Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][CH2:15][F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][N:25]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH2:14][CH2:15][F:16])=[CH:3][C:2]=2[F:1])[CH2:24]1
Reactant: CC1CNCC1CN
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)CC1CN
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A mixture of 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.21 g) and DBU (0.26 g) was refluxed for an hour and then stirred at room temperature for 5 hours. The resulting precipitate was collected by filtration and washed with ether to give the title compound (0.45 g) as pale yellow powder, mp 228°-232° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][C:10](=[O:13])/[C:11](=[CH:16]\[N:17]([CH3:19])[CH3:18])/[CH2:12]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Yield: 90 %

Procedure:
A solution of 13.5 mmol N—BOC-3-pyrrolidone and 13.5 mmol N,N-dimethylformamide-dimethylacetal in 50 ml N,N-dimethylformamide was hold overnight at 60° C. The reaction mixture was quenched by addition of 50 ml water and extracted 3 times with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give the crude title compound as a yellowish oil. Yield=90%. MS (m/e): 241.4 ([M+H]+, 100%).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][C:7](=O)[NH:6][C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C=O)C.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][C:7]1[N:6]=[C:5]2[O:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:2]([I:1])[C:3](=[O:19])[C:4]2=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1ccc2c(=O)c(I)c(-c3ccccc3)oc2[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1c(I)c(-c2ccccc2)oc2nc(Cl)ccc12
Reaction time: 144 h
Yield: 74 %

Procedure:
To a suspension of 3-iodo-2-phenyl-8H-pyrano[2,3-b]pyridine-4,7-dione (13 mg, 0.036 mmol) in DCM (3 mL) was added DMF (0.03 mL) and thionyl chloride (0.1 mL). The mixture was heated under reflux for 3 hours, followed by standing at RT for 6 days. Upon evaporation, the residue was subjected to flash chromatography (SiO2, gradient 10 to 25% ethyl acetate in cyclohexane) to afford the title compound (10 mg, 74%) as a colourless gum. LCMS (Method B): RT=4.35 min, [M+H]+=384/386.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:26](=[O:27])[N:25]([CH3:28])[C:16]2[N:17]=[C:18](S(C)(=O)=O)[N:19]=[CH:20][C:15]=2[CH:14]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[C:31]=1[NH2:39].CC(C)([O-])C.[K+]>CN(C=O)C.CCOC(C)=O>[NH2:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[C:31]=1[NH:39][C:18]1[N:19]=[CH:20][C:15]2[CH:14]=[C:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])[C:26](=[O:27])[N:25]([CH3:28])[C:16]=2[N:17]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3cnc(S(C)(=O)=O)nc3n(C)c2=O)c1Cl
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
To a mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (9) (1.0 g, 2.26 mmol) and 2-methyl-6-nitrobenzenamine (684 mg, 4.5 mmol) in DMF (20 mL), potassium tert-butoxide (756 mg, 6.75 mmol) was added at ˜10° C., and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with EtOAc (150 mL), and the organic phase was separated, washed with water (2×150 mL) and then brine (150 mL), dried over sodium sulfate, filtered, and concentrated. The residue was recrystallizated with EtOAc to give 2-(2-amino-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (10) (810 mg, yield 70%) as a yellow solid. MS (ES+) C23H19Cl2N5O5 requires: 515, 517. found: 516, 518 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:29]([C:26]1[CH:25]=[N:24][C:23]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:19][CH:18]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:28][CH:27]=1)[CH3:30]
Reactant: CCc1cnc(Cl)nc1
Reactant: Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCc1cnc(N(CCc2ccc(O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Yield: 85.9 %

Procedure:
Condensation of 4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenol (1.20 g; 4.06 mmol) with 2-chloro-5-ethyl-pyrimidine (0.52 ml; 4.27 mmol) as per general procedure E (conditions: 1.1 eq. DIEA, toluene, 210C, 16 hr) provided the title compound (1.40 g; 85% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[NH:16][C:15]([NH2:18])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].N[C:20]1C([N+]([O-])=O)=CC(C)=CC=1C(O)=O>>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH2:18])[NH:14][C:13]=2[CH:12]=[C:11]([CH3:20])[CH:10]=1)=[O:8]
Reactant: Cc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Product: Cc1cc(C(=O)Nc2ncc[nH]2)c2nc(N)[nH]c2c1

Procedure:
0.25 g of 2-amino-6-methyl-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide was synthesized according to procedures described for the synthesis of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B) starting from 2.5 g (12.7 mmol) of above synthesized 2-amino-5-methyl-3-nitrobenzoic acid. LCMS: 257 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]#[N:28])[C:17]([O:29][CH3:30])=[CH:16][N:15]=2)=[N:6]1.[OH-:35].[Na+].OO>CS(C)=O>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([NH2:28])=[O:35])[C:17]([O:29][CH3:30])=[CH:16][N:15]=2)=[N:6]1
Reactant: [OH-]
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1C#N
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1C(N)=O
Temperature: 63 °C
Reaction time: 3 h

Procedure:
54 mg of 4-({2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile (24-1, 0.12 mmol, 1. eq.) were dissolved in 1.6 ml of dimethyl sulfoxide under nitrogene atmosphere. 42 μl of 3 M aqueous sodium hydroxide solution (0.126 mmol, 1.05 eq.) were added. The mixture was oilbath heated to 63° C. bath temperature. At this temperature 302 μl hydrogen peroxide (30% in water) (9.87 mmol, 82.2 eq.) were added dropwise. The reaction mixture was stirred at 65° C. bath temperature for 3 hours and at room temperature for 24 hours. After stirring the mixture one hour with ice-water it was extracted three times with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/methanol 9:1) to yield 12.0 mg (0.02 mmol, 20.5%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:7]1=[N:6]2.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].C>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]3[NH:21][N:20]=[N:19][N:17]=3)[CH:14]=[CH:15][C:7]1=[N:6]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1sc(C)c2c(=O)n3cc(C#N)ccc3nc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1sc(C)c2c(=O)n3cc(-c4nnn[nH]4)ccc3nc12
Temperature: 120 °C
Yield: 60.4 %

Procedure:
A mixture of 4.4 g (0.0172 mol) of 1,3-dimethyl-10-oxo-10H-pyrido-[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile (Example 51), 6.5 g (0.1 mol) of sodium azide and 5.3 g (0.1 mol) of ammonium chloride in 180 ml of dimethylformamide is stirred and heated in a wax bath at 120° C. for seventeen hours under nitrogen. The reaction mixture is cooled, filtered and the filtrate evaporated. The residue is treated with 250 ml of water and acidified with concentrated hydrochloric acid. This mixture is warmed on a steam bath, cooled and filtered to give 5.1 g of crude product. This material is dissolved in hot pyridine, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Mansville). The filtrate is cooled to give 3.1 g of 1,3-dimethyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno-[3,4-d]pyrimidin-10-one; mp 292° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]([N:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:9]1[C:10]([C:23](OCC)=[O:24])=[N:11][CH:12]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)=[O:7])[CH3:2].[O-]CC.[Na+]>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:13]2[CH:14]=[C:9]3[C:10]([C:23]([OH:24])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:32])[C:6](=[O:7])[N:8]3[CH2:28][CH:29]([CH3:31])[CH3:30])=[N:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)N(CC(C)C)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(C)C)c1=O
Reaction time: 8 h
Yield: 100 %

Procedure:
To a cold (0° C.) solution of ethyl 3-[[3-(ethyloxy)-3-oxopropanoyl](2-methylpropyl)amino]-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (309 mg, 0.70 mmol) in ethanol (20 mL) was added sodium ethoxide (104 mg, 1.53 mmol). The resultant solution was warmed to room temperature as the bath warmed and stirred overnight. Solvents were removed in vacuo and the residue was taken up in water. The pH was adjusted to 5 with 1 N HCl (aq) and the aqueous layer extracted with ethyl acetate. The organics were dried over sodium sulfate filtered and concentrated to give ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(2-methylpropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (279 mg, 99%) as a clear foam. 1H NMR (CDCl3) δ 13.77 (broad, 1 H), 8.49 (s, 1 H), 7.23 (s, 1 H), 7.15 (dd, J=8.4, 5.6 Hz, 2 H), 7.04 (dd, J=8.8, 8.4 Hz, 2 H), 4.50 (q, J=7.2 Hz, 2 H), 4.11 (s, 2 H), 3.95 (broad, 2 H), 1.97 (m, 1 H), 1.45 (t, J=7.2 Hz, 3 H), 0.87 (d, J=6.4 Hz, 6 H); HRMS calcd for C22H24FN2O4 399.1720 (M+H); found 399.1720.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[C:11]([OH:21])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[C:3]1([C:9]2[CH:10]=[C:11]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[O:21][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: Oc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.7 %

Procedure:
To a suspension of 0.78 g of sodium hydride (55% w/w dispersion in mineral oil) in 300 cc of dimethylformamide was added a solution of 2 g of 3,5-diphenyl-phenol in 10 cc of dimethylformamide. The mixture was stirred for 5 hours at room temperature until effervescence had stopped. 2.2 g of ethyl 6-bromohexanoate was then added and the resultant mixture stirred at room temperature overnight. The mixture was then heated for 20 hours to 40° C. After cooling, the resultant mixture was poured into 100 cc of cold water and extracted with ethyl acetate (3#100 cc). The combined extracts were washed with water, dried (Na2SO4) and concentrated in vacuo. The resultant residue was flash chromatographed on silica gel (30-60 mm; eluent: 92:8 n-hexane/ethyl acetate) to give 1 g of ethyl 6-(3,5-diphenyl-phenoxy)hexanoate as a oil, used without further purification in the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[NH:9][C:8]2=[N:13][CH:14]=[CH:15][C:7]=12.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([NH:23][C:24]([NH:12][C:10]1[NH:9][C:8]2=[N:13][CH:14]=[CH:15][C:7]2=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nc(-c2ccco2)c2ccnc-2[nH]1
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1nc(-c2ccco2)c2ccnc-2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
A solution of 4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine (192 mg, 0.96 mmol) in THF (3 mL) was treated with benzyl isocyanate (118 μL, 0.96 mmol), stirred at room temperature for 16 h and the resulting solid filtered and washed with EtOAc to give the title compound (61 mg, 19%) as a yellow solid.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:35][C@H:36]([CH3:46])[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C:44]#[N:45])=[O:38]>C(Cl)Cl>[C:44]([C@@H:40]1[CH2:41][CH2:42][CH2:43][N:39]1[C:37](=[O:38])[C@H:36]([NH:35][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=[CH:3][CH:4]=1)=[O:13])[CH3:46])#[N:45]
Reactant: O=C(Cl)c1ccnc2ccccc12
Reactant: C[C@@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1ccnc2ccccc12)C(=O)N1CCC[C@H]1C#N

Procedure:
Quinoline-4-carbonyl chloride hydrochloride (0.067 g, 0.295 mmol) was added to a mixture of DIPEA (0.160 ml, 0.913 mmol) and (S)-1-((R)-2-aminopropanoyl)pyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (0.100 g, 0.295 mmol) in DCM. After 3 h the mixture was washed with 1N citric acid and saturated sodium bicarbonate and brine. The organic layer was dried sodium sulfate, filtered and purified by column chromatography using a mixture of ethylacetate and methanol as eluents.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9](O)[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:8]=[CH:7][CH:6]=[CH:5]C=1.CN(C)[CH:19]=[O:20]>>[C:9]1([C:9]2([CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:3][CH2:8][C:7]32[CH2:6][CH2:5]3)[CH:3]=[CH:8][CH2:7][O:20][CH:19]=1
Reactant: OC(Cn1cncn1)c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C1=CC(C2(Cn3cncn3)CCC23CC3)=COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.9 %

Procedure:
33.2 mg (0,496 mmole) of sodium hydride (as a 60% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 69.8 mg (0.207 mmole) of 1-[1-methanesulfonyloxymethyl)cyclopropan-1-yl]-1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanol in dimethylformamide, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, eluted with a 1:1 by volume mixture of hexane and ethyl acetate, to afford 5 mg (yield 9.9%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9](O)=[O:10])[CH2:2][CH2:3][CH3:4].C([N:28](CC)CC)C.CS(Cl)(=O)=O.N>CC(C)=O>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([NH2:28])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CC(C)=O
Product: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 3-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g) in dry acetone (10 ml), triethylamine (0.278 g) was added. Methanesulphonyl chloride (0.315 g) in dry acetone (5 ml) was added to the reaction mixture, while stirring. The agitation was continued for 1.5 hours at 20°C. The resulting solution of the mixed anhydride was added dropwise to aqueous ammonia (30 ml containing 7 g of ammonia), while stirring. The excess of ammonia and acetone were removed by evaporation under reduced pressure. The pH of the reaction mixture was adjusted to 7.5 by means of 4N hydrochloric acid, and the precipitated 3-butylamino-4-phenoxy-5-sulphamyl-benzamide was isolated by filtration and recrystallized several times from aqueous ethanol. After drying in vacuo at 115°C, the compound was obtained with a melting point of 223°-224°C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1)C.O.[NH2:17][NH2:18]>C(O)C>[NH:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[CH2:5][C:4]([NH:17][NH2:18])=[O:3]
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1nc2ccccc2[nH]1
Yield: 76 %

Procedure:
15 g 1H-benzo[d]imidazole-2-acetic acid ethyl ester (0.074 mol), 100 mL anhydrous ethyl alcohol and 37 mL of 80% hydrazine hydrate were added to a three-necked bottle and reacted under reflux for 4 hours. A white solid was isolated. After sucking filtration, the filter cake was washed with ethanol. After drying, 10.7 g white solid was obtained. Yield: 76%, MS: 191(M+1).
Reaction SMILES: C[N:2]([CH3:13])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:14][C:15]1[CH:16]=C([CH:19]=[CH:20][CH:21]=1)N>CCO.O>[Br:14][C:15]1[CH:16]=[C:13]([NH:2][CH2:3][CH2:4][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: Nc1cccc(Br)c1
Solvent: O
Solvent: CCO
Product: O=C(CCNc1cccc(Br)c1)c1ccccc1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
A mixture of 3-(dimethylamino)-1-phenylpropan-1-one (0.1 mol) and 3-bromoaniline (0.1 mol) in 1:1 EtOH/H2O (100 mL) was heated at 80° C. overnight. The resulting mixture was concentrated and the residue was washed with H2O and then EtOH several times to give to give 3-(3-bromophenylamino)-1-phenylpropan-1-one (27 g, 90%). 1H NMR (400 MHz, CDCl3): δ=3.52 (m, 2H), 4.33 (m, 2H), 4.51 (m, 1H), 6.8 (m, 1H), 7.05 (m, 2H), 7.28 (m, 1H), 7.72 (m, 2H), 7.80 (m, 1H), 8.2 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[N:24]([C:20]2[CH:19]=[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:23]=[CH:22][CH:21]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Agent: Cl
Product: O=c1cc(CO)n(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1

Procedure:
To a suspension of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (92.9 g, 0.40 mol) in dilute aq hydrochloric acid (0.5 N, 800 mL) was added biphenyl-3-amine (74.4 g, 0.44 mol). The resulting mixture was heated under refluxed for 16 h. Concentration of the solvent gave a residue which was purified by silica gel chromatography (EtOAc:MeOH/20:1) to afford 5-(benzyloxy)-1-(biphenyl-3-yl)-2-(hydroxymethyl)pyridin-4(1H)-one as pale solid MS (ESI) (M+H)+ 384.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]1)=[O:5].[C:37]([C:39]1[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=1)#[CH:38].C(N(CC)CC)C>CC#N.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.[Cu]I>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:37]#[C:38][C:33]2[CH:34]=[CH:35][C:2]([F:1])=[C:3]([CH:32]=2)[C:4]([NH:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[O:5])=[CH:40][N:41]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Reactant: C#Cc1cnc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Reaction time: 0.5 h

Procedure:
In a 25-mL RBF (S)-tert-butyl 1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate (0.496 g, 0.80 mmol), 5-ethynylpyrimidin-2-amine (0.19 g, 1.6 mmol), Bis(triphenylphosphine)palladium(II) dichloride (0.028 g, 0.040 mmol), and Copper(I) iodide (0.0076 g, 0.040 mmol) were taken up in CH3CN and Triethylamine (1.7 ml, 12 mmol) was added, and the tube was flushed with nitrogen. The tube was sealed and the reaction heated to 70 deg. C for 16 h. The reaction was cooled and transferred to a larger flask with EtOAc and concentrated in vacuo. The solid was adsorbed onto 4 g silica gel from 10% MeOH/MC purified by Isco {Redi-Sep® pre-packed silica gel column (80 g); eluent 0-75% EtOAc/hexanes over 30 min}. Product-containing fractions were concentrated to afford (S)-tert-butyl 1-(2-(5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluorobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate as a orange foam. MS m/z=613 [M+H]+. Calc'd for C31H32F4N6O3: 612.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:28][CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([N:33]3[CH2:32][CH2:31][NH:30][CH:29]([CH3:28])[CH2:34]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: CC1CNCCN1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(Cl)nc1
Product: CC1CN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)cn2)CCN1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.18 mmol) was used in general procedure 3 with 2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 468.3 (M)+
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:13][CH:12]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(C2CCCCC2)cc1

Procedure:
Using the same method as in Example 1-(ii), 4-cyclohexylaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4-cyclohexylphenyl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 89%).