Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:23])[C:7](=[O:22])[C:8]([C:20]#[N:21])=[C:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]1[CH:16]=[CH:17][CH:18]=[CH:19][C:10]3=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31](O)[CH3:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-:35].[K+].[K+].CN(C)C=O>C(O)(C)C>[C:20]([C:8]1[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:4]=[CH:3][C:2]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:35])=[CH:27][CH:26]=3)=[C:13]3[C:12](=[O:15])[C:11]4[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]=1[C:14]=23)#[N:21]
Reactant: O=C([O-])[O-]
Reactant: CC(O)c1ccc(N)cc1
Reactant: Cn1c(=O)c(C#N)c2c3c(c(Br)ccc31)C(=O)c1ccccc1-2
Agent: [K+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C#N)c2c3c(c(Nc4ccc(CCO)cc4)ccc31)C(=O)c1ccccc1-2
Temperature: 70 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A sample of 6-bromo-1-cyano-3-methyl-3H-dibenz[f,ij]isoquinoline-2,7-dione (36.5 g of 96% assay material - 35.0 g pure material, 0.10 m) prepared is in Example 2, p-aminophenylethanol (55.0 g), potassium carbonate (10.0 g), cupric acetate (12.0 g) and N,N-dimethylformamide (100 ml) were mixed and heated at about 70° C. for 1 hr. The temperature was then increased to about 80° C. and held for 1 hr, increased to about 90° C. and held for 1 hr, increased to about 100° C. and held for 1 hr and finally increased to 110° C. and held for 2 hrs. Additional N,N-dimethylformamide (140 ml) and isopropanol (280 ml) were added at about 80° C. and the reaction mixture allowed to cool to room temperature. The product was collected by filtration, washed with isopropanol, water and again with isopropanol. After drying the product weighed 34.97 g (85.5% weight yield) and was determined to have an assay of 95.2% by high pressure liquid chromatography to give an assay yield of 0.952×0.855×100 or 81.3% of 1-cyano-6-[4-(2-hydroxyethyl)anilino]-3-methyl-3H-dibenz[f,ij]isoquinoline-2,7-dione. The product as produced was very pure and did not require further purification by recrystallization. The overall percent assay yield for the three steps, based on starting with 1-methylamino-4-bromoanthraquinone, was 0.97×0.844×0.813×100 or 66.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][N+:19]([O-])=O)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:19][CH2:18][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COP(C)(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)CC(CN)c1ccc(Cl)cc1

Procedure:
A solution of 6.8 g of isobutyl 2-(4-chlorophenyl)-3-nitro-propyl(methyl)phosphinate in 80 ml of ethanol is added to 64 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel slurry and the resulting mixture is hydrogenated at 1 bar until hydrogen treated under reduced pressure to give isobutyl 3-amino-2-(4-chlorophenyl)-propyl(methyl)phosphinate as a viscous oil, 31P N.M.R. spectrum: δ=±54.0 and +53.4 ppm (CDCl3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:21][CH2:22][CH2:23][C:24]1[C:29]([OH:30])=[C:28]([C:31]([CH3:33])=[O:32])[CH:27]=[CH:26][C:25]=1[OH:34]>>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[C:24]([CH2:23][CH2:22][CH3:21])[C:29]=1[OH:30])(=[O:32])[CH3:33]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)C(C)(C)CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCc1c(OCCCCC(C)(C)C(=O)OC)ccc(C(C)=O)c1O

Procedure:
Following the procedure of Example 15, 2.5 g. of methyl 6-bromo-2,2-dimethylhexanoate, 1.46 g. of potassium carbonate, a catalytic amount of potassium iodide, and 2.14 g. of 2,4-dihydroxy-3-propylacetophenone were reacted to give 2.96 g. of the title product as a brown oil. IR, NMR.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][CH2:11][CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2.[OH-].[Na+]>O1CCCC1.CN(C)C=O.N1C=CC=CC=1>[O:22]=[C:16]1[CH2:15][C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:17]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1Cc2c(CCOC(=O)Nc3ccccc3)cccc2N1
Temperature: 70 °C
Yield: 80.4 %

Procedure:
Phenyl isocyanate (0.652 mL, 6 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (709 mg, 4 mmol) in tetrahydrofuran (8 mL), dimethylforamide (2 mL) and pyridine (3 drops). The mixture was heated at 70° C. for 15 hours. The reaction was cooled, poured into 1 N sodium hydroxide solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with 1 N hydrochloric acid (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from methanol/ethyl acetate/hexane to give 953 mg (80%) of phenyl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester as an off-white powder.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid as in EXAMPLE 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=9.72 min. MS (ESI−): mass calcd. for C22H15BrClFN4O5S2, 613.87; m/z found, 611/613 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.36 (s, 1H), 8.34 (d, J=6.9, 1H), 8.16 (d, J=8.7, 1H), 7.74-7.67 (m, 1H), 7.66-7.63 (m, 1H), 7.38-7.32 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.05 (m, 1H), 7.05-6.98 (m, 1H), 6.91-6.84 (m, 1H), 6.68 (d, J=6.7, 1H), 6.09 (s, 2H), 5.04-4.94 (m, 1H), 3.35-3.15 (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH2:11]([N:13]([CH2:16][C:17]1[S:21][C:20]2=[N:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:24][N:19]2[N:18]=1)[CH2:14][CH3:15])[CH3:12].[OH-].[Na+]>O>[CH2:11]([N:13]([CH2:16][C:17]1[S:21][C:20]2=[N:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:24]([CH:8]=[O:9])[N:19]2[N:18]=1)[CH2:14][CH3:15])[CH3:12]
Reactant: CCN(CC)Cc1nn2cc(-c3ccccc3)nc2s1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Temperature: 100 °C

Procedure:
2.3 ml (0.025 mol) of phosphorus oxychloride are added dropwise to 20 ml of dimethylformamide at 0°-5° C. 5.7 g (0.02 mol) of 2-diethylaminomethyl-6-phenyl-imidazo-[2,1-b]-1,3,4-thiadiazole are then added and the mixture is warmed at 100° C. for 2 hours. After cooling, 50 ml of water are added and the mixture is neutralised with 20% strength sodium hydroxide solution and extracted with ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2(=[O:21])=[O:20])[CH:5]=[N:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25][N:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10](=[O:20])(=[O:21])[N:9]([C:4]2[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[C:14]1=[O:15]
Reactant: Cc1cc(N2C(=O)Nc3ccccc3S2(=O)=O)cnc1C
Reactant: COc1cc(F)c(CBr)c(F)c1
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3cnc(C)c(C)c3)S(=O)(=O)c3ccccc32)c(F)c1
Yield: 26.5 %

Procedure:
The title compound (58 mg, 0.13 mmol) was prepared from 2-(5,6-dimethylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (IntA29) (150 mg, 0.49 mmol), 2,6-difluoro-4-methoxybenzyl bromide (129 mg, 0.54 mmol) and K2CO3 (102 mg, 0.74 mmol) in DMF (3 mL) at 50° C. using the methods of (115).
Reaction SMILES: [N:1]1[CH2:5][CH:4]=[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:2]=1.CC(C)([O-])C.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[C:28]([C:33]2([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:35][CH2:34]2)[N:27]=3)=[C:20]([F:42])[CH:19]=1>C(O)C>[F:42][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:24]1[S:25][C:26]2[C:31]([N:32]=1)=[CH:30][CH:29]=[C:28]([C:33]1([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:34][CH2:35]1)[N:27]=2)[CH2:17][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:2]1.[F:42][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:24]1[S:25][C:26]2[C:31]([N:32]=1)=[CH:30][CH:29]=[C:28]([C:33]1([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:34][CH2:35]1)[N:27]=2)[CH2:17][N:2]1[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:5]=[N:1]1
Reactant: Fc1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reactant: CCOC(=O)C1=CCN=N1
Agent: CC(C)(C)[O-]
Solvent: CCO
Product: CCOC(=O)c1ccn(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)n1
Product: CCOC(=O)c1ccnn1Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 70 °C

Procedure:
In a sealable tube was dissolved ethyl 5H-pyrazole-3-carboxylate (0.137 g, 0.979 mmol) in ethyl alcohol (3 mL). To the solution was added tert-butoxide (0.0941 g, 0.979 mmol) followed by 2-(4-(bromomethyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (0.215 g, 0.489 mmol) and the reaction mixture was heated to 70° C. for 1 h. The crude reaction mixture containing an isomeric mixture was concentrated in vacuo and purified by silica gel chromatography to afford ethyl 1-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-pyrazole-3-carboxylate and ethyl 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-pyrazole-5-carboxylate. MS (ESI) m/z: calculated: 498.2; Observed: 499.0 (M++1).
Reaction SMILES: [CH2:1]([N:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[Li+].[OH-]>C(#N)C>[CH2:1]([N:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=1)[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of ethyl(2S)-3-[4-(2-{butyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoate (0.311 g, 0.61 mmol) in acetonitrile (30 mL) was added aqueous 0.10 M LiOH (15 mL) and the solution was stirred at room temperature overnight. After acidification with 5% HCl, the mixture was extracted with ethyl acetate (3×100 mL) and the combined organic phase was washed with 5% HCl (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.232 g (79%) of a colourless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:15]2[CH2:16][CH2:17][C:18]3[CH2:19][CH2:20][C:21]([F:23])=[CH:22][C:13]([C:14]=32)=[CH:12][N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:23][C:21]1[CH2:20][CH2:19][C:18]2[CH2:17][CH2:16][N:15]3[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][CH:12]=[C:13]([C:14]=23)[CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C1=NC=C2C=C(F)CCC3=C2N1CC3
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To an ice-cooled solution of [(S)-1-(5-fluoro-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen-1-yl)ethyl]carbamic acid tert-butyl ester (252.6 mg, 0.7576 mmol) in DCM (8 mL) was added TFA (2 mL) and the mixture was stirred at RT for 1.5 h. Toluene was added and volatiles were removed under reduced pressure, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a light pink solid (144.5 mg, 82%). LCMS (Method J): RT 1.93 min [M+H]+ 234
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([NH:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=O)[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CCN=C=NCCCN(C)C>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([N:21]3[CH2:22][CH2:23][CH2:24][C:25]3=[O:27])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCNC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CCCN1C1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4-[[1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentyl]amino]butanoate (333 mg/0.83 mmol) and 2 N—NaOH (1.3 ml/2.6 mmol) in dioxane (6 ml) was stirred for 8 hours at 80° C., and then the mixture was acidified with sat.NaH2PO4 (10 ml). The mixture was concentrated in vacuo. The residue was suspended in dichloromethane-methanol (5:1, 30 ml) and the mixture was refluxed for 1 hour. After filtration, the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (20 ml). To the mixture was added WSC (431 mg/2.25 mmol) and the mixture was refluxed for 2 d. After cooling to room temperature, the mixture was washed with water (10 ml×2). The combined extracts were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si, 230-400 mesh/dichloromethane:methanol=30:1-15:1) to give a yellow oil (150 mg/ 51%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1cncc(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (2 g, 8.9 mmol) in tetrahydrofuran (50 ml) was treated with 10% palladium on carbon (200 mg) and stirred at ambient temperature under an atmosphere of hydrogen for 5 hours. The reaction mixture was filtered through a short pad of hyflo and the filtrate was concentrated under vacuum to give 5-phenylethyl-pyridine-3-carboxylic acid as white solid (2 g). 1H NMR [(CD3)2SO, 500 MHz]: δ 8.90 (m, 1H), 8.60 (m, 1H), 8.12 (m, 1H), 7.21 (m, 5H), 3.38 (br s, 1H), 2.95 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][N:59]([CH2:66][C:67]([NH2:69])=[O:68])[C:60]2=[O:65]>>[NH2:69][C:67](=[O:68])[CH2:66][N:59]1[CH:58]=[CH:57][C:56]2[C:61](=[CH:62][CH:63]=[CH:64][C:55]=2[NH:54][C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=2)[C:60]1=[O:65]
Reactant: NC(=O)Cn1ccc2c(N)cccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)Cn1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (170 mg, 0.00072 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (400 mg, 0.001 mol), N,N-diisopropylethylamine (0.2 mL, 0.001 mol), N,N-dimethylformamide (2 mL, 0.03 mol) and 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)acetamide (120 mg, 0.00055 mol). The reaction was stirred for 16 h at room temperature and the solvent was removed and the residue purified by preparative HPLC (reverse phase) to yield the product as a white powder. MS m/z=437.8 (M+1). 1H NMR (400 MHz; DMSO-d6) δ 10.09 (s, 1H), 8.04 (d, J=8.07 Hz, 1H), 7.89 (bs, 1H), 7.83 (d, J=8.07 Hz, 1H), 7.73-7.70 (m, 2H), 7.63 (bs, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.42 (d, J=7.76 Hz, 1H) 7.19 (bs, 1H), 6.64 (d, J=7.70 Hz, 1H), 4.56 (s, 2H), 3.92 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:5][CH:4]=1.[OH-].[Na+]>C(Cl)Cl.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:10]([OH:20])=[C:11]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:17]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: ClCCl
Product: COc1ccc(-n2nc3ccccc3c2O)cc1
Temperature: 80 °C
Yield: 84.7 %

Procedure:
A mixture of the product from step 1 (16 g, 0.059 mol), NaOH (9.4 g, 0.235 mol) and zinc (23 g, 0.352 mol) in methylene chloride (250 mL) was heated to 80° C. for 24 h. After the methanol was removed in vacuo, the aqueous residue was acidified with 10% HCl (aq.) to pH to 2. The product was collected on a filter, washed with 1N HCl, water and hexane. After dried under vacuum, the title compound (12 g, 86%) was obtained; MS (ESI+) m/z 241 (M+1, 100).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10](Br)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:29])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=c1c2ncccc2c(Br)cn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2ncccc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
A mixture of 7-benzyl-5-bromo-1,7-naphthyridin-8(7H)-one (0.574 g, 1.82 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.385 g, 2.73 mmol) and Na2CO3 (0.579 g, 5.46 mmol) was degassed under nitrogen. Then toluene (30 mL), ethanol (30 mL) and water (3 mL) were added. The reaction mixture was degassed again and Pd(PPh3)4 (0.210 g, 0.12 mmol) was added and degassing procedure was repeated. The reaction was stirred at 90° C. for 6 h under nitrogen. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water then brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 97:3 dichloromethane/methanol) to give 7-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1,7-naphthyridin-8(7H)-one (0.341 g, 56%) as a tan solid: mp 168-170° C.; 1H NMR (400 MHz, CDCl3): δ 8.92-9.00 (m, 1H), 7.52-7.60 (m, 2H), 7.29-7.42 (m, 5H), 7.04 (s, 1H), 5.26-5.43 (m, 2H), 2.22 (s, 3H), 2.04 (s, 3H); ESI MS m/z 332.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH2:9][CH2:10]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:14]>>[Cl-:14].[CH:1]1([CH2:7][NH2+:8][CH2:9][CH2:10][Cl:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCNCC1CCCCC1
Reactant: O=S(Cl)Cl
Product: ClCC[NH2+]CC1CCCCC1
Product: [Cl-]

Procedure:
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclohexylmethyl)-1,3-thiazolidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:16][NH2:17].C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[NH:16][NH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Reactant: NN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)NN
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of carbamoyl chloride 1 (1.00 g; from above) in dry THF (3.5 ml) was added over 10 minutes to an ice-cold solution of anhydrous hydrazine (0.269 g; 0.310 ml; 8.40 mmol) and triethylamine (0.708 g; 0.975 ml; 7.00 mmol) in dry THF (4 ml). Stirring was continued overnight at room temperature. The mixture was filtered and evaporated to a light yellow solid. Recrystallization from hexanes-ethyl/acetate gave pure carbazide 3 (0.533 g; 2.33 mmol; 52%) as a white solid, mp 83°-84° C. TLC (silica gel; CH2Cl2 --CH3OH, 10:1)Rf=0.25-0.35. MS m/e 173 (M+ -56). Analysis: Calculated for C10H19N3O3 : C, 52.39; H, 8.35; N, 18.33. Found: C, 52.08; H, 8.58; N, 18.01; NMR (CDCl3); δ1.43 (9H.S); 2.0-2.3 (4H,m); 3.1-3.4(2H,m); 3.8(2H,bs): 4.3-4.6(1H,m); 6.2(1H,bs); IR(CHCl3 ): 3500-3300, 1730, 1660, 1640 cm-1. [α]D =-46.5±0.5°.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (60%).