Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[S:17][CH:18]=[C:19]([N+:21]([O-])=O)[CH:20]=2)(=[O:15])=[O:14])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.BrC1C(NCCNS(C2SC([N+]([O-])=O)=CC=2)(=O)=O)=NC(Cl)=NC=1.[OH-].[Na+]>C1COCC1.Cl>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[S:17][CH:18]=[C:19]([NH2:21])[CH:20]=2)(=[O:14])=[O:15])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1csc(S(=O)(=O)NCCNc2nc(Cl)ncc2Br)c1
Agent: Cl
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)NCCNc2nc(Cl)ncc2Br)s1
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1csc(S(=O)(=O)NCCNc2nc(Cl)ncc2Br)c1
Reaction time: 46 h

Procedure:
A solution of 600 mg (1.35 mmol) of a mixture of 4-nitro-thiophene-2-sulfonic acid [2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-ethyl]-amide and 5-nitro-thiophene-2-sulfonic acid-[2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-ethyl]-amide (ratio 10/6) in 40 ml of THF is mixed under argon at room temperature with 6.4 ml of a 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid. After 46 hours, the reaction solution is mixed again with 2.0 ml of Ti(III)Cl solution and stirred for another 7 hours. The batch is made basic with 2N NaOH solution and then filtered. The filter cake is rewashed 2× with 50 ml of ethyl acetate/MeOH (30 ml/20 ml) in each case. The filtrate is concentrated by evaporation in a rotary evaporator and then extracted with ethyl acetate (2×). The combined organic phases are filtered through a Whatman filter and concentrated by evaporation. The residue is purified by chromatography (hexane/ethyl acetate 1:4). 178 mg (0.43 mmol, corresponding to 32% of theory) of the product is obtained.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[BH4-].[Na+].[NH4+].[Cl-].O>CO>[OH:2][CH2:1][C@@H:3]1[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C1CC1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOC(=O)[C@@H]1C[C@H]1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-formyl-1-cyclopropanecarboxylate (1.5 eq.) in methanol (0.7 M) at 0° C. was added sodium borohydride (1.5 eq.) in portions over 30 min. The mixture was allowed to stir at rt for 1.5 h and then cooled in an ice bath. Saturated aqueous NH4Cl solution was added dropwise, and the mixture was stirred for 1.5 h. Water was added, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated to afford a racemic mixture of the title compound as a clear oil. Racemic trans 2-(hydroxymethyl)cyclopropanecarboxylate was purified by a Chiral Pak AD preparative column (10% EtOH/Hex) to afford two enantiomers. Ethyl (1R,2R)-2-(hydroxymethyl)cyclopropanecarboxylate was eluted as the faster enantiomer (retention time=12.94 min).
Reaction SMILES: [S:1]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>CS(O)(=O)=O>[CH:4]1[C:3]2[C:13](=[O:15])[C:12]3[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:1][C:2]=2[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Sc2ccccc2C(=O)O)cc1
Agent: CS(=O)(=O)O
Product: O=C(O)c1ccc2sc3ccccc3c(=O)c2c1
Temperature: 85 °C

Procedure:
Next, thioxanthen-9-one-2-carboxylic acid was prepared. A mixture of 2,4′-thiobis(benzoic acid) (50 g, 182 mmol) and methansulfonic acid (600 mL) was heated at 85° C. for 5 h and then cooled to ambient. The reaction mixture was poured onto ice, and the resulting precipitate was collected, washed with water, and dried.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([Cl:26])=[C:6]([C:8]2[C:9](=[O:25])[N:10]([CH2:23][CH3:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][S:21][CH3:22])[CH:12]=3)[CH:7]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[Cl:26][C:5]1[C:6]([C:8]2[C:9](=[O:25])[N:10]([CH2:23][CH3:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][S:21][CH3:22])[CH:12]=3)=[CH:7][C:2]([NH:1][C:35]([NH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])=[C:3]([F:27])[CH:4]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NCCSC)cc21
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NCCSC)cc21
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-(methylthio)ethylamino)-1,6-naphthyridin-2(1H)-one (400 mg, 0.99 mmol) in DCM (20 mL) was added phenyl isocyanate (200 mg, 1.68 mmol) and the mixture was stirred overnight. The reaction mixture was quenched with MeOH and concentrated under reduced pressure. The residue was washed with Et2O to give 1-(4-chloro-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (200 mg, 39% yield).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.CC1(C)N([O-])C(C)(C)CC(OC)C1.[Br-].[K+].Cl[O-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: OC(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: COC1CC(C)(C)N([O-])C(C)(C)C1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanol (0.29 g; 1.00 mmole), 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy free radical (4-methoxy-TEMPO free radical; 4.4 mg; 0.03 mmoles) and potassium bromide (KBr; 13 mg; 0.11 mmoles) were dissolved in THF (2.9 mL). The reaction mixture was stirred while cooled to −10° C., after 10 min. a sodium hypochlorite solution (bleach; 10-13% aqueous; 2.10 mL; 3.53 mmoles) was added and allowed to stir for 15 min., then warmed to room temperature and stirred for 15 min. The reaction mixture was diluted with water (20 mL) and ethyl acetate (30 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×30 mL). The extracts were combined and washed with water (30 mL) and brine (40 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo and purified by column chromatography (SiO2; 100% ether) to yield the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-])=O>[Fe].C(O)(=O)C>[NH2:14][C:3]1[CH:4]=[C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1C[C@H](c2ccc(Cl)c([N+](=O)[O-])c2)CN1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
(4R)-4-(4-Chloro-3-nitrophenyl)pyrrolidin-2-one (24 g, 100 mmol) was treated with acetic acid (100 mL) and warmed to 50° C. Iron(0) (19.5 g, 350 mmol) was added in portions. After the addition, the reaction mixture was stirred for 1 h at 50° C. The mixture was then cooled and filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layers were washed with water (3 times), brine, and concentrated to provide the title compound as a yellow oil. (18.9 g, 90% yield). 1H-NMR (400 MHz, CD3OD): δ 7.11-7.12 d, J=8.4 Hz, 1H), 6.73-6.74 (d, J=2.0 Hz, 1H), 6.52-6.55 (m, 1H), 3.70-3.74 (m, 1H), 3.54-3.62 (m, 1H), 3.29-3.34 (m, 1H), 2.63-2.69 (dd, J=16.4, 8.8 Hz, 1H), 2.37-2.43 (dd, J=16.4, 8.4 Hz, 1H); MS (ESI) m/z 211.07 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:9]=1.[N:20]1([C:26]2[N:27]=[C:28]([CH2:33][C:34]([O-])=[O:35])[NH:29][C:30](=[O:32])[CH:31]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[Na+]>CN(C)C=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:34](=[O:35])[CH2:33][C:28]2[NH:29][C:30](=[O:32])[CH:31]=[C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:27]=2)=[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:9]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COCCOc1cc(F)ccc1N
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCCOc1cc(F)ccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.9 %

Procedure:
3 ml of pyridine, 500 mg of N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride and 590 mg of 4-fluoro-2-(2-methoxyethoxy)phenylamine are added to a solution of 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 155 mg of N-[4-fluoro-2-(2-methoxyethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:11]1(=[O:18])OC(=O)[CH2:14][CH2:13][CH2:12]1.C[N:20]([CH:22]=[O:23])C>CN(C)C1C=CN=CC=1>[C:11]([NH2:1])(=[O:18])[CH2:12][CH2:13][CH2:14][C:22]([NH2:20])=[O:23].[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CN(C)C=O
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: NCCCC[C@H](N)C(=O)O
Product: NC(=O)CCCC(N)=O
Reaction time: 0.08 h

Procedure:
In this example that demonstrates how this method could be performed, 5 g Lysine, 8.7 g glutaric anhydride and 2.0 g 4-Dimethylaminopyridine (DMAP) are weighed into a 100 ml flask fitted with a condenser and nitrogen inlet. 100 ml DMF is added and the mixture stirred under nitrogen atmosphere for 5 min and immersed into an oil bath preheated to 90° C. for 1.5 h until HPLC assay indicated completion of reaction. DMF is evaporated under vacuum (distilled below 40° C. and the residue is used directly for the subsequent reaction. The residue can be purified by chromatography on silica gel.
Reaction SMILES: [N:1]1[C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+:3]([O-])[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12>P(OCC)(OCC)OCC>[CH2:14]([O:13][C:11]([C:2]1[N:1]=[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1nc2cnccn2[n+]1[O-]
Agent: CCOP(OCC)OCC
Product: CCOC(=O)c1nc2cnccn2n1
Yield: 22.8 %

Procedure:
Ethyl 1,2,4-triazolo[1,5-a]pyrazine-2-carboxylate-3-oxide (prepared as described in J. Chem. Soc., Perkin Trans. 1, 1976, 2166) (2.0 g, 9.6 mmol) was stirred in triethyl phosphite (20 ml) at 100° C. for 1 h. The solvent was concentrated in vacuo, and the crude product was triturated with diethyl ether (50 ml). The precipitated solid was separated by filtration, and purified by flash chromatography on silica gel, eluting with 1:1 dichloromethane:ethyl acetate, yielding [1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester as a pale orange solid (420 mg). Data for the title compound: 1H NMR (360 MHz, CDCl3) δ 1.51 (3H, t, J=7.1 Hz), 4.59 (2H, q, J=7.1 Hz), 8.34 (1H, d, J=4.5 Hz), 8.63 (1H, d, J=4.5 Hz), 9.43 (1H, s); MS (ES+) m/e 193 [MH]+.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:7]=1)[CH2:3][C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:5][CH2:4][CH2:3][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[N:7]=1)[OH:1]
Reactant: N#CCC(=O)c1cccc(OCC2CCOCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCCC(O)c1cccc(OCC2CCOCC2)n1

Procedure:
Reduction of 3-oxo-3-(6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-2-yl)propanenitrile by LiAlH4 following the method used in Example 2 gives Example 38.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36].O>C(#N)C>[CH2:35]([N:37]([CH2:38][CH3:39])[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4])[CH3:36]
Reactant: CCNCC
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC)CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and diethyl amine (63 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. Product was purified by column chromatography using 10% methanol in methylenechloride as eluant. 2-Diethylamino-N-[6-(2-phenyl-chroman-6-yloxy)pyridin-3-yl]acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO) δ: 11.1 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 2.0, 10.0 Hz), 4.14 (d, 2H, J 4.9 Hz), 3.24 (k, 4H, J 7.2 Hz), 3.01-2.92 (m, 1H), 2.76-2.70 (m, 1H), 2.19-2.15 (m, 1H), 2.04-1.94 (m, 1H), 1.24 (t, 6H, J 7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13](OC)[O:14]C)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.CCOC(C)=O.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1
Reactant: COCCCc1cc(C(OC)OC)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COCCCc1cc(C=O)c(Cl)cn1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
5-Chloro-4-dimethoxymethyl-2-(3-methoxy-propyl)-pyridine (25.5 g, 98.2 mmol) was dissolved in aq. 1M HCl (500 mL), and the mixture was heated to 80° C. for 2 h. The mixture was allowed to cool to rt, and EtOAc was added. The mixture was cooled to 0° C., and was basified with aq. 2.5M NaOH to pH=10. The layers were separated, and the org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (98.1 mmol, 99%) that was used further without purification. LC-MS: tR=0.62 min; ES+: 246.12.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN1CCCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[N:9]1[CH2:8][C:7]2[CH:13]=[C:3]([Br:2])[CH:4]=[CH:5][C:6]=2[O:12][CH2:11][CH2:10]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Brc1ccc2c(c1)CNCCO2
Agent: CN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: COc1cc2nccc(N3CCOc4ccc(Br)cc4C3)c2cc1OC
Temperature: 160 °C
Reaction time: 17 h
Yield: 17 %

Procedure:
A mixture of 7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (300 mg, 1.13 mmol), 4-chloro-6,7-dimethoxyquinoline (253 mg, 1.13 mmol), and potassium carbonate (470 mg, 3.40 mmol) in N-methylpyrrolidine (2 mL) was stirred at 160° C. for 17 h. Ethyl acetate (75 mL) was added and the mixture was washed with water (3×25 mL) and brine (25 mL), dried over sodium sulfate, and concentrated. Column chromatography on silica (dichloromethane:methanol 95:5) afforded 4-[6,7-bis(methyloxy)quinolin-4-yl]-7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine (80 mg). MS (EI) for C20H19BrN2O3: 416 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:19])[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[CH3:20][C@H:21]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:31]3[CH2:33][O:32]3)[CH:28]=2)[C:23](=[O:34])[O:22]1>CCO>[OH:32][CH:31]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:34])[O:22][C@@H:21]([CH3:20])[CH2:30]2)[CH2:33][N:8]1[CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4][C:3]1([CH2:2][OH:1])[CH3:19]
Reactant: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: CC1(CO)CN(C(=O)OCc2ccccc2)CCN1
Solvent: CCO
Product: C[C@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)CC3(C)CO)ccc2C(=O)O1
Temperature: 80 °C

Procedure:
To a solution of racemic benzyl 3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate (1.0 g, 3.8 mmol) (prepared as described in US Patent Application Publication No. US2007/0088039A1, Example 10) in EtOH (13 mL) was added (3S)-3-methyl-6-(oxiran-2-yl) isochroman-1-one (773 mg, 3.80 mmol), the resulting mixture was heated at 80° C. for 16 h, the reaction mixture was concentrated to dryness and purified on silica gel to afford the title compound: LC/MS: m/e 469.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([CH:7]=[CH:8][C:9]2[N:19]=[C:12]3[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[N:4]([CH3:20])[N:3]=1.[O-]C1C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[NH:71]1[CH2:74][CH2:73][CH2:72]1>O1CCOCC1.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].C(Cl)(Cl)Cl>[N:71]1([C:2]2[N:6]=[C:5]([CH:7]=[CH:8][C:9]3[N:19]=[C:12]4[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[N:11]4[N:10]=3)[N:4]([CH3:20])[N:3]=2)[CH2:74][CH2:73][CH2:72]1
Reactant: Cc1ncc(C)n2nc(C=Cc3nc(Br)nn3C)nc12
Reactant: C1CNC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1ncc(C)n2nc(C=Cc3nc(N4CCC4)nn3C)nc12
Yield: 15.4 %

Procedure:
A solution of 2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (28 mg, 83.8 μmol, Eq: 1.00) in dioxane (1 ml) was purged with argon, then sodium phenoxide (14.6 mg, 126 μmol, Eq: 1.5), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xant-phos) (3.88 mg, 6.7 μmol, Eq: 0.08), tris(dibenzylideneacetone)dipalladium chloroform complex/Pd2(dba)3CHCl3 (3.47 mg, 3.35 μmol, Eq: 0.04) and azetidine (9.57 mg, 11.3 μl, 168 μmol, Eq: 2) were added. The vial was capped and irradiated at 140° C. for 30 minutes in the microwave oven. The crude material was applied on silicagel and purified by chromatography over a 5 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 2-[2-(5-azetidin-1-yl-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (4 mg/15.4%) as a light yellow solid. MS: m/e=311.4 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1.[CH3:23][C:24]1[C:29]([CH2:30][C:31](O)=[O:32])=[CH:28][CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[N:25]=1.ClC1C=CC=CC=1C1N=NC(NNC(=O)CC2C=CC(C(F)(F)F)=CC=2)=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH:15][C:31](=[O:32])[CH2:30][C:29]2[C:24]([CH3:23])=[N:25][C:26]([C:34]([F:35])([F:37])[F:36])=[CH:27][CH:28]=2)=[N:12][CH:13]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Reactant: Cc1nc(C(F)(F)F)ccc1CC(=O)O
Agent: O=C(Cc1ccc(C(F)(F)F)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Product: Cc1nc(C(F)(F)F)ccc1CC(=O)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Yield: 100.4 %

Procedure:
The title compound (80 mg, 99%) as a white solid was prepared from 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (50 mg, 0.15 mmol) and 2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetic acid (49.3 mg, 0.225 mmol) in a manner analogous to that in which N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide (Example 11 A) was prepared. HPLC/MS: retention time=3.63 min, [M+H]+=531.1.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3]1=[O:30].[Br:31][C:32]1[CH:37]=[CH:36][C:35](I)=[C:34]([O:39][CH3:40])[CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([C:6]2[C:5]3[CH:17]=[CH:18][N:19]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:21])=[O:22])[C:4]=3[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=2)=[C:34]([O:39][CH3:40])[CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: COc1cc(Br)ccc1I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: COc1cc(Br)ccc1-c1cn(C)c(=O)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
The product from Example 6a (0.2 g, 0.467 mmol), 4-bromo-1-iodo-2-methoxybenzene (0.16 g, 0.514 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.014 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.014 g, 0.047 mmol) and potassium phosphate tribasic (0.347 g, 1.634 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (7.5 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred at ambient temperature for 20 minutes and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), treated with 3-mercaptopropyl functionalized silica gel for twenty minutes, filtered, and concentrated. Purification by chromatography (silica gel, 10-80% ethyl acetate in heptanes) afforded the title compound (0.2 g, 88%)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:12][C:13]1[N:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:16][C:17]=1[CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:19][CH2:18][C:17]3[S:16][C:15]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=4)=[N:14][C:13]=3[CH3:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2cc(O)ccc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(C)c[nH]c2c1

Procedure:
In analogy to the procedure described in example 3 c], 3-methyl-1H-indol-6-ol was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (example 5 c]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield 3-methyl-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-1H-indole as yellow solid.