Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][NH:12][C:11]2=O>S1(CCCC1)(=O)=O>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Solvent: O=S1(=O)CCCC1
Product: COc1cc2ncnc(Cl)c2cc1OC
Temperature: 120 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Sulfolane (250 ml) and phosphorus oxychloride (250 ml=412.5 g, 2.69 mol) were added to 6,7-dimethoxy-4-quinazolone (50.1 g, 0.24 mol), and the mixture was stirred at 120° C. for one hr. The reaction mixture was cooled to room temperature, and the excess phosphorus oxychloride was then removed by distillation under the reduced pressure. The residue was poured into ice water (1000 ml), and chloroform (1000 ml) was added thereto. The aqueous layer was adjusted to pH 6.5 by the addition of a 20% sodium hydroxide solution, followed by the separation of the organic layer from the aqueous layer. The separated organic layer was washed with water (1000 ml×six times), was dried over sodium sulfate, and was then concentrated under the reduced pressure. Tetrahydrofuran (470 ml) was added to the residue, and the mixture was refluxed. The reaction solution was cooled to −5° C. to −10° C. and was filtered and dried to give 38.5 g (yield 71.4%) of the target product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:12])=[CH:8][C:9]=1[Br:10])=[O:4].I(O)(=O)(=O)=[O:14]>CC#N.CCOC(C)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:14])=[O:12])=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: COC(=O)c1sc(CO)cc1Br
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C(=O)O)cc1Br
Reaction time: 2 h
Yield: 101.3 %

Procedure:
A mixture of 3-Bromo-5-hydroxymethyl-thiophene-2-carboxylic acid methyl ester (0.19 g, 0.76 mmol) and Periodic Acid (0.38 g, 1.66 mmol) in MeCN (10 ml) was stirred for 30 min A solution of PCC (0.010 g, 0.015 mmol) in MeCN (0.2 ml) was added. After 2 h, the reaction mixture was diluted with EtOAc (50 ml), washed with sodium sulfite, brine, dried over sodium sulfate, filtered and evaporated. Isolate 0.204 g (100%) of yellow solid product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>O>[CH3:2][O:3][C:4](=[O:11])[CH:5]([N:6]=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)[CH2:7][CH2:8][S:9][CH3:10]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(CCSC)N=Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 91 %

Procedure:
To a solution of L-methionine methyl ester hydrochloride (2 g, 10.0 mmol) and sodium carbonate (1.06 g, 10.0 mmol) in water (46 mL) was added p-chlorobenzaldehyde (1.4 g, 10.0 mmol). The resulting mixture was stirred at 40° C. for 45 minutes then 17 h at room temperature. The white cloudy solution was extracted with dichloromethane (3×50 mL). The organic phase was washed with water (2×50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound 2.6 g (91%) which was used in next step with out further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].C([O:34][C:35](=[O:38])[CH2:36]Br)(C)(C)C>CN(C=O)C>[CH3:24][C:21]12[CH2:23][CH:17]([N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][CH2:36][C:35]([OH:38])=[O:34])=[CH:13][CH:12]=3)=[O:15])[CH2:22]1)[CH2:18][C:19]([CH3:25])([CH3:26])[CH2:20]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NCC(=O)O)cc2)C1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (5.0 g, 13.42 mmol) in dry DMF (75 ml) was added sodium hydride (750 mg, 33.3 mmol in 60% mineral oil) and the mixture was stirred for 30 min. Bromo-acetic acid tert-butyl ester (3.14 g, 16.11 mmol) was added and the stirring was continued for an additional 1 hr. at 50° C. The reaction was quenched by addition of water (50 ml) and extracted with diethyl ether (2×50 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (75 ml) and TFA (40 ml) was added. The resulting mixture was stirred for 16 hrs. at room temperature and evaporated in vacuo. To the residue was added water (75 ml) and diethyl ether (25 ml) and the precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50° C. affording 3.3 g (74%) of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]-octane-6-carbonyl)-phenylamino]-acetic acid an solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([N+:15]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)C>[Pd].O1CCOCC1>[NH2:12][C:10]1[C:9]([NH2:15])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:1])[CH:11]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)c1cc(N)c(N)cc1C
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of 5.3 g of methyl 2-methyl-4,5-dinitrobenzoate, 1.06 g of 10% palladium on carbon (50% wet), 53 mL of ethanol, and 53 mL of dioxane was thoroughly stirred at room temperature under a hydrogen atmosphere. The insoluble materials were filtered and washed sufficiently with methanol. The filtrate and the washing liquid were concentrated together, and then dried under reduced pressure to obtain 3.98 g of methyl 4,5-diamino-2-methylbenzoate.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.F[B-](F)(F)F.[CH3:28][O+](C)C.O>C(Cl)Cl>[CH3:28][O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C[O+](C)C
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19-Hydroxyandrost-4-ene-3,17-dione is dissolved in methylenechloride and trimethyloxonium fluoroborate added. After stirring at room temperature for a period of two hours, water is added to the reaction mixture, the organic layer is separated, dried over magnesium sulfate and the solvent removed under vacuum. The residue is crystallized from an acetone-hexane solution to yield the desired 19-methoxyandrost-4-ene-3,17-dione.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:14]([OH:16])[CH:15]=1.[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl.Cl>C(Cl)Cl.O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]#[C:18][Si:19]([CH3:20])([CH3:22])[CH3:21])=[C:14]([O:16][CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[CH:15]=1
Reactant: COc1ccc(C#C[Si](C)(C)C)c(O)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: Cl
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1ccc(C#C[Si](C)(C)C)c(OCOCC[Si](C)(C)C)c1
Yield: 73.8 %

Procedure:
Add diisopropylamine (11.0 mL, 78.3 mmol) to a rapidly stirred solution of 5-methoxy-2-trimethylsilanylethynyl-phenol (11.5 g, 52.2 mmol) in CH2Cl2 at room temperature under N2. Add 2-(trimethylsilyl)ethoxymethyl chloride (13.9 mL, 78.3 mmol) dropwise over 5 minutes and stir at room temperature under N2 overnight Acidify with aqueous 1N HCl solution, add water, separate layers. Extract from aqueous layer with CH2Cl2 (×2), dry combined organic layers over MgSO4 and concentrate. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-5% EtOAc/hexanes to afford 4-methoxy-2-(2-trimethylsilanyl-ethoxymethoxy)-1-trimethylsilanylethynyl-benzene (13.5 g, 74%). MS (IS) 351 (M+1)+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][C:14](=[O:16])[CH:13]=[C:12]([CH3:17])[CH2:11]1.Cl>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH:14]([OH:16])[CH:13]=[C:12]([CH3:17])[CH2:11]1
Reactant: CC1=CC(=O)CC(c2ccccc2F)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1=CC(O)CC(c2ccccc2F)C1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a stirred mixture of sodium borohydride (2.0 g, 0.05 mole) in 400 ml of ethanol was added in one portion 5-(2-fluorophenyl)-3-methyl-2-cyclohexen-1-one (42.3 g, 0.21 mole) in 50 ml of ethanol. The reaction mixture was heated under reflux for 16 hours. An additional 2.0 g of sodium borohydride was then added to the reaction mixture and heating under reflux continued for an additional 2 hours. Again, 2.0 g of sodium borohydride was added to the reaction mixture and heating under reflux continued for a 2 hour period. The reaction mixture was stirred with ice, then acidified with aqueous 10% hydrochloric acid. The mixture was extracted with diethyl ether, and the ether extract was washed with an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 5-(2-fluorophenyl)-3-methyl-2-cyclohexen-1-ol (41.2 g) as an oil.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl.CCOCC.CCCCCC>[F:1][C:2]1([F:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH2:3]1.[C:27]([OH:29])([C:26]([F:31])([F:30])[F:25])=[O:28]
Reactant: CC(C)(C)OC(=O)NCC1CCC(F)(F)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: NCC1CCC(F)(F)CC1
Reaction time: 24 h

Procedure:
A solution of EXAMPLE 396A (3 g) in dichloromethane (35 mL), trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was concentrated, then condensed from toluene, and left under high vacuum for 24 hours. The semi-solid was taken up in ether/hexane and filtered to give the title compound as its TFA salt.
Reaction SMILES: C[O:2][C:3]([P:5]([OH:8])([OH:7])=[O:6])=O.[CH3:9][NH:10][NH2:11]>O.CO.C(O)C>[CH3:9][N:10]([C:3]([P:5]([OH:8])([OH:7])=[O:6])=[O:2])[NH2:11]
Reactant: CNN
Reactant: COC(=O)P(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CO
Product: CN(N)C(=O)P(=O)(O)O
Temperature: 80 °C
Reaction time: 7 h
Yield: 38 %

Procedure:
46 parts by weight of Na2 -salt of phosphonoformic acid methyl ester are dissolved in 90 parts by volume of water and 46 parts by weight of methyl hydrazine are added at 25° C. The mixture is stirred at 80° C. for 7 hours and allowed to cool. The residue is removed by suction filtration and the filtrate is evaporated in vacuo. The residue after evaporation is digested with ethyl alcohol and the such obtained crystals are again dissolved in a mixture of 70 parts by volume methanol and 200 parts by volume ethyl alcohol and thereafter precipitated. 90 parts by weight of Na2 -salt of phosphonoformic acid methyl hydrazide are obtained (yield 38%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11]C(=O)C)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.C(OCC(C)C)(=O)C>C(O)C(C)C>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][OH:11])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: Cl
Solvent: CC(C)CO
Solvent: CC(=O)OCC(C)C
Product: CCOP(=O)(CCO)OCC
Yield: 62.8 %

Procedure:
100 g of 2-acetoxyethane phosphonic acid diethyl ester are blended with 200 ml of isobutyl alcohol containing 2 g of HCl and heated to 120°-150°C for 5 hours. A mixture of isobutyl acetate and isobutanol is removed continuously by distillation in the course of the reaction. By gas chromatography of the mixture of isobutyl acetate/isobutanol, no ethyl acetate and only traces of ethanol were found. 51 g of 2-hydroxyethane-phosphonic acid diethyl ester are obtained after distillation under reduced pressure, corresponding to a yield of 62% of the theoretical.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 3 °C
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was filtered and the solids washed with MTBE (about 3 L). The filtrate was concentrated and the residue was purified over silica gel (7:1 to 3:1 Hex/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle, washed with hexanes (about 1000 mL) and dried to afford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:36][CH2:37][CH2:38][OH:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]([CH2:37][CH2:38][OH:39])[C:26](=[O:27])[CH2:25][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=1)(=[O:12])=[O:13])[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCCNCc1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)N(CCO)Cc2ccccc2)c2ccc3ncccc3c2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: [S:1]1[C:5]([C:6](OC)=[O:7])=[CH:4][C:3]2[S:10][CH:11]=[CH:12][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[OH:7][CH2:6][C:5]1[S:1][C:2]2[CH:12]=[CH:11][S:10][C:3]=2[CH:4]=1
Reactant: COC(=O)c1cc2sccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1cc2sccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
A solution of methylthieno[3,2-b]thiophene-2-carboxylate (6) (37.04 g., 186.9 mmoles) in ether (850 mL) was added at a rapid drip (1 hr. 45 min.) to a suspension of lithium aluminum hydride (14.18 g., 373.7 mmoles) in ether (500 mL) which had been cooled in an ice-water bath. After the addition was completed, the mixture was stirred at room temperature for three hours. The reaction was worked up by cooling in an ice-water bath with successive dropwise addition of water (14 mL), 15% aqueous sodium hydroxide (14 mL) and water (42 mL) with vigorous stirring. Vigorous stirring was continued until the salts are well granulated. The ether solution of the product was decanted and the salts washed further with ether. The combined ether solutions were dried (MgSO4), filtered, and the solvent evaporated in vacuo to leave 31.4 g of 2-hydroxymethylthieno[3,2-b]thiopene (7) (mp 91° to 93° C.) which was used in the next step without purification. A small sample was recrystallized from hexane for analysis (mp 93°-94° C.).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37]([OH:39])=O)[CH:32]=[CH:33][C:34]=1[F:35]>>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([C:11]([N:13]3[CH2:14][CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH:16]([N:18]([CH3:19])[C:37](=[O:39])[CH2:36][C:31]4[CH:32]=[CH:33][C:34]([F:35])=[C:29]([F:28])[CH:30]=4)[CH2:17]3)=[O:12])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Product: CN(C(=O)Cc1ccc(F)c(F)c1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(3,4-difluoro-phenyl)-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 3,4-difluorophenylacetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 564.3 [M]+.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)C=CC=2OC(F)F)CC1>C(OCC)(=O)C>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:24][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(COCC2CC2)c2c(=O)[nH]ncc21
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Solvent: CCOC(C)=O
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(COCC3CC3)c12
Yield: 65 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 581 mg (1.06 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-cyclopropylmethoxymethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Example 59-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water was added to the obtained concentrate, and precipitated solid was collected by filtration and washed with water. The obtained crude solid was applied to silica gel column chromatography (Eluent; ethyl acetate), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 287 mg of the title compound as a white solid. (Yield: 65%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH:20]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2].[Br:28][CH2:29][C:30](Br)=[O:31].[Cl-].[Cl-].[Cl-].[Al+3]>CCOCC>[Br:28][CH2:29][C:30]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH3:27])[N:18]=[C:19]([CH:20]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]3[N:11]=2)[CH:6]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: CCOc1ccccc1-c1nn2c(C3CCCCCC3)nc(C)c2c(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOc1ccc(C(=O)CBr)cc1-c1nn2c(C3CCCCCC3)nc(C)c2c(=O)[nH]1
Yield: 66.5 %

Procedure:
Analogously to example 57A, 1.36 g (3.7 mmol) of the compound from example 28A were reacted with 1.5 g (7.4 mmol) of bromoacetyl bromide and 1.48 g (1.1 mmol) of aluminum trichloride. Trituration with ether gave 1.2 g (66.3%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH3:19][NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)=[O:22].C1COCC1>C(N(CC)CC)C>[CH3:19][NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:24]1)=[O:22]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CNC(=O)[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Yield: 86 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3R)—N-methylpiperidine-3-carboxamide (Preparative Example 31) by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and (3R)—N-methylpiperidine-3-carboxamide. After 3 hr the reaction mixture was evaporated in vacuo and filtered with the aid of water. The resulting solids were then washed with a 1 N aqueous HCl solution followed by water. The material was air dried to afford product as a colorless solid (157 mg, 86%). LC/MS 6.00 min, [M+1]+ 402.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:9]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([OH:28])=[O:27])[CH:23]=2)[CH:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([OH:28])=[O:27])[CH:23]=3)[CH:18]=[CH:17]2)=[CH:4][CH:5]=1.[CH2:9]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26]([OH:28])=[O:27])[CH:23]=2)[CH:18]=[CH:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClCc1ccncc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccncc3)c2c1

Procedure:
The titled compound (12 mg) as a yellow solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 4-(chloromethyl)pyridine according to the method of the process (7) of Example 4.