Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][C:53]=1[O:58][CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[CH3:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][C:53]=1[O:58][CH:59]1[CH2:64][CH2:63][N:62]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:61][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ccncc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
DIPEA (154 mg, 1.4 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (107 mg, 0.4 mmol) in DMF (2 mL) followed by HOBt (54 mg, 0.4 mmol) and EDCI.HCl (84 mg, 0.44 mmol). After 2 minutes 4-methyl-3-(piperidin-4-yloxy)-pyridine hydrochloride (100 mg, 0.4 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, the solid collected. Purification of the solid by washing with 10% MeOH in CHCl3 afforded 106 mg (66% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(4-methyl-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 420, 98.9%. 1H NMR (300 MHz, DMSO-d6): δ 14.0 (b, 1H), 8.6 (s, 1H), 8.4 (d, 1H), 8.2 (b, 1H), 7.8 (m, 3H), 7.5 (m, 2H), 7.4 (m, 1H), 7.2 (s, 1H), 4.9 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 3.5 (m, 2H), 2.4 (s, 3H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [CH:1]([S:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:27](Br)[C:28]#[CH:29]>O1CCCC1>[CH:1]([S:14][C:15]1[N:19]=[N:18][N:17]([CH2:29][C:28]#[CH:27])[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: c1ccc(C(Sc2nnn[nH]2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCn1nnc(SC(c2ccccc2)c2ccccc2)n1
Reaction time: 2.5 h
Yield: 42.9 %

Procedure:
To a solution of 5-benzhydrylthio-1H-tetrazole (29 g) in tetrahydrofuran (145 ml) were added triethylamine (12.0 g) and 2-propynyl bromide (19.3 g) at room temperature. The resulting mixture was stirred for 2.5 hours at 40° to 45° C. The reaction mixture was filtered and the filtrate was evaporated. The residue was shaken with a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residual oil (27.7 g) was subjected to column chromatography on silica gel, and eluted with a mixture of n-hexane, chloroform and ethyl acetate (5.5:4.5:0.5), to give 5-benzhydrylthio-2-(2-propynyl)-2H-tetrazole (14.2 g), mp 85° to 86° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: CC(C)S(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)c1ccc(Br)c(C(N)=O)c1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
2-Bromo-5-(isopropylsulfonyl)benzoic acid (Preparation 23, 623 mg, 2.03 mmol) and HATU (925 mg, 2.44 mmol) were dissolved in DMF (10 mL) and diisopropylethylamine (1.74 mL, 10.0 mmol) was added dropwise to the mixture. The mixture was stirred for 1 hour and then partitioned between water (50 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic extracts were washed with saturated brine (20 mL) and dried (MgSO4). The solvent was removed under reduced pressure to leave a pale yellow solid. This material was purified by silica gel column chromatography eluting with MeOH/CH2Cl2 3:97 to give the title compound as a white solid 59% yield, 362 mg.
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)C.Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[C@H:14]([CH3:20])[NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)[CH3:19]
Reactant: CCOC(=O)C(C)Br
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)[C@H](C)Nc1ccc(CCC(=O)O)cc1

Procedure:
This compound was prepared in a manner analagous to the process described in synthesis example 14, except using ethyl-4-aminobenzoate and ethyl 2-bromoproprionate.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=2C(O)=O)[CH2:24][CH2:23]1)=O)(C)(C)C.NC1C=CC=C(Cl)C=1C(O)=O.C([O:54][C:55]([N:57]1CCC(=O)CC1)=O)(C)(C)C>ClC(Cl)C>[Cl:38][C:34]1[C:30]2[NH:57][C:55](=[O:54])[N:28]([CH:25]3[CH2:24][CH2:23][NH:22][CH2:27][CH2:26]3)[C:29]=2[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(Cl)c2C(=O)O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1cccc(Cl)c1C(=O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=c1[nH]c2c(Cl)cccc2n1C1CCNCC1
Reaction time: 5 h

Procedure:
2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}-6-chlorobenzoic acid Sodium triacetoxyborohydride (3.09 g, 14.6 mmol) was added to a solution of 2-amino-6-chlorobenzoic acid (1.00 g, 5.83 mmol) and N-(t-butoxycarbonyl)-4-piperidone (2.32 g, 11.7 mmol) in dichloroethane (20 mL) at room temperature. After 5 h, the reaction was quenched with saturated aqueous ammonium chloride. This mixture was separated and extracted with ethyl acetate (3×). After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatorgraphy (silica gel, 0 to 15% methanol in methylene chloride gradient elution), which gave the title compound contaminated with some ketone starting material (3.60 g). MS 335.1 (M+1).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH2:6])[NH2:5])#[N:2].Cl.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[O-]CC.[Na+].[Cl:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21](OC)=O>COCCO.O>[NH2:6][C:4]1[N:3]=[C:1]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:2]=[C:21]([C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[Cl:18])[N:5]=1
Reactant: N#CN=C(N)N
Reactant: COC(=O)c1ccccc1Cl
Reactant: C1CCNCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: Nc1nc(-c2ccccc2Cl)nc(N2CCCCC2)n1
Yield: 24.7 %

Procedure:
Dicyandiamide (8.4 grams) and piperidine hydrochloride (12.1 grams) were heated at 145° to 150° C. for four hours in 20 milliliters of methylcellosolve. After cooled, the reaction solution was mixed with 6.8 grams of sodium ethoxide and 30 milliliters of methylcellosolve, then heated to reflux for four hours with 15 grams of methyl o-chlorobenzoate, cooled, diluted with 200 milliliters of water, the crystals separated out therefrom were collected by filtration, and washed with methanol to give 6.3 grams of 2-amino-4-piperidino-6-(2-chlorophenyl)-s-triazine, melting point 184° to 186° C.
Reaction SMILES: CON=C(C1N=C(NC=O)SC=1)C(N[CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=O.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:22]([N:21]1[C:17]([S:16][CH2:15][C:12]2[CH2:13][S:14][C@@H:9]3[CH2:8][C:41](=[O:42])[N:10]3[C:11]=2[C:25]([OH:27])=[O:26])=[N:18][N:19]=[N:20]1)[C:23]#[CH:24]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Yield: 114.3 %

Procedure:
To a mixture of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.8 g) in methylene chloride (24 ml) were added anisole (2.8 g) and trifluoroacetic acid (7.5 g) with stirring under ice-cooling and then the resulting mixture was stirred for one hour and 15 minutes at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate. The mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The aqueous layer was separated and washed with ethyl acetate (x2) and thereto were added ethyl acetate and tetrahydrofuran. The mixture was adjusted to pH 2.0 with 10% hydrochloric acid. The organic layer was separated, washed with water, dried over magnesium sulfate, treated with activated charcoal and evaporated. The residue was pulverized in isopropyl ether, collected by filtration, washed with isopropyl ether and dried to give 7-[2-methoxyimino-2-(2-formamidothiazol-4 -yl)acetamido[-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.48 g).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:10][CH2:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[CH2:35](Br)[C:36]#[CH:37].O>CN(C)C=O>[O:8]=[C:9]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:10][CH2:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:37][C:36]#[CH:35])[CH2:14][C@@H:13]1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: C#CCBr
Reactant: COC(=O)C[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](CC(=O)OC)C1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
4.8 cm3 of triethylamine were added with stirring, at a temperature in the region of 20° C. and under an inert atmosphere, to a solution of 5 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate in 60 cm3 of dimethylformamide. After stirring for 15 minutes at this temperature, 1.5 cm3 of propargyl bromide were added over approximately 15 minutes and then, after 15 minutes, the mixture was heated at a temperature in the region of 45° C. for 4 hours. After cooling to approximately 20° C., the reaction mixture was poured onto approximately 700 cm3 of water and then the mixture was extracted with 4 times 80 cm3 of diethyl ether. The combined extracts were washed with 3 times 80 cm3 of water, dried, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 4 cm; silica volume 500 cm3), elution was carried out with pure ethyl acetate, and 60-cm3 fractions were collected. Fractions 9 to 20 were combined and then concentrated as under the above conditions. 4.3 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[prop-2-ynyl]piperidine-3-acetate were obtained in the form of an oil with a yellow color.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]N(C=O)C.[H-].[Na+].CI>O>[CH3:27][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12]1
Reactant: c1ccc(CN(CCc2c[nH]c3ccccc23)Cc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1cc(CCN(Cc2ccccc2)Cc2ccccc2)c2ccccc21
Reaction time: 0.25 h

Procedure:
N,N-dibenzyl-tryptamine (1.72 g) was added to an anhydrous DMF solution containing 0.24 g of NaH (60% nujol) and the mixture was stirred for 15 minutes. Methyl iodide (0.31 ml) was added and the mixture was stirred for one hour. Water was added and the solvent was evaporated off. The residue to which water was added was extracted with IPE, the extract was washed with water and the brine and dried over magnesium sulfate. The crude product was purified by column chromatography on silica gel. Eluates with ethyl acetate/hexane (1/9) afforded 1.58 g of the oily title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:15].Cl>CN(C=O)C>[CH3:15][O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1
Reactant: OB1OCc2ccc(O)cc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
H181 (150 mg, 1.0 mmol) was dissolved in DMF (8.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 120 mg, 3.0 mmol) and iodomethane (0.1 mL, 2.0 mmol). The reaction mixture was stirred for 2 h then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (81.9 mg, 50% yield). 1H NMR (400 MHz, CDCl3): δ 7.26 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.07 (dd, J=8.1 & 2.4 Hz, 1H), 5.06 (s, 2H) and 3.84 (s, 3H) ppm; Mp: 107-109° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.B(O)O.[C:40]([O-:43])([O-])=O.[Na+].[Na+].CO>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:24]([C:4]1[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH:7]=[C:2]([C:10]2[CH:11]=[N:12][C:13]([CH:40]=[O:43])=[CH:14][CH:9]=2)[CH:3]=1)=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 152.6 %

Procedure:
Tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) carbamoyl)-2-methylphenyl)(methyl)amino)piperidin-1-carboxylate (0.5 g, 0.892 mmol), (6-formylpyridin-3-yl))boronic acid (0.31 g, 1.33 mmol) and Pd(PPh3)4 (0.103 g, 0.082 mmol) in 1,4-dioxane (10 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (0.34 g, 3.21 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using 5% MeOH in DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (0.40 g, 87.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([C:18]([O:20][CH3:21])=[O:19])[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[CH2:30]Br>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[CH2:30][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[NH:10][C:9]1([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:18]([O:20][CH3:21])=[O:19]
Reactant: Fc1cccc(F)c1CBr
Reactant: COC(=O)C1(c2c(F)cccc2F)N=c2ccccc2=N1
Product: COC(=O)C1(c2c(F)cccc2F)Nc2ccccc2N1Cc1c(F)cccc1F
Yield: 76 %

Procedure:
Methyl 2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (4004) (16.15 g, 56.0 mmol) was reacted with 2,6-difluoro-a-bromo-toluene (14.67 g, 70.86 mmol, 125 M %). The crude product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2, and recrystallization from diethylether, yielding white crystals of methyl 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (4005) (17.63 g, 42.55 mmol, 76% yield). M.p. 185-186° C. 1H-NMR (200 MHz, CD2Cl2) δ 7.94 (dd, J=1.1, 7.6 Hz, 1H, H5), 7.72 (dd, J=1.1, 8.2 Hz, 1H, H7), 7.56 (m, 1H, H4′), 7.37 (dd, J=7.6, 8.2 Hz, 1H, H6), 7.26 (m, 1H, H4″),7.09 (m,2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.39 (s, 2H, CH2PhF2), 3.95 (s, 3H, CO2CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]=2[N:8]([CH3:16])[C:7]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:5])[CH3:2].[C:24](OC(OC(C)(C)C)N(C)C)(C)(C)C.Cl.[NH2:39][C:40]([NH2:42])=[NH:41].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][C:11]3[C:10]([C:9]=2[N:8]([CH3:16])[C:7]=1[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[N:39][C:40]([NH2:42])=[N:41][CH:24]=3)=[O:5])[CH3:2]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CCOC(=O)c1c2c(n(C)c1C(=O)OC(C)(C)C)C(=O)CCC2
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2c(n(C)c1C(=O)OC(C)(C)C)-c1nc(N)ncc1CC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester XXVIA (4.67 mmol) in DMF (20 mL), N,N-dimethylformamide di -tert-butyl acetal (2 mL) was added and the solution was stirred at 100° C. overnight. After cooling to rt guanidine hydrochloride (14 mmol) and K2CO3 (14 mmol) were added and the mixture was heated at 100° C. for 24 h. The organic solvent was evaporated to dryness. Chromatography on silica gel (AcOEt/hexane 1:1) afforded the title compound (80% yield). ESI (+) MS: m/z 373 (MH+). 1H NMR: 1.28 (t, J=7.07, 3H), 1.55 (s, 9H), 2.68 (t, J=7.80, 2H), 2.79 (t, J=7.80, 2H), 4.18 (s, 3H), 4.23 (q, J=7.07, 2H), 6.40 (bs, 2H), 7.97 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23](O)=O.B.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[CH3:23]
Reactant: Nc1c(C(=O)O)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 8 h

Procedure:
To a stirred solution of 5-amino-4-carboxy-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (15.0 g; hereinbefore described in Reference Example 24) in dry tetrahydrofuran (50 ml) was added, under nitrogen, a solution of boranetetrahydrofuran complex (1 Molar, 27.5 g) during 10 minutes keeping at -20° C. The solution was allowed to reach room temperature and stirred overnight. A further addition of the borane was made (10 ml), and the solution heated under reflux overnight. After cooling, a further addition of the borane (20 ml) was made, and the solution again heated under reflux for 4 hours. After cooling, sodium hydroxide (6 N) solution was added to pH 11, and the solution extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a brown oil. Purification by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm-2) eluting with hexane-ethyl acetate (2:1) gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methyl-3-trifluoromethylpyrazole (2.0 g) from toluene-hexane, m.p. 97°-100° C., in the form of white crystals. ##STR3##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([S:15](F)(=[O:17])=[O:16])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1.O1CCCC1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O.C(OCC)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:15]([C:4]2[C:3]([O:2][CH3:1])=[CH:14][C:7]3[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=3[CH:5]=2)(=[O:17])=[O:16])=[CH:27][CH:26]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COc1cc2c(cc1S(=O)(=O)F)CCN(C)CC2
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(cc1S(=O)(=O)c1ccc(F)cc1)CCN(C)CC2
Reaction time: 8 h
Yield: 51 %

Procedure:
The sulfonyl fluoride D4 from Description 4 (25 g) was dissolved it dry tetrahydrofuran (250 mL) and 4-fluorophenylmagnesium bromide in tetrahydrofuran (2.5 equivalents) added over 15 min with ice bath cooling, an exotherm only apparent during the first part of the addition. Stirred overnight without cooling then added over 10 min to a solution of sodium potassium tartrate tetrahydrate (250 g) in water (450 mL) with stirring. Diethyl ether was added (400 mL) and the organic layer separated, dried, evaporated, and crystallised from diethyl ether to give crystalline fluorophenyl sulfone D5 17 g (51%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:8]([NH:9][CH2:10][CH3:11])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1.CCN(C(C)C)C(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:3][C:4]1[C:8]([N:9]([CH2:10][CH3:11])[C:39]([CH:36]2[CH2:37][CH2:38][N:34]([C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:33])[CH2:35]2)=[O:41])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(=O)C1CCN(C(=O)OC(C)(C)C)C1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a stirred solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine dihydrochloride (0.20 g, 0.68 mmol) in CH2Cl2 (1.4 mL) were added DIPEA (0.35 g, 2.7 mmol) followed by 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (0.22 g, 1.0 mmol) and EDCI (0.20 g, 1.0 mmol). The reaction mixture was stirred at room temperature for 16 hours, then concentrated. The residue was purified by silica gel chromatography eluting with 0%-50% acetone/hexanes to afford a colorless oil (0.14 g, 49%).
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[C:18]([CH3:26])[CH:17]=1)[CH3:14].CN(CC1OC(CSC[CH2:39][NH:40][C:41]2[C:45](OC)=[N:44][S:43](=[O:49])(=[O:48])[N:42]=2)=C(C)C=1)C.CN>CO>[CH3:14][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:45]2[C:41]([NH:40][CH3:39])=[N:42][S:43](=[O:49])(=[O:48])[N:44]=2)=[C:18]([CH3:26])[CH:17]=1)[CH3:12]
Reactant: Cc1cc(CN(C)C)oc1CSCCN
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1oc(CN(C)C)cc1C
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1oc(CN(C)C)cc1C

Procedure:
When a methanol suspension of 3,4-dimethoxy1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 2-[(5-dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamine [prepared in Step B] and the resultant 3-{2-[(5-dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with an excess of methylamine, the title compound is thereby produced.