Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:17])[CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:26])[CH3:25])[CH2:19]2)=[O:17])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1-c1cc(NC(=O)C2CCCNC2)ncn1
Solvent: ClCCl
Product: COc1ccccc1-c1cc(NC(=O)C2CCCN(C(C)=O)C2)ncn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]amide (compound #16A) (110 mg, 0.352 mmol) was dissolved in 5 ml of anhydrous dichloromethane, cooled to 0° C. and 4-N,N-dimethylaminopyridine (90 mg, 0.70 mmol) and acetic anhydride (54 mg, 0.53 mmol) were added simultaneously. The reaction mixture was stirred for 3 hours at room temperature, treated with crushed ice and partitioned between water and dichloromethane. The organic layer was separated, dried over sodium sulfate and concentrated to provide 1-acetyl-piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #20A) (105 mg, 84.13%).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:27]C(=O)OC(C)(C)C)[CH2:11][NH:12][C:13]2[S:14][CH:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[C:16](=[O:18])[N:17]=2)=[CH:5][CH:4]=1>>[ClH:2].[ClH:1].[NH2:27][C@@H:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[CH2:11][NH:12][C:13]1[S:14][C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:16]([OH:18])[N:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNC1=NC(=O)C(c2ccc(F)c(F)c2)S1)Cc1ccc(Cl)cc1
Agent: Cl
Product: N[C@H](CNc1nc(O)c(-c2ccc(F)c(F)c2)s1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Hydrogen chloride (4.0 M solution in 1,4-dioxane, 5 mL) was added to tert-butyl (S)-3-(4-chlorophenyl)-1-(5-(3,4-difluorophenyl)-4-oxo-4,5-dihydrothiazol-2-ylamino)propan-2-ylcarbamate (0.0940 g, 0.190 mmol). The mixture was stirred at room temperature for 90 minutes in a sealed vessel. The solvent was removed in vacuo to give the product as a white solid, 89.3 mgs, 100%. 1H NMR (300 MHz, CD3OD) δ 2.90-3.12 (m, 2H), 3.64-3.87 (m, 3H), 7.13-7.44 (m, 7H). LCMS (API-ES): 396.0/398.0 (M++H), chloro pattern.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:43][O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:11]([NH:13][CH:14]2[C:41](=[O:42])[N:16]3[C:17]([C:38]([OH:40])=[O:39])=[C:18]([CH:21]([S:32][C:33]4[NH:37][N:36]=[N:35][N:34]=4)[CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:19][S:20][C@H:15]23)=[O:12])[N:5]=1)=[O:2]>C(O)=O>[CH:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[N:43][O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:11]([NH:13][CH:14]2[C:41](=[O:42])[N:16]3[C:17]([C:38]([OH:40])=[O:39])=[C:18]([CH:21]([S:32][C:33]4[NH:37][N:36]=[N:35][N:34]=4)[CH2:22][CH2:23][NH2:24])[CH2:19][S:20][C@H:15]23)=[O:12])[N:5]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOc3ccccc3)c3nccc(NC=O)n3)[C@H]2SC1
Solvent: O=CO
Product: NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOc3ccccc3)c3nccc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) (1.7 g) was added formic acid (17 ml) and the solution was stirred at ambient temperature for 4 hours. After the reaction mixture was evaporated, the residue was pulverized with ethyl acetate to give a brown powder (1.5 g) of formic acid salt of 7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([Cl:11])=[C:9]([C:12]([N:14]3[CH2:17][CH:16]([N:18]4[CH2:23][CH2:22][N:21](C(=O)C(F)(F)F)[CH2:20][CH2:19]4)[CH2:15]3)=[O:13])[S:8][C:7]=2[CH:30]=1>CCN(CC)CC.CO>[Cl:11][C:10]1[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:30][C:7]=2[S:8][C:9]=1[C:12]([N:14]1[CH2:17][CH:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:15]1)=[O:13]
Reactant: O=C(c1sc2cc(C(F)(F)F)ccc2c1Cl)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(c1sc2cc(C(F)(F)F)ccc2c1Cl)N1CC(N2CCNCC2)C1

Procedure:
A solution of compound 1c (0.30 g, 0.60 mmol) in Et3N (1 mL) and MeOH (9 mL) was stirred at room temperature for 3 days. It was then concentrated to give compound 1d, which was used in the next reaction without further purification.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:26]=[CH:25][C:11]([C:12]([CH3:24])=[CH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:10][CH:9]=1)=[O:7])C>O.C(O)C>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([CH3:24])=[CH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:25][CH:26]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)c1ccc(C(C)=Cc2ccc3ccccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=Cc1ccc2ccccc2c1)c1ccc(C(=O)O)cc1
Yield: 76.8 %

Procedure:
10 g of potassium hydroxide are dissolved in 50 cm3 of water and 200 cm3 of ethanol. 10 g of the compound prepared in Example 7 are added and the reaction mixture is heated under reflux for one hour, cooled and then acidified. The precipitate is filtered off and the insoluble matter is recrystallised from acetic acid. 7 g of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].O.[C:13](OCC)(=[O:15])C>>[N+:8]([C:4]1[C:3]2[O:11][C:13](=[O:15])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: Nc1cccc([N+](=O)[O-])c1O
Reactant: CCOC(C)=O
Solvent: O
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2o1
Reaction time: 3 h
Yield: 73 %

Procedure:
2.27 g of N,N′-carbonyldiimidazole (14 mmol, 1.4 eq) in a homogeneous suspension in 6 ml of ethyl acetate were added to 1.54 g of 2-amino-6-nitrophenol (10 mmol, 1 eq) in solution in 10 ml of ethyl acetate. The reaction medium was vigorously stirred for 3 hours, and then 10 ml of water were added. The stirring was continued for 15 minutes, before evaporating off approximately ¾ of the ethyl acetate. The reaction medium was brought to 0° C. and then 2 ml of 37% hydrochloric acid were added. The stirring was again continued for 15 minutes. The reaction medium was filtered. The solid obtained was washed with a 1 N hydrochloric acid solution, with water and with a water-ethanol (4:1) mixture, and then oven-dried. 1.3 g of product were obtained in the form of a pale yellow solid. Yield=73%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C([Li])CCC.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O1CCCC1.CCCCCC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:3](=[O:11])[CH2:2]1
Reactant: O=C1COc2ccccc2N1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1COc2ccccc2N1C(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Under an anhydrous atmosphere, a solution of 10 mmol of 2H-1,4-benzoxazin-3-one in 50 ml of tetrahydrofuran is cooled to −78° C. At that temperature, 11 mmol of a 1.6M solution of n-butyllithium in hexane are added dropwise. After being in contact for 30 minutes at −78° C., 11 mmol of phenyl chloroformate are added dropwise and stirring is carried out for a further 2 hours. After returning to ambient temperature, the solution is hydrolysed and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated. After purification by chromatography over silica gel (petroleum ether/ethyl acetate: 8/2), the expected product is isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([NH:10][S:11]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])(=[O:13])=[O:12])[C:7]([OH:23])=[C:6]([Cl:24])[CH:5]=1.Br[CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([Cl:24])[C:7]2[O:23][CH2:28][CH2:27][N:10]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:8]=2[CH:9]=1)=[O:25]
Reactant: BrCCBr
Reactant: COC(=O)c1cc(Cl)c(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Product: COC(=O)c1cc(Cl)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=534.8 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-chloro-5-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 50, step 2) and 1,2-dibromoethane, yielding 8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 8-chloro-4-(5-chloro-2-methoxybenzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][S:5]1)#[N:2].[OH:9][C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[C:1]([N:3]=[C:4]1[N:8]([CH2:12][C:11]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:10]=2[OH:9])[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: N#CN=C1NCCS1
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CN=C1SCCN1Cc1cc([N+](=O)[O-])ccc1O
Yield: 61.1 %

Procedure:
3.82 g (30 mmoles) of 2-cyanimino-thiazolidine, 5.63 g (30 moles) of 2-hydroxy-5-nitro-benzyl chloride and 4.3 g of anhydrous potassium carbonate are boiled in 100 ml of acetone for 6 hours. The mixture is cooled and the precipitate is filtered off. 9.85 g of a crude material are obtained, which is then dissolved in 600 ml of hot water, the impurities are filtered off, the pH is adjusted to 3, the mixture is cooled, filtered and the precipitate is dried. 5.1 g of 2-cyanimino-3-(2-hydroxy-5-nitro-benzyl)-thiazolidine are obtained, melting at 253° to 255° C. after crystallization from pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[NH2:40])[O:5][C:6]1[C:7]([CH:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[O:36])[CH3:35])=[CH:8][C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:11][C:10]=2[CH:28]=1.[CH:41](O)=O>>[N:40]1[C:39]2[CH:38]=[CH:37][C:4]([O:5][C:6]3[C:7]([CH:29]4[CH2:33][CH2:32][CH2:31][N:30]4[C:34](=[O:36])[CH3:35])=[CH:8][C:9]4[NH:13][C:12]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)=[N:11][C:10]=4[CH:28]=3)=[CH:3][C:2]=2[NH:1][CH:41]=1
Reactant: O=CO
Reactant: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc(N)c(N)c1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc2nc[nH]c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
19 mg of 1-(2-(6-(3,4-diamino-phenoxy)-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 155 (step 2) was dissolved in 1 ml of formic acid, and the reaction liquid was stirred at 100° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] to obtain the entitled compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]1[C:15](O)=[CH:14][CH:13]=[CH:12][O:11]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: OC1=CC=COC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Ic1ccc(OC2CCCCO2)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
20 g (89 mmol) of 4-iodophenol was dissolved in 45 ml (2.0 mol/l) of toluene. To this was added 16.4 ml (0.18 mol) of 2,3-dihydroxypyrane and 1.15 g (4.5 mmol) of pyridinium p-toluenesulfonic acid, and the mixture was stirred for 2 hours under a nitrogen atmosphere. After completion of the reaction, a saturated sodium hydrogen carbonate aqueous solution was added and the mixture was extracted with ethyl acetate, then, the organic layer was washed with water, and the solvent was distilled off. As a result, 26.5 g (87.1 mmol) of (h) was obtained. The yield was 98% based on 4-iodophenol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]([CH:23]2[CH2:25][CH2:24]2)(O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[C:15]([CH:23]2[CH2:24][CH2:25]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(CC(O)(c2ccccc2)C2CC2)ccn1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cc(C=C(c2ccccc2)C2CC2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
[4-(2-Cyclopropyl-2-hydroxy-2-phenyl-ethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (280 mg, 0.79 mmol) and 4-dimethylaminopyridine (97 mg, 0.79 mmol) are dissovled in pyridine (3.0 mL) and thionyl chloride (0.12 mL, 1.6 mmol) is added at 0° C. After the mixture is stirred for 3 hrs at room temperature, saturated NaHCO3 aqueous solution (4 mL) is added along with water (20 ml). The mixture is extracted with EtOAc (3×25 mL) and the organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 6%) affords 94 mg of the desired product.
Reaction SMILES: [F-:1].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[N+]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[O:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)([O-])=O.O>C1COCC1>[F:1][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][N:36]=[C:35]2[O:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1
Reactant: CC(C)(C)c1ccc(CCOc2ncnc3ccc([N+](=O)[O-])cc23)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCOc2ncnc3ccc(F)cc23)cc1

Procedure:
To a 25 ml round bottom flask is added potassium fluoride (82.6 mg, 1.42 mmol) and kryptofix 222 (0.53 g, 1.42 mmol). The above mixture is stirred in THF for 20 minutes after which 6-Nitro-4-(2-(4-tert-butylphenyl)ethoxy)quinazoline (0.1 g, 0.284 mmol) is added to it. The solution is refluxed for 30 minutes after which it is cooled and water is added to it. It is then extracted in dichloromethane, washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) gives the above compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:5]([C:10]#[N:11])=[C:6]([CH3:9])[C:7]=1I.[C:21]1(B2OCCCO2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.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>[Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:5]([C:10]#[N:11])=[C:6]([CH3:9])[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(B2OCCCO2)cc1
Reactant: COc1c(Br)c(I)c(C)c(C#N)c1NC(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1c(Br)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Temperature: 95 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
N-(3-Bromo-6-cyano-4-iodo-2-methoxy-5-methylphenyl)-2,2,2-trifluoroacetamide (I-36) (1.29 g, 2.79 mmol), 2-phenyl-1,3,2-dioxaborinane (474 mg, 2.93 mmol), tripotassium phosphate (74-85%, 1.48 g, 5.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (406 mg, 0.352 mmol) were added to a 30-ml eggplant-type flask, followed by purging with nitrogen, N,N-dimethylformamide (50 ml) was injected into it with a syringe, followed by stirring overnight at 95° C. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with saturated brine (×3), 1 N hydrochloric acid, saturated brine, an aqueous saturated sodium hydrogencarbonate solution and saturated brine. The organic layer was dried on anhydrous magnesium sulfate, then the solvent was concentrated under reduced pressure to obtain a brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (968 mg, 84%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.F[C:18](F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:18][O:15][C:14]([C:3]1[C:2]([NH2:1])=[CH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1)=[O:16]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1cnc(-c2ccccc2)nc1C(=O)O
Product: COC(=O)c1nc(-c2ccccc2)ncc1N
Temperature: 25 °C

Procedure:
To 4.0 g (0.0186 mole) of 5-amino-2-phenyl-pyrimidine-4-carboxylic acid in an ice bath was slowly added 48 mL of trifluoroacetic anhydride and the mixture was heated to 50° C. for 5 h. The reaction mixture was filtered, washed with a little trifluoroacetic anhydride and dried. To a suspension of the resulting product in 50 mL of methanol, was added 0.1 mL of 0.5M sodium methoxide in methanol. The mixture was refluxed for 15 minutes, cooled to room temperature, and HCl gas was bubbled in for one hour. After cooling and filtering, the solid was treated with 200 ml of 1N NaOH and 200 ml ether. The organic layer was dried over magnesium sulfate, filtered, evaporated to yield 2.43 g of 5-amino-2-phenyl-pyrimidine-4-carboxylic acid methyl ester, as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[O:5])[CH3:2]>CO.[Pd]>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)N(CCN(C)C)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N(CCN(C)C)c1ccccc1N
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of N-ethoxycarbonyl-N-(2-nitrophenyl)-N',N'-dimethylethylenediamine (1.08 g) in methanol (25 ml) was added 10% palladium-on-carbon (0.1 g). The mixture was stirred under a hydrogen atmosphere at atmospheric pressure for 30 minutes, and filtered. The solvent was distilled off under reduced pressure to give 0.93 g of N-(2-aminophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)Cc1ccc(Nc2nc3cc(F)ccc3s2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2nc3cc(F)ccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
In THF (5 ml) was dissolved methyl (3-chloro-4-(5-fluoro-2-benzothiazolyl)aminophenyl)acetate (292 mg, 0.83 mmol). To the resulting solution was added 0.5N NaOH (5.0 ml, 2.50 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured in ice-1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (3-chloro-4-(5-fluoro-2-benzothiazolyl)aminophenyl)acetic acid (226 mg, 81%) as a pale solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC[O-].[Na+].Cl[CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[OH:32])=[O:24]>CCO>[C:1]([NH:4][C:5]([CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[OH:32])=[O:24])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Cc1ccc(O)c(C(=O)CCCl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCC(=O)c1cc(C)ccc1O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
Diethyl acetamidomalonate (12.84 g, 59.11 mmol) was added to freshly prepared 0.29 M NaOEt (225 ml) in EtOH at 0° C. The solution resulting after brief sonication was transferred to an addition funnel and added over six minutes to a suspension of 20 (10.68 g, 53.74 mmol) in EtOH (50 ml) at 0° C. After stirring the reaction mixture for 18 hours at room temperature, solvent was removed in vacuo. Cold 0.25 N HCl (200 ml) was added and the aqueous phase was extracted with CHCl3 (200 ml, 2×100 ml). The organic layer was washed with H2O (100 ml). After solvent removal, the solid was purified by silica gel flash column chromatography using 4% acetone/-CH2Cl2 to furnish 18.1 g (89%) of diethyl (acetylamino)[3-(2-hydroxy-5-methylphenyl)-3-oxopropyl]propanedioate (I) as a solid: NMR δ 1.26 (t, 6H, J=7), 2.04 (s, 3H), 2.30 (s, 3H), 2.78 (t, 2H, J=7), 2.98 (t, 2H, J=7), 4.17-4.34 (m, 4H), 6.79 (s, 1H), 6.88 (d, 1H, J=8), 7.25-7.30 (m, 1H), 7.47 (s, 1H), 11.97 (s, 1H). Anal. calcd. for C19H25NO7 : C 60.15, H 6.64, N 3.69. Found: C 60.23, H 6.73, N 3.77.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=2[O:24]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.C(#N)C>[O:24]1[C:25]2[CH:26]=[CH:27][C:28]([C:2]3[N:3]=[N:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]([CH:14]5[CH2:16][CH2:15]5)[CH2:10][CH2:9]4)=[CH:6][CH:7]=3)=[CH:29][C:30]=2[O:31][CH2:23]1
Reactant: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1cc2c(cc1-c1ccc(N3CCN(C4CC4)CC3)nn1)OCO2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-Chloro-6-(4-cyclopropylpiperazin-1-yl)pyridazine (8.0 g, 33.5 mmol), acetonitrile (100 mL), 1 M sodium carbonate solution (100.5 mL, 100.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.17 g, 1.67 mmol) were mixed and degassed in vacuo under nitrogen. 3,4-Methylenedioxybenzeneboronic acid (8.34 g, 50.3 mmol) was added and the mixture was heated to 80° C. for 16 h. The precipitated product was filtered and washed with acetonitrile and water, and dried in vacuo. The solid was suspended in methanol (500 mL) and 2,2 equivalents of a 4M HCl in dioxane solution was added. The formed solution was filtered, concentrated in vacuo and acetonitrile (100 mL) was added. The suspension was stirred for 1 h, filtered and the solid dried in vacuo to yield 3-(1,3-benzodioxol-5-yl)-6-(4-cyclopropylpiperazin-1-yl)pyridazine as a yellow powder, 11.4 g, 86%.