Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[C:18](=[CH:22][N:23]([CH3:25])C)[C:19](=O)[CH3:20])=[CH:11][C:10]=3[F:27])[N:7]=[C:6]([C:28]([F:31])([F:30])[F:29])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(=O)C.C(N)=[NH:37].CC[O-].[Na+]>C(O)C>[CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:18]4[C:19]([CH3:20])=[N:37][CH:25]=[N:23][CH:22]=4)=[O:26])=[CH:11][C:10]=3[F:27])[N:7]=[C:6]([C:28]([F:30])([F:29])[F:31])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)C(=CN(C)C)C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ncncc1C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Yield: 5 %

Procedure:
Step-3: N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3,5-difluorophenyl}-2-[(dimethylamino)methylene]-3-oxobutanamide (700 mg, 1.6 mmol) and formamidine acetate (282 mg, 2.7 mmol) were dissolved in ethanol and added NaOEt (120 mg, 3.4 mmol). The above mixture was refluxed for 3 hr. Ethanol was removed on rotavapour and worked up (H2O/AcOEt) to obtain the crude. Crude was purified by column on 60-120 mesh silica gel using AcOEt and Petether (35:65) as eluent to obtain the title compound (34 mg) as a pale-yellow solid. M.P.: 147-150° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.25 (s, 1H), 9.18 (s, 1H), 8.96 (s, 1H), 7.73 (d, J 9.9, 2H), 6.69 (s, 1H), 2.61 (s, 3H), 1.65-1.56 (m, 1H), 0.95-0.86 (m, 2H), 0.80-0.72 (m, 2H). MS (m/z): 424.09 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][C:7]1([CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=O.[C:17](=[N:23][Si](C)(C)C)=[N:18][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][C:7]1([CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6]/[C:5]/2=[N:23]\[C:17]#[N:18]
Reactant: O=C1CC2(CCOC2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC2(CCOC2)Oc2ccc(Br)cc21
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 6-bromo-4′,5′-dihydro-2′H-spiro[chroman-2,3′-furan]-4-one (206 mg, 0.731 mmol) in anhydrous DCM (6 mL) was added TiCl4(281 mg, 1.48 mmol) dropwise within 15 minutes at room temperature and resulting mixture was stirred for 1 h. To this mixture was added N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (300 mg, 1.61 mmol). The resulting mixture was stirred for another 18 hours after addition. The reaction mixture was poured into water-ice and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give crude product (225 mg, 100%), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Brc1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(Br)ccc1Br
Temperature: 0 °C
Reaction time: 14 h

Procedure:
1,4-Dibromobenzene (25 g) was dissolved in concentrated sulfuric acid (30 ml). Thereto was added dropwise under ice cooling a mixed solution of concentrated sulfuric acid (30 ml)/nitric acid (8.9 ml). After 14 hours at room temperature, the reaction mixture was poured into ice water, was mixed with potassium carbonate and was extracted with ethyl acetate. The extract was washed successively with an aqueous solution of potassium bicarbonate and an aqueous saturated solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was then concentrated. The residue was subjected to purification using silica gel column chromatography (hexane) to obtain 1,4-dibromo-2-nitrobenzene (13.3 g) as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](Cl)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:39][C:16]2[N:17]=[C:18]3[C:13]([C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=2[F:20])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 53 %

Procedure:
To a mixture of 325 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 325 mg of 1-t-butoxycarbonyl-3hydroxypyrrolidine, 194 mg of DBU and 3 ml of DMF was added 46 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1.5 hours at room temperature, the reaction mixture was treated in a similar manner to Example 1-(1), whereby 240 mg of ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Na].[CH3:16][CH:17]([C:19]1[N:23]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30](O)=[O:31])[C:22]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[C:21]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:20]=1[C:48]([NH:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:49])[CH3:18].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:22]2[N:23]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:31])[C:19]([CH:17]([CH3:18])[CH3:16])=[C:20]([C:48](=[O:49])[NH:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:21]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NCCOCCN
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: [Na]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)NCCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 2-(2-aminoethoxyl)ethylcarbamate (150 mg, 0.735 mmol) is then taken up in CH3CN (10 mL) along with the sodium salt of atorvastatin (0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture is stirred at room temperature for 18 h. It is then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-((3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanamido)ethoxy)ethylcarbamate.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:47])[CH2:24][C@@H:25]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:21].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1COCC1.CO>[CH2:20]([O:22][C:23](=[O:47])[CH2:24][C@@H:25]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[N:26]([CH3:1])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)(=[O:28])=[O:29])[CH3:21]
Reactant: CCOC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)nc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (3.9 g, 15 mmol) was added to a solution of sulfonamide 16-6 (4.5 g, 10 mmol) in THF (30 mL). To this solution was added a solution of diethyl azodicarboxylate (2.4 mL, 15 mmol) in THF/MeOH (10 mL/2.02 mL). A vigorous exotherm occurred and the reaction was stirred overnight at room temperature. The dark mixture was concentrated. The dark oily residue was purified by flash chromatography (40% EtOAc/hexanes) to give the desired product 16-7.
Reaction SMILES: ClC1C(Cl)=CC=CC=1[NH2:4].N1C=CC=CC=1.O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:4])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(N)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 175.8 %

Procedure:
A solution of 2,3-dichloroaniline (162.0 g) in p-toluenesulfonyl chloride (190.7 g) is heated at 100° C. for one hour allowing the temperature to rise to 115° C. with the exotherm. The thick mixture is then cooled to 50° C. and pyridine (250 ml) is added carefully. The reaction mixture exotherms to 150° C. After stirring for one hour the mixture is cooled and poured into water (2.5 liter). The precipitated solid is collected and dried to yield 301 g of tosylamide, m.p. 112°-118° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[S:17][CH2:16][CH2:15]1.O>C(Cl)Cl>[C:5]([C:23]1[S:24][C:18]2[S:17][CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][Cl:9])[C:20](=[O:21])[C:19]=2[CH:22]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: O=C1c2ccsc2SCCN1CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc2c(s1)SCCN(CCCCCl)C2=O
Reaction time: 0.25 h

Procedure:
To a suspension of 13 g of aluminum chloride in 150 ml of methylene chloride was added 4.6 ml of acetyl chloride under ice-cooling and the mixture was stirred for 15 minutes. To the mixture was added a solution of 9.0 g of 4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 20 ml of methylene chloride and the mixture was stirred at room temperature of 2 hours. Then, the mixture was poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The resulting crystals were recrystallized from ethyl acetate to give 6.9 g of 7-acetyl-4-(4-chlorobutyl)-2,3-dihydrothieno-[3,2-f]-1,4-thiazepin-5(4H)-one as white crystals, melting at 132°-134° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][CH:38]=O)[C:32](=[O:40])[CH:31]=[CH:30]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:33]4[C:34]5[C:29](=[CH:28][C:27]([Cl:26])=[CH:36][CH:35]=5)[CH:30]=[CH:31][C:32]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=CCn1c(=O)ccc2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To 4 mL of a chloroform solution containing 0.68 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.44 g of (6-chloro-2-oxoquinolin-1(2H)-yl)acetaldehyde and 40 μL of acetic acid were added, then, to the reaction mixture, 0.62 g of sodium triacetoxyborohydride was added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.65 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]([CH3:17])[C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][CH:7]=1)=[O:4].[Cl:20]N1C(=O)CCC1=O>C(#N)C>[Cl:20][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:10][C:6]=1[N:5]([CH3:17])[C:3](=[O:4])[C:2]([F:18])([F:1])[F:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C(=O)C(F)(F)F)c1cnc(-c2cccnc2)s1
Solvent: CC#N
Product: CN(C(=O)C(F)(F)F)c1sc(-c2cccnc2)nc1Cl
Temperature: 63 °C

Procedure:
A suspension of 2,2,2-trifluoro-N-methyl-N-(2-pyridin-3-yl-thiazol-5-yl)-acetamide (1.0 g, 3.5 mmol) and N-chlorosuccinimide (0.557 g, 4.2 mmol) in acetonitrile (30 mL) was heated to 63° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and it was treated with additional N-chlorosuccinimide (0.557 g, 4.2 mmol) and heated to 35° C. under nitrogen for 2 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was redissolved in dichloromethane (80 mL) and washed with water (70 mL). The aqueous layer was re-extracted with methylene chloride (100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure and purified using reverse phase chromatography. The product eluted with a gradient of acetonitrile in water. The desired product was isolated as a thick brown gum (0.337 g, 30%): 1H NMR (400 MHz, CDCl3) δ 9.12 (br, 1H), 8.75 (br, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.28 (br, 1H), 3.40 (s, 3H); 19F NMR (376 MHz, CDCl3) δ−69.3; ESIMS m/z 324.3 (M+2); IR (thin film) 1772 cm−1.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([N:9]([C:19]2[CH:23]=[C:22]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])[S:21][C:20]=2[C:30]([OH:32])=[O:31])[C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[CH3:33][O:34][P:35]1(=[O:42])[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:29][C:26]([CH3:27])([CH3:28])[C:25]#[C:24][C:22]1[S:21][C:20]([C:30]([OH:32])=[O:31])=[C:19]([N:9]([CH:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH:38]3[CH2:39][CH2:40][P:35]([O:34][CH3:33])(=[O:42])[CH2:36][CH2:37]3)[CH2:8][CH2:7]2)[C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH3:18])[CH2:16][CH2:17]2)=[O:11])[CH:23]=1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(N)CC2)CC1
Reactant: COP1(=O)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COP1(=O)CCC(NC2CCC(N(c3cc(C#CC(C)(C)C)sc3C(=O)O)C(=O)[C@H]3CC[C@H](C)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(N-(4-aminocyclohexyl)-4-methylcyclohexanecarboxamido)-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylic acid hydrochloride (40 mg, 0.083 mmol) and 1-methoxy-1-oxo-1λ5-phosphinan-4-one (27 mg, 0.166 mmol) were dissolved in 2 mL of DMF. Sodium triacetoxyborohydride (35 mg, 0.166 mmol) was added. The reaction mixture was allowed to stir at room temperature over 18 hours, and then diluted with EtOAc, washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid) to give title compound (38.6 mg): MS (m/z): 591.3 [M+H]−; HPLC retention time: 3.28 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[NH:9]2)=[CH:4][CH:3]=1.I[C:27]1[CH:28]=[C:29]([CH3:35])[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[N:9]2[C:27]2[CH:28]=[C:29]([CH3:35])[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(I)cn(C)c1=O
Reactant: COc1ncccc1-n1nc(C)c2c1C(=O)NC2c1ccc(Cl)cc1
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(C)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 23 using 4-(4-chlorophenyl)-1-(2-methoxypyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 71.4) and 5-iodo-1,3-dimethylpyridin-2(1H)-one (step 23.2) at 100° C. for 16 hr. Further purification by preparative achiral SFC (column Silica, gradient 22-27% in 6 min_total 11 min). tR: 4.34 min (HPLC 1); tR: 1.00 min (LC-MS 2); ESI-MS: 476 [M+H]+ (LC-MS 2); Rf=0.51 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16].[OH2:19]>C(O)(=O)C.N1C=CC=CC=1.[Ni]>[CH3:1][O:2][C:3]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:6]([CH:7]=[O:19])=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O
Reactant: COc1c(C(F)(F)F)cc(C#N)cc1C(F)(F)F
Agent: [Ni]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: COc1c(C(F)(F)F)cc(C=O)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-methoxy-3,5-bis(trifluoromethyl)benzonitrile (868 mg, 3.23 mmol, 1.00 equiv), a solution of NaH2PO2.H2O in water (10.0 mL), acetic acid (10.0 mL), pyridine (20.0 mL), Raney-Ni (0.9 g). The resulting solution was stirred for 3 h at 45° C. in an oil bath. The reaction progress was monitored by GCMS. The solids were filtered out. 20.0 mL EtOAc and 20.0 mL H2O were added into the mixture. The organic phase was washed by H2O with 2*20 mL and dried over Na2SO4. The solvent was removed and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 0.43 g (49%) of 4-methoxy-3,5-bis(trifluoromethyl)benzaldehyde as yellow oil. Mass spectrum (GC, m/z): Calcd. for C10H6F6O2, 272.0 (M). found 272.0.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:35][CH:31]3[CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: NC1CCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CNC1CCC1)C2

Procedure:
The title compound was prepared (0.027 g, 21%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and cyclobutylamine (0.49 g, 6.77 mmol). mp 203-205° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH:13]([CH2:14][CH3:15])[CH2:12][O:11][CH2:10][C:9]1=[O:16].[N:17](OCC(C)C)=[O:18]>O1CCCC1>[N:17](=[C:10]1[C:9](=[O:16])[N:8]([CH3:7])[CH:13]([CH2:14][CH3:15])[CH2:12][O:11]1)[OH:18]
Reactant: CCC1COCC(=O)N1C
Reactant: CC(C)CON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1COC(=NO)C(=O)N1C
Yield: 92.9 %

Procedure:
A quantity of 33.7 g of potassium t-butoxide, 40.0 g of 4-methyl-5-ethyl-tetrahydro-1,4-oxazin-3-one, and 29.3 g of isobutyl nitrite were caused to react sequentially in 800 ml of anhydrous tetrahydrofuran in a manner similar to that described in Example III. Following a similar workup, 44.7 g of a thick oil were obtained which could not be induced to crystallize. Part (10 grams) was chromatographed on silica gel eluting the product band (3.0 grams) with acetone after unchanged starting material (5.4 grams) had been eluted with isopropyl ether/acetone mixtures. Trituration of the product fraction with ethyl acetate afforded pure oxime product, 2.9 g, mp. 168.5°-170.0°, equivalent to a total yield (in 44.7 g of crude product) of 13.0 grams.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[CH2:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)[CH3:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:45](=[O:46])[C:44]4[CH:48]=[CH:49][C:41]([CH2:39][CH3:40])=[CH:42][CH:43]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccc(CC)cc3)cc1)n2C)c1ccccn1
Yield: 64 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 4-ethylbenzoylchloride. Yield: 64% of theory, C36H37N7O4 (631.7) Rf value: 0.78 (silica gel; dichloromethane/methanol=9:1) ##EQU130##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].Br[C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21])[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CC1(C)OB(c2cc(Cl)c(F)c(Cl)c2)OC1(C)C
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 56.8 %

Procedure:
A mixture of 2-(3,5-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.56 g, 8.83 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (1.85 g, 10.6 mmol), Cs2CO3 (11.5 mL, 2M, 17.7 mmol) and Pd(PPh3)2Cl2 (200 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel eluted with hexanes to give 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.3 g; yield 56%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.412 (d, J=6.5 Hz, 2 H), 6.057 (s, 1 H), 5.806 (s, 1 H) ppm.