Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH2:24][CH:25]([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH2:24][CH:25]([C:30]([F:33])([F:32])[F:31])[C:26]([F:27])([F:28])[F:29])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.8 %

Procedure:
A solution of 30 mg (0.051 mmol) of rac-{1-[({2,5-dimethyl-7-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]pyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 142A) in 2 ml of dichloromethane was admixed with trifluoroacetic acid (0.117 ml). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated off under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was removed and concentrated under reduced pressure, and the residue was purified by preparative HPLC chromatography (Method 21), which gave 1.68 mg (7% yield) of the target compound.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[N:23]=[C:22]([C:24]([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[CH2:43][OH:44])[CH:20]=2)[N:15]=1.[CH3:45]N(C)CCN.Cl.C(=O)(O)[O-]>N1C=CC=CC=1>[CH3:45][N:10]([CH3:9])[CH2:11][CH2:12][NH:8][C:1](=[O:2])[O:44][CH2:43][C:36]1[CH:37]=[C:38]([F:42])[C:39]([F:41])=[CH:40][C:35]=1[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:13])[N:23]=[C:22]2[C:24]([N:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34]1)=[O:25]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCN
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CN(C)CCNC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
400 mg of 1,1′-carbonyldiimidazole are dissolved in 10 ml of pyridine and cooled to 0° C. A solution of 1.0 g of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone dissolved in 10 ml of pyridine is added. The mixture is subsequently stirred at 0° C. for 2 h and at 25° C. for 2 h. 300 μl of N,N-dimethylethylenediamine are then added, and the mixture is stirred at 25° C. for a further 18 h. The mixture is added to 250 ml of 1 N HCl, neutralised using bicarbonate solution and washed 3 times with 150 ml of dichloromethane each time. The organic phases are washed twice with 50 ml of water each time, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH3:29][C:30]1[O:34][C:33]([CH:35]([CH:37]2[CH2:41][CH2:40][CH2:39][S:38]2)O)=[CH:32][CH:31]=1.O>C1(C)C=CC=CC=1>[N:15]([CH:35]([CH:37]1[CH2:41][CH2:40][CH2:39][S:38]1)[C:33]1[O:34][C:30]([CH3:29])=[CH:31][CH:32]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(O)C2CCCS2)o1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N=[N+]=[N-])C2CCCS2)o1
Temperature: 0 °C
Reaction time: 48 h
Yield: 80.5 %

Procedure:
39.3 ml (0.18 mol; 1.2 eq) of diphenylphosphoryl azide and then 27.3 ml (0.18 mol; 1.2 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise to a solution of 30.21 g (0.15 mol; 1.0 eq) of (5-methylfuran-2-yl)-(tetrahydrothiophen-2-yl)methanol in 350 ml of toluene cooled to 0° C. The mixture was allowed to return to ambient temperature gently and was then stirred for 2 days. The reaction medium was treated with water and extracted with ethyl acetate. The organic phases were combined, washed with a 1 M sodium hydrogen phosphate solution, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column puriFlash IR-50SI/800G, puriFlash) eluted with heptane/ethyl acetate (95/5). 26.95 g of 2-[azido-(tetrahydrothiophen-2-yl)methyl]-5-methylfuran were obtained (mixture of the 2 diastereoisomers). Yield=79%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.[C:23](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a stirred solution of 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid (200 mg, 0.65 mmol, prepared as described in the procedure for example 6) in methanol (10 mL) was added concentrated sulfuric acid (5 drops). The solution was heated at reflux for 36 h then cooled to room temperature, basified with aqueous sodium bicarbonate (40 mL) and extracted with CH2Cl2 (2×40 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified twice by silica gel chromatography eluting with MeOH:CH2Cl2 0%→1%) to yield 63.4 mg (30.3%) of methyl 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate EXAMPLE 10. 1H NMR (400 MHz, CDCl3): δ=10.11 (br s, 1H), 8.08 (s, 1H), 7.76-7.74 (m, 1H), 7.58-7.51 (m, 3H), 7.47-7.42 (m, 3H), 6.99 (d, J=1.6 Hz, 1H), 3.93 (s, 3H). MS (ES+): m/z 324.23 (100) [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[S:11][CH:12]=1)[CH3:2].C1C(=O)N([Cl:25])C(=O)C1>CN(C)C=O>[Cl:25][C:4]1[C:3]([CH2:1][CH3:2])=[C:7]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[S:11][CH:12]=2)[N:6]([CH3:17])[N:5]=1
Reactant: CCc1cnn(C)c1-c1csc(C(=O)OC)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCc1c(Cl)nn(C)c1-c1csc(C(=O)OC)c1
Reaction time: 1 h
Yield: 55.6 %

Procedure:
A solution of methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (202 mg, 0.81 mmol) and NCS (108 mg, 0.81 mmol) in N,N-dimethylformamide (4 ml) was stirred in a sealed tube for 1 h at 100° C. Additional NCS (108 mg, 0.81 mmol) was added and the solution stirred 1 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (2-30% EtOAc in hexanes) affording methyl 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (135 mg, 0.45 mmol, 56% yield) as a yellow oil: LCMS (ES) m/e 285 (M+H)+.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.FC(F)(C(F)(F)C(F)(F)F)C([O-])=[O:13]>>[CH:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:4]1([CH:3]2[O:13][CH:2]2[CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C/C=C/c1ccccc1
Reactant: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Product: CC1OC1c1ccccc1
Product: O=Cc1ccccc1
Yield: 30 %
Yield: 70 %

Procedure:
The metal-catalyzed epoxidation of trans-β-methylstyrene was performed as described in Example 2 with the substitution of [Ru3O(pfb)6 (Et2O)3 ](pfb) (where pfb= perfluorobutyrate) (0.0449 g, 2.3×10-5 moles) as the catalyst. After 6 hours of reaction, the complete oxidation of the substrate produced benzaldehyde (30%) and 1-phenylpropylene oxide (70%).
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([O:6][C:7](=[O:39])[C:8](O)=[CH:9][C:10]([C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:13]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:11])[CH3:5].O>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][C:13]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11][N:2]=1)=[O:39])[CH3:5]
Reactant: NO
Reactant: CCOC(=O)C(O)=CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Yield: 89.1 %

Procedure:
Hydroxylamine hydrochloride (3.6 g, 52 mmol) was added to a solution of 4-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (9.0 g, 18.5 mmol) in ethanol (75 ml) and the suspension heated under reflux for ˜4 hrs. The resulting solution was allowed to cool and poured into water (200 ml) to give an off-white precipitate. The solids were removed by filtration and taken up in dichloromethane (150 ml). The solution was washed with water (150 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous sodium sulphate and concentrated to an off-white solid. Solids were washed with hexane and dried in vacuo (40° C.), to give 5-(2,4-bis-benzyloxy-5-tert-butyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester as a pale brown powder (8.0 g, 89%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[N:10].[C:11]([C:15]1[C:24]2[O:23][CH2:22][CH2:21][NH:20][C:19]=2[CH:18]=[C:17]([C:25](=[O:27])[CH3:26])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>CN(C)C=O>[C:25]([C:17]1[CH:16]=[C:15]([C:11]([CH3:14])([CH3:12])[CH3:13])[C:24]2[O:23][CH2:22][CH2:21][N:20]([CH2:8][C:9]#[N:10])[C:19]=2[CH:18]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2CC#N
Temperature: 90 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
Potassium carbonate (3.6 g, 26 mmol) and bromoacetonitrile (15.4 g, 128.6 mmol) were added to a solution of 1-[8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1-ethanone (6.0 g, 25.5 mmol) in dimethylformamide (100 ml) and the mixture was stirred at 90° C. for 6 hours. Ethyl acetate was added, the reaction mixture was washed with water and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (6.9 g) as a light yellow oil.
Reaction SMILES: [Mg].O1C[CH2:5][CH2:4][CH2:3]1.C(Cl)C=C.[CH:11]12[CH2:21][CH:17]([C:18](=[O:20])[CH2:19]1)[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1>C(O)(=O)C>[CH2:5]([C:18]1([OH:20])[CH2:19][CH:11]2[CH2:21][CH:17]1[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1)[CH:4]=[CH2:3]
Reactant: C1CCOC1
Reactant: O=C1CC2CC1C1CCCC21
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C=CCCl
Product: C=CCC1(O)CC2CC1C1CCCC21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a one litre reaction vessel, equipped with a stirrer, a cooler and a dropping funnel, 26.4 g magnesium, 100 g tetrahydrofurane and 1 g allyl chloride were heated to about 40° C. to start the reaction. A mixture of 76.5 g allyl chloride, 250 g tetrahydrofurane and 150 g tricyclo [5,2,1,02,6 ] decan-8-one was added in four hours, keeping the temperature at 35°-40° C. The reaction mixture was stirred for an additional 30 minutes and subsequently poured into a mixture of 600 g of ice and 80 g of acetic acid. The layers were separated and the water layer extracted twice with toluene. The combined organic layers were washed with 5% soda solution until alkaline and subsequently with water until neutral. The organic solvent was removed by distillation under reduced pressure. The residue was distilled on a Vigreux head at 2 mm.Hg. The fraction boiling between 93° and 95° C. was collected.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.O.[C:24](OCC)(=O)C>CO>[C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH3:24])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Solvent: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(C)(C)C)cc([N+](=O)[O-])c1OC
Temperature: 0 °C

Procedure:
5.4 g 5-tert-butyl-2-methoxy-3-nitro-benzoic acid are dissolved in 50 ml of methanol, cooled to 0° C. and combined dropwise with 2.32 ml of thionyl chloride. After the addition has ended the mixture is heated for 12 hours to 60° C. Then the solvents are eliminated in vacuo, the residue is divided between water and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue thus obtained is chromatographed on silica gel (cyclohexane/ethyl acetate (98:2 to 60:40).
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].Br[CH:28]1[O:33][C:31](=[O:32])[CH2:30][CH2:29]1>>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])([O:4][CH:28]1[O:33][C:31](=[O:32])[CH2:30][CH2:29]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(Br)O1
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCP(=O)(OC1CCC(=O)O1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 1, P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid is reacted with 4-bromo-γ-butyrolactone to give 4-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxy]-γ-butyrolactone. ##STR7##
Reaction SMILES: BrCC1C=C(C=CC=1)[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][C:48]=1OC)[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][C:34](=[CH:37][C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=3[F:45])[CH2:33][CH2:32]2)=[O:30])[CH2:24][CH2:23]1.O>CN(C=O)C>[C:6]([C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][CH:48]=1)[CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][C:34](=[CH:37][C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=3[F:45])[CH2:33][CH2:32]2)=[O:30])[CH2:26][CH2:27]1)#[N:7]
Reactant: COc1ccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1Cl
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
3-Bromomethylbenzonitrile (160 mg, 0.81 mmol) was dissolved in DMF (3.0 mL), and potassium carbonate (220 mg, 1.62 mmol) and the compound (300 mg, 0.81 mmol) obtained in Example 36 (1) were added thereto, followed by stirring overnight while heating at room temperature. Water was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:200), thereby giving the title compound (151 mg, 42%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH2:22][C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=2[F:32])=[CH:15][C:13]=1[NH2:14].C(N(CC)C(C)C)(C)C.O>C(#N)C>[NH2:8][C:7]1[C:2]([NH:14][C:13]2[CH:15]=[C:16]([O:21][CH2:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=3[F:32])[C:17]([O:19][CH3:20])=[CH:18][C:12]=2[Cl:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Cl)c(Nc2ncccc2N)cc1OCc1c(OC)ccc(F)c1F
Temperature: 130 °C
Yield: 19.4 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (0.12 g), 2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyaniline (0.26 g) and N,N-diisopropylethylamine (0.14 mL) in acetonitrile (3 mL) was stirred at 130° C. in a reaction vessel equipped with a reflux condenser overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL)-methanol (4 mL). To the solution were added nickel(II) bromide (9 mg) and sodium borohydride (89 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=67/33−35/65) to give 3-amino-2-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]pyridine (62 mg). This material was dissolved in tetrahydrofuran (2 mL). To the solution were added sodium hydride (55%, 20 mg) and thiophosgene (0.012 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/2) to give the title compound (28 mg).
Reaction SMILES: S1(CCCC1)(=O)=O.P(Cl)(Cl)(Cl)=O.[C:13]([C:15]1[C:16](O)=[C:17]2[C:27]3[CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][C:22]=3[S:21][C:18]2=[N:19][CH:20]=1)#[N:14].[Cl-:36].[Na+]>C(N(CC)CC)C>[Cl:36][C:16]1[C:15]([C:13]#[N:14])=[CH:20][N:19]=[C:18]2[S:21][C:22]3[CH2:23][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][CH2:26][C:27]=3[C:17]=12
Reactant: [Cl-]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(O)c23)C1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S1(=O)CCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To sulfolane (10 mL) was added phosphoryl chloride (1.39 g, 9.05 mmol) at rt. Triethylamine (0.92 g, 9.05 mmol) was added dropwise with cooling. tert-Butyl 3-cyano-4-hydroxy-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 52A (1.00 g, 3.02 mol) was added, and the mixture was heated to 70° C. for 1.5 h. The mixture was cooled to rt, and triethylamine (2.3 mL) was added. A semi-saturated aqueous sodium chloride solution (10 L) was added whilst cooling with an ice-bath. The mixture was stirred at rt for 30 min and then extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed in vacuo. Toluene was added, and the mixture was washed with water. The organic layer was again dried over sodium sulfate, and the solvent was removed in vacuo. After crystallization, the product was triturated with water, collected by suction filtration and dried to yield 543 mg (51%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH:17]=[O:18])=[N:2]1.[CH2:19]([Mg]Br)[CH:20]=[CH2:21]>O1CCCC1.C(OCC)C>[OH:18][CH:17]([CH2:21][CH:20]=[CH2:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1
Reactant: C=CC[Mg]Br
Reactant: O=CCc1ccccc1-c1noc2ccccc12
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2 g of 2-[2-(1,2-benzisoxazol-3-yl)-phenyl]acetaldehyde in 50 ml of tetrahydrofuran at −78° C. under a nitrogen atmosphere was added 10 ml of a 1 M solution of allyl magnesium bromide in diethyl ether. The solution was warmed to room temperature and stirred for a further 2 h then quenched by addition of 50 ml of saturated aqueous ammonium chloride. The aqueous layer was extracted with 150 ml then 100 ml of dichloromethane and the combined organic extracts dried over sodium sulfate and evaporated to give crude product which was purified by chromatography eluting with 20% ethyl acetate in hexane, affording 1 g of 3-[2-(2-Hydroxy-4-pentenyl)phenyl]-1,2-benzisoxazole, 1H-NMR (200 MHz, CDCl3) d 5.8 (CH═CH2).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Si]([C:14]#[N:15])(C)(C)C.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CCOCC.CO.[Zn+2].[I-].[I-]>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([CH:4]([C:14]#[N:15])[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(C#N)c2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To 2-fluorobenzaldehyde (10.0 g, 80.57 mmol) in ether (10 mL) was added TMSCN (9.97 g, 100.72 mmol) followed by a catalytic amount of ZnI2 and the solution was stirred while cooling with an ice bath as necessary until the catalyst dissolved and re-precipitated out. Boc-piperazine (14.9 g, 80.57 mmol) in MeOH (60 mL) was then added and the solution was allowed to stir at reflux for 4 h and then at room temperature for 18 h. The reaction mixture was then cooled to 0° C. and the product was collected by filtration. Concentration of the mother liquor and recrystallization from methanol provided 20.0 g (78%) product.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1)=[C:16]=[S:17]>>[OH:4][CH2:3][CH:2]([NH:1][C:16]([NH:15][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:31][CH:30]=3)[N:25]=2)=[CH:22][CH:23]=1)=[S:17])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(C(F)(F)F)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-(trifluoromethyl)phenyl)ethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.250 g, 53%): ESIMS m/z 568 ([M+H]+).