Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH2:7].[C:9]([O:13][C:14](=O)[O:15]C(C)(C)C)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH:7][C:14](=[O:15])[O:13][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CN(CCN)CCN
Solvent: ClCCl
Product: CN(CCN)CCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 118.5 %

Procedure:
N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 mm. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g of tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([OH:15])=O.[N:16]1([CH:22]2[CH2:25][N:24]([C:26](=[O:29])[CH:27]=[CH2:28])[CH2:23]2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([N:19]1[CH2:20][CH2:21][N:16]([CH:22]2[CH2:25][N:24]([C:26](=[O:29])[CH:27]=[CH2:28])[CH2:23]2)[CH2:17][CH2:18]1)=[O:15]
Reactant: C=CC(=O)N1CC(N2CCNCC2)C1
Reactant: O=C(O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)N1CC(N2CCN(C(=O)Cc3c[nH]c4cc(Cl)c(Cl)cc34)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
A mixture of 2-(5,6-dichloro-1H-indol-3-yl)acetic acid (90 mg, 0.372 mmol), 1-(3-(piperazin-1-yl)azetidin-1-yl)prop-2-en-1-one (87 mg, 0.446 mmol), EDCI.HCl (107 mg, 0.558 mmol), HOBt (75 mg, 0.558 mmol) in DMF (3 mL) at 0° C., Et3N (112 mg, 1.11 mmol) was added. The resulting mixture was stirred at RT for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=30:1) to afford the desired product (12 mg, 7.66% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ:11.19 (bs, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 7.35 (d, 1H), 6.28 (dd, J=9.6, 16.8 Hz, 1H), 6.09 (dd, J=2.4, 17.2 Hz, 1H), 5.66 (dd, J=2.4, 10.4 Hz, 1H), 4.21-4.18 (m, 1H), 4.02-3.98 (m, 1H), 3.93-3.88 (m, 1H), 3.78 (s, 2H), 3.74-3.70 (m, 1H), 3.53-3.47 (m, 4H), 3.10-3.07 (m, 1H), 2.25-2.19 (m, 4H). ESI-MS m/z: 423.3[M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([N:15]5[CH2:16][CH2:17][O:18][CH2:19][CH2:20]5)[CH:10]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 75.6 %

Procedure:
Using 1.18 g of t-butyl N-{2-amino-5-[3-(morpholin-4-yl)phenoxy]phenyl}-N-methylcarbamate, 0.92 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.53 g of diethyl cyanophosphonate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to Example (2-1), whereby 1.48 g of the desired compound were obtained.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[NH:5][CH2:4][CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[C@@H:26]1[CH2:28][O:27]1>CCO>[OH:27][C@H:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:21](=[O:25])[O:22][CH2:23][C:24]=2[C:16]=1[CH3:15])[CH2:28][N:5]1[CH:6]2[CH:1]([CH2:7]2)[N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: CC(C)(C)OC(=O)N1CCNC2CC21
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(C(=O)OC(C)(C)C)C3CC32)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
In a microwave vial charged with stirring bar, tert-butyl (±)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (341 mg, 1.72 mmol) was dissolved in EtOH (20 mL). 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (654 mg, 3.44 mmol) was added. Then mixture was sealed and put on microwave reactor. It was heated up to 145° C. and was stir at 145° C. for 60 minutes. After cooling down to room temperature, solution was transferred to a round bottom flask and was concentrated on rotavapor to give crude product, which was purified by ISCO (80 gram silica gel column, eluted by 0-10% MeOH/DCM gradient). Removing solvent gave the title compound. LC/MS: (M+1)+=389.14;
Reaction SMILES: Cl.C(N=C=N[CH2:7][CH2:8][CH2:9]N(C)C)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:20]=2)[CH:15]=[CH:14]1.C(O)C=C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23]([O:25][CH2:9][CH:8]=[CH2:7])=[O:24])[CH:20]=2)[CH:15]=[CH:14]1
Reactant: O=C(O)Cc1ccc2cc[nH]c2c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C=CCO
Solvent: ClCCl
Product: C=CCOC(=O)Cc1ccc2cc[nH]c2c1
Yield: 86.8 %

Procedure:
750 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to a solution of 450 mg of 2-(indol-6-yl)acetic acid [synthesized according to the procedures described in Chem. Pharm. Bull., 20, 2163 (1972)], 0.27 ml of allyl alcohol and 480 mg of 4-dimethylaminopyridine in 20 ml of methylene chloride, at room temperature, and the resulting mixture was stirred overnight. After completion of the reaction, the reaction mixture was acidified by the addition of a 3% aqueous solution of hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 10 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 480 mg of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([NH:12][CH3:13])=[N:6][C:5]2=O.CN(C)C1C=CC=CC=1.[OH-].[Na+].P(Cl)(Cl)([Cl:28])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH3:13])[N:6]=[C:5]2[Cl:28]
Reactant: CNc1nc(=O)c2cc(Br)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Product: CNc1nc(Cl)c2cc(Br)ccc2n1
Yield: 46.6 %

Procedure:
To a solution of phosphorus oxychloride (50 mL) was added powdered 6-bromo-2-methylamino-1H-quinazolin-4-one (10.0 g, 39.4 mmol) followed by dimethyl-phenyl-amine (8 mL) and the mixture was heated to reflux under N2 atmosphere for half an hour. After cooling down, the mixture was poured onto ice and basified with aqueous NaOH solution (2 M). The precipitate was collected by filtration and purified by column to afford (6-bromo-4-chloro-quinazolin-2-yl)-methyl-amine (5 g, 18.3 mmol, 46.6%) as a yellow solid. 1H NMR (DMSO-d6): δ 8.03 (s, 1H), 7.86-7.84 (m, 2H), 7.47-7.45 (d, 1H), 2.86-2.84 (d, 3H).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[C:11]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:12][CH:13]=[C:14]([CH:18]=3)[C:15](O)=[O:16])[CH:8]=[CH:9][C:2]=12.[F:25][C:26]([F:35])([F:34])[C:27]1[N:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[C:11]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[N:12][CH:13]=[C:14]([CH:18]=3)[C:15]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([C:26]([F:35])([F:34])[F:25])[N:31]=3)=[O:16])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc3nonc3c2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc3nonc3c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-benzo[1,2,5]oxadiazol-5-yl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example CH) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; MS (ESI) 489.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Li]CCCC.CCCCCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>C1COCC1>[CH3:10][O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][C:7]=1[B:24]([OH:29])[OH:25]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(F)(F)F)cc1B(O)O
Temperature: -30 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A solution of 4-trifluoromethylanisole (8 g; 45 mmol) in dry THF (80 ml) at −30° C. under N2 was added a solution of 2.5 M n-BuLi in hexane (20 ml; 50 mmol). The reaction mixture was stirred for 1 h at −30° C., then cooled to −70° C. and added B(Oi-Pr)3 (14.1 ml; 64 mmol). The reaction mixture was allowed to slowly warm up to rt. over night. The reaction mixture was added 2 M HCl (40 ml) and THF was removed by evaporation. The aqueous remanense was extracted with Et2O (4×20 ml) and the combined organic fractions were extracted with 1 M NaOH (5×17 ml). The combined aqueous fractions were neutralized by 10 M HCl. The precipitate formed was isolated by filtration and washed with 1 M HCl to give 8.1 g (81%) product.
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][SiH:9]([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:10][Si:9]([Cl:11])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CC(C[SiH](Cl)Cl)c1ccccc1
Reactant: C=CCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCC[Si](Cl)(Cl)CC(C)c1ccccc1
Yield: 60.6 %

Procedure:
in the same apparatus and procedures as EXAMPLE 1, 5.0 g (0.023 mole) of 3-phenyl-1,1-dichloro-1-silabutane, 5.8 g (0.07 mole) of 1-hexene, and 100 μl of 1% chloroplatinic acid in isopropanol were placed and reacted under the dry nitrogen atmosphere. Vacuum distillation of the reaction products gave 4.23 g (bp, 115°-8° C./0.6 mmHg) of 4,4-dichloro-2-phenyl-4-siladecane.
Reaction SMILES: O.C[O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]2)[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[CH:7][CH:6]=1.FC(C1C=C(C=C(C(F)(F)F)C=1)COCC(C1C=CC(C(OC)=O)=CC=1)[N:51]1CCN(CC(O)=O)CC1)(F)F.N>CO>[F:28][C:25]([F:26])([F:27])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=1)[CH2:14][O:13][CH2:12][CH:11]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]1)[C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:3])[NH2:51])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N2CCN(CC(=O)O)CC2)cc1
Agent: N
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N2CCN(CC(=O)O)CC2)cc1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
In a small autoclave, 1.5 g (2.73 mmoles) of 4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-carboxymethyl-piperazin-1-yl)-ethyl]-benzoic acid methyl ester (compound 318) were dissolved in methanol. The solution was saturated with NH3 and heated at 100° C. for three days. Methanol was then evaporated and the crude product was purified by chromatography (eluent: CH2Cl2/MeOH/NH3: 80/20/0.5 v/v/v) to give 880 mg of {4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-carbamoyl-phenyl)-ethyl]-piperazin-1-yl}-acetic acid (compound 321) as a grey solid. 4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-(4-carbamoylmethyl-piperazin-1-yl)-ethyl]-benzamide (compound 322) was isolated as a side product (150 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][C:9]2=[C:10]3[C:14](=[CH:15][CH:16]=[C:8]2[O:7][CH2:6][CH2:5]1)[NH:13][CH:12]=[CH:11]3.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])#[N:19].O>CN(C=O)C>[CH3:3][N:4]1[CH2:17][C:9]2=[C:10]3[C:14](=[CH:15][CH:16]=[C:8]2[O:7][CH2:6][CH2:5]1)[N:13]([S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]#[N:19])(=[O:28])=[O:27])[CH:12]=[CH:11]3
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CN1CCOc2ccc3[nH]ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3C#N)c2C1
Reaction time: 1 h
Yield: 35.4 %

Procedure:
NaH (60% in mineral oil, 0.040 g, 1.0 mmol) was charged into a pyrex tube under nitrogen gas and 2-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Intermediate 6, 100 mg, 0.492 mmol) in dry DMF (1 mL) was added. The reaction mixture was stirred at room temperature for 20 minutes before 2-cyanobenzenesulfonyl chloride (0.11 g, 0.50 mmol) was added and the reaction mixture was stirred for 1 hour. Water (2 mL) was added and the solution was extracted with DCM. The combined organics were evaporated and the solid residue was washed with diethyl ether to give 64 mg of the title compound. MS m/z 368 [M+H]+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C=O)cc1OC

Procedure:
A flask containing vanillin (20 g, 0.13 mol), ethyl bromoacetate (28.4 g, 0.17 mol) and potassium carbonate (32.7 g, 0.24 mol) and acetone 200 mL were heated to reflux for 3 hours. The reaction was allowed to come to rt. The acetone was stripped off and the residue partitioned between water and ethyl acetate. The ethyl acetate was washed with brine and dried over magnesium sulfate. The organic layer was concentrated and the solid triturated with hexanes to yield 28.4 grams of example No. 169.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=2.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>C1(O)C=CC=CC=1>[CH2:20]([NH:27][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)c1ccc2c(Cl)c3c(nc2c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: CC(C)(C)c1ccc2c(NCc3ccccc3)c3c(nc2c1)CCCC3
Yield: 55.4 %

Procedure:
9-Chloro-6-(1,1-dimethylethyl)-1,2,3,4-tetrahydroacridine (3.0 g) was dissolved in 60 ml of phenol and heated at 150° C. with 3.54 g of benzylamine. After 2 hours the reaction mixture was poured into 10% NaOH and extracted with Et2O. The organic phase was separated, washed with H2O, and then treated with 5% HCl. The insoluble hydrochloride was filtered off and recrystallized from isopropanol/ether and then from methanol/ether to give 2.09 g of product, m.p. 247° (d).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13]2>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13]3)[N:3]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(Oc3cncc(Cl)n3)ccc21
Yield: 100 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 5-hydroxyindanone (219 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (350 mg). Yield: 100%. 1H NMR (250 MHz, DMSO-d6) δ 2.67 (t, 2H, H3, J=5.9 Hz), 3.13 (t, 2H, H2, J=5.5 Hz), 7.31 (dd, 1H, Harom 6, Jm=1.9 Hz, Jo=8.3 Hz), 7.47 (d, 1H, Harom 4, J=1.3 Hz), 7.73 (d, 1H, Harom 7, J=8.3 Hz), 8.59 (s, 1H, HPz 5), 8.64 (s, 1H, HPz 3). m/z: 261.0 [(M+H)+, calcd for C13H9ClN2O2 260.0].
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=[O:11])[O:9][C:7](=[O:8])[CH2:6]1)[C:2](=[CH2:4])[CH3:3].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([CH:5]1[CH2:6][C:7](=[O:8])[O:9][C:10]1=[O:11])[CH:2]([CH3:4])[CH3:3]
Reactant: C=C(C)CC1CC(=O)OC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)CC1CC(=O)OC1=O
Reaction time: 2 h
Yield: 97.5 %

Procedure:
β-Methallylsuccinic anhydride (539 g, 3.50 mole) was dissolved in toluene (800 mL) in a 1700 mL Parr stainless steel bottle fitted with a heating jacket. 10% Pd/C (3.60 g) was added and the bottle was connected to a Parr 2 L shaker fitted with two 4 L hydrogen tanks. After several evacuations and refilling with hydrogen, the shaker was started with the heater controlled for 60° C. The initial pressure was 60 lbs. When the pressure fell to 10 lbs, the tanks were repressurized to 60 lbs. After two hours, the controller was reset to 70° C. and the reaction was continued for another 12 hours. The heat was then turned off and after another 5 hours, the shaker was stopped. The reaction vessel was evacuated and the reaction mixture was filtered and concentrated. Distillation of the residue through the Vigreux column described above (P=9-10 mm Hg, T=180° C.) gave isobutylsuccinic anhydride (532.9 g, 97.6% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([OH:53])(=[O:52])[CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[CH:51]>CN(C=O)C.[Cu]I>[C:18]([C:14]1[C:13](=[O:20])[NH:12][C:11]2[S:10][CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:51]#[C:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([OH:53])=[O:52])[CH:7]=[CH:6][CH:5]=3)[C:16]=2[C:15]=1[OH:17])#[N:19]
Reactant: C#CCCCCC(=O)O
Reactant: N#Cc1c(O)c2c(-c3cccc(Br)c3)csc2[nH]c1=O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: N#Cc1c(O)c2c(-c3cccc(C#CCCCCC(=O)O)c3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(3-bromo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (50 mg, 0.15 mmol) in 1.5 mL DMF was added diethylamine (0.16 mL, 1.5 mmol), followed by copper(I) iodide (trace), Pd(PPh3)Cl2 (3.5 mg, 0.005 mmol), and triphenylphosphine (12 mg, 0.04 mmol). The resulting mixture was stirred at rt for 5 min, after which hept-6-ynoic acid (63 μL, 0.5 mmol) was added. The reaction was then heated to 120° C. using microwave reactor for 25 min, filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 391 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.54 (m, 4H), 2.22 (m, 4H), 6.68 (s, 1H), 7.21–7.26 (m, 2H), 7.37–7.44 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[N:33][C:32]([C:35](O)=[O:36])=[N:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:32]4[N:33]=[CH:34][NH:30][N:31]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1nc[nH]n1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nc[nH]n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1H-1,2,4-triazole-3-carboxylic acid (17 mg, 0.15 mmol).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:16][CH:17]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.[OH-].[NH4+]>C(O)C>[C:1]1([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:32]5[N:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:20][CH2:19]4)=[N:16][CH:17]=3)[NH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnc(-c3ccc(N4CCNCC4)nc3)[nH]2)cc1
Reactant: Clc1ncccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc(-c2c[nH]c(-c3ccc(N4CCN(c5ncccn5)CC4)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.2 %

Procedure:
(Reference: J. Am. Chem. Soc. 1954, 1484) A solution of 1-[5-(5-phenyl-1H-imidazol-2-yl)-pyridin-2-yl]-piperazine (0.16 g, 0.52 mmol), triethylamine (0.22 ml, 0.16 g, 1.58 mmol, 3.0 equiv) and 2-chloro-pyrimidine (0.90 mg, 0.79 mmol, 1.5 equiv) in absolute ethanol (5 ml) under nitrogen atmosphere was heated at reflux for 1 hour, after which additional triethylamine (0.22 ml, 0.16 g, 1.58 mmol, 3.0 equiv) and 2-chloro-pyrimidine (0.90 mg, 0.79 mmol, 1.5 equiv) were added. The reaction was heated at reflux for an additional 1.5 hour, then stirred at room temperature for two days. The mixture was basified to pH 10 with concentrated ammonium hydroxide, and then concentrated in vacuo. The residue was partitioned between water (20 ml) and ethyl acetate (50 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a solid, which was triturated with ether to give the desired product (0.15 g, 74%). MS m/z 446 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([F:17])=[CH:4][C:3]=1[NH2:18].[C:19]([OH:27])(=[O:26])[C:20]([CH2:22][C:23](O)=[O:24])=[CH2:21]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([F:17])=[CH:4][C:3]=1[N:18]1[C:23](=[O:24])[CH2:22][CH:20]([C:19]([OH:27])=[O:26])[CH2:21]1
Reactant: Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2cc(F)c(OCc3cccc(F)c3)cc2F)C1
Yield: 34.5 %

Procedure:
In an analogous manner to that described in Example 1a), 2,5-difluoro-4-(3-fluorobenzyloxy)-phenylamine was reacted with itaconic acid to yield (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (34.5% of theory) as a grey solid; MS: m/e=363 (M−H)+.