Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=O)[CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1.P(Br)(Br)[Br:14]>>[CH3:1][C:2]1[C:7]2[C:8]([Br:14])=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)OCC2=O
Reactant: BrP(Br)Br
Product: Cc1cc(C)c2c(Br)coc2c1
Temperature: 100 °C
Yield: 60 %

Procedure:
4,6-dimethyl-3-benzofuranone (0.09 moles) was slowly added in phosphorus tribromide (30 ml), previously heated to 100° C. The mix is cautiously treated with ice, extracted with methylenechloride. The organic phase is made anhydrous (Na2SO4) and freed from the solvent under reduced pressure to produce 4,6-dimethyl-3-bromobenzofuran (60% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1.Cl([O-])(=O)(=O)=O.CS[C:24]1[S:28][CH:27]=[CH:26][S+:25]=1.O>O1CCCC1>[S:25]1[CH:26]=[CH:27][S:28][C:24]1=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)OC(=O)Cc1ccc(F)cc1
Reactant: CSc1scc[s+]1
Agent: [H-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)C(=C1SC=CS1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (2.2 g, 55 % dispersion in mineral oil) is added to a solution of isopropyl 4-fluorophenylacetate (3.9 g) in dry tetrahydrofuran (50 ml). The mixture is stirred for two hours at room temperature. 2-Methylthio-1,3-dithiolium perchlorate (5.5 g) is then added and the mixture is heated under reflux for seven hours. After cooling to room temperature, water (300 ml) is slowly added. The solution is extracted with ether (3×200 ml). The combined organic solutions are washed with water (100 ml), dried over magnesium sulphate and the solvents are evaporated in vacuo. The residue is purified by column chromatography on silica gel using hexane/toluene 1:9 as eluant. The product is recrystallized from ligroin and dried -in vacuo to constant weight to yield isopropyl (1,3-dithiol-2-ylidene)-(4-fluorophenyl)-acetate, m.p. 86° (as Example 8).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH2:14]CN(CC)CC2)=[O:7])=[CH:4][C:3]=1[Cl:19].[N:20]1(CCN)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:14][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:7])=[CH:4][C:3]=1[Cl:19]
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Reactant: NCCN1CCCC1
Product: Nc1ccc(C(=O)NCCN2CCCC2)cc1Cl

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 15 mmol scale utilising 2-pyrrolidin-1-ylethanamine (Aldrich; 1.885 g, 16.5 mmol), as a tan coloured solid (2.67 g, 66%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][O:27][C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44])=[O:24].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][O:27][C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:2]([O:4][CH2:5][Cl:6])=[O:3])=[O:24])=[O:3]
Reactant: O=C(Cl)OCCl
Reactant: O=C(CCCCCCCCCCCCCCCO)OCOC(=O)CCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCCCCCCCCCCCOC(=O)OCCl)OCOC(=O)CCCCCCCCCCCCCCCOC(=O)OCCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
Chloromethyl chloroformate (0.93 g, 7.2 mmol) was added to an ice-cooled solution of methylene bis(16-hydroxyhexadecanoate) (2.0 g, 3.6 mmol) in methylene chloride (80 ml). Pyridine (0.57 g, 7.2 mmol) was added and the reaction mixture was stirred for 15 minutes at 0° C. and 4 hours at room temperature The reaction mixture was washed with hydrochloric acid (1M, 50 ml) saturated aqueous sodium bicarbonate (50 ml), water (50 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography (silica/methylene chloride). Yield: 84% 1H NMR (200 MHz, CDCl3): δ 1.25 (m, 44H), 1.72 (m, 8H), 2.31 (t, 4H), 4.20 (t, 4H), 5.72 (m, 6H).
Reaction SMILES: [CH3:1][C:2](=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][CH:2]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1
Reactant: CCCCCCCCc1ccc(C(C)=Nc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCc1ccc(C(C)Nc2ccccc2)cc1
Yield: 82.1 %

Procedure:
N-(α-methyl-p-octyl benzylidene) aniline (49 g), prepared by the procedure described in Example IA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. N-(α-methyl-p-octyl-benzyl)aniline (II) (40.5 g) was obtained by fractional distillation. The desired product II had a boiling point of 173° to 178° C. at 0.025 millimeter.
Reaction SMILES: Cl[Si:2]1([CH3:7])[CH2:5][CH2:4][CH:3]1[CH3:6].[CH3:8][N:9]([Si](C)(C)C)[C:10](=[O:12])[CH3:11]>>[CH3:7][Si:2]1([N:9]([CH3:8])[C:10](=[O:12])[CH3:11])[CH2:5][CH2:4][CH:3]1[CH3:6]
Reactant: CC1CC[Si]1(C)Cl
Reactant: CC(=O)N(C)[Si](C)(C)C
Product: CC(=O)N(C)[Si]1(C)CCC1C

Procedure:
In accordance with the general procedure of Example 1, when 1-chloro-1,2dimethylsilacyclobutane and N-methyl-N-(trimethylsilyl)acetamide are reacted it is predicted that the title compound is obtained.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17](=O)[CH2:18][C:19](OCC)=[O:20])=[CH:11][CH:10]=1.C1(O)C=CC=CC=1>C([O-])(O)=O.[Na+]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][CH2:16][C:17]2[N:7]=[CH:5][NH:6][C:19](=[O:20])[CH:18]=2)=[CH:13][CH:14]=1
Reactant: N=CN
Reactant: CCOC(=O)CC(=O)CSc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: O=c1cc(CSc2ccc(Cl)cc2)nc[nH]1
Temperature: 140 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A mixture of formamidine acetate (1508 mg, 14.48 mmol), ethyl 4-(4-chlorophenylthio)-3-oxobutanoate Part A (790 mg, 2.90 mmol) and phenol (8178 mg, 87 mmol) was stirred at 140° C. for 18 hours. After the reaction cooled to RT, the mixture was diluted with saturated NaHCO3 (65 mL) and extracted with EtOAc (80 mL). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, using LC-MS to identify fractions containing the desired product) to afford 6-((4-chlorophenylthio)-methyl)pyrimidin-4(3H)-one 10B (169 mg, 22% yield). 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (1H, s), 7.07-7.25 (4H, m), 6.06 (1H, s), 3.80 (2H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[C:12]([O:20][CH2:21][CH:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)[CH:11]=1)#[N:2].[OH-].[Li+].Cl>C1COCC1>[C:31]([O:30][C:28]([N:24]1[CH2:25][CH2:26][O:27][CH:22]([CH2:21][O:20][C:12]2[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=3[C:1]#[N:2])[CH:11]=2)[CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1cc(OCC2CN(C(=O)OC(C)(C)C)CCO2)cc(-c2ccc(C)cc2C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(OCC3CN(C(=O)OC(C)(C)C)CCO3)cc(C(=O)O)c2)c(C#N)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 2-((2′-cyano-5-(methoxycarbonyl)-4′-methylbiphenyl-3-yloxy)methyl)morpholine-4-carboxylate (107 mg, 0.23 mmol) in THF (2 mL) was added 2.5 M of aq. lithium hydroxide solution (0.52 mL, 1.3 mmol). The reaction mixture was stirred at 60° C. overnight, and then acidified with 15% HCl (aq.) to pH=5, and extracted with EtOAc. The combined organic layers were concentrated in vacuo to get the title compound. 1H NMR (CDCl3, 400 MHz): 7.86 (t, 1H, J=1.6 Hz), 7.70 (t, 1H, J=1.6 Hz), 7.59 (s, 1H), 7.47 (dd, 1H, J=8.0, 1.2 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.37 (s, 1H), 4.20-3.56 (m, 7H), 3.10-2.90 (m, 2H), 2.45 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1([CH3:21])[CH2:12][CH2:11][C:10]([C:14]2[CH:15]=[CH:16][C:17](=[O:20])[NH:18][CH:19]=2)(O)[CH2:9][CH2:8]1.[C-]#[N:23].[K+].[ClH:25].FC(F)(F)[C:28]([OH:30])=O>CO.C(OCC)C>[ClH:25].[O:20]=[C:17]1[NH:18][CH:19]=[C:14]([C:10]2([NH:23][CH:28]=[O:30])[CH2:11][CH2:12][C:7]([CH3:21])([CH3:6])[CH2:8][CH2:9]2)[CH:15]=[CH:16]1
Reactant: CC1(C)CCC(O)(c2ccc(=O)[nH]c2)CC1
Reactant: [C-]#N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: CC1(C)CCC(NC=O)(c2ccc(=O)[nH]c2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Concentrated sulfuric acid (54 ml) was added dropwise over 45 minutes to a suspension of 5-(4,4-dimethyl-1-hydroxycyclohexyl)-2(1H)-pyridinone (15 g) and potassium cyanide (13.2 g) in 272 ml of trifluoroacetic acid at 0° C. The resulting suspension was stirred at room temperature for 17 hours and then cooled to 0° C., and diethyl ether was added slowly. The solvent was decanted, and the solids were washed with diethyl ether. The product was then dissolved in methanol and neutralized with poly-4-vinylpyridine. The polymer was removed by filtration, and the filtrate concentrated, yielding a foam, which was dissolved in methanol and acidified with ethereal HCl. The volume of solvent was reduced in vacuo, and the precipitated solid (7.1 g) was collected and used in subsequent reactions without further purification.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=2[C:19]([F:22])([F:21])[F:20])=[CH:9][CH:8]=1)[NH2:5].[CH3:27][O:28][CH2:29][CH2:30][C:31]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:27][O:28][CH2:29][CH2:30][C:31]1([C:36]([NH:5][C@H:4]([C:3]([OH:2])=[O:26])[CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:14](=[O:25])[N:15]([CH3:24])[C:16]([CH3:23])=[CH:17][C:18]=3[C:19]([F:22])([F:20])[F:21])=[CH:11][CH:12]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3c(C(F)(F)F)cc(C)n(C)c3=O)cc2)C(=O)O)CCCC1

Procedure:
N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (mp 181-183° C.) was prepared from 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester and 1-(2-methoxyethyl)cyclopentane carboxylic acid (obtained as described in WO 9910313) using the general procedures described in example 36. ES-HRMS m/e calcd for C26H31F3N2O5 (M+Na) 531.2077. found 531.2084.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[S:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][N:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[S:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][N:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: FC(F)(F)c1nnc(Cl)s1
Product: C[C@@H](c1ccc(-c2nnc(C(F)(F)F)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI−): m/z=550 [M+HCOO]−.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CCO.[Pd]>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C2=CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(C2CCCCC2)cc1
Temperature: 25 °C

Procedure:
4-Cyclohexenylbenzonitrile (404 mg, 2.2 mmol) was dissolved in 15 ml EtOH and 40 mg 10% Pd/C was added. The reaction mixture was stirred under H2 at 3.0 atm. over night at room temperature. The mixture was filtered through celite with EtOAc washing. The filtrate was concentrated and the crude product 350 mg (86%) was used directly in the next step.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:15]([NH:17][C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[CH2:12][CH2:13][CH3:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]>C(O)=O>[NH:6]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]1[C:8]([NH:10][C@H:11]([C:15]([NH:17][C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[CH2:12][CH2:13][CH3:14])=[O:9]
Reactant: CCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(N)=O
Solvent: O=CO
Product: CCC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCSC)C(N)=O
Reaction time: 2 h
Yield: 97.6 %

Procedure:
3.8 g (8 mmoles) of BOC-Gln-Nva-Met-NH2 are dissolved in 100 ml of a 98% formic acid, the solution is allowed to stand at room temperature for 2 hours, and then evaporated in vacuo. The oily residue is dissolved in 50 ml of acetic acid, the solution is boiled for 2 minutes, and then evaporated in vacuo. The gelly residue is triturated with ether to obtain 2.8 g (98%) of Glp-Nva-Met-NH2 ; m.p.: 249°-250° C. (decomposition), Rf5 =0.58, [α]D25 =-48.4° (c=1%, in acetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]3[C:23]([O:25]C)=[O:24])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]3[C:23]([OH:25])=[O:24])(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of methyl 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylate (164 mg, 0.41 mmol), [prepared as described in Example 3] and NaOH (33 mg, 0.82 mmol) in methanol/water (5 ml of 9:1 ratio) was heated at reflux. After 2 h, the reaction mixture was concentrated in vacuo, diluted with water (5 ml) and extracted with diethyl ether. The aqueous phase was acidified to pH 3 with 5% potassium bisulfate solution and the product was extracted into ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated to yield 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid as a foam (125 mg, 79%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=[CH2:32])[N:26]=2)[N:4]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH3:32])[N:26]=2)[N:4]=1)[CH3:2]
Reactant: C=Cc1cccc(Cn2nc(CC)c3c(NC(=O)c4cnc5ccccn45)cccc32)n1
Agent: [Pd]
Solvent: CO
Product: CCc1cccc(Cn2nc(CC)c3c(NC(=O)c4cnc5ccccn45)cccc32)n1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To N-(3-ethyl-1-((6-vinylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11 mg, 0.026 mmol) in MeOH (3 mL) was added palladium on carbon (10% wt, 8 mg). The reaction mixture was purged with N2 three times followed by a purge with H2. A H2 balloon was applied to the reaction mixture. The mixture was stirred for one hour and filtered through a plug of silica gel. The plug was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH 10:1) to give the final product (6 mg). MS (ES+APCI) m/z=425 (M+H).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:15]([Cl:16])=[C:14]([O:17][CH2:18][C:19]#[N:20])[CH:13]=[C:12]2[C:4]=1[C:5]1[C:10]([CH2:21][CH2:22][CH3:23])([CH2:11]2)[CH2:9][CH2:8][C:7](=[O:24])[CH:6]=1.[ClH:25].[CH3:26][NH:27][CH3:28]>CO>[OH2:17].[ClH:2].[CH3:26][N:27]([CH3:28])[C:19](=[NH:20])[CH2:18][O:17][C:14]1[CH:13]=[C:12]2[C:4]([C:5]3[C:10]([CH2:21][CH2:22][CH3:23])([CH2:11]2)[CH2:9][CH2:8][C:7](=[O:24])[CH:6]=3)=[C:3]([Cl:25])[C:15]=1[Cl:16].[CH3:26][N:27]([CH3:28])[C:19](=[NH:20])[CH2:18][O:17][C:14]1[CH:13]=[C:12]2[C:4]([C:5]3[C:10]([CH2:21][CH2:22][CH3:23])([CH2:11]2)[CH2:9][CH2:8][C:7](=[O:24])[CH:6]=3)=[C:3]([Cl:25])[C:15]=1[Cl:16].[ClH:2]
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)C2
Reactant: CNC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC(=N)N(C)C)c(Cl)c1Cl)C2
Product: O

Procedure:
To a solution of sodium metal (20 mg) in methanol (30 ml) was added the R(+)-enantiomer of [(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)oxy]acetonitrile (1.0 g, 2.9 mMole). The reaction mixture was stirred for 1-1/2 hours in a dry nitrogen atmosphere then treated with dimethylamine hydrochloride (475 mg, 5.8 mMole) and stirring was continued for 21/2 hours. The methanol was evaporated in vacuo, the residue was dissolved in water, treated with 10N NaOH (1 ml), extracted with diethyl ether containing 10% tetrahydrofuran, washed with water and brine, dried over potassium carbonate and evaporated in vacuo. The residue was dissolved in a mixture of ethanol and diethyl ether, treated with ethanolic HCl, filtered under nitrogen and washed with diethyl ether to give 0.8 g of the R(+)-enantiomer of N,N-dimethyl-2-[(5,6-dichloro-9a-propyl-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]ethanimidamide hydrochloride hemihydrate.
Reaction SMILES: [C:1]([O:6]C)(=O)[C:2]([CH3:4])=[CH2:3].[CH2:8]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11].Cl.C(NCCCC)CCC.C1(C=CC(O)=CC=1)O>>[CH2:8]([N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNCCCC
Reactant: C=C(C)C(=O)OC
Agent: Cl
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)N(CCCC)CCCC
Yield: 15 %

Procedure:
200 g of methyl methacrylate, 129 g of dibutylamine, 8.25 g of dibutylamine hydrochloride, 5 g of Fe-(III)-acetylacetonate, and 0.5 g of hydroquinone were heated for 3 hours at 230° C. in an autoclave (pmax =10 atmospheres). In this way, a 15% yield of N,N-dibutylmethacrylic acid amide form. The selectivity, calculated on the methyl methacrylate reacted, was greater than 80%.
Reaction SMILES: N#N.[C:3]([NH:6][C:7]1[NH:8][C:9](=[O:23])[C:10]2[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[N:13][C:14]=2[N:15]=1)(=[O:5])[CH3:4].[C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][Br:32])(=[O:26])[CH3:25]>CN(C=O)C>[Br-:32].[C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][N:13]1[CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[C:9](=[O:23])[NH2+:8][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[N:15][C:14]1=2)(=[O:26])[CH3:25]
Reactant: CC(=O)OCCOCBr
Reactant: CC(=O)Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Agent: N#N
Solvent: CN(C)C=O
Product: CC(=O)NC1=NC2=C(C(=O)[NH2+]1)N(Cc1ccccc1)CN2COCCOC(C)=O
Product: [Br-]
Temperature: 80 °C

Procedure:
To a mixed solution containing 100 mg (0.35 mmol) of N2 -acetyl-7-benzylguanine and 1 ml of DMF was added 72 mg (0.37 mmol) of (2-acetoxyethoxy)methyl bromide [prepared by the method described in M. J. Robins et al., Can. J. Chem., 60, 547 (1982)]. The mixture was heated at 80° C. for 20 h, and then allowed to cool. The reaction solution was concentrated, and purified by silica-gel column chromatography to yield 9-(2-acetoxyethoxy)methyl-7-benzyl-N2 -acetylguaninium bromide.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=[O:4].CN1[C:11](=[O:12])[CH2:10][S:9]C1=O.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:1]1[N:2]([CH3:5])[C:3](=[O:4])[S:9][C:10]=1[CH:11]=[O:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CN1C(=O)CSC1=O
Product: Cn1c(Cl)c(C=O)sc1=O
Temperature: 110 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
At 0° C., N,N-dimethylformamide (2 mL, 27 mmol) was added to a solution of 3-methyl-thiazolidine-2,4-dione (33a) (1.77 g, 13.5 mmol) in phosphorus oxychloride (3.77 mL, 40.5 mmol). The reaction mixture was stirred at 110° C. for 3 hours, cooled to room temperature and quenched with a mixture of ice and ethyl acetate. The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the desired aldehyde (33b) as a yellow solid (1.9 g, 10.7 mmol, 79%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=2)[CH2:22][CH:21]1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)=[O:19].[BH3-][C:45]#[N:46].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[Cl:43][C:38]1[CH:37]=[C:36]([CH:21]2[CH2:22][N:23]([C:26](=[O:35])[C:27]3[CH:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[CH:32]=3)[CH2:24][CH2:25][N:20]2[C:18](=[O:19])[CH2:45][NH:46][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH:10]2[CH3:15])[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CBr)C(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: [BH3-]C#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCN(Cc4ccccc4)CC3C)C(c3ccc(Cl)c(Cl)c3)C2)c1
Reaction time: 8 h

Procedure:
A mixture of the ketone 4 from step 3 (70 mg, 0.13 mmol) and the compound 3 (34 mg, 0.17 mmol) was stirred in titanium isopropoxide (45 mg, 0.16 mmol) for 1.5 h. To the mixture were added ethanol (1.0 mL) and NaCNBH3 (5.4 mg, 8.6 mmol) and the mixture was stirred overnight. The reaction mixture was filtered and washed with EtOAc. The filtrate was washed with H2O and brine, dried with MgSO4 and concentrated. The residue was chromatographed on silica gel eluting with 5% NH3 sat. MeOH in CH2Cl2 to give both diastereomers pure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:16])C.[NH4+]>C(O)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][NH:3][C:2]2=[O:16])=[CH:7][C:8]=1[F:13]
Reactant: Fc1cc2ccnc(Cl)c2cc1Cl
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]ccc2cc(F)c(Cl)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
41.13 g (190.4 mmol) 1,7-dichloro-6-fluoro-isoquinoline (6) were dissolved in 670 ml of acetic acid. After addition of 148.8 g (1.90 mol) of ammonium acetate, the solution was stirred at 100° C. After 3 h, the solvent was removed under reduced pressure and the residue was poured into water. The aqueous phase was extracted three times with dichloromethane, the combined organic layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated to dryness. The crude product was crystallized from ethyl acetate/heptane to yield 14.85 g of the desired product. Another 4.5 g could be obtained upon evaporation and silica gel chromatography of the mother liquor.