Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CO.ClCCl.CCOCC>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:16])[F:17])[N:22]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=c1cc(C(F)F)n(C2CC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 35.6 %

Procedure:
A mixture of 5-benzyloxy-2-difluoromethyl-pyran-4-one (4.0 g, 15.8 mmol) and cyclopropylamine (3.6 mL, 47.5 mmol) in methanol (40 mL) was stirred at room temperature for 7.5 hrs. The reaction mixture was concentrated in vacuo to obtain an oil. The oil was diluted with dichloromethane and ether, and a solid precipitated out. The solid was collected by suction filtration to afford 1.64 g of the title compound as the first crop. The filtrate was concentrated and then purified by column chromatography using a mixture of methanol and dichloromethane (1:20, v/v) as eluant. Fractions rich in the product were pooled together and evaporated to dryness, thereby affording a second crop (2.4 g). Crops 1 and 2 were combined to give 4.0 g (87%) of the title product. HPLC purity (peak area percent) is 98.8% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.57 (s, 1H), 7.21-7.48 (m, 6H, 5ArH+CF2H), 6.44 (s, 1H), 5.05 (s, 2H, OCH2), 3.50-3.56 (m, 1H), 1.10-1.16 (m, 2H, CH2), 1.05-1.09 (m, 2H, CH2).
Reaction SMILES: C1(COC([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:13]2=[O:27])=O)C=CC=CC=1.C(O)C.C([O-])=O.[NH4+]>[Pd].C1COCC1>[NH2:11][C@H:12]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])[C:13]1=[O:27]
Reactant: O=C(N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a 30° C. mixture of 1-[((3S)-3-[(phenylmethoxy)carbonyl]amino-hexahydro-2-oxo-1H-azepin-1-yl)acetyl]pyrrolidine (20 g, 54 mmol), ethanol (100 mL), THF (100 mL) and wet 10% Pd/C (4 g) was added ammonium formate (5.1 g, 81 mmol) over 45 min. After stirring for 3 h, the reaction was cooled to room temperature and filtered. The filtrate was concentrated, taken up in TBME (150 mL) and filtered again. The filtrate was concentrated in vacuo to provide 12.3 g (95%) of (S)-1-[(3-amino-hexahydro-2-oxo-1H-azepin-1-yl)acetyl]pyrrolidine.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH3:19][CH:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:21]>CC(C)=O.CN(C=O)C>[C:23]1([N:22]([C:16]2[S:15][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:17]=2)[CH:20]([CH3:21])[CH3:19])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Reactant: CC(C)Nc1ccccc1
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)N(c1ccccc1)c1nc(=O)c2cccnc2s1
Yield: 83.3 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.753 g (11.1 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 894 mg of ammonium thiocyanate, 15 ml of acetone, 1.59 g of N-(2-propyl)aniline and 10 ml of acetone were used. The product was then recrystallized from ethanol to obtain 2.75 g of 2-(N-phenyl-N-(2-propyl)amino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.C([N:29]1[CH2:37][CH2:36][C:35]2[CH2:34][NH:33][CH2:32][C:31]=2[CH2:30]1)C1C=CC=CC=1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:33]4[CH2:32][C:31]5[CH2:30][NH:29][CH2:37][CH2:36][C:35]=5[CH2:34]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ccc(CN2CCC3=C(CNC3)C2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNCC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 60.9 %

Procedure:
0.3 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.6 g of 3-benzyl-3,8-diazabicyclo[4.3.0] non-1(6)-ene hydrobromide were suspended in 30 ml of acetonitrile. 0.6 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) was added to the suspension. The reaction mixture was refluxed for 5 hours and then kept overnight at room temperature. The produced precipitate was filtered and dissolved in 30 ml of 5% acetic acid in ethanol. After adding 0.5 g of 10% palladium charcoal, the reaction mixture was stirred under the hydrogen stream for 6 hours and then filtered. The filtrate was concentrated under reduced pressure. 0.25 g of the title compound was obtained (yield 61%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[F:14][C:15]([F:20])([CH2:18][NH2:19])[CH2:16][NH2:17].[S:21]1(=[O:32])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][NH:24][CH2:23][CH2:22]1>>[F:14][C:15]([F:20])([CH2:18][NH2:19])[CH2:16][NH:17][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([N:24]2[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:21](=[O:32])[CH2:22][CH2:23]2)[N:11]=1
Reactant: O=S1CCNCc2ccccc21
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCC(F)(F)CN
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC(F)(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (s, 1 H), 7.82-7.80 (d, 1 H), 7.74-7.69 (m, 2 H), 7.63-7.53 (m, 3 H), 5.40 (d, 1 H), 5.10 (m, 1 H), 4.75 (m, 1 H), 4.60-4.33 (m, 3 H), 3.63 (m, 4 H), 2.45 (s, 3 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]1[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[S:30]([N:25]1[C:26]2[C:22](=[C:21]([CH2:20][N:3]3[C:4]4([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)[CH2:5][CH2:6][CH2:7][C:2]3=[O:1])[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)([C:33]1[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=1)(=[O:31])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(C(=O)OC(C)(C)C)CC5)cccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCNCC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116 %

Procedure:
To a stirred solution of tert-butyl 2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undecane-9-carboxylate (0.12 g, 0.21 mmol) in DCM (5.0 mL), TFA (0.5 mL) was added at 0° C. and the reaction mixture was stirred for 16 h at rt under a nitrogen atmosphere. The reaction mixture was concentrated to yield the title compound as colourless oil (0.11 g, 95%) which was used in the next step.
Reaction SMILES: C([O:3][CH3:4])=O.[CH2:5]([N:7](CC)CC)C.C(=O)C1C=[CH:17][C:16]([O:19][CH3:20])=[CH:15]C=1>>[CH3:20][O:19][C:16]([CH3:15])([CH3:17])[CH2:5][NH:7][CH:4]=[O:3]
Reactant: COC=O
Reactant: COc1ccc(C=O)cc1
Reactant: CCN(CC)CC
Product: COC(C)(C)CNC=O
Temperature: 25 °C
Reaction time: 68 h
Yield: 98 %

Procedure:
A suspension of MIBAHCl (220.00 g, 99.0% (GC), 1.56 mol) in methyl formate (767.32 g, 12.73 mol) was heated to reflux, and triethylamine (175.39 g, 1.73 mol) was added dropwise. The reaction mixture was heated to reflux. The reaction was monitored by TLC until disappearance of MIBAHCl. After 68 hours, the resulting white suspension was cooled to room temperature the solution was filtered and the residue rinsed with diethyl ether (2862 mL). The filtrate was concentrated by rotary evaporation under reduced pressure and the product, a yellow oil, was distilled under reduced pressure (1.5 mmHg). MIBF was yielded as a colorless liquid (201.34 g, 98% yield, 99.8% (GC), b.p.: 120.0-120.5° C./1.50 mmHg); TLC Rf 0.2 (4:1 ethyl acetate/hexanes, detection with p-anisaldehyde spray); FTIR(neat): ν 3300, 3061, 2977, 2938, 2831, 2751, 1671, 1534, 1469, 1385, 1368, 1287, 1238, 1183, 1164, 1079, 1034, 1004, 957, 858, 721, 666 cm−1; 1H-NMR (600 MHz, CDCl3): δ 1.13 (s, 6H, 2 CH3), 3.16 (s, 3H, OCH3), 3.28 (d, J=5.9 Hz, 2H, CH2), 6.12 (br s, 1H, NH), 8.19 (s, 1H, CHO); 13C-NMR (151 MHz, CDCl3): δ 22.5 (2 CH3), 46.0 (CH2), 49.4 (OCH3), 74.1 (C), 161.4 (CHO); MS (EI): m/z=132[M+H]+; MS (Cl): m/z=132[M+H]−.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:8](=[O:23])[C:7]1=[O:24].FC(F)(F)C(O)=O.[C:38]1(OC)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(C(C2C=CC=CC=2)=[N+]=[N-])C=CC=CC=1>C(OCC)(=O)C.CO>[O:23]=[C:8]1[C:7](=[O:24])[NH:6][CH2:11][CH2:10][N:9]1[CH2:12][C:13]([O:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:14]
Reactant: COc1ccccc1
Reactant: COc1ccc(CN2CCN(CC(=O)OCc3ccccc3)C(=O)C2=O)c(OC)c1
Agent: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCNC(=O)C1=O)OC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 10.0 g of benzyl [4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin- 1-yl]acetate, 40 ml of trifluoroacetic acid and 20 ml of anisole was refluxed for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and 20 ml of ethyl acetate and 10 ml of diethyl ether were added to the resulting residue, and the solid was collected by filtration. The solid obtained was dissolved in a mixed solvent of 9 ml of ethyl acetate and 1 ml of methanol, followed by adding thereto 25 ml of a 1M solution of diphenyldiazomethane in ethyl acetate, and the resulting mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=10:1) to obtain 6.8 g of diphenylmethyl (2,3-dioxopiperazin-1-yl)acetate as a white foamy substance.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[O:12][N:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1cccc(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2cccc(F)c2F)n1
Yield: 7.8 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(2,3-difluorophenyl)acetic acid (0.651 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.079 g (8%) of ethyl 5-(2,3-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([N:2]2[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: O=C(N[C@H]1CCN(C(=O)C2CC2)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][NH2:22]>CO.C(O)(=O)C>[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][N:22]=[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)ccn1
Reactant: Cn1c(NN)nc2ccccc21
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NNc1nc2ccccc2n1C)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 2-acetyl-4-chloropyridine (0.50 g, 3.20 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.52 g, 3.20 mmol) in 5 ml of methanol is stirred for 4 days at room temperature after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with water, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.60 g (62% of theory).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][CH:8]=1.[CH3:13][N:14]([CH:16]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23])[CH3:15].[Cl-].[NH4+].[CH3:33]COCC>>[ClH:2].[CH3:15][N:14]([CH:16]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1([CH2:33][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1)[OH:23])[CH3:13]
Reactant: CN(C)C(c1ccc(F)cc1)C1CCCCC1=O
Reactant: CCOCC
Reactant: FC(F)(F)c1cccc(Cl)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CN(C)C(c1ccc(F)cc1)C1CCCCC1(O)Cc1cccc(C(F)(F)F)c1
Product: Cl
Temperature: 25 °C
Yield: 69.1 %

Procedure:
0.29 g (12.1 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.35 g (12.1 mmole) of 3-chlorobenzotrifluoride dissolved in 5 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 2.51 g (10.1 mmole) of the 2-[dimethylamino-(4-fluorophenyl)methyl]cyclohexanone prepared according to Example 41 were dissolved in 5 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 15 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.15 g of crude base (101% of theory) were obtained, from which 3.10 g of 2-[dimethylamino-(4-fluorophenyl)methyl]-1-(3-trifluoromethylbenzyl)cyclo-hexanol, hydrochloride (69.1% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=1[CH2:5][CH:6]([C:12]([CH3:14])=O)[C:7]([O:9]CC)=O.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[CH:25]=[C:24]([NH2:29])[N:23]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>O.C(O)C>[NH2:21][C:22]1[N:23]=[C:24]([NH2:29])[C:25]2[C:12]([CH3:14])=[C:6]([CH2:5][C:4]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:3]=3[O:2][CH3:1])[C:7](=[O:9])[NH:28][C:26]=2[N:27]=1
Reactant: CCOC(=O)C(Cc1cc(OC)ccc1OC)C(C)=O
Reactant: Nc1cc(N)nc(N)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(Cc2c(C)c3c(N)nc(N)nc3[nH]c2=O)c1
Yield: 65.8 %

Procedure:
A mixture of ethyl α-(2,5-dimethoxybenzyl)acetoacetate (21.2 g), 2,4,6-triaminopyrimidine (10 g) and diphenyl ether (100 ml) was heated at 190°-230° C. for 1.5 hours in an apparatus fitted with a Dean-Stark trap and water-ethanol (4 ml) was collected. Methanol (200 ml) and ethanel (50 ml) were added to the cooled reaction mixture. The resulting solid was collected by filtration and treated with boiling water (1 l) to give 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine (17 g), m.p. 325°-326° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Reactant: Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(OCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (635 mg), 4-methylphenol (432 mg), tributylphosphine (607 mg) and tetrahydrofuran (5 ml) was added 1,1′-(azodicarbonyl)dipiperidine (757 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(4-methylphenoxy)propyl]oxazole was obtained as an oil (475 mg, 58%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[N:19][NH:18][C:17](=O)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(Cl)[Cl:27].[P+5]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([Cl:27])[N:18]=[N:19][C:20]=2[C:21]([F:24])([F:23])[F:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)cc2)c(C(F)(F)F)n[nH]1
Reactant: ClOCl
Agent: [P+5]
Product: FC(F)(F)c1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 90 °C

Procedure:
A mixture of the 5-(4-benzyloxy-phenyl)-6-trifluoromethyl-2H-pyridazin-3-one (0.491 mmol, 170 mg) and phosphorus(V) oxychloride may be heated at 90° C. for 2 h. The reaction mixture may be concentrated in vacuo, and ice may be added to the residue. The mixture may be neutralized with solid sodium bicarbonate and extracted with diethyl ether. Purification by column chromatography on silica gel gives 4-(4-benzyloxy-phenyl)-6-chloro-3-trifluoromethyl-pyridazine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([F:9])=[CH:4][N:3]=1.[CH:10]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:12][CH2:11]1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH:17]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[N:14]=[CH:15]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)cc1I
Reactant: c1nc(C2CC2)c[nH]1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [Cs+]
Solvent: CCCC#N
Product: Fc1cnc(Cl)cc1-n1cnc(C2CC2)c1
Yield: 295.4 %

Procedure:
A suspension 2-chloro-5-fluoro-4-iodopyridine (1.8 g, 1.00 mmol), 4-cyclopropyl imidazole (982 mg, 9.10 mmol), Cu2O (100 mg, 0.700 mmol), 8-hydroxyquinoline (152 mg, 1.05 mmol), cesium carbonate (4.60 g, 14.0 mmol), and PEG-3350 (1.4 g) in butyronitrile (50 mL) was heated at 65° C. for 16 hours. The reaction mixture was filtered through Celite, concentrated and the residue was partitioned between dichlormethane and water. The layers were separated and the aqueous layer washed twice with dichloromethane. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (15→60% EtOAc in hexanes) to afford 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (702 mg, 42% yield).
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:64][N:65]1[C:69]([SH:70])=[N:68][N:67]=[N:66]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:70][C:69]1[N:65]([CH3:64])[N:66]=[N:67][N:68]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:34]
Reactant: Cn1nnnc1S
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnnc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.0386 ml) in methylene chloride (0.347 ml) was added to a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (100 mg) and 4-(N,N-dimethylamino)pyridine (2.3 mg) in methylene chloride (5 ml) at -30° C. A solution of trifluoromethanesulfonic anhydride (0.0326 ml) in methylene chloride (0.293 ml) was then added thereto at -30° C. After the mixture was stirred at the same temperature for an hour, a solution of N,N-diisopropyl-N-ethylamine (0.129 ml) in methylene chloride (1.16 ml) and a solution of 1-methyl-1H-tetrazole-5-thiol (42.9 mg) in methylene chloride (2.15 ml) were added successively at -30° C. The mixture was stirred at -30° C. for 30 minutes and allowed to warm to ambient temperature over a period of 30 minutes. After stirring at ambient temperature for 2 hours, the mixture was allowed to stand at 4° C. for 2 days. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed three times with water and an aqueous sodium chloride, dried over magnesium sulfate and then evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 10% water (2 g), eluting with a mixture of benzene and acetone (50:1 to 10:1) to give 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(1-methyl-1H-tetrazol-5-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (89 mg) as an oil.