Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12](OC(N3C=CN=C3)=S)[C:13]([F:16])([F:15])[F:14])[CH:11]=1)[O:8][CH:7]([C:25]([F:28])([F:27])[F:26])[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:5]2.[SiH](CC)(CC)CC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][C:13]([F:14])([F:15])[F:16])[CH:11]=1)[O:8][CH:7]([C:25]([F:28])([F:26])[F:27])[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C(OC(=S)n3ccnc3)C(F)(F)F)c2OC1C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(C)cc(CC(F)(F)F)c2OC1C(F)(F)F
Reaction time: 8 h

Procedure:
The ester from Step 1 (2.1 g, 4.25 mmol) was dissolved in toluene (15 mL). The Et3SiH (30 mL, 0.18 mol) was added to above solution. The mixture was heated to reflux. The benzoyl peroxide (1.03 g, 4.25 mmol) in toluene (15 mL) was added in 4 portions at 15 min intervals. The mixture was heated to reflux for 2 hours and stirred at r.t overnight. The mixture was passed through silic plug and plug was washed with 5% to 10% EtOAc in hexane to give crude product: LCMS m/z 369.15 (M+H). This ester was of suitable purity to use without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:18]#[N:19])[CH2:2][CH2:3][CH3:4].COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:16]\[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:18]#[N:19])=[C:6]3[O:5][CH2:1][CH2:2][CH2:3][CH3:4])/[C:36](=[O:37])[N:38]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCCCOc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCOc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 4-butoxy-6-formyl-quinoline-3-carbonitrile (example 79b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-butoxy-quinoline-3-carbonitrile. LC-MS m/e 381 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([CH2:11][CH2:12][OH:13])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][C:24]=2[F:33])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[C:9]([CH:8]([C:6]1[N:7]=[C:2]([NH:14][C:15]2[S:16][C:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][C:24]=3[F:33])=[CH:18][C:19]=2[C:20]([NH2:22])=[O:21])[CH:3]=[CH:4][CH:5]=1)[CH2:11][CH2:12][OH:13])#[N:10]
Reactant: N#CC(CCO)c1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(C#N)CCO)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-(6-bromopyridin-2-yl)-4-hydroxybutanenitrile (97 mg, 0.40 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (118 mg, 0.40 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19](=[O:20])[NH:18][C:13]2=[N:14][CH:15]=[CH:16][N:17]=[C:12]2[C:11]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O([CH2:42][C:43]([F:46])([F:45])[F:44])S(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19](=[O:20])[N:18]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:13]2=[N:14][CH:15]=[CH:16][N:17]=[C:12]2[C:11]=1[O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2nccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)n(CC(F)(F)F)c2nccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,2-dimethyl-propionic acid 7-(2-chloro-3,6-difluoro-phenyl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (is this correct or did the reaction start with the unprotected species?) (Example 1.3) (0.10 g), potassium carbonate (0.053 g) and 2,2,2-trifluoroethyl triflate (0.130 g) were heated in a microwave at 150° C. for 30 minutes, and then at 170° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and was then partitioned between dichloromethane and aqueous hydrochloric acid (2M). The phases were separated. The organic layer was dried over magnesium sulfate and concentrated. The residue was dissolved in dichloromethane and treated with trimethylacetyl chloride (0.063 ml) and pyridine (0.061 ml) and stirred at ambient temperature. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: acetone/iso-hexane 0:10 to 1:9) to give Compound No. C8 of Table C as a beige solid (0.049 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: OB(O)c1cncnc1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cncnc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 75 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and 5-pyrimidinylboronic acid (42 mg, 0.337 mmol). The final product was collected as a white solid (77 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H) 9.35 (s, 2H) 9.21-9.26 (m, 1H) 8.63 (t, J=4.93 Hz, 1H) 8.45 (s, 1H) 8.38 (s, 1H) 7.99 (d, J=1.26 Hz, 1H) 5.92 (s, 1H) 5.18 (quin, J=6.57 Hz, 1H) 4.44 (s, 1H) 4.42 (s, 1H) 2.52-2.56 (m, 2H) 2.13 (s, 3H) 1.52-1.56 (m, 4H) 1.48-1.52 (m, 4H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=445.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25]Br)=[CH:20][CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(N(CC)CC)C.CN(C)C=O>[C:9]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[O:27])[CH2:25][N:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]2=[O:8])=[CH:22][CH:23]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccc(NC(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49.6 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (338 mg) and 4'-benzamido-2-bromoacetophenone (766 mg) in triethylamine (1 ml) and dimethylformamide (10 ml) was stirred at ambient temperature, giving a solution, quickly followed by formation of a precipitate. After 45 mins, water (100 ml) was added to the suspension. The collected solid was crystallised from glacial acetic acid to give the title pyrimidinone (439 mg,); m.p. 290°-303°; λmaxEtOH 226 nm (ε 16230), 302.5 nm (ε 20370).
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCN=C1CCCCC2.C(OC(C)C)(=O)C.S(Cl)(Cl)=O.[NH2:44][OH:45]>O>[OH:45][NH:44][C:19](=[O:21])/[CH:18]=[CH:17]/[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:8](=[O:10])(=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1.[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NO
Agent: O=C(O)/C=C/c1cccc(S(=O)(=O)Nc2ccccc2)c1
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(/C=C/c1cccc(S(=O)(=O)Nc2ccccc2)c1)NO
Temperature: 5 °C
Reaction time: 18.5 h

Procedure:
To the 30 gallon (˜136 L) reactor was charged (E)-3-(3-phenylsulfamoyl-phenyl)-acrylic acid (6) (3.37 kg; 303.34 g/mol; 11.1 mol) and a pre-mixed solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in isopropyl acetate (IPAc) (27 g in 30 L; 152.24 g/mol; 0.18 mol). The slurry was stirred and thionyl chloride (SOCl2) (960 mL; density ˜1.631 g/mL; 118.97 g/mol; ˜13 mol) was added to the reaction mixture and the batch was stirred at 20-30° C. overnight. After 18.5 hours, the batch was sampled and deemed to be complete with no compound (6) being detected by HPLC. The resulting solution was transferred to a 100 L Schott reactor for temporary storage while the 30 gallon (˜136 L) reactor was rinsed with isopropyl acetate (IPAc) and water. Deionized water (28.9 L) was then added to the 30 gallon (˜136 L) reactor followed by 50% (w/w) hydroxylamine (6.57 L; ˜1.078 g/mL; 33.03 g/mol; ˜214 mol) and another charge of deionized water (1.66 L) to rinse the lines free of hydroxylamine to make a 10% (w/w) hydroxylamine solution. Tetrahydrofuran (THF) (6.64 L) was then charged to the 30 gallon (˜136 L) reactor and the mixture was stirred and cooled to 0-10° C. The acid chloride solution (from the 100 L Schott reactor) was then slowly charged into the hydroxylamine solution over 1 hour maintaining a batch temperature of 0-10° C. during the addition. The batch was then allowed to warm to 20-30° C. The aqueous layer was separated and discarded. The organic layer was then reduced in volume under vacuum while maintaining a batch temperature of less than 30° C. The intention was to distill out 10-13 L of solvent, but this level was overshot. A larger volume of isopropyl acetate (IPAc) (16.6 L) was added and about 6 L of solvent was distilled out. The batch had precipitated and heptanes (24.9 L) were added and the batch was held at 20-30° C. overnight. The batch was filtered and the residue was washed with heptanes (6.64 L). The filtrate was discarded and the residue was dried at 45-55° C. under vacuum with a slight nitrogen bleed over the weekend. The title compound (PXD101) was obtained as a light orange solid (3.11 kg, 89% yield with respect to compound (6)) with a purity of 99.25% (AUC) by HPLC.
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CN(C=O)C.C1COCC1.C(OCC)(=O)C.ClCCl>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:18])=[CH:6][CH:5]=1
Reactant: Oc1ccc(I)cc1
Reactant: CCCCCC(O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: OCCCCCCOc1ccc(I)cc1
Temperature: 60 °C
Yield: 69 %

Procedure:
A solution of NaOH (0.327 g, 8.18 mmol) and 4-iodophenol (1.5 g, 6.82 mmol) in 7.5 ml of DMF and 3.5 ml of THF was stirred at room temperature for 15 minutes. Then bromohexanol (1.482 g, 8.18 mmol) was added and the reaction mixture was warmed at 60° C. When the reaction is over, water was added (15 ml) and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and after filtration the solvent was removed at reduced pressure. The product was isolated by silica gel column chromatography using a mixture of ethyl acetate:dichloromethane 3:7 as eluant. A white solid was obtained (1.509 g, yield 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]2[N:19]([CH3:20])[C:18]3[C:21]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)=[C:6]([CH:13]=1)[O:7]C(CC)C#N.[OH-:32].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]2[N:19]([CH3:20])[C:18]3[C:21]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)=[C:6]([CH:13]=1)[O:7][CH2:3][CH2:4][CH2:5][C:6]([OH:7])=[O:32]
Reactant: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OC(C#N)CC)n(C)c12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OCCCC(=O)O)n(C)c12
Temperature: 75 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a solution of 63 mg (0.14 mmol) of 4-[(5-chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy]butanenitrile in 3 mL of EtOH and 1 mL of water was added 29 mg (0.72 mmol) of sodium hydroxide pellets and the reaction was stirred at 75° C. for 48 h. To the reaction mixture was added 75 mg (1.87 mmol) of sodium hydroxide pellets and the reaction heated at 75° C. for 24 h and concentrated in vacuo to a residue. The thus obtained residue was dissolved in 5 mL of water and the pH was adjusted to 4-5 using hydrochloric acid (1N aqueous solution). The resulting slurry was filtered, and the solids were washed with water and dried under high vacuum to give 46 mg (70%) of the title compound as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([N:70]1[CH2:76][CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:70]1[CH2:76][CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCNCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 1-tert.-butyloxycarbonyl-[1,4]diazepan in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[Mg].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O.[Cl-].[NH4+]>C(OCC)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[C:13](/[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)\[CH3:12]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C/C(=C\c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Yield: 71.9 %

Procedure:
118 g of 2,4-dichlorobenzyl chloride were added dropwise to 14.6 g of magnesium turnings in 400 ml of dry diethyl ether at the boiling point. After the reaction was complete, a solution of 77.3 g of 4-chloroacetophenone in 400 ml of dry diethyl ether was added. Thereafter, decomposition was effected with aqueous ammonium chloride solution, the organic phase was separated off, washed neutral, dried over sodium sulfate and evaporated down under reduced pressure, the residue was taken up in 1 liter of toluene and the solution was refluxed with 4 g of 4-methylbenzenesulfonic acid, in a water separator. After dehydration was compelete, the toluene phase was washed with sodium carbonate solution and water and dried over sodium sulfate, the solvent was evaproated off and the residue was recrystallized from methanol to give 107 g (81.9%) of E-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-prop-1-ene of melting point 84°-85° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH:40]([CH3:43])[CH2:41][OH:42]>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH:40]([CH3:43])[CH2:41][OH:42])=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: CC(N)CO
Solvent: CCO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 2-amino-1-propanol (0.0041 mL, 0.051 mmol) for 10 min. (150° C. in a microwave vessel. An additional 0.001 mL of the amine was added to the reaction and it was further microwaved for 20 min.@150° C. The reaction was then cooled to ambient temperature and the resulting suspension was filtered, washed with EtOH and then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J=6.59 Hz, 3 H), 3.25-3.31 (m, 2 H), 3.86-3.95 (m, 3 H), 4.11 (s, 2 H), 4.43-4.52 (m, 1 H), 4.57-4.65 (m, 1 H), 4.90 (t, J=5.31 Hz, 1 H), 7.10-7.16 (m, 2 H), 7.31-7.38 (m, 2 H), 7.80-7.85 (m, 4 H), 8.15-8.18 (m, 1 H), 8.52 (d, J=1.46 Hz, 1 H), 9.96 (d, J=7.87 Hz, 1 H), 17.25 (s, 1 H); ES+ MS: 545 (M+H+).
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[O:24])[CH2:18][C@@H:17]1[C:34](O)=[O:35])=[O:15])([CH3:12])([CH3:11])[CH3:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:34]([C@H:17]1[CH2:18][C@H:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[O:24])[CH2:20][CH2:21][N:16]1[C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1C(=O)O
Reactant: Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Benzene-1,2-diamine (365 mg, 3.38 mmol) was added to a mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(4-cyanophenyl)ureido)piperidine-2-carboxylic acid (1400 mg, 3.60 mmol), BOP (1600 mg, 3.6 mmol) and DIEA (1.2 mL, 6.9 mmol) in DMF (20 mL), and the resulting solution was stirred at room temperature for 8 hours. Water (100 mL) was added to the reaction mixture and it was then extracted with ethyl acetate (2×200 mL). The organic layers were dried over MgSO4 and concentrated to give a red solid. Further purification by Companion (ReadySep, 80 g, silica gel packed) using ethyl acetate/heptane from 50-80% as eluent provided the title compound as a white solid 1600 mg (93%). LC-MS: 479.1, 477.2 (t=2.3 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=[S:18]>CC(CC)=O>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([SH:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCc2ccccc2)nn1
Reactant: NC(N)=S
Solvent: CCC(C)=O
Product: Sc1ccc(OCc2ccccc2)nn1
Yield: 15.2 %

Procedure:
A mixture of 3-benzyloxy-6-chloro-pyridazine (18.2 mmol, 4 g), thiourea (36.3 mmol, 2.8 g) and ethyl methyl ketone (75 mL) was refluxed overnight. Excess ethyl methyl ketone was evaporated, the residue was extracted with 2M sodium hydroxide (25 mL) and the sodium hydroxide solution was washed with EtOAc (2×30 mL). The aqueous layer was collected and sufficient conc. HCl was added to bring the pH to 5 and extracted with EtOAc (2×30 mL). The EtOAc extract was collected, dried, filtered and the filtrate was evaporated to yield 3-benzyloxy-6-mercapto-pyridazine (15%, 605 mg); mp 155° C.-157° C.
Reaction SMILES: ClCC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[F:34].[Cl:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([NH:45][C:46]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([O:26][C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][CH:18]=3)=[C:28]([F:34])[CH:29]=2)=[S:47])=[O:44])=[CH:41][CH:42]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C(N=C=S)c1ccc(CCl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(CCl)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
4-(Chloromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-(chloromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(chloromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:28])[CH3:29]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Yield: 89.4 %

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(3-fluorophenyl)methyl]-1-indanol (98% trans, 2% cis) and 0.93 g (0.004 mole) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.55 g of trans-3-[(3-fluorophenyl)methyl]-1-indanyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[NH:16][CH:17]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.C(N(CC)CC)C.O>C(COC)OC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N+:16]#[C-:17])[S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:21])=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(OCc3ccccc3)cc2)cc1
Solvent: COCCOC
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: [C-]#[N+]C(c1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc(C)cc1
Yield: 107.9 %

Procedure:
To a solution of N-((4-(Benzyloxy)phenyl)(tosyl)methyl)formamide (3.2 g, 8.1 mmol) in 43 mL of DME (dimethoxy ethane) at 0° C. was added POCl3 (2.27 mL) followed by the dropwise addition of triethylamine (5.6 mL). The resultant solution was then stirred at 0° C. for 3 h and finally poured into cooled water. The precipitate was collected and dried to give 3.3 g of pale yellow solid. MS m/z: 378 [M+1]+.