Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[S:19][C:20]([CH:23]=O)=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:11]([CH3:25])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28]OS(O)(=O)=O>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[S:19][C:20]([C:23]#[N:28])=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:11]([CH3:25])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOS(=O)(=O)O
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccc(C=O)s3)cc21
Solvent: O
Solvent: CC#N
Product: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccc(C#N)s3)cc21
Temperature: 65 °C
Yield: 43.8 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-6-(5-formyl-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline (12 mg, 0.03 mmol) in acetonitrile/water (10 ml/0.5 ml) was added hydroxylamine-O-sulphonic acid (5 mg, 0.04 mmol). The reaction mixture was heated to 65° C. for 1 h. The reaction was quenched with 10% NaOH (5 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water and brine (3×5 mL each), dried (Na2SO4), and concentrated in vacuo to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20×20 cm, 250 μm, 25% EtOAc:hexane) to afford 5 mg (40%) of 1-tert-butyloxycarbonyl-6-(5-cyano-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline as a yellow oil. This product was dissolved in CH2Cl2 (5 mL) and treated with TFA (0.1 ml) at rt with stirring. After 2 h, the reaction was quenched with 10% NaOH (5 mL). The organic layer was washed with water and brine (3×5 mL each), dried (Na2SO4) and concentrated in vacuo to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20×20 cm, 250 μm, 25% EtOAc:hexane) to afford 2 mg (60%) of Compound 451 as a yellow oil. Data for Compound 451: Rf 0.3 (silica gel, 25% EtOAc:Hex); 1H NMR(400 MHz, CDCl3) 7.52 (d, J=4.0, 1H), 7.23 (s, 1H), 7.22 (d, J=7.4, 1H), 7.07 (d, J=4.0, 1H), 6.43 (d, J=7.4, 1H), 5.38 (s, 1H), 2.02 (s, 3H), 1.31 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=1[F:16])=[O:6].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][N:21]=1.[OH-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][N:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=1[F:16])=[O:6]
Reactant: COC(=O)CC(=O)Nc1ccc(SC)cc1F
Reactant: ClCc1ccncn1
Agent: [K+]
Agent: [OH-]
Product: COC(=O)C(Cc1ccncn1)C(=O)Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
N-(2-Fluoro-4-methylsulfanyl-phenyl)-malonamic acid methyl ester (15.4 g, 59.9 mmol), 4-chloromethyl-pyrimidine (5.13 g, 39.9 mmol) and potassium hydroxide (3.36 g, 59.9 mmol) were dissolved in IMS (150 mL). The reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (4.9 g, 23%). LCMS (Method B): RT=3.02 min, M+H+=350.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][N:7]=1)=[O:5])[CH3:2].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Cl:12])=[C:9]([CH3:11])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c(C)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.4 %

Procedure:
A mixture of 5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (4.45 g, 28.9 mmol) and N-chlorosuccinimide (5.01 g, 37.5 mmol) in dimethylformamide (60 mL) was stirred for 24 hours at ambient temperature. The reaction was then concentrated down and purified by eluting through a silica gel column with a 0 to 100% ethyl acetate/heptane gradient to afford the title compound (5.2 g, 96% yield) as a white solid. MS (ESI) [m/e, (M+H)+]=189.3. 1H NMR (400 MHz, chloroform-d) δ ppm 9.39 (br. s., 1H), 4.44 (q, J=7.1 Hz, 2H), 2.35 (s, 3H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH:10]=[C:9]([O:12][Si](C(C)(C)C)(C)C)[NH:8]2)=[CH:3][CH:2]=1.C([Li])CCC.[CH3:26][C:27]([CH3:29])=[O:28]>O1CCCC1.CCCCCC>[OH:28][C:27]([CH:10]1[CH2:11][N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=2)[NH:8][C:9]1=[O:12])([CH3:29])[CH3:26]
Reactant: CC(C)=O
Reactant: Cc1ccc(N2CC=C(O[Si](C)(C)C(C)(C)C)N2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(N2CC(C(C)(C)O)C(=O)N2)cc1
Temperature: -78 °C
Yield: 63.2 %

Procedure:
A solution of 1-p-tolyl-3-(t-butyldimethylsiloxy)-pyrazoline (218 g, 0.75 mole) in 750 ml anhydrous tetrahydrofuran was added dropwise over a 30 minute period to a solution of n-butyllithium (51.5 g, 0.80 mole) in 350 ml n-hexane and 3.0 l anhydrous tetrahydrofuran stirred under nitrogen and cooled to -78° C. in a dry ice-acetone bath. The mixture was stirred for another 30 minutes then treated with one portion of acetone (58. g, 1.0 mole), and stirred at -78° C. for an additional 30 minutes. After removal of the dry ice-acetone bath, one portion of 250 ml 5% aqueous hydrochloric acid was added and the mixture was stirred an additional 25 minutes. The mixture was extracted with 1.0 l of ether and then with a (1:1) mixture of ether and ethyl acetate. The combined extracts were dried over magnesium sulfate. After removal of solvent, the residue was digested in a hot (3:2) mixture of ether and n-hexane. Upon cooling to 0° C. and filtering, 111 g of 4-(1-hydroxy-1-methylethyl)-1-p-tolyl-3-pyrazolidinone was obtained. Analysis was confirmed by infrared and NMR spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([O:18]C)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a mixture of methyl 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylate (Intermediate 2) (9 g, 0.03 mol) in methanol (200 mL) was added NaOH (2.4 g) and water. The mixture was stirred overnight. Water was added and the solvent was evaporated. The residue was extracted with DCM (twice). The aqueous phase was adjusted to pH=2 with a 2N HCl solution. The formed precipitate was filtered to give the title compound as white solid (7.2 g, 84%). LC/MS: m/z 287 (M+H)+. Rt: 2.52 min.
Reaction SMILES: C(O)CC.Cl.[CH3:6][O:7][NH2:8].[CH3:9][C:10]1[CH:14]=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][O:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[CH3:32])=O)[O:12][N:11]=1>O>[CH3:6][O:7][N:8]=[C:15]([C:13]1[O:12][N:11]=[C:10]([CH3:9])[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[CH3:32]
Reactant: CON
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2cc(C)no2)c1
Agent: Cl
Solvent: CCCO
Solvent: O
Product: CON=C(c1cc(C)no1)c1ccccc1COc1cc(C)ccc1C
Yield: 42.8 %

Procedure:
n-Propanol (2 ml) and methoxyamine hydrochloride (0.25 g, 3 mmol) were added to 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone (0.33 g, 1 mmol), and the mixture was stirred under reflux for 15 hours. After completion of the reaction, water (200 ml) was added, the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.18 g, 51.4%, as colorless crystals) and isomer B (0.15 g, 42.8%, as colorless crystals) of 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime. One of the isomers A and B is the E-isomer and the other is Z-isomer.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:17][NH:18][C:19]([C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1)=[O:20].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>O>[C:39]([O:1][CH2:2][C:3]1[C:12]2[C:11]([CH3:13])([CH3:14])[CH2:10][CH2:9][C:8]([CH3:15])([CH3:16])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:17][NH:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=1)=[O:20])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCOC(=O)c1ccc(C(=O)NCc2ccc3c(c2CO)C(C)(C)CCC3(C)C)cc1
Solvent: O
Solvent: c1ccncc1
Product: C=CCOC(=O)c1ccc(C(=O)NCc2ccc3c(c2COC(C)=O)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
395 mg (0.9 mmol) of allyl 4-[α-hydroxymethyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)methylcarbamoyl]benzoate, 15 ml of pyridine and 200 μl (1.8 mmol) of acetic anhydride were introduced into a round-bottomed flask. The mixture was stirred at room temperature for 8 hours, the reaction medium was poured into water, and extracted with ethyl ether. The organic phase was decanted off, washed with water, dried over magnesium sulfate and evaporated. 435 mg (100%) of the expected compound were recovered in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:15])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:16](OC(OCC)CBr)[CH3:17]>>[Br:1][C:2]1[C:3]2[N:4]([CH:16]=[CH:17][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1ncc(-c2ccc(Cl)cc2)cc1Br
Product: Clc1ccc(-c2cc(Br)c3nccn3c2)cc1

Procedure:
Prepared from crude 3-bromo-5-(4-chloro-phenyl)-pyridin-2-ylamine (example C.27 step 2) (ca. 50 mmol) and bromoacetaldehyde diethyl acetal (90%, 17.2 mL, 100 mmol) as described in example C.20 step 1. Obtained the pure 8-bromo-6-(4-chloro-phenyl)-imidazo[1,2-a]pyridine after chromatography as a light brown solid (11.91 g, 77%). MS (ISP) 307.1 [(M+H)+], 309.1 [(M+2+H)+], 311.1 [(M+4+H)+].
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:9][O:8][C:6]([CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:4]([O:11][CH3:12])=[O:10])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: BrCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Sodium methoxide (1.42 g, 26.2 mmol) was dissolved in dry MeOH (90 mL). Dimethyl malonate (3.0 mL, 26.2 mmol) was added and the mixture was stirred at r.t. for one hour. (6-Bromohexyloxy)triphenylmethane (3.7 g, 8 7 mmol) was added and the mixture was refluxed overnight. The mixture was cooled to r.t. and 50 mL 10% citric acid was added. The mixture was then stirred at r.t. for 5 min. The product was extracted with CH2Cl2 (3×100 mL) and evaporated to dryness. The residue was dissolved in CH2Cl2 and dried with Na2SO4. Purification on silica gel (petroleum ether, by 40-60° C./ethyl acetate 10:1) yielded 2.3 g (56%) of the title compound. ESI-TOF-MS [M+Na]+: calc. for C30H34NaO5+ 497.23. found 497.17.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:15]=[N:17][N:18]=3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: NNC=O
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: Clc1ccc(-c2ccc3nncn3n2)cc1

Procedure:
A mixture of 9.0 g. of 3-chloro-6-(p-chlorophenyl)pyridazine (prepared as in Example 12), 5.1 g. of formylhydrazine and 60 ml. of butyl alcohol is heated at reflux temperature for 40 hours. The reaction mixture is cooled, filtered and the solid washed with petroleum ether and with water. The material is then heated with 125 ml. of ethanol and the insoluble material is collected by filtration. The filtrate is cooled and the precipitate is collected and combined with the insoluble material collected above. The combined solids are recrystallized from 130 ml. of ethyl alcohol to provide the product of the example as crystals, m.p. 216°-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19]>C(O)=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:13])[F:14])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([OH:24])=[O:23])=[O:19]
Reactant: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O
Solvent: O=CO
Product: CCOC(=O)N(CC(=O)O)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
A suspension of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(ethoxycarbonyl)glycine, 1,1-dimethylethyl ester (3.13 g, 6.39 mmol) in formic acid (120 mL) was stirred for 3 hours at room temperature under a dry nitrogen atmosphere. Dissolution occurred after an hour. The reaction mixture was diluted with water (1.5 L) and extracted with ether. The extracts were combined, washed well with water and concentrated to leave an oil. The oil was diluted with water and extracted with chloroform. The extracts were combined, dried over magnesium sulfate, filtered and concentrated. The crude solid was recrystallized from benzene:petroleum ether and dried overnight at 90° C. in vacuo to give the title compound as a white solid (2.31 g, 85%), m.p. 144°-146° C.
Reaction SMILES: C([O:5][C:6](=[O:32])[C@H:7]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18](C(OC(C)(C)C)=O)[CH:19]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:13]=12)[CH2:8][CH3:9])(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:24][O:23][C:21]([C:20]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][C@H:7]([CH2:8][CH3:9])[C:6]([OH:32])=[O:5])[NH:18][CH:19]=1)=[O:22]
Reactant: CC[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](NCc1ccnc2[nH]cc(C(=O)OC)c12)C(=O)O
Yield: 99 %

Procedure:
To a 100 mL round bottom flask equipped for stirring was added (R)-1-tert-butyl 3-methyl 4-((1-tert-butoxy-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (1.45 g, 3.24 mmol) and DCM (10 mL). TFA (10 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and dried in vacuo to afford the title compound as a yellow oil (1.3 g, 99%) (TFA salt). [M+H] calc'd for C14H17N3O4, 292; found, 292.6.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])[C:5]([C:14]([OH:16])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:26]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])[C:5]([C:14]([F:26])=[O:16])=[CH:4][N:3]=1
Reactant: CC(C)(O)CNc1nc(Cl)ncc1C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)CNc1nc(Cl)ncc1C(=O)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution containing 12.64 g (51.45 mmol) of the acid prepared in step 17.1 and 7.89 mL (56.60 mmol) of triethylamine in 250 mL of dichloromethane are added 6.51 mL (77.18 mmol) of cyanuric fluoride. The mixture is stirred at room temperature overnight and the solution is diluted with 590 mL of CH2Cl2 and 190 mL of ice-cold aqueous NaHCO3. The organic phase is washed twice with 250 mL of ice-cold aqueous NaHCO3 and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 12.3 g of the expected product are obtained in the form of a yellow oil that solidifies slowly, and which is used as obtained in the following step. Yield=96%.
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[SH:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:5][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(SCCO)c1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
3-Chloro-2-nitro-aniline (1.12 g, 6.5 mmol), 2-mercaptoethanol (0.60 ml, 8.6 mmol), and potassium carbonate (0.99 g, 7.1 mmol) were combined in dry DMF (15 ml) and stirred at 130° C. for 4 h. The solution was allowed to cool and was concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/hexanes) gave 1.29 g (93%) of 2-(3-amino-2-nitro-phenylsulfanyl)-ethanol as a bright red solid. 1H NMR (300 MHz, DMSO-d6) δ 7.20 (t, 1H, J=8.1 Hz), 6.80 (s, 2H), 6.73 (dd, 1H, J=8.4, 0.9 Hz), 6.63 (dd, 1H, J=7.8, 1.2 Hz), 4.92 (t, 1H, J=6.0 Hz), 3.58 (q, 2H, J=6.0 Hz), 2.98 (t, 2H, J=6.0 Hz). 2-(2,3-Diamino-phenylsulfanyl)-ethanol. 2-(3-Amino-2-nitro-phenylsulfanyl)-ethanol (1.02 g, 4.8 mmol) was reduced by hydrogenation using 45 psi of H2 with 109%0 Pd—C, (180 mg) in EtOAc (25 mL) for 6 h. After filtering through Celite, solvent was removed in vacuo. Purification by silica gel chromatography (EtOAc) gave 762 mg (87%) of 2-(2,3-diamino-phenylsulfanyl)-ethanol as a faintly yellow solid. 1H NMR (300 MHz, CDCl3) δ 6.98 (dd, 1H, J=7.5, 10.5 Hz), 6.60-6.72 (m, 2H), 3.65 (t, 2H, J=5.7 Hz), 3.55 (br s, 5H), 2.91 (t, 2H, J=5.7 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([NH2:16])[N:3]=1.[C-:17]#[N:18].[K+]>CN(C=O)C.CCOC(C)=O>[NH2:16][C:4]1[N:5]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([C:17]#[N:18])[N:3]=1
Reactant: [C-]#N
Reactant: CN(c1ccccc1)c1nc(N)nc(Cl)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1nc(N)nc(C#N)n1
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a stirring solution of 6-chloro-N-methyl-N-phenyl-[1,3,5]triazine-2,4-diamine (Intermediate 41, 360 mg, 2.67 mmol) in DMF (25 ml) was added potassium cyanide (435 mg, 6.68 mmol). The reaction was stirred at 120 C under nitrogen for 2 h. The reaction mixture was diluted with EtOAc (80 ml); the solution was then extracted with 5% aq. sodium hydrogencarbonate solution (2×20 mL), and saturated brine (2×5 mL). After evaporation of the solvent, the crude residue was purified by FCC over silica gel eluting with heptane:EtOAc 1:0 to 8:2 to 6:4 to furnish the desired product (380 mg, 63%). Method C HPLC-MS: MH+ requires m/z=227. Found: m/z=227, Rt=1.24 min (95%).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([NH:14][NH2:15])=[O:13])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([O:11][C:12]([NH:14][N:15]=[C:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCCC1
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A mixture of cyclopentanone (20 g, 238 mmol) and hydrazinecarboxylic acid tert-butyl ester (31.4 g, 0.238 mol) in MeOH (300 mL) was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resulting solid was dried under vacuum to give 1-cyclopentylidenehydrazine-2-carboxylic acid tert-butyl ester (47.1 g, 100% yield).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]#[CH:20]>CN(C)C=O>[CH2:20]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]#[CH:18]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCON=C(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 56.7 g), N,N-dimethylformamide (280 ml), potassium carbonate (72.3 g) and propargyl bromide (43 g) was stirred at room temperature for 4 hrs. The reaction mixture was treated in a conventional manner to give ethyl 2-propargyloxyimino-3-oxobutyrate (syn isomer, 71.2 g).
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([S:20]([NH2:22])=[O:21])([CH3:19])[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][C:10](=[N:22][S:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: CC(C)(C)S(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 70.5 %

Procedure:
To a solution of 5.00 g (21.9 mmol) of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanone in 100 mL THF was added 9.18 mL (43.8 mmol) of Ti(OEt)4 and 2.78 g (23.0 mmol) of 2-methyl-2-propanesulfinamide. The resulting mixture was stirred under reflux for 12 h, before being poured into an equal volume of saturated aqueous NaHCO3 with rapid stirring and filtered through celite. The filter cake was washed with ethyl acetate, the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography to yield 5.12 g of the title compound (25) as diastereomeric mixture. Rt=1.87 min, 1.92 min (Method C). Detected mass: 332.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:5](=[C:10]([CH3:26])[C:11]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:12][C:13]=1[O:14]CC=C)[C:6]([O:8][CH3:9])=[O:7].C(NCC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:5](=[C:10]([CH3:26])[C:11]([O:18][S:19]([C:22]([F:23])([F:25])[F:24])(=[O:21])=[O:20])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=CCOc1cc(OS(=O)(=O)C(F)(F)F)c(C)c(C(=O)OC)c1C(=O)OC
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: COC(=O)c1c(O)cc(OS(=O)(=O)C(F)(F)F)c(C)c1C(=O)OC
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of 6-allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester (8.39 g, 20.3 mmol) in toluene (20 mL) was added tetrakistriphenylphosphine palladium (0.47 g, 0.40 mmol) and diethylamine (2.97 g, 40.86 mmol) at room temperature under an atmosphere of nitrogen. Stirring at room temperature was continued until all starting material was consumed. The crude reaction mixture was partitioned between diethyl ether and HCl (0.1 N). The organic layer was washed with brine and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded a crude material, which was purified by silica gel chromatography to provide 4.16 g (55%) of the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ=2.20 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 7.01 (s, 1H) ppm; 19F NMR (282 MHz, CDCl3): δ=−74 ppm.