Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:5]=[C:4]2[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:15](=[O:18])[NH:16][CH2:17][C:3]=12.O.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:42]2[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=2)O1>O1CCOCC1.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>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:7]=[C:2]([C:42]3[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=3)[C:3]=2[CH2:17][NH:16][C:15]1=[O:18]
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCNc1nc(-c2ccc(C(=O)O)cc2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 77.7 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)-ethyl]-amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (150 mg, 0.39 mmol) in dioxane (12 mL)/water (4 mL) were added potassium carbonate (325 mg, 2.36 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.019 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (146 mg, 0.59 mmol). The reaction mixture was bubbled with N2 for about 5 mins, then microwaved at about 150° C. for about 30 mins. The reaction mixture was concentrated. To the concentrated mixture were added DMSO (2 mL), H2O (0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided the title compound as a white solid (142 mg, 77%). LC-MS m/z 469 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11]I)=[CH:4][CH:3]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][S:8][C:5]2[CH:6]=[C:13]([OH:16])[CH:2]=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(SCCCI)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1cccc(SCCCSc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
A mixture of 12.6 g of monothioresorcinol, 31.3 g of 1-(4-chlorophenylthio)-3-iodopropane (prepared from 4-chlorothiophenol and 1-bromo-3-chloropropane followed by replacement of chlorine by iodine with sodium iodide in acetone), 16.6 g of potassium carbonate and 60 ml of acetone was stirred at room temperature for 24 hours, then the solvent was removed by distillation under reduced pressure, methylene chloride was added, the solution was washed several times with water and dried, and then 14.5 g of 3-(4-chlorophenylthiopropylthio)phenol were isolated by chromatography on silica gel using methylene chloride as mobile phase. This product was stirred together with 9.5 g of 6-chloromethyl-4-methyl-2-pyrone, 10.4 g of potassium carbonate and 60 ml of acetone at 50° C. for 31 hours, then the solvent was removed by distillation under reduced pressure, the residue was taken up in methylene chloride, and the solution was washed several times with water, dried and chromatographed on silica gel. 11.2 g of the main fraction were heated with 50 g of 2-aminopyridine at 75° C. for 65 hours, and a total of 12 g of hydroxylamine hydrochloride was added in several portions. The residue was then taken up in methylene chloride, and the organic phase was extracted by shaking with dilute hydrochloric acid and several times with water and was dried, and the solvent was removed by distillation. The residue amounted to 9.9 g. Treatment with methanol resulted in 2.7 g of pure hydroxypyridone of melting point 102° C.
Reaction SMILES: [NH3:1].Br[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8]>C(O)C>[NH2:1][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(CBr)c1
Reactant: N
Solvent: CCO
Product: NCc1cc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
An aqueous solution of 25% w/v ammonia (100 mL) was treated with EtOH (200 mL) and cooled to −78° C. The mixture was slowly treated with a cooled (−78° C.) solution of the benzylbromide (2.58 g, 10.0 mmol) in ethanol (100 mL). The mixture was then allowed to come to room temperature and stirred for 48 h. The mixtures were evaporated under reduced pressure and the residue solid was washed with CH2Cl2 to afford 3-(aminomethyl)-4-nitrobenzoic acid (1.7 g, 87% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.IC1C=CC=CC=1.C(O)(=O)C.C(O)(=O)C>ClCCl>[CH:2]([CH2:3][C:4]1([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:1]
Reactant: COC(=O)c1ccccc1OCCC1(CCO)CCCCC1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccccc1OCCC1(CC=O)CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.6 %

Procedure:
To a solution of methyl 2-[2-[1-(2-hydroxyethyl)cyclohexyl]ethoxy]benzoate (synthesized in Example 36) (226 mg) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (23 mg) in dichloromethane (4 mL) was added diacetic acid iodobenzene (261 mg) at room temperature. The solution was stirred at room temperature for 48 hours. Silica gel was added to the reaction solution and it was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (5:1)] to give the title compound (118 mg).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:22][C:13]1[CH:14]=[CH:15][C:9]2[C:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]=2[CH:12]=1
Reactant: c1ccc(-c2oc3ccccc3c2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(-c3ccccc3)c(-c3ccccc3)oc2c1
Temperature: 70 °C
Yield: 72 %

Procedure:
43.2 g of 2,3-diphenylbenzo[b]furan, 31.3 g of N-bromosuccinimide, and 400 mL of N,N-dimethylformamide were loaded into a flask, and the mixture was stirred under heat at 70° C. for 8 hours. After having been cooled to room temperature, the reaction solution was poured into 2 L of water. The precipitated crystal was separated by filtration, washed with methanol, water, and methanol in the stated order, and purified by silica gel column chromatography, whereby 40.2 g of a pale yellow crystal were obtained (72% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>ClCCl.CN(C)C=O>[N:24]([CH2:9][C@@H:6]1[CH2:5][CH2:4][C@H:3]2[CH2:8][C@@H:7]1[C:2]2([CH3:11])[CH3:1])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)[C@H]2CC[C@@H](CO)[C@@H]1C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@@H](CN=[N+]=[N-])[C@@H]1C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol (500 mg,) was dissolved in dichloromethane (15 mL). The solution was chilled in an ice bath and triethylamine (0.633 mL) was added, followed by methanesulfonyl chloride (0.278 mL). The reaction was stirred for 2 hours at 0° C., and was transferred to a separatory funnel and washed with 1N aqueous HCl (15 mL), saturated aqueous NaHCO3 (20 mL) and brine (15 mL), then dried (Na2SO4), filtered and concentrated to give a crude oil, which was dissolved in N,N-dimethylformamide (7.5 mL). Sodium azide (1054 mg) was added and the mixture was heated to 110° C. for 1.5 hours, and was cooled and partitioned between water (30 mL) and ethyl acetate (3×25 mL). The organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated to give a crude oil, which was purified by flash chromatography on silica gel eluting with 50 to 100% dichloromethane in hexanes to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3](=[N:7][C:8]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[O:4][CH2:5][CH3:6].CN(C)C=O.[N-:30]=[N+:31]=[N-:32].[Na+].C(OCC)(=O)C>O>[N:30]([CH2:2][C:3](=[N:7][C:8]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[O:4][CH2:5][CH3:6])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(CBr)=Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(CN=[N+]=[N-])=Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 3.3 parts of 2-(2-bromo-1-ethoxyethylideneamino)-5-nitrobenzophenone produced in Step (1) in 15 parts by volume of dimethylformamide is added 0.5 part of sodium azide at a room temperature with stirring. After the stirring is continued for further 40 minutes. Ethyl acetate and water are added to the reaction mixture and shaken well. The ethyl acetate layer separated is washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gives 2-(2-azido-1-ethoxyethylideneamino)-5-nitrobenzophenone as an oily substance. The product shows an absorption band at 2077 cm-1 due to N3 in an infrared absorption spectrum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.[NH2:13][C@H:14]1[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][C@H:14]2[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: N[C@@H]1CC=C(CO)C1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Product: Nc1nc(Cl)c(NC=O)c(N[C@@H]2CC=C(CO)C2)n1

Procedure:
By the method of Exaple 7, N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.56 g, 52.4 mmol) was reacted with (4R)-4-amino-1-cyclopentene-1-methanol (1.4 g, 52.4 mmol), available from (-)-2-azabicyclo[2.2]hept-5-en-3one (Chiroscience) by methods described in Examples 1-4 and 42 of U.S. Pat. No. 5,049,671. Crystallization from ethyl acetate--methanol gave title compound as white crystals, m.p. 148-150° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+M); 1H-NMR (DMSO-d6)δ: 8.97 and 8.55 (s and d with J=11.3 Hz, total 1, NHCHO), 8.12 and 7.80 (s and d with J=11.5 Hz, total 1, CHO), 7.00 and 7.78 (both d, J=7.4 Hz, total 1, NH), 6.60 and 6.40 (both 8, total 2, NH2), 5.48 (s, 1, =CH), 4.74 (t, J=5.5 Hz, 1, OH), 4.74-4.60 (m, 1, NCH), 4.0-3.90 (m, 2, CH2O), 2.75-2.55 and 2.40-2.15 (both m, 2 each, 2CH2); [α]58920 -4.4°, [60 ]57820 -5.2°, [α]54620 -4.8°, [α]43620 -20.0°, [α]36520 -60.4°, (c 0.25, methanol).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CO[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([Br:26])=[CH:23][CH:24]=3)[NH:19][N:18]=2)[CH2:13][CH2:12]1)=O.O>C1COCC1>[Br:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([CH:14]3[CH2:15][CH2:16][N:11]([CH3:9])[CH2:12][CH2:13]3)=[N:18][NH:19]2)=[CH:24][CH:23]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Yield: 55.3 %

Procedure:
To a stirred suspension of LiAlH4 (6.2 g, 0.083 mol of a 50-55% oil dispersion) in THF (175 ml), under nitrogen, was added, dropwise, 4-(6-bromo-1H-indazol-3-yl)piperidine-1-carboxylic acid methyl ester (28.1 g, 0.083 mol) of Example 106(a). The reaction was refluxed for 1 hour, cooled in an ice bath, and water was added. The reaction was filtered and the filtrate was concentrated to yield 13.5 g of a solid. The solid was recrystallized from toluene to yield 10.2 g (42%) of a solid, mp 203°-205° C. An analytical sample was obtained by chromatography of a 3.4 g sample on a preparative HPLC (silica gel column) utilizing CH2Cl2 -CH3OH-(C2H5)2NH (95:4:1) as eluent. After evaporation of the appropriate fractions there remained 2.8 g of 6-bromo-3-(1-methyl-4-piperidinyl)-1H-indazole, mp 205°-207° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:5]=2[CH:4]=[CH:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>[Fe].C(O)(=O)C>[C:16]([NH:12][C:9]1[CH:10]=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([CH3:15])([CH3:1])[O:7][C:6]=2[CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC1(C)C=Cc2ccc([N+](=O)[O-])cc2O1
Reactant: CC(=O)OC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)OC(C)(C)C=C2
Temperature: 120 °C

Procedure:
2,2-Dimethyl-7-nitro-2H-benzo[b]pyran (40.00 g, the preparation of which is disclosed in British Pat. No. 1,548,222), glacial acetic acid (200 ml), acetic anhydride (120 ml) and electrolytic iron powder (88 g) were stirred and heated at 120° C. for 16 hours. Dilution with water, extraction via chloroform followed by washing of the organic layer with water and sodium bicarbonate solution, drying evaporation etc., gave a crude gum which was chromatographed on a silica gel column using ethyl acetate--60°-80° petroleum ether mixtures in a gradient elution technique. Fractions homogeneous by TLC were combined and recrystallised from 60°-80° petroleum ether to give 7-acetamido-2-,2-dimethyl-2H-benzo[b]pyran (5.27 g) as white needles of mp 80°-81° C.; nmr (CDCl3) 1.39 (6H), 2.12 (3H), 5.48 (1H, d, J=10), 6.21 (1H, d, J=10), 6.76-7.34 (3H, m), 8.95 (1H). Anal. Calcd for C13H15NO2 ; C, 71.87; H, 696; N, 6.45. Found: C, 72.00; H, 7.11; N, 6.23%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4](Cl)[CH:3]=1.[OH-:12].[Na+].[CH3:14]O>>[Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]([NH2:7])=[O:12])=[C:4]([CH3:14])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Br)cc(Cl)c1C#N
Reactant: [OH-]
Agent: [Na+]
Product: Cc1cc(Br)cc(C)c1C(N)=O
Yield: 76 %

Procedure:
4-Bromo-2-chloro-6-methyl-benzonitrile (1.65 g, 7.16 mmol) was dissolved in methanol (20 mL) and 6M NaOH (20 mL) was added. The mixture was heated to reflux for seventeen hours. After cooling, the reaction was partitioned between diethyl ether and water. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Trituration with 10% EtOAc/Hexanes provided the title compound as a brick coloured solid (1.35 g, 76%). 1H NMR CDCl3: δ 7.41 (s, 1H), 7.29 (s, 1H), 6.33 (br s, 1H), 5.90 (br s, 1H), 2.37 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][C:17]([OH:28])=[N:16]2)=[CH:11][CH:10]=1.[F:29][C:30]([F:34])([F:33])[CH2:31]I.C(OCC)(=O)C>CN(C)C=O.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:18][C:17]([O:28][CH2:31][C:30]([F:34])([F:33])[F:29])=[N:16]2)=[CH:13][CH:14]=1
Reactant: FC(F)(F)CI
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(OCC(F)(F)F)nn2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
Potassium carbonate (697 mg, 5.05 mmol) was added to a solution of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (0.3 g, 1.01 mmol) in dimethylformamide (3 mL). After 10 minute stirring, 2,2,2-trifluoroethyl iodide (0.497 mL, 5.05 mmol) was added to the mixture and the mixture was heated at 100° C. for 3 hours. After cooling, 100 mL of ethyl acetate and 20 mL of water were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 10:1-5:1). The desired product was triturated with hexane, isolated by filtartion, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazole (205 mg, 53.6%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)C>[CH3:12][C:10]1[CH:9]=[CH:8][C:7](=[O:13])[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[CH:11]=1
Reactant: CCOC(=O)Cn1cc(C)ccc1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(=O)n(CC(=O)NN)c1
Yield: 92 %

Procedure:
As described for example 112a, (5-methyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 16 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 92%). MS: m/e=204.1 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:15]([F:18])([F:17])[F:16])[CH:4]=2)=[CH:9][CH:10]=1
Reactant: O=c1ccc(-c2ccc(F)c(C(F)(F)F)c2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2ccc(Cl)nn2)cc1C(F)(F)F

Procedure:
A mixture 10 g. of 6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone in 50 ml. of trifluoroacetic acid is reduced with hydrogen and palladium on carbon to give 6-[4-amino-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone. The preceding compound is converted to 6-[4-fluoro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone by the procedure described in J. Org. Chem., 26, 468 (1961). The preceding compound is reacted with phosphorus oxychloride as described in Example 47 to give 3-chloro-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyridazine., which is reacted with formylhydrazine as described in Example 48 to give the product of the example.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.C1COCC1.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)NCc2cccc(N)c2)cc(C(C)(C)C)c1O
Yield: 42.8 %

Procedure:
In a 250 ml Parr flask, 2.40 g (6.2 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide is dissolved in 45 ml of an absolute ethanol/THF mixture (1/2) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for three hours. After filtration on celite, the filtrate is concentrated to dryness and the residue is purified on a silica column (eluant:heptane/ethyl acetate: 60/40). The pure fractions are collected and concentrated under reduced pressure to produce 0.94 g (45%) of a white powder. Melting point: 171-172° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[C:16]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:34](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][C:20]([O:22][CH3:34])=[O:21])[C:16]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of [1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl]acetic acid (4.16 g), methyl iodide (0.95 ml), potassium carbonate (2.76 g), and N,N-dimethylformamide (50 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl [1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl]acetate (4.21 g, yield 98%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 58–59° C.
Reaction SMILES: C(OC(=O)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[C:15]([CH:25]([CH3:27])[CH3:26])[S:16][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)[C:8]=1[O:28][CH3:29])C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.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:24][C:20]1[N:19]=[C:18]([C:17]2[S:16][C:15]([CH:25]([CH3:27])[CH3:26])=[N:14][C:13]=2[C:9]2[C:8]([O:28][CH3:29])=[C:7]([CH:12]=[CH:11][CH:10]=2)[NH2:6])[CH:23]=[CH:22][N:21]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1c(N)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.2 %

Procedure:
To the solution of 2-propen-1-yl[3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]carbamate (12.1 g, 22.5 mmol) in DCM (200 mL), acetic acid (3.8 mL, 66.6 mmol), Pd(PPh3)2Cl2 (0.45 g, 0.56 mmol) were added. Then tri-n-butyl tin hydride (8.5 mL, 33 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by added the saturated NaHCO3 (200 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (200 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (500 mL) to afford the title compound of Step G (10 g, 60.8% yield), which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:18][S:17][CH2:16][C@H:12]1[C:13](O)=O.[CH2:19]([N:29]1[C:33](=[O:34])C=[CH:31][C:30]1=[O:35])[C:20]1[CH:28]=[CH:27][C:26]2[O:25][CH2:24][O:23][C:22]=2[CH:21]=1>CO>[O:25]1[C:26]2[CH:27]=[CH:28][C:20]([CH2:19][N:29]3[C:30](=[O:35])[CH:31]4[CH:7]([C:6]5[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[N:11]5[CH:12]([CH:13]4[C:33]3=[O:34])[CH2:16][S:17][CH2:18]5)=[CH:21][C:22]=2[O:23][CH2:24]1
Reactant: O=C1C=CC(=O)N1Cc1ccc2c(c1)OCO2
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C(O)[C@@H]1CSCN1
Solvent: CO
Product: N#Cc1ccc(C2C3C(=O)N(Cc4ccc5c(c4)OCO5)C(=O)C3C3CSCN32)cc1

Procedure:
7.B)h) (5RS,5aRS,8aSR,8bRS)-4-[7-(Benzo[1,3]dioxol-5-ylmethyl)-6,8-dioxo-octahydro-pyrrolo[3',4':3,4]pyrrolo[1,2-c]thiazol-5-yl]-benzonitrile was prepared analogously to Example 4.B)g) from 4-cyano-benzaldehyde, L-thioproline and N-piperonylmaleimide. Colourless needles. M.p.: 142°-143° C. (methanol). ISP-MS: 434.2 ([M+H]+, 100).