Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1.[C:27]([O-:30])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO.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>[C:23]([C:4]1[C:5]([O:21][CH3:22])=[C:6]([CH:20]=[C:2]([C:9]2[C:27](=[O:30])[NH:15][CH:12]=[CH:11][CH:10]=2)[CH:3]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
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: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
step 5—A mixture of 120 (0.20 g, 0.46 mmol), 112 (0.095 g, 0.69 mmol), Pd(PPh3)4 (0.053 g, 0.046 mmol) and Na2CO3 (0.15 g, 1.4 mmol) in DCM/MeOH (3:1, 8 mL) was irradiated in microwave synthesizer at 115° C. for 35 min. The reaction mixture was filtered and the filtrate concentrated. The crude residue was purified by SiO2 chromatography eluting with DCM/MeOH/NH4OH and the recovered product triturated with ether to afford I-71 as a solid.
Reaction SMILES: C[C:2]([C:9]1[C:10]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[C:11]2[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[S:16][C:12]2=[N:13][C:14]=1[CH3:15])([CH2:6][CH2:7][CH3:8])[C:3]([O-:5])=[O:4].[OH-].[Na+].Cl>CO>[CH3:15][C:14]1[N:13]=[C:12]2[S:16][C:17]3[CH2:21][CH2:20][CH2:19][C:18]=3[C:11]2=[C:10]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[C:9]=1[CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCCC(C)(C(=O)[O-])c1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Temperature: 100 °C
Yield: 67.9 %

Procedure:
To a solution of Methyl[2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.335 g, 0.907 mmol) in methanol (9 mL) was added a solution of sodium hydroxide 10 N (0.9 ml) and the mixture was heated at 100° C. for 18 h in a sealed tube. After cooling, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.219 g (68%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])=[O:5])[CH3:2].[Cl-].[CH3:14][NH2+]C.C=O>>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][C:10](=[CH2:14])[CH:11]=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)COCCCC=O
Reactant: C[NH2+]C
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCOCC(=O)OCC

Procedure:
11 g (63.1 mmol) of 4-ethoxycarbonylmethoxybutanal, 5.8 g (71.4 mmol) of dimethylammonium chloride and 5.5 ml (73.5 mmol) of a 37% solution of formaldehyde are stirred for 1 hour at a bath temperature of 110° C. The reaction mixture is allowed to cool and extracted three times with CH2Cl2The combined organic phases are dried over Na2SO4 and concentrated by evaporation giving 4-ethoxycarbonylmethoxy-2-methylene-butanal as a yellowish liquid which is further reacted without purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[CH3:36]S(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>>[CH3:36][N:3]1[C:4]2[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=2[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:2]1=[O:1]
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-n5c(=O)[nH]c6ccccc65)cc4)CC3)C2)c2ccncc21
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1c(=O)n(-c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4cnccc45)CC3)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of (1R)-1′-({1-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (50 mg, 0.0001 mol) in dimethyl sulfoxide (1 mL, 0.01 mol) were added potassium carbonate (16.3 mg, 0.000118 mol) and methyl iodide (6.67 μL, 0.000107 mol), and the mixture was stirred at room temperature for. 2 hours. The crude product was purified by prep-HPLC.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[NH4+:11]>O>[C:1]([O-:9])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[NH4+:11].[NH4+:11]
Reactant: O=C(O)CCCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCC(=O)[O-]
Reaction time: 36 h

Procedure:
A 10% solution of diammonium glutarate was prepared by neutralizing 50 g. of glutaric acid in water with aqueous ammonium hydroxide and bringing the final solution to 500 ml. with water. This was sprayed on wild ivy and quakegrass. Both were dead within 36 hours.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[CH:8][CH:7]=1)(C)(C)C.CC(=C)C.[OH-].[Na+]>S(=O)(=O)(O)O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=1
Reactant: CC(=O)CCc1ccc(OC(C)(C)C)cc1
Agent: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
100 g (0.45 mole) of 1-(4-tert.-butoxy-phenyl)-butan-3-one are suspended in 250 ml of 2N sulfuric acid and the mixture is refluxed for about 3 hours, with vigorous stirring. The course of the reaction can be followed by measuring the isobutylene liberated. After completion of the reaction, the mixture is cooled to room temperature and brought to pH 6 with dilute sodium hydroxide solution, after which the product crystallizes out in about 95% purity. It is isolated by filtering off or centrifuging (73 g of 95% pure material; yield 93%), and is recrystallized from water/ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH:5]=[C:6]([C:9]#[N:10])[C:7]#[N:8].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH2:5][CH:6]([C:7]#[N:8])[C:9]#[N:10]
Reactant: N#CC(C#N)=Cc1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(F)c(F)c1
Yield: 79.7 %

Procedure:
Using 10.0 g of (3,4-difluorobenzyliden)malononitrile, 200 ml of ethanol and 0.6 g of sodium borohydride, and according to the process described in the Reference Production Example 3, there was obtained 8.05 g of (3,4-difluorobenzyl)malononitrile (the intermediate (23)).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(C1=C(Cl)CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(C1=C(Cl)CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 73 %

Procedure:
89 g (1-benzyl-5-chloro-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl-methanol in 800 mL dichlormethane was dropped to 115.4 g pyridiniumchlorchromate in 600 mL dichlormethane. The reaction was stirred 2.5 days at RT. Potassium carbonate solution was added to the reaction, the mixture was stirred 2 h at RT and filtered over celite. The layers were separated and the organic layer was washed with water. The solvent was removed and the residue was purified by chromatography to yield 64.6 g of the desired compound. Rf: 0.5 (toluol/EE: 8.5/1.5)
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>>[C:1]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(C(C)=O)CCOCC1
Agent: Cl
Product: CC(=O)C1CCOCC1
Yield: 89.7 %

Procedure:
In a flask made of glass having an inner volume of and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99% and synthesized in the same manner as in Reference example 1 and 2.52 ml (10 mmol) of 4 mol/l hydrochloric acid, and the mixture was reacted at 120° C. for 4 hours with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.23 g (Reaction yield: 90%) of 4-acetyltetrahydropyran was found to be formed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][N:10]2[C:11](=[O:13])[N:12]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[NH:16][CH2:15][CH2:14][N:10]2[C:11](=[O:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(Cl)c1)nc2=O
Solvent: CN(C)C=O
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(F)c3)c(Cl)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((3-chloro-4-(3,4-difluorophenoxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1 (5H)-carboxylate (50 mg, 0.099 mmol) in DMF (2 mL) and silica gel (150 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[C:4]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(O)C>[Br:1][C:2]1[C:3]([F:22])=[C:4]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(Br)c1F
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
To a solution of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (1.75 g) in absolute ethanol (5 ml) was added a solution of cyclopropylamine (0.32 g) in absolute ethanol (2 ml) under ice-cooling during 30 minutes. The mixture was stirred at 5°-20° C. for 2.5 hours and concentrated. The residue was recrystallized from petroleum ether to give the title compound (1.36 g), mp 74°-76° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23]Br>>[Cl:18][C:7]1[CH:6]=[CH:5][C:4]2[N:3]3[CH2:20][CH2:21][CH2:22][CH2:23][N:1]=[C:2]3[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([OH:11])[C:9]=2[CH:8]=1
Reactant: BrCCCCBr
Reactant: NC1=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Product: OC1(c2ccccc2)C2=NCCCCN2c2ccc(Cl)cc21
Yield: 30.1 %

Procedure:
2-Amino-5-chloro-3-phenyl-3H-indol-3-ol (5.16 g) was heated under reflux with 1,4-dibromobutane (4.32 g) for 24 hours. After cooling the solid was filtered off affording 1.88 g of the title compound as its hydrobromide, m.p. 298°-300°C (decomp.) after recrystallization from methanol/ethyl acetate.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1
Reactant: FCCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(CCCF)cc1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
4.1 g of (3-fluoro-propyl)-benzene (29.67 mmol) were dissolved in 40 ml of dichloromethane. At 0-5° C., 6.91 g of chlorosulfonic acid (59.34 mmol), dissolved in 10 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 45 min at 0-5° C. and then added to a solution of 6.8 g of phosphorous pentachloride (32.63 mmol) dissolved in 50 ml of dichloromethane. The reaction mixture was stirred for 1 h rat 5-10° C. The solvent was evaporated, 150 ml of diethyl ether added, washed once with 150 ml of ice water, and the organic layer dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (11:9) as eluent to give 5.5 g of the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6](=[CH:9][CH2:10][CH3:11])[C:7]#[N:8])[CH2:4][CH3:5].[CH2:12](Cl)[CH:13]=[C:14]([CH3:16])[CH3:15]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][C:6]([CH:3]=[CH:4][CH3:5])([CH2:9][CH2:10][CH3:11])[C:7]#[N:8]
Reactant: CC(C)=CCCl
Reactant: CCC=C(C#N)CCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC=CC(C#N)(CC=C(C)C)CCC
Temperature: 75 °C

Procedure:
In analogy to Example 1, 64 g (1.6 moles) of NaOH, 200 ml of toluene, and 15 g of tetrabutylammonium bromide were first introduced and heated to 75° C. To this mixture was added a mixture of 147.6 g (1.2 moles) of 2-propyl-2-pentenenitrile and 157 g (1.5 moles) of prenyl chloride within 2 hours in individual doses. The reaction mixture was further heated for 3 hours at 85° C. and subsequently processed according to Example 1. The yield in desired product was 103 g, corresponding to 44.9% of the theoretical.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:11]=[N:10]1.Br[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1.[F-].[K+]>C1(C)C=CC=CC=1.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.CO>[CH3:8][N:9]1[C:13]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)=[CH:12][N:11]=[N:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cnnn2C)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 115.1 %

Procedure:
Triethylamine (0.28 ml, 2.00 mmol) was added to a mixture of 1-methyl-5-(tributylstannanyl)-1H-1,2,3-triazole (781 mg, 2.1 mmol), methyl 4-bromobenzoate (430 mg, 2.0 mmol), and BIS(TRIPHENYLPHOSPHINE)PALLADIUM(II) CHLORIDE (70.2 mg, 0.10 mmol) in toluene (10 ml) to give a yellow suspension. The reaction mixture was purged with N2, sealed and stirred at 100° C. for 3 hr. Potassium fluoride (465 mg, 8.00 mmol) and MeOH (2 mL) were added. The mixture was stirred at RT for 2 h, filtered on celite, and rinsed with EtOAc. The combined filtrates were concentrated and the residue was purified on a 25M biotage column to give 0.5 g of methyl 4-(1-methyl-1H-1,2,3-triazol-5-yl)benzoate as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:5]2=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:7][NH:23][N:22]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: O=c1c(-c2ccccc2F)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccccc2F)cc1Cl
Yield: 72.4 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(2-fluoro-phenyl)-7-hydroxy-chromen-4-one (0.37 g, 1.27 mmol), hydrazine hydrate (5 ml), ethanol (15 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-chloro-6-[4-(2-fluoro-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.28 g, 72.4%); Rf 0.8 cf SM 0.9 ethyl acetate/hexane (70/30).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24])#[N:20]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:17]=[CH:18][C:9]=1[N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:19]#[N:20])=[O:24])[CH2:6][CH:5]2[CH2:1]1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: N#Cc1ccccc1C(=O)O
Product: N#Cc1ccccc1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-cyano-benzoic acid. MS (ESI): mass calculated for C22H19N5O, 369.43; m/z found 370.3 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:18]1[S:22][C:21]([NH:23][C:24]([N:26]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:25])=[N:20][C:19]=1[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(Cl)Cl>[CH:27]1([N:26]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:24](=[O:25])[NH:23][C:21]2[S:22][C:18]([N:14]3[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]3)=[C:19]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[N:20]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
DIPEA (60 μl, 0.35 mmol) and N-methylpiperazine (33 μl, 0.298) were added to a solution of ethyl {5-chloro-2-[3,3-dicyclohexylureido]-thiazol-4-yl}-acetate (100 mg, 0.234 mmol) in methylene chloride (5 mL). The reaction mixture was stirred at room temperature for 48 h, filtered and evaporated to dryness in vacuo. The crude product was purified by HPLC to give ethyl {2-[3,3-dicyclohexylureido]-5-[4-methylpiperazin-1-yl]-thiazol-4-yl}-acetate. Yield: 13 mg (11%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24](OCC)=[O:25]>CCOCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][N:17]([CH:24]=[O:25])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Reactant: CCOC=O
Solvent: CCOCC
Product: COC(=O)[C@@H]1CN(C=O)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Yield: 84 %

Procedure:
A solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine (620 mg, 1.94 mmol) in 5 mL of ethyl formate was heated at reflux for 3 hr. The reaction was diluted with ether and concentrated. The residue was dissolved in ether and washed with 1M H3PO4. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (2:1, ethyl acetate:hexanes) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-1-formyl-4-(methoxycarbonyl)pyrrolidine as a colorless oil (567 mg, 84%). 1H-NMR (300 MHz): δ 3.11-3.21 (1, m), 3.65 (s, 3), 3.82 (s, 3), 6.73-6.82 (m, 3), 8.26 (s, 1).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[NH:41])[NH2:40])=[CH:35][CH:34]=1)=[O:5])C.[OH-].[Na+]>>[OH:5][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:23])=[O:24])[CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[NH:40])[NH2:41])=[CH:35][CH:34]=1)=[O:3]
Reactant: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(N(CCN(C)C)S(=O)(=O)c3ccccc3)ccc21
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2CC(=O)O)S(=O)(=O)c1ccccc1

Procedure:
Prepared analogously to Example 3 from 1-ethoxycarbonylmethyl-2-[(4-amidinophenyl)-oxymethyl]-5-[N-(2-dimethylaminoethyl)-benzenesulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)OCC.CCCCCCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][CH2:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=3)=[CH:3][S:4][C:5]=2[CH:6]=[N:7]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=c1c2c(Br)csc2cnn1CCc1ccc2ccccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=c1c2c(-c3ccc(C(F)(F)F)cc3)csc2cnn1CCc1ccc2ccccc2n1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-5-[2-(quinolin-2-yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one Example 3.4 (100 mg, 0.26 mmol), 4-(trifluoromethyl)phenylboronic acid (0.26 mmol), Pd(dppf)Cl2 (12.7 mg) and K2CO3 (72 mg, 0.527 mmol) were dissolved in dioxane/H2O (3/1, 2.8 mL). The mixture was stirred at 110° C. for 0.5 h in a microwave tube. The solution was concentrated and purified by prep-TLC to give the title product.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[CH2:22]([CH:24]1[CH2:28][CH:27]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:26][CH:25]1[C:36](O)=[O:37])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:22]([CH:24]1[CH2:28][CH:27]([O:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[CH2:26][CH:25]1[C:36]([NH:2][NH:1][C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[C:6]2=[N:7][CH:8]=1)=[O:37])[CH3:23]
Reactant: CCC1CC(OC2CCOCC2)CC1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCC1CC(OC2CCOCC2)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
To a solution of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.233 g, 0.767 mmol, WO2009152133 Preparation #9) and 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic acid (0.190 g, 0.767 mmol) in DCM (8.00 mL) was added HATU (0.350 g, 0.920 mmol, Novabiochem) and TEA (0.43 mL, 3.07 mmol). The resulting suspension was stirred at ambient temperature for about 4 h. The reaction was partitioned between DCM (50 mL) and water (25 mL) and the layers were separated. The organic layer was washed with water (2×25 mL) and brine (30 mL), dried over anhydrous MgSO4, filtered, and concd to give a brown residue. The crude material was purified by silica gel chromatography using a gradient of 1-10% MeOH in DCM to give 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (0.300 g, 74%); LC/MS (Table 1, Method b) Rt=2.20 min; MS m/z: 528 (M+H)+.