:12]5[O:13][CH:14]=[CH:15][CH:16]=5)[N:11]=[C:4]4[N:3]=3)[CH2:28][CH:27]12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cc(Cl)nc2nc(-c3ccco3)nn12
Reactant: c1ccc(CN2CCC3CNCC32)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: Nc1cc(N2CC3CCN(Cc4ccccc4)C3C2)nc2nc(-c3ccco3)nn12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
5-Chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine (0.5 mmol; see WO 99/43678 A1) was dissolved in 4 mL of DMSO along with 2-benzyl-2,7-diazabicyclo[3.3.0]octane (2 mmol; see U.S. Pat. No. 5,071,999) and 0.7 mmol of CsF. The reaction mixture was stirred at 120° C. for 8 hours. It was then cooled to room temperature and purified by preparative HPLC to afford the title compound. 1H NMR (400 Hz, DMSO-d6) 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.0-7.2 (m, 5H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H) 5.2 (s, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 10H). m/z: 402 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:21][CH3:22])[C:11]=3[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:29]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)(=[O:31])[CH3:30]>CN(C)C=O.O>[C:29]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:8]=[CH:9][C:10]4[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:21][CH3:22])[C:11]=4[N:12]=3)[CH2:6][CH2:5]2)=[CH:35][CH:34]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Nc1ccc(CBr)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc(NC(C)=O)cc4)CC3)nc21
Yield: 80.7 %

Procedure:
To a suspension of 35.3 g of 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid in 500 ml of dimethylformamide was added a solution of 39.0 g of potassium carbonate in 50 ml of water and then 39.5 g of p-acetamidobenzyl bromide. The mixture was heated at 80°-90° C. for 1.5 hours with stirring. After removal of a small amount of the insoluble material by filtration, the filtrate was concentrated to dryness under reduced pressure and the residue was dissolved in 100 ml of water. The solution was adjusted to pH 7.0 with acetic acid. The precipitate was collected by filtration and recrystallized from a mixture of dimethylformamide and ethanol to give the product (42.3 g), m.p. 216.5°-219° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[Br:15]Br.O>CC(O)=O.II>[Br:15][C:9]1[C:2]([OH:1])=[C:3]([O:13][CH3:14])[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:8]=1)[CH:6]=[O:7]
Reactant: BrBr
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: COc1c(O)c(Br)cc(C=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.9 %

Procedure:
To the mixture of aldehyde 153 (28.0 g, 142 mmol) and I2 (1.5 g) in AcOH (160 mL) was added Br2 (8.0 mL, 157 mmol) at 0° C. The mixture was warmed up to r.t. and stirred at r.t. for 15 hours. The mixture was poured into water (2.0 L) with stirring. The mixture was stirred at r.t. for 30 min. The mixture was extracted with EtOAc (1 LX2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide the compound 154 (38 g, 98%).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:22][C:21]3[C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18][C:17]([CH3:26])([CH3:25])[C:16]=3[CH2:15]2)=[O:13])=[N:7][CH:6]=1)C.[OH-].[K+].Cl>C(O)C.O>[CH3:25][C:17]1([CH3:26])[CH2:18][CH2:19][C:20]([CH3:23])([CH3:24])[C:21]2[CH2:22][C:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:32])=[O:3])=[CH:6][N:7]=3)=[O:13])[CH2:15][C:16]1=2
Reactant: CCCCCC1(C(=O)Nc2ccc(C(=O)OCC)cn2)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC1(C(=O)Nc2ccc(C(=O)O)cn2)CC2=C(C1)C(C)(C)CCC2(C)C

Procedure:
The ester was dissolved in 20 ml of ethanol and treated with a solution of 1 g of KOH (potassium hydroxyde) in 2 ml of water. After 2 hours at 40° C. the reaction mixture was poured on ice/water, acidified with 2 N HCl and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and the solvent evaporated. The residue was crystallized from ethyl acetate/pentane and gave 0.6 g of 6-[(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbonyl)-amino]-nicotinic acid as colorless crystals, m.p. 172-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[NH2:10])[C:5]#[N:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:22](Cl)(=[O:24])[CH3:23].Cl>C1COCC1.O.C(Cl)Cl>[C:22]([NH:10][C:9]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[Cl:11])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(Cl)cc(C#N)cc1Cl
Reaction time: 8 h

Procedure:
Step B (1): To a solution of 3,5-dichloro-4-amino-benzonitrile (187 mg, 1 mmol) in 4 mL of THF at room temperature was added 2.2 mL of 1.0 M NaHMDS in THF. The resulting reaction mixture was stirred at room temperature for 30 min, at which time acetyl chloride (3.1 mmol) was added. DCM (100 mL) and water (100 mL) were added to the reaction mixture after being stirred overnight, followed by the addition of 5 mL of a 1.4 N HCl aqueous solution. The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The extracts were combined and solvents were evaporated in vacuo. The residue was purified by HPLC to give 4-acetamido-3,5-dichloro-benzonitrile. MS (ESI) (M−H)+=227.05. 1H-NMR (300 MHz, CDCl3) δ 7.63 (s, 2 H), 2.21 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6].Cl[CH:20](OCC)[CH2:21]Cl>CCOC(C)=O>[Cl:18][C:3]1[C:2]2[N:9]([CH:20]=[CH:21][N:1]=2)[CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cnc(N)c1Cl
Reactant: CCOC(Cl)CCl
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1Cl
Temperature: 150 °C
Yield: 59.4 %

Procedure:
In a sealed tube, a mixture of 2-amino-3-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (285 mg, 0.96 mmol) and 1,2-dichloro-1-ethoxy-ethane (0.64 mL, 5.25 mmol) was heated at 150° C. for 17 min under microwave irradiation. The reaction mixture was cooled to RT, poured into AcOEt (75 mL) and washed with a 2.0 M Na2CO3 solution in water (2×25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (185 mg, 0.57 mmol, 60%) as a brownish solid. MS: 322 [M+1]+; HPLC: AtRet=2.17; TLC: RF 0.13 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[C:12]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1)#[N:13]
Reactant: CC(C)c1cc(Br)ccc1O
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)c1cc(C#N)ccc1O
Yield: 60 %

Procedure:
4-Bromo-2-isopropyl-phenol (500 mg, 2.3 mmol), Zn(CN)2 (270 mg, 2.3 mmol) and tetrakis(triphenylphosophine)palladium (237 mg) were mixed in DMF (1 mL) in a microwave reaction tube. It was reacted under microwave condition at 180° C. for 20 minutes. The mixture was filted and purified by by silica gel chromatography (40% -60% EtOAc/Hexane) to provide the title compound (220 mg, 60%). MS (DCI) m/z 162 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:19].[K+]>O>[Br:1][C:2]1[CH:3]=[C:4]([I:19])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: [I-]
Reactant: Cc1ccc(N)cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1ccc(I)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a vigorously stirred mixture of 3-bromo-4-methylaniline (40 g, 215 mmol), sulfuric acid (360 mL) and H2O (900 mL) at 0° C. was added dropwise a NaNO2 solution (16.6 g, 240 mmol in 80 mL of H2O). The mixture was stirred at 0° C. for 1 hour and a solution of potassium iodide (64 g, 387 mmol in 160 mL of H2O) was added. The reaction was stirred for 8 hours at r.t. The aqueous layer was extracted with Et2O and the combined organic layers were washed with a 10% aqueous solution of Na2S2O3, dried over Na2SO4 and concentrated. The residue was filtered through a silica gel pad eluted with 10% EtOAc/hexane and concentrated to give 60 g of the title compound as a reddish syrup used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:29]=[N+:30]=[N-:31]
Reactant: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)CN=[N+]=[N-])n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 2',5-dichloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.533 g) in dimethylformamide (15 ml), sodium azide (0.228 g) is added portionwise, and the resultant mixture is stirred at room temperature for 2.25 hours and allowed to stand overnight. The reaction mixture is evaporated under reduced pressure to remove the solvent, and the residue is shaken with chloroform. The organic layer is washed with water, dried and evaporated to remove the chloroform. The residue is washed with ether to give 2',5-dichloro-2-[3-(2-azidoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.45 g). The yield is 93.2%.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[CH:6]3[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1.IC.[CH3:23]C(C)([O-])C.[Na+]>CS(C)=O.O.ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:7](=[O:16])[C:6]3([CH3:23])[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Solvent: ClCCl
Product: CC12COCCN1c1nc(Cl)ncc1N(CC1CC1)C2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 20.7 %

Procedure:
To 2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (3.57 g, 12.11 mmol) in DMSO (28 mL) was added iodomethane (0.907 mL, 14.54 mmol), and the mixture was cooled in an ice-water bath. Then sodium tert-butoxide (1.39 g, 14.54 mmol) was added. After 5 minutes stirring at 0° C., the mixture was allowed to warm up to room temperature and stirred for 17 hours. The reaction mixture was cooled in an ice-water bath and more iodomethane (0.378 mL) was added, followed by more sodium tert-butoxide (582 mg). The mixture was warmed up to room temperature and stirred for 55 minutes, then sealed and heated at 50° C. (bath temperature) for 1 hour. The reaction was cooled to room temperature and additional iodomethane (3 mL) was added, then sealed and heated at 50° C. (bath temperature) for another 27 minutes then cooled in an ice-water bath and more sodium tert-butoxide (582 mg) was added. The mixture was then warmed up to room temperature and stirred for 75 minutes. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layers were combined and solvent was removed to give a brown solid. The solid was dissolved in dichloromethane and purified on silica gel eluting with Hexanes-EtOAc (0-50%), to give 2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a solid (773 mg, 33%). MS [M+H] found 309.2.
Reaction SMILES: C1(O)C=CC=CC=1.[CH3:8][NH:9][CH2:10][C:11]1[N:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[S:14][CH:15]=1.[O:19]([C:26]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])=O)C1C=CC=CC=1.O>C1COCC1>[CH3:8][N:9]([C:26]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:19])[CH2:10][C:11]1[N:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[S:14][CH:15]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Solvent: O
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 4.5 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a solution of LiOH monohydrate (970 mg, 23.2 mmol) and phenol (2.18 g, 23.2 mmol) dissolved in 25 mL of THF and cooled with an ice bath to 3-6° C. was added N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.95 g, 23.2 mmol) followed by a 1 mL THF rinse. To this mixture was slowly added a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) dissolved in 20 mL of THF maintaining the temperature between 3° C. and 8° C. Following the addition and a 5 mL THF rinse, the cooling bath was removed, and the reaction was allowed to warm to ambient temperature. After stirring for 3 hours at ambient temperature, an additional aliquot of LiOH monohydrate (440 mg, 10.4 mmol) was added. One hour later, the reaction was treated with 100 mL of water and the THF removed under reduced pressure. The aqueous phase was adjusted to pH 9 using concentrated HCl and then washed with MTBE (3×60 mL). Toluene (60 mL) was added to the aqueous phase which was then acidified to pH 2.5 using 4 N HCl. The toluene phase was separated, and the aqueous phase was back extracted with four 60 mL aliquots of toluene. The combined organic extracts were concentrated under reduced pressure. The oil obtained was crystallized from toluene-heptane to give the title compound (5.41 g, 82%).