Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:18][CH2:17]3)[CH2:11][CH2:10]2)[N:3]=1.C(=[NH:32])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1COCC1.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:16]1([CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:4]3[N:3]=[C:2]([NH2:32])[CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Clc1cccc(OC2CCN(CC3CC3)CC2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1cccc(OC2CCN(CC3CC3)CC2)n1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Combine 2-chloro-6-(1-cyclopropylmethyl-piperidin-4-yloxy)-pyridine (preparation 56, 480 mg, 1.80 mmol), benzophenone imine (391 mg, 2.16 mmol), BINAP (67 mg, 0.11 mmol), pd2(dba)3 (33 mg, 0.036 mmol), sodium t-butoxide (242 mg, 2.52 mmol) and toluene (8 mL) and heat at 100° C. for 14 hr. Quench the reaction with saturated NaHCO3 solution, extract with ethyl acetate three times. Combine the organic layers, dry over Na2SO4, filter and concentrate under reduced pressure to give a residue. Dissolve the residue in THF (10 mL), add 5N HCl (1.0 mL) and stir for 30 min. Dilute the mixture with 0.1N HCl solution, extract twice with ethyl acetate-hexanes (1:2). Keep the aqueous layer and adjust pH>11 with 5N NaOH solution, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 7% 2M NH3-methanol in methylene dichloride provides 310 mg (70%) of the title compound as a white solid: mass spectrum (ion spray): m/z=248.1 (M+1); 1H NMR (CDCl3, ppm): 7.23 (t, 1H), 5.95 (pseudo-t, 2H), 4.81 (m, 1H), 4.14 (s, br, 2H), 2.76 (m, 2H), 2.26 (m, 2H), 2.18 (d, 2H), 1.92 (m, 2H), 1.71 (m, 2H), 0.80 (m, 1H), 0.44 (m, 2H), 0.00 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.[NH3:18]>CO>[NH2:18][CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1
Reactant: N
Reactant: BrCc1ccc2nc(-c3ccccc3)sc2c1
Solvent: CO
Product: NCc1ccc2nc(-c3ccccc3)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Add 6-bromomethyl-2-phenyl-benzothiazole (2 g, 6.57 mmol) as a suspension in methanol (100 mL) to 7M ammonia in methanol (400 mL) at 0° C. over 10 min and then stir for 3 h at room temperature. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with dichloromethane/methanol (1:0 to 3:1) to obtain the title compound (1.2 g, 76%). MS (ES+) m/z: 241 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23]O)[N:21]=1)=[CH:5]2.[CH2:25]([O:27][C:28]([C:30]1[NH:31][CH:32]=[N:33][C:34]=1[CH3:35])=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1[N:31]([CH2:23][CH2:22][C@@H:20]2[CH2:19][S:18][C:17]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:21]2)[CH:32]=[N:33][C:34]=1[CH3:35])=[O:29])[CH3:26]
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: CCOC(=O)c1c(C)ncn1CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1

Procedure:
2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol prepared in Example 5 and 5-methyl-3H-imidazole-4-carboxylic acid ethyl ester were reacted according to the same procedure as Example 156 to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][C@@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)#[N:17]>N1C=CC=CC=1>[C:16]([C:18]1[CH:19]=[C:20]([S:24]([N:11]2[C@H:10]([CH3:15])[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][C@@H:12]2[CH3:14])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)#[N:17]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Solvent: c1ccncc1
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1

Procedure:
A solution of cis-4-benzyl-2,6-dimethylpiperazine (1 g), 4-N,N-dimethylaminopyridine(0.54 g), 3-cyanobenzenesulphonyl chloride (2.13 g) in pyridine (3 ml) were stirred at ambient temperature. After 1 h the mixture was partitioned between dichloromethane and water. The organic phase further washed with brine, collected, dried, (MgSO4) and solvent evaporated under reduced pressure to leave the subtitle compound as an orange gum. Yield: 1 g
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@H:9]1[C:17]2[C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[N:15][CH:14]=[N:13][C:12]=2[C:11](=[O:31])[CH2:10]1.O[C@H]1C2N=CN=C(N3CCN(C(OC(C)(C)C)=O)CC3)C=2[C@H](C)C1>C(Cl)Cl>[OH:31][C@@H:11]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:17]=2[C@H:9]([CH3:8])[CH2:10]1
Reactant: C[C@@H]1CC(=O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
Triethylamine (4.33 ml, 31.1 mmol; degassed with nitrogen 30 minutes prior to use) and formic acid (1.36 ml, 36.1 mmol; degassed with nitrogen 30 minutes prior to use) were added to a solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutes prior to use). The mixture was stirred for 5 minutes, then a Ru catalyst (0.0933 g, 0.147 mmol) was added. The reaction was stirred under positive nitrogen pressure overnight (18 hours). The reaction mixture was concentrated to dryness and dried on high vacuum. The impure material was flashed on Biotage 65M loaded 1:1 DCM:ethyl acetate 500 mL flushed, then 1:4 DCM:ethyl acetate until product (2nd spot), then gradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest of product. The fractions were combined and concentrated on a rotary evaporator. The residue was concentrated again from DCM/hexanes to give a mixture of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (major) and tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (minor) (9.35 g, 95.3% yield) as a beige foam. LC/MS (APCI+) m/z 335 [M+H]+. 1H NMR (CDCl3) shows 88% de by integration of carbinol methine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:26]3[NH:25][C:24](=[O:27])[O:23][C:22]([CH3:29])([CH3:28])[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:30]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:26]3[NH:25][C:24](=[O:27])[O:23][C:22]([CH3:29])([CH3:28])[C:21]=3[CH:20]=[CH:19][CH:18]=2)=[O:30])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)Nc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2cccc3c2NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 8-[4-(4-acetamidophenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([C:25]([NH:27][CH:28]4[CH2:30][CH2:29]4)=[O:26])[CH:19]=3)=[CH:14][CH:13]=2)=[N:9][N:8]=1>O.CN(C=O)C.C(O)C>[N:1]([CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30]4)=[O:26])[CH:19]=3)=[CH:16][CH:17]=2)=[N:9][N:8]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN=[N+]=[N-])o2)cc1

Procedure:
A solution of sodium azide (14.8 mg) in water (1.25 ml) was added to 4′-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (40 mg) in DMF (0.5 ml) and ethanol (2.5 ml) and the mixture heated at reflux for 2 hours. The solvents were evaporated under vacuum and the residue partitioned between water (20 ml) and chloroform (15 ml). The aqueous was extracted with chloroform (15 ml) and the combined organic phases dried (sodium sulphate) and reduced to dryness in vacuo to give 4′-[5-(azidomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide,
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7]>BrCC(N)=O.COCCOC>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:5][C:6]([NH2:8])=[O:7])[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: NC(=O)CBr
Solvent: COCCOC
Product: NC(=O)CN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=529.2 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-bromoacetamide in 1,2-dimethoxyethane as solvent.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1Cl.[N-:15]=[N+]=[N-].[Na+]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1[NH2:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1nc(-n2cccn2)nc(Cl)c1Br
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(-n2cccn2)nc(N)c1Br
Reaction time: 0.5 h

Procedure:
A solution of 0.10 g (0.37 mmol) of 5-bromo-6-chloro-2-(1H-pyrazol-1-yl)pyrimidine-4-amine (Intermediate 5) and 0.05 g (0.77 mmol) of sodium azide in dioxane (10 mL) was stirred at 80° C. for 6 h. The solvent was then evaporated, and the residue dissolved in methanol, Pd on charcoal added (10 mg) and hydrogenated for 30 min. The solvent was again evaporated and the residue crystallizes from ethanol.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C-]#N.[K+]>O>[CH3:9][C:8]([CH3:11])([CH3:10])[C:7]#[C:6][C:3]#[C:2][CH2:1][OH:4]
Reactant: C#CCO
Reactant: CC(C)(C)C#CBr
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CC(C)(C)C#CC#CCO
Reaction time: 1 h

Procedure:
Nitrogen was bubbled through a mixture of cupric chloride (154 mg), NH2OH.HCl (0.45 g), and 70% aqueous diethylamine (9 ml) in 11 ml of water and 23 ml of methanol, for a few minutes. Propargyl alcohol (3.8 g, 0.068 mol) was added with stirring under nitrogen whereupon a yellow precipitate formed immediately. The mixture was warmed to 35°-40° C. for 15 minutes and 1-bromo-2-t-butyl-acetylene (8.57 g, 0.053 mmol) was added over 15 minutes. The mixture was stirred at 35°-40° C. for 45 minutes, then at room temperature for 1 hour. Aqueous potassium cyanide (0.45 g in 45 ml of water) was added and the mixture was stirred for one minute. The mixture was poured into 50 ml of water and extracted 5 times with ether. The combined organic phase was washed with water and dried over magnesium sulfate. The solvents were removed and the residue was distilled under reduced pressure through a column packed with glass helices. 6,6-Dimethyl-2,4-heptadiyne-1-ol (3.63 grams) was collected at 85° C. and 0.5 mm of mercury.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>>[C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([N:7]([CH2:29][C:30]([OH:32])=[O:31])[S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[CH2:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(NS(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)cc1
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
prepared by reaction of 2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid p-tolylamide with tert-butyl bromoacetate
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C(N)CCC.O>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CCCCN
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
Triethyl orthoformate (3 ml, 18 mmol) and p-Toluenesulfonic acid (30 mg, 0.16 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (3 g, 8.72 mmol) in ethanol (20 ml). The mixture was stirred at room temperature for 1 h. Butylamine (1 ml, 9.72 mmol) was added and the mixture was heated at 30° C. for 2 h, cooled to 10° C. and water (10 ml) was then added. The precipitate was filtered, washed with water and dried under vacuum, to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (2.2 g, yield: 88%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH:10][C@H:11]([CH2:16][C:17]#[CH:18])[C:12](OC)=[O:13])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[NH4+].[Cl-].CCN(CC)CC>CO.[Fe]>[CH2:16]([C@@H:11]1[C:12](=[O:13])[NH:1][C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]=2[NH:10]1)[C:17]#[CH:18]
Reactant: C#CC[C@@H](Nc1cccnc1[N+](=O)[O-])C(=O)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCN(CC)CC
Product: C#CC[C@H]1Nc2cccnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of (R)-methyl 2-(2-nitropyridin-3-ylamino)pent-4-ynoate (220 mg, 0.883 mmol), iron (296 mg, 5.30 mmol) and NH4Cl in 10 mL of MeOH was heated to reflux for 4 h. After cooling to room temperature, 0.5 mL of NEt3 was added and the solution was stirred overnight. The solvent was evaporated and the residue was redissolved with EtOAc and filtered through a pad of silica gel. The filtrate was evaporated to dryness the title compound that was used directly in the next step.
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.[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]2)=[O:23])[CH:36]=[CH:35][N:34]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccnc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 10 %

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), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a off-white foam (10%).
Reaction SMILES: [CH2:1](/[C:8](=[CH:13]\[C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=2)[C:17]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:16][C:15]=1[Cl:31])/[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([O:35][C:36]1[C:37](=[O:54])[C:38](=[O:53])[C:39]=1[Sn](CCCC)(CCCC)CCCC)([CH3:34])[CH3:33]>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.CN(C)C=O>[CH2:1](/[C:8](=[CH:13]\[C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:39]3[C:38](=[O:53])[C:37](=[O:54])[C:36]=3[O:35][CH:32]([CH3:34])[CH3:33])=[CH:22][CH:21]=2)[C:17]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:16][C:15]=1[Cl:31])/[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reactant: CCCCc1nc(Cl)c(/C=C(\Cc2ccccc2)C(=O)OC)n1Cc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(/C=C(\Cc2ccccc2)C(=O)OC)n1Cc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.9 %

Procedure:
A mixture of the product of Example 30 (c) (0.8 g), 3-isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (0.9 g), tetrakis(triphenylphosphine)palladium(0) (0.2 g), cuprous iodide (0.1 g) and dry dimethylformamide (5 ml) was stirred at ambient temperature under a nitrogen atmosphere for approximately 17 hours. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in diethyl ether (150 ml). The solution obtained was washed with saturated aqueous ammonium chloride solution (50 ml), then with saturated aqueous potassium fluoride solution (2×50 ml) and then dried over magnesium sulphate. The solvent was evaporated and the residue obtained was purified by flash chromatography on silica gel (eluting with dichloromethane/methanol (50:1)) to give the intermediate compound (E)-methyl 2-benzyl-3-[2-butyl-4-chloro-1-[4-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)benzyl]-1H-imidazol-5-yl]propenoate as an oil (0.4 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:19]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])=[CH:20]1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][O:19][CH:20]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCc1ccoc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCc2ccoc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(3-furyl)pentanoate (1.5 eq., prepared in Synthetic Example 19) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(3-furyl)propyl]-1,8-naphthyridin-2(1H)-one, mp 185 to 186° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [O:1]1CCN=[C:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].N1CCCC1=[O:18].ClCC(O)=O>>[N:7]1([CH2:6][C:2]([OH:1])=[O:18])[CH2:11][CH2:10][CH2:9][C:8]1=[O:12]
Reactant: O=C1CCCN1CC1=NCCO1
Reactant: O=C1CCCN1
Agent: O=C(O)CCl
Product: O=C(O)CN1CCCC1=O

Procedure:
--[(2-oxazolin-2-yl)methyl]-2-pyrrolidone, for example, can be obtained by condensation of pyrrolidone and chloroacetic acid to form 2-pyrrolidone acetic acid, where m =I in the above formula (II), or, alternatively, by condensing butyrolactone with glycine, and the starting carboxylic acid condensed with ethanolamine and cyclodehydrated to form 1-[(2-oxazolin-2-yl)methyl]-2-pyrrolidone.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([OH:18])=O)=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:52]1[CH2:57][CH2:56][CH:55]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:54][CH2:53]1>C(Cl)Cl.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:52]2[CH2:57][CH2:56][CH:55]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:54][CH2:53]2)=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1

Procedure:
1-(4-chlorobenzyl)-1H-indole-2-carboxylic acid (2.4 g, 8.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (2.4 g, 12.60 mmol), and 1-Hydroxybenzotriazole hydrate (1.9 g, 12.60 mmol) were dissolved in 20.0 mL of DCM. The resulting suspension was stirred for twenty minutes where it turned into a clear, yellow solution. N,N-Diisopropylethylamine (2.2 mL, 12.60 mmol) and ethyl piperidine-4-carboxylate (1.94 mL, 12.60 mmol) were added to the reaction. The reaction was stirred overnight. Water was added to the reaction followed by ethyl acetate. The layers were separated and the organic layer was washed sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting crude mixture was triturated with diethyl ether to obtain pure product as a white solid. Yield: 2.79 g, (White solid)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.[OH-].[Na+].[CH3:12][CH:13]([CH3:28])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].[N+](C1C=C(O)C(O)=CC=1)([O-])=O.Cl>C(O)C.ClCCl>[OH:9][C:4]1[CH:3]=[C:2]([NH:1][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH3:12])[CH3:28])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: CC(C)CCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc(O)c(O)c1
Agent: Cl
Agent: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)CCCCCCCCCCCC(=O)Nc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
Dissolve 4-amino-1,2-benzenediol (23.2 g, 0.18 mole) in 95% ethanol. Under salt ice bath 140 ml 2M NaOH solution and 150 ml dichloromethane solution of 13-methyltetradecanoyl chloride (23.2 g, 0.18 mole) were added simultaneously to the benzenediol solution. Stir at room temperature for 6 hours. Adjust pH to 3.0 with HCl, freeze, and filtrate. Wash the filtrate to neutral with water and recrystallize with 50% ethanol to yield N-(3,4dihydroxyl-phenyl)-13-methyl-tetradecanamide (55.8 g, m.p. 85–86° C., yield rate 85%).