Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH3:5].CN(C)C=O.[Cl:21][CH2:22][C:23](Cl)=[O:24].Cl>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]([N:6]([C:23](=[O:24])[CH2:22][Cl:21])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH3:5])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C(C)Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: COC(=O)C(C)N(C(=O)CCl)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
18.4 g of α-(2,6-dichloroanilino)-propionic acid methyl ester, 1 ml of dimethylformamide and 100 ml of chlorobenzene are heated to 100° (internal temperature). An addition is made dropwise at this temperature, with stirring, of 8 ml of chloroacetyl chloride. After the evolution of HCl has ceased, stirring is maintained for 1 hour at 130°-140° bath temperature. The reaction mixture is allowed to cool to room temperature, the solvent is removed in a rotary evaporator, and the yellow oil remaining as residue is crystallised from diisopropyl ether. There is obtained 16 g of final product having a melting point of 82°-85° (Compound No. 10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-:10].[K+].[CH2:12]=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[C:7]=1[CH2:12][OH:10]
Reactant: C=O
Reactant: Oc1cc(F)cc(Cl)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: OCc1c(F)cc(O)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
3-Chloro-5-fluorophenol (703 mg, 4.8 mmol) was added to a solution of potassium hydroxide (297 mg, 5.3 mmol) in H2O (1.45 mL) and heated at 60° C. Formaldehyde (37 wt % in H2O, 0.74 mL, 9.12 mmol) in H2O (1.45 mL) was added dropwise and the reaction mixture left to stir at 40° C. overnight. The reaction mixture was cooled to rt and conc. HCl (approximately 6 mL) was added. The resultant precipitate was filtered, washed with H2O and dried to yield the title compound as a cream solid (334 mg, 1.89 mmol).
Reaction SMILES: Cl.[S:2]1[CH:6]=[N:5][N:4]=[C:3]1[C:7](=[NH:9])[NH2:8].[Br:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O.O=[C:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Br:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH3:28])[NH:8][C:7]([C:3]2[S:2][CH:6]=[N:5][N:4]=2)=[N:9]1
Reactant: N=C(N)c1nncs1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(F)cc1Br
Yield: 47.1 %

Procedure:
1,3,4-thiadiazole-2-carboximidamide hydrochloride (1.43 g, 8.69 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (1.76 g, 8.69 mmol) and ethyl 3-oxobutanoate (1.36 g, 10.5 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (1.74 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: O[N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[C:4]1=[O:15].[H][H]>CCO.N.[Ni]>[NH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[C:4]1=[O:15]
Reactant: [H][H]
Reactant: CN1CCc2ccccc2C(=NO)C1=O
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CN1CCc2ccccc2C(N)C1=O

Procedure:
1-Hydroxyimino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one was dissolved in EtOH/NH3 (20:1) and hydrogenated in a bomb using Raney nickel and hydrogen (500 psi/3447 kPa) at 100° C. for 10 hours. The resulting mixture was filtered and concentrated to provide an oil which was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=CC=[C:19](OC)[CH:18]=2)[CH2:9][N:10]2[C:14](=O)[CH2:13][CH2:12][C:11]2=O)=[CH:4][CH:3]=1.[C:25](Cl)(=O)[CH3:26].[CH3:29][CH2:30][O:31][C:32]([CH3:34])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C:17]3[C:18](=[CH:19][CH:34]=[C:32]([O:31][CH2:30][CH2:29][CH2:11][N:10]4[CH2:26][CH2:25][CH2:5][CH2:8][CH2:9]4)[CH:22]=3)[C@H:14]3[CH2:13][CH2:12][CH2:11][N:10]3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc(C(CN2C(=O)CCC2=O)c2ccc(Br)cc2)c1
Reactant: CCOC(C)=O
Reactant: CC(=O)Cl
Product: Brc1ccc([C@@H]2CN3CCC[C@@H]3c3ccc(OCCCN4CCCCC4)cc32)cc1
Yield: 75 %

Procedure:
1-[2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-pyrrolidine-2,5-dione. A solution of the crude product from Step 7 (54.9 mmol) in EtOAc (55 mL) was treated with acetyl chloride (14.0 mL) and then was heated at reflux overnight. The mixture was cooled, and a precipitate formed. The solid was filtered to provide 15.9 g (75%) of the desired product. The filtrate was purified by chromatography (EtOAc/hexanes) to give an additional 3.28 g, for a combined yield of 19.2 g (90%). MS: exact mass calcd for C19H18BrNO3, 387.1; m/z found, 410.0 [M+Na]+, 412.0 [M+Na]+. 1H NMR (CDCl3): 7.38 (m, 2H), 7.19 (m, 3H), 6.81 (d, J=7.6, 1H), 6.73 (m, 2H), 4.60 (t, J=8.4, 1H), 4.06 (m, 2H), 3.74 (s, 3H), 2.51 (s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:25]S(C2C=CC(C)=CC=2)(=O)=O)=[N:10][N:11]2[C:16]=1[C:15]([CH3:17])=[N:14][N:13]=[C:12]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].[CH3:36][N:37]1[C:41]([CH2:42]O)=[N:40][CH:39]=[N:38]1.[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:25][CH2:42][C:41]2[N:37]([CH3:36])[N:38]=[CH:39][N:40]=2)=[N:10][N:11]2[C:16]=1[C:15]([CH3:17])=[N:14][N:13]=[C:12]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2-c2ccccc2F)cc1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccccc2F)n2nc(OCc3ncnn3C)c(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To toluene-4-sulfonic acid 3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (200 mg, 0.407 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (57.5 mg, 0.0509 mmol; prepared as described in EP-A-170073) in DMF (5 ml) was added sodium hydride (23.7 mg of a 60% dispersion in mineral oil; 0.593 mmol) and the mixture was stirred at room temperature for 30 min. Water (50 ml) was added, then the solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate in dichloromethane. 3,7-Bis(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under isohexane (75 mg). 1H NMR (400 MHz, CDCl3) δ 2.52 (3H, s), 3.73 (3H, s), 5.44 (1H, d, J=13 Hz), 5.49 (1H, d, J=13 Hz), 7.18-7.31 (3H, m), 7.36-7.46 (3H, m), 7.63 (1H, m), 7.78 (1H, m), 7.82 (1H, s); MS (ES+) m/e 434 [MH]+. Anal. Found C, 61.03; H, 4.08; N, 21.95%. C22H17F2N7O.0.1 C6H14 requires C, 61.41; H, 4.20; N, 22.18%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]1=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:6]([CH2:5][CH2:4][CH2:3][NH:2][C:32](=[O:34])[CH3:33])[C:7](=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Reaction time: 2 h

Procedure:
N-[3-(3-Aminopropyl)-4-(4-bromophenyl)-thiazol-2(3H)-ylidene]aniline hydrochloride (730 mg) obtained in Example 132 and triethylamine (0.77 ml) were dissolved in N,N-dimethylformamide (5 ml), and thereto were added dropwise acetic anhydride in an ice bath under nitrogen atmosphere. The mixture was stirred at the same temperature for 2 hours, and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl alcohol to give the title compound (580 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:33]=[CH:32][C:19]2[NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1>>[CH3:14][O:15][C:16]1[CH:33]=[CH:32][C:19]2[NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:28])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1
Reactant: COc1ccc2[nH]c(-c3ccc(C(=O)[O-])cc3)nc2c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: COc1ccc2[nH]c(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc2c1

Procedure:
Compound 460 was prepared from 4-morpholinoaniline and 4-(5-methoxy-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C25H24N4O3: 429.18; found: 428.97.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33]N)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1>>[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccc2c(c1)OCCO2
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc4c(c3)OCCO4)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to the method described for example 91. MS: M=403.4 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[F:21][C:22]([F:38])([F:37])[C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]I)[N:33]=2)[CH:26]=[CH:27][CH:28]=1>>[F:38][C:22]([F:21])([F:37])[C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:33]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2cccc(C(F)(F)F)c2)nc1CI
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(C(F)(F)F)c4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-trifluoromethylphenyl)4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 54 of molecular weight 503.52 (C27H28F3NO5), MS(ESI): 504.37 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.C(N(CC)CC)C>ClCCl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:5](=[O:6])[C:4]2[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:29][C:30]=1[C:36]([F:37])([F:38])[F:39])#[N:33]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH3:24])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH2:27][CH2:26]1>>[CH2:23]([O:22][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:34]([CH2:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)(=[O:36])=[O:35])=[CH:7][C:6]=1[C:8]1[NH:9][C:10](=[O:21])[C:11]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=2[N:13]=1)[CH3:24]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Reactant: O=S(=O)(Cl)CCCN1CCOCC1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NS(=O)(=O)CCCN4CCOCC4)ccc3OCC)nc12

Procedure:
The title compound was prepared from 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and 3-morpholinopropyl-sulfonyl chloride, following the procedure of Example 91, and was obtained as brown crystals (14%), m.p. 157-159° C. Found: C,55.42; H,6.53; N,16.01. C24H34N6O5S requires C,55.58; H,6.61; N,16.21%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:26][CH3:27])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:23]([OH:25])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(OCC)(=O)C>[F:29][C:30]([F:34])([F:33])[CH2:31][NH:32][C:23]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:26][CH3:27])=[O:25]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC)cc2C[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC)cc2CC1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-t-Butoxycarbonyl-2(S)-aminobutyryl)-5-methoxy-indoline-2(S)-carboxylic acid (0.38 g, 1 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.271 g, 2.0 mmol) were dissolved in dried dichloromethane (20 ml) under nitrogen at 0° C., and triethylamine (0.7 ml, 5 mmol) was added followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.509 g, 2 mmol). The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under vacuum to give a brown solid which was columned on silica gel using 7:3 petroleum spirit:ethyl acetate as eluent to provide a white solid as the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([C:72](=[O:82])[CH2:73][O:74][Si](C(C)(C)C)(C)C)=[CH:68][CH:67]=1>ClCCl.O>[OH:74][CH2:73][C:72]([C:69]1[CH:70]=[CH:71][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])=[CH:67][CH:68]=1)=[O:82]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.35 g, 0.749 mmol) in dichloromethane (25 ml) was added iPr2NEt (242 mg, 1.87 mmol) was added, followed by the addition of HATU (513 mg, 1.35 mmol) and 1-(4-aminophenyl)-2-(tert-butyldimethylsilyloxy)ethanone (398 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into H2O (50 mL) and extracted with dichloromethane (3×25 mL). The organic layers were combined, washed with H2O (1×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in THF (25 mL) and then an aqueous solution (1 N) of HCl (10 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo. The residue was poured into 20 mL saturated aqueous NaHCO3 and extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with H2O (25 mL), brine (25 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 20% to 100% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-hydroxy-acetyl)-phenyl]-amide as a light yellow solid (0.17 g, 38%).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH:19]([Mg]Br)=[CH2:20].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])[CH:19]=[CH2:20]
Reactant: COCOCC(C)=CCCC(C)=CCCC(C)=O
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)COCOC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A solution of 6,10-dimethyl-11-(methoxymethyl)oxy-5,9-undecadien-2-one (60 mg, 0.24 mmol) in tetrahydrofuran (2 ml) was stirred on an ice bath under argon atmosphere. To the solution was added vinylmagnesium bromide in tetrahydrofuran (1.0 ml, 1.0 mmol, 1.0 M), and the mixture was warmed to room temperature and stirred for 4 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(methoxymethyl)oxy-1,6,10-dodecatrien-3-ol (54 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:15]1([O:14][N:13]=[C:7]([C:4]2[N:3]=[C:2]([NH:1][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[S:6][N:5]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=NOC1CC1)c1nsc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 4 h
Yield: 107.5 %

Procedure:
A mixture of ethyl 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(5.26 g), trityl chloride (12.9 g) and 4-dimethylaminopyridine (224 mg) in pyridine (25 ml) was stirred at 50°-60° C. for 4 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to give a crystal. The crystal was washed with n-hexane and diisopropyl ether, heated in methanol (80 ml) under reflux, and finally cooled to give ethyl 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer)(11 g) as a crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1Br)[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[C:21]1[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOc1cc(C(=O)OC)cc(OC)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOc1cc(C(=O)OC)cc(OC)c1-c1cnn(C)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Methyl 3-ethoxy-4-bromo-5-methoxybenzoate (300 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (324 mg) were dissolved in DME in a nitrogen atmosphere, and potassium phosphate (661 mg) and 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride-CH2Cl2 complex (85 mg) were added to it at room temperature and degassed. The reaction liquid was stirred overnight at 90° C., then cooled to room temperature, water was added to it, and filtered through Celite. The filtrate was extracted with chloroform, washed with saturated saline water, and dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 40/60) to obtain the title compound as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].BrCCCCN1[C:39](=O)[C:38]2=CC=[CH:43][CH:44]=[C:37]2C1=O>CN(C=O)C>[F:12][C:13]1[N:14]=[CH:15][C:16]([C:19]2[N:20]=[CH:21][N:22]([CH2:43][CH2:44][CH2:37][CH2:38][CH2:39][N:2]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])[CH:23]=2)=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Fc1ccc(-c2c[nH]cn2)cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCn1cnc(-c2ccc(F)nc2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
2-14-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-ylmethyl]-butyl)-isoindole-1,3-dione. To a solution of 2-fluoro-5-(1H-imidazol-4-yl)-pyridine (1.72 g, 7.3 mmoles) in DMF (15 ml) was added potassium carbonate (5.0 g, 36.4 mmoles) at room temperature under dry conditions. After heating the reaction mixture in a 80° C. oil bath for 1 hour, N-(4-bromobutyl)phthalimide (8.2 g, 29.2 mmoles) was added to the mixture. The solution was left stirring in an 80° C. oil bath for 24 hours. Upon cooling, the reaction was filtered and the solid was washed with ethyl acetate (25 ml). The filterate was diluted with ethyl acetate and washed with NH4Cl (sat.) (50 ml), H2O (50 ml), NaCl (sat.) (75 ml), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash 40 chromatography using an initial solvent gradient of 99% DCM, 1% MeOH, and 0.1% TEA (1 L), then a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to yield 2-{4-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-ylmethyl]-butyl}-isoindole-1,3-dione (1.476 g, 55%). MH+(365)