Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].C([C:6]1([O:15][CH3:16])[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH2:7]1)C.O>C(O)C>[CH3:16][O:15][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:2][NH2:3])=[O:11])=[CH:8][CH:7]=1
Reactant: NN
Reactant: CCC1(OC)C=CC(C(=O)O)=CC1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)NN)cc1
Yield: 64.5 %

Procedure:
303 g of hydrazine hydrate was added to a solution of 150 g of p-ethylanisic acid in 300 ml of ethanol, followed by heat-refluxing for 20 hours. After the reaction, the reaction mixture was poured into 1.5 liters of iced water to precipitate a crystal. The crystal was recrystallized from ethanol to obtain 88.2 g of 4-methoxybenzohydrazide.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[CH:21]4)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([C:36]([O:38][CH3:39])=[O:37])#N>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:1]1([C:7]2([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[C:36]([O:38][CH3:39])=[O:37])[CH2:18][CH2:19]3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(N3CCC(n4cnc5ccccc54)CC3)CCCCCC2)cc1
Reactant: COC(=O)C#N
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)c1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a stirred solution of 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole (as prepared in WO 00/008013, 7.828 g, 20.957 mmol) in THF (200 ml) and HMPA (70 ml) was added dropwise a solution of n-BuLi (1.54 M solution in hexane, 20.4 ml, 31.435 mmol) at −78° C. After 1 hour stirring at −78° C., methyl cyanoformate was added to the reaction mixture at −78° C. After 2 hours stirring, the reaction mixture was quenched with NH4Cl solution and warmed to room temperature. The reaction mixture was extracted with ethyl acetate. The extracts combined were washed with NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated to give oil. This oil was purified by column chromatography (silica gel:200 g, ethyl acetate/n-hexane:1/2 as an eluent) to afford 1.53 g (17%) of title compound as colorless foam.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].[NH2:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=2[N:16]=1.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=1[CH2:2][O:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([NH2:11])[S:13][C:14]=2[CH:20]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Nc1nc2ccc(O)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2s1
Temperature: 20 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
add 289 mg of 2-(bromomethyl)-1,3-dichlorobenzene to a solution of 200 mg of 2-amino-1,3-benzothiazol-6-ol in 12.1 cm3 of a 0.1N aqueous solution of sodium hydroxide. The suspension obtained is stirred for 24 hours at about 20° C. The pH is then adjusted to the range 4-5 by adding glacial acetic acid then to 6-7 by adding solid sodium hydrogen carbonate. The mixture obtained is extracted 3 times with 40 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, treated with vegetable black, then filtered and concentrated under reduced pressure (0.2 kPa). After purification of the residue by filtration on silica [eluent: dichloromethane/methanol (95/5 by volume)], we obtain 70 mg of 6-[(2,6-dichlorobenzyl)oxy]-1,3-benzothiazol-2-amine in the form of a grey meringue, which has the following characteristics:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:16]=[C:15]2[CH:28]=O.[BH3-]C#N.[Na+]>CO>[NH2:10][C:8]([C:7]1[NH:6][CH:5]=[N:4][C:3]=1[NH:2][CH2:28][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([F:11])[CH:13]=2)[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:16]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2cc(F)ccc21
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(CNc2nc[nH]c2C(N)=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
A reaction mixture of 4-amino-5-imidazolecarboxamide hydrochloride (0.20 g, 1.23 mmol), tert-butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate (0.39 g, 1.48 mmol, obtained from Example 6(a)), and NaCNBH3 (0.078 g, 1.23 mmol) in methanol (3 mL) was stirred at r.t. for 1 h. Additional 5-fluoro-3-formyl-indole-1-carbonylic acid tert-butyl ester (0.31 equiv.) was added and after stirring at r.t. for 1 h the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate (1:0 to 0:1) then CH2Cl2), obtaining 0.32 g (70%) of the title compound. MS (ESI) m/z 374 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1O)([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:19]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=2[CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (2.96 g), 2-isopropyl-4-nitrophenol (2.66 g) and triphenylphosphine (5.00 g) in dichloromethane (80 ml) was added diethyl azodicarboxylate (3.0 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane as an eluant to give the desired compound (4.07 g, yield 76%) as a brown solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[CH2:1]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:46]1[CH:47]2[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]2)[CH2:45]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(NCc1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A mixture of 2-(benzylamino)-2-phenylacetic acid (I23) (0.94 g, 3.90 mmol), DCC (0.97 g, 4.70 mmol), HOBt (0.63 g, 4.07 mmol) and 3(R)-quinuclidinol (1.51 g, 11.7 mmol) in dry THF (30 mL) is stirred at room temperature overnight under nitrogen flowstream (LC-MS monitoring: complete conversion). The solvent is evaporated and the residue is taken up with EtOAc and washed twice with water. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is purified by flash chromatography (DCM/MeOH=98/2, 0.2% NH3(aq.) to 95/5, 0.5% NH3(aq)) to give a mixture of diastereoisomers 1 and 2 of C24 (231 mg, 52% yield, mixture of diasteroisomers).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2[CH:24]=[CH:25][CH:26]=[N:27]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:27][CH:26]1[CH2:24][CH2:25]1)=[O:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(Br)cc(C(=O)O)c1C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)cc(C(=O)NC2CC2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred DMF (0.2 M) solution of 5-bromo-2,3-dimethylbenzoic acid (1 eq.) from the previous step was added HATU (1.3 eq.), cyclopropylamine (1.2 eq.) and Hunig's base (3 eq.). The resulting reaction mixture was stirred at RT for 18 h. The reaction was then quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 7:3 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[NH:16][N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:20]([C:23]1[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21]>CC(O)=O.CO>[N+:20]([C:23]1[O:27][C:26](/[CH:28]=[N:1]/[C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[O:18][C:17](=[O:19])[NH:16][N:15]=4)[CH2:12][CH2:13]3)=[CH:6][CH:7]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Nc1ccc(N2CCC(c3n[nH]c(=O)o3)CC2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)o1
Yield: 80 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 0.26 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9a, 306 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1.C[CH2:18][O:19]CC>C(O)=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][O:15][CH:18]=[O:19])=[C:4]([NH2:16])[N:3]=1
Reactant: Nc1nc(N)c2ncn(COCCO)c2n1
Reactant: CCOCC
Solvent: O=CO
Product: Nc1nc(N)c2ncn(COCCOC=O)c2n1

Procedure:
A solution of 2-amino-9-(2-hydroxyethoxymethyl)adenine (0.5 g) in 97% formic acid (2.5 ml) was stirred in an ice bath for 3 hours, and then at room temperature overnight. Dry ether (80 ml) was added and the mixture chilled. The solid was removed by filtration and dissolved in hot acetonitrile (125 ml); residual solids were removed by filtration. The filtrate was applied to a column containing silica gel (14 g) in acetonitrile. The column was eluted with dry acetone. The eluate was evaporated and the residual solid recrystallized from acetonitrile to give 2-amino-9-(2-formyloxyethoxymethyl)adenine (93 mg, m.p. 238°-240° C.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[N:20]=2)[CH:14]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27]>>[CH3:24][C:21]1[N:20]=[C:19]([C:15]2[CH:14]=[C:13]([N:12]3[C:3]4[CH:4]=[CH:5][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=5[C:2]=4[NH:1][C:26](=[O:27])[C:25]3=[O:29])[CH:18]=[CH:17][CH:16]=2)[O:23][N:22]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1noc(-c2cccc(Nc3ccc4ccccc4c3N)c2)n1
Product: Cc1noc(-c2cccc(-n3c(=O)c(=O)[nH]c4c5ccccc5ccc43)c2)n1

Procedure:
1-Amino-2-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]aminonaphthalene and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound.
Reaction SMILES: C1(C)C=CC(S([O:10][C@@:11]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])([C@H:18]([N:20]2[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]2)[CH3:19])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)(=O)=O)=CC=1.[OH-].[Na+]>C(OCC)C>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[C@:11]([OH:10])([C@H:18]([N:20]1[CH2:25][CH2:24][C:23](=[CH2:26])[CH2:22][CH2:21]1)[CH3:19])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: C=C1CCN([C@H](C)[C@@](Cn2cncn2)(OS(=O)(=O)c2ccc(C)cc2)c2ccc(F)cc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C=C1CCN([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)CC1
Yield: 74.3 %

Procedure:
To 18.3 g of the p-toluenesulfonate obtained above there were added 40 ml of ethyl ether and 35 ml of 1N aqueous solution of sodium hydroxide. The organic phase was taken out, and dried over 5 g of anhydrous magnesium sulfate and then the solvent was removed. There was added 40 ml of n-hexane to the residual liquid, and the precipitated crystal was separated by filtration, and dried to obtain 9.43 g of the desired (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol. 1H-NMR spectrum of this compound coincided with that of the compound in Example 1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][CH2:13][CH2:12][CH2:11][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: ClCCCBr
Reactant: OCc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccccc1SCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 11.9 g of 2-(hydroxymethyl)thiophenol, 35.44 g of 1-bromo-3-chloropropane, 11.58 g of potassium carbonate and 150 ml of dimethylformamide is stirred at room temperature for 2 hours. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is distilled under reduced pressure. 16.8 g of 2-(3-chloropropylthio)benzylalcohol are obtained as colorless oil. Yield: 93%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[OH:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([O:24][S:43]([CH3:42])(=[O:45])=[O:44])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccn3)cc(OC)c21
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(OS(C)(=O)=O)c3ccccn3)cc(OC)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 330 mg (0.76 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-pyridin-2-yl-methanol, 0.6 ml ethyl-diisopropyl-amine and 0.25 ml methanesulfonyl chloride is stirred at 0° C. for 1 h. Then the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title product as an oil that is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH:18]=O)=[CH:15][CH:16]=3)[N:11]([CH2:20][CH3:21])[C:10](=[O:22])[C:9]=2[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:30][OH:31]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH:18]=[N:30][OH:31])=[CH:15][CH:16]=3)[N:11]([CH2:20][CH3:21])[C:10](=[O:22])[C:9]=2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCn1c(=O)c(CCC(=O)OC)c(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Agent: Cl
Solvent: O
Product: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C=NO)nc21
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To a 33 ml methanol-pyridine (10:1) solution containing 1.50 g of methyl 3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoate was added 300 mg of hydroxylamine hydrochloride under ice cooling. After stirring for 1 hour, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then the solvent was evaporated. The resulting residue was treated in a similar manner to Example 2 to obtain 72 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-hydroxyiminomethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid as colorless crystals.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.C([Sn](CCCC)(CCCC)[C:24]1[N:25]=[CH:26][S:27][CH:28]=1)CCC>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>[S:27]1[CH:28]=[C:24]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]23)[N:25]=[CH:26]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1C=C2c3cccc(-c4cscn4)c3CCN2C(=O)CN1
Temperature: 150 °C
Yield: 86.6 %

Procedure:
To a degassed solution of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (1 g, 2.82 mmol) and 4-(tributylstannyl)thiazole (1.48 g, 3.95 mmol) in dioxane (16 mL) was added Pd(PPh3)4 (130 mg, 0.11 mmol) and the mixture was heated in the microwave at 150° C. for 2 h. The solvent was removed under reduced pressure. The crude product was crystallized from DCM to yield the title compound (760 mg). UPLC-MS: MS 312.1 (M+H+); UPLC rt 0.66 min.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10](F)=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>CO>[F:4][C:5]1[C:10]([O:2][CH3:1])=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1
Reactant: C[O-]
Reactant: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1F
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)ccc(-c2ccc(F)cc2)c1F
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Sodium methoxide (28% methanol solution, 7.37 g) was added at room temperature to a methanol (160 mL) solution of 2,3,4′-trifluorobiphenyl-4-carbaldehyde (6.01 g), and the mixture was heated to reflux for 18 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate and water, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (6.18 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:21][C:22]([F:30])(S(F)(=O)=O)C(O)=O>C(#N)C.[Cu]I>[F:21][CH:22]([F:30])[O:1][CH2:2][C@@H:3]([N:10]1[C:11](=[O:20])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]1=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CO)c1ccccc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1[C@H](COC(F)F)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(S)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione (1.06 g, 3.97 mmol) was dissolved in anhydrous acetonitrile (20 ml), charged with copper (I) iodide (1.133 g, 5.95 mmol), 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.615 ml, 5.95 mmol), degassed under nitrogen and heated to 80° C. The solution was allowed to stir at 80° C. for 1 hr. The reaction was cooled in an ice bath, quenched with 5 mL water, filtered through a 10 g celite cartridge, and the solvents were removed in vacuo. The residue was purified by MPLC 10-50% EtOAc/hexanes to provide (S)-2-(2-(difluoromethoxy)-1-phenylethyl)isoindoline-1,3-dione. MS: [M+H]+ m/z 318.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17](O)=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH:22]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([C:23]5[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=5)=[CH:32][CH:31]=4)=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cnc(O)nn23)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)cc1

Procedure:
[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-pyridin-3-yl-phenyl)-amine was prepared from 7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (37 mg, 28%). LCMS (m/e) 442 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.82 (s, 1H), 9.10 (s, 1H), 8.94 (s, 1H), 8.58-8.46 (m, 3H), 8.17-8.05 (m, 3H), 7.90 (d, 2H, J=7.9 Hz), 7.76 (d, 2H, J=7.9 Hz), 7.54-7.44 (m, 1H), 7.44-7.35 (m, 1H), 7.09-7.01 (m, 1H), 2.50 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[I:7][C:8]1[CH:9]=[C:10]([C:13]([O:15][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Br:16])=[O:14])[NH:11][CH:12]=1
Reactant: O=C(O)c1cc(I)c[nH]1
Reactant: Oc1ccccc1Br
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1Br)c1cc(I)c[nH]1
Temperature: 18 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Oxalyl chloride (203 mL, 2.32 mmol) was added to a magnetically stirred suspension of 4-iodopyrrole-2-carboxylic acid (8) (500 mg, 2.11 mmol) in dry CH2Cl2 (15.0 ml) containing dmf (1 drop). After stirring the resulting solution at 18° C. for 2 h it was added to a magnetically stirred solution of o-bromophenol (363 mg, 2.11 mmol), triethylamine (660 ml, 4.73 mmol) and 4-(N,N-dimethylamino)pyridine (dmap, several crystals) in CH2Cl2 (10 ml). After 1 h the reaction mixture was concentrated onto silica gel (5 g) and the residue subjected to flash chromatography (silica gel, 3:1 hexane/ether elution). Concentration of the appropriate fractions (Rf 0.2) then gave the title compound (761 mg, 92%) as a white crystalline solid, m.p. 126-127° C. (Found: C, 33.9; H, 1.7; Br, 20.4; I, 32.4; N, 4.0. C11H7BrINO2 requires C, 33.7; H, 1.8; Br, 20.4; I, 32.4; N, 3.6%). nmax (KBr) 3383, 2969, 1709, 1580, 1541, 1472, 1444, 1377, 1312, 1218, 1169, 1133, 1043 cm−1. 1H n.m.r. d 9.57, broad s, 1H; 7.65, dd, J 8.1 and 1.5 Hz, 1H; 7.37, td, J 8.1 and 1.5 Hz, 1H; 7.27, m, 2H; 7.18, td, J 8.1 and 1.5 Hz, 1H; 7.08, m, 1H. 13C n.m.r. d 158.0 (C), 148.3 (C), 134.0 (CH), 129.8 (CH), 129.1 (CH), 128.1 (CH), 124.4 (CH), 124.3 (CH), 123.6 (C), 116.9 (C), 62.9 (C). Mass spectrum m/z 393 (24%) 391 (22) (M+.); 220 (100) [(M−C6H4BrO)+.].