Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH:23]1([NH:26][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH2:25][CH2:24]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC4CC4)cc3)c2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (59 mg, 0.2 mmol), cyclopropylamine (11 mg, 0.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.2 mmol) were suspended in dry DCM (7 ml) and stirred at room temperature under nitrogen for 20 h. Cyclopropylamine (33 mg, 0.6 mmol) was added and the reaction stirred at room temperature for 21 h. 1-Hydroxybenzotriazole (27 mg, 0.2 mmol) was added and the reaction heated at 35° C. for 70 h. Water (10 ml) was added to the cooled reaction, and the organic fraction separated. The organic phase was absorbed onto a silica flash column and eluted with DCI/ethanol/ammonia (300:8:1). Solvent was evaporated from the product fractions under vacuum to give N-(cyclopropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide (26 mg, 39%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][CH2:10][C@H:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1.O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17]([C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:7][CH:6]=3)[C@H:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][O:11]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 75 °C

Procedure:
cis-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane (74.3 g) was dissolved in a mixture of toluene (700 ml), water (12 ml) and sodium hydroxide (24.3 g) by heating the mixture to 75° C. 2-Chloroethylpyrrolidin hydrochloride (46.2 g) was added in six portions at 75° C. with half an hour between each portion. After the last addition the mixture was heated at 75° C. for 4 hours. Water (1000 ml) was added and the mixture stirred until all salt was dissolved. The aqueous phase was separated and extracted with another portion of toluene (300 ml). The combined organic phases was dried over potassium carbonate and evaporated to an oil. The oil was dissolved in refluxing methanol (1000 ml) and the product crystallised by cooling in an ice bath.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[C:19]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH3:40]>>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:33][NH:32][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:19]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:20][C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:40]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)c(OC/C=C(\C)CCC=C(C)C)c1
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1OC/C=C(\C)CCC=C(C)C
Yield: 76 %

Procedure:
In a manner identical to Example 15, 2,4-digeranyloxybenzoic acid (2.13 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 2.03 g (76%) of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[C:49]2[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=2)[C:52]([OH:54])=[O:53])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:49]3[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=3)[C:52]([OH:54])=[O:53])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Nc1ccn(Cc2cccc(C(=O)O)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)O)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 760 mg, 2.30 mmol) was dissolved in methylene chloride (10 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (1.15 mL, 2.30 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (0.536 mL, 4.6 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid (500 mg, 2.30 mmol) was added as a pre-dissolved reaction in methylene chloride (10 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Recrystallization from 17% ethyl acetate/methylene chloride afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (684 mg, 56%) as a white powder: ESI-LRMS m/e calcd for C26H28ClN3O5S [M+] 529.14, found 530.26 [M+H+].
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:9]=[C:10]([C:14]([O:16]C)=O)[Se:11][C:12]=1[CH3:13])[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:9]=[C:10]([C:14]([NH2:2])=[O:16])[Se:11][C:12]=1[CH3:13])[CH3:5]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(N=NN(C)C)c(C)[se]1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1[se]c(C(N)=O)cc1N=NN(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 42 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (40 mL) was added a solution of methyl 4-[(dimethylamino)diazenyl]-5-methylselenophene-2-carboxylate (550 mg) in THF (10 mL) for 5 min and stirred at rt for 40 h. The solution was poured into ice cooled water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (96:4) as eluents to give the product as off-white solid (220 mg, 42%), mp 170-172° C. IR (neat) νmax 3385, 3188, 2914, 1644, 1604, 1326, 1120, 1066 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.87 (1H, s, H-3), 5.67 (2H, br s, —CONH2), 3.28 (6H, br s, N(CH3)2), 2.63 (3H, s, Ar—CH3); LC-MS (positive ion mode): m/z 261, 259 (M+H)+.
Reaction SMILES: [Na+].[C:2]1(=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](S([O-])(=O)=O)=[CH:4][C:3]1=[O:16].O.[CH2:19]([N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:23][OH:24])[CH3:20]>CO>[CH2:19]([N:21]([CH2:22][CH2:23][OH:24])[C:25]1[CH:26]=[CH:27][C:28]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:17])[C:3](=[O:16])[CH:4]=2)=[CH:29][CH:30]=1)[CH3:20]
Reactant: O=C1C=C(S(=O)(=O)[O-])c2ccccc2C1=O
Reactant: CCN(CCO)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CCO)c1ccc(C2=CC(=O)C(=O)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A suspension of 1,2-napthoquinone-4-sulfonic acid sodium salt (10.5 g, 40.35 mmol) in a 9:1 mixture of water:MeOH (250 ml) was treated in one portion with 2-(ethyl(phenyl)amino)ethanol (6.67 g, 40.35 mmol) and stirred at 50° C. for 18 hrs. The mixture was then cooled, the MeOH removed in vacuo and the resulting suspension filtered. The precipitate was then washed with water and oven dried at 50° C. to give the product, 4-(4-(ethyl(2-hydroxyethyl)amino)phenyl)naphthalene-1,2-dione, as a dark purple solid (6.8 g, 54%). Analysis of the product by 1H NMR gave a spectrum consistent with the structure.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([OH:11])[CH2:5][C:4]1([CH3:13])[CH3:12].C[O:15][C:16]([Cl:18])=O>>[Cl:18][C:16]([O:11][CH:6]1[CH2:7][C:8]([CH3:9])([CH3:10])[N:3]([O:2][CH3:1])[C:4]([CH3:13])([CH3:12])[CH2:5]1)=[O:15]
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)Cl
Product: CON1C(C)(C)CC(OC(=O)Cl)CC1(C)C

Procedure:
The title compound is prepared by reacting 1-methoxy-2,2,6,6-tetramethylpiperidin-4-ol (1 mole) with methylchloroformate (1 mole).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:22])=[O:21]
Reactant: OCCOc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: -8 °C
Reaction time: 1 h

Procedure:
To a solution of 61.3 g of 2-(p-chlorophenoxy)ethanol, 73.5 ml of triethylamine and 900 ml of dichloromethane chilled at -10° C. is added dropwise a solution of 30.2 ml of methanesulfonyl chloride in 60 ml of dichloromethane. The mixture is stirred at -8° C. for 1 hour and worked up as described in Example 11 to give the product as a white solid. A dried sample of product melted at 75°-77° C.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>CN(C=O)C>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]2[CH2:22][CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=3[NH:13][C:6]2=[O:7])[CH2:25][CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(F)cccc1CCNC1CCN(Cc2ccccc2)CC1
Solvent: CN(C)C=O
Product: O=C1Nc2c(F)cccc2CCN1C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
11.0 g (65.8 mmol) CDI were added to 13.1 g (40.0 mmol) [2-(2-amino-3-fluoro-phenyl)-ethyl]-(1-benzyl-piperidin-4-yl)-amine in 120 mL DMF. The mixture was heated to 100° C. and stirred for 1 h. After the reaction mixture had cooled to RT it was poured onto 300 mL ice water. The aqueous phase was extracted several times with DCM, the organic phases were combined, dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined and evaporated down.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][NH:7][C:6]2=[N:10][CH:11]=[CH:12][C:5]=12.Cl[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:15][CH2:14][N:10]1[C:6]2[N:7]=[CH:8][N:9]=[C:4]([Cl:3])[C:5]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCOCc1ccccc1
Reactant: Clc1nc[nH]c2nccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ncnc2c1ccn2COCc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a oven dried 250 mL three-neck round bottom flask equipped with a stir bar, thermocouple, septa and nitrogen inlet was charged sodium hydride (NaH, 60 wt %, 1.56 g, 0.0391 mol, 1.2 equiv) and anhydrous tetrahydrofuran (THF, 25.0 mL, 0.308 mol) and the resulting mixture was chilled to 0-5° C. To a 100 ml oven dried round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol) and anhydrous tetrahydrofuran (50 mL, 0.616 mol), and the resulting slurry was added portion wise via large bore canula over 20 minutes to the sodium hydride (NaH) suspension in THF. The cooling bath was removed after the addition is complete and the reaction mixture was stirred at room temperature for 1 hour. The slurry becomes green in color after it is warmed to 16.5° C. The mixture was cooled to 0-5° C. before neat benzyl chloromethyl ether (5.28 mL, 0.0342 mol, 1.05 equiv) was charged over 13 minutes via syringe. The cold bath was removed and the reaction mixture was warmed to room temperature gradually and stirred at room temperature for 20 h. The reaction mixture was quenched with 20% aqueous brine (50 mL) and diluted with ethyl acetate (100 mL) when the reaction was deemed complete. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrate under reduced pressure. The residue was then purified by flash chromatography (SiO2, 10% to 15% ethyl acetate/hexane gradient elution) to afford 7-[(benzyloxy)methyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3e, 6.31 g, 8.92 g theoretical, 70.7%) as a green oil. For 3e: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.69 (s, 1H), 7.90 (d, 1H, J=3.7 Hz), 7.26 (m 5H), 6.71 (d, 1H, J=3.7 Hz), 5.75 (s 2H), 4.51 (s, 2H); C14H12ClN3O (MW, 273.72), LCMS (EI) m/e 274/276 (M++H).
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([C:16]#[N:17])=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([O:18][CH2:19][CH3:20])[CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:21]([CH2:2][C:3]1[C:15]([C:16]#[N:17])=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([O:18][CH2:19][CH3:20])[CH:4]=1)=[N+:22]=[N-:23]
Reactant: CCOc1cc(CBr)c(C#N)cc1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
After dissolving tert-butyl 4-(bromomethyl)-5-cyano-2-ethoxybenzoate (2.20 g, 70% purity) in dimethylformamide (25 ml), sodium azide (2.1 g) was added and the mixture was stirred at 50° C. for 30 minutes. It was then diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to yield the title compound (1.913 g).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:7]=2[N:8]=1)([OH:3])=[O:2].[CH2:14](O)[CH2:15][CH3:16]>S(=O)(=O)(O)O>[CH2:14]([O:2][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:7]=2[N:8]=1)=[O:3])[CH2:15][CH3:16]
Reactant: O=C(O)c1nc2cc(O)ccc2o1
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)c1nc2cc(O)ccc2o1

Procedure:
12.72 g (49.2 mmoles) of 2-carboxy-5-hydroxybenzoxazole is dissolved in 200 ml of n-propanol and 1 drop of concentrated sulfuric acid is added. The mixture is refluxed for 30 hours, concentrated. The resulting solid is suspended in water, neutralized with sodium bicarbonate and filtered, washing the solid with water, then drying. This gives n-propyl-5-hydroxybenzoxazole-2carboxylate which is purified by recrystallization from n-propanol/acetone or by HPLC.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.Cl.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([N:1]2[CH2:2][CH2:3][C:4](=[C:7]3[C:8]4[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=4[CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=4)[CH2:5][CH2:6]2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccncc1)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 0.15 g (0.6 m mole) of 10,11-dihydro-5-(4-piperidylidene)-5H-dibenzo[a,d]cycloheptene, 0.096 g (0.55 m mole) of 4-pyridylacetic acid hydrochloride, 0.16 g (0.83 m mole)of DEC and 0.075 g (0.55 m mole) of HOBT in 5 mL of DMF and stir at room temperature for 18 hours under nitrogen. Concentrate under vacuo and partition between 100 mL each of EtOAc and 10% aqueous sodium hydrogenphosphate. Dry the organic layer over MgSO4 and concentrate under vacuo. The resulting residue is chromatographed on silica gel using 98% dichloro methane and 2% MeOH, saturated with ammonia as the solvent, giving the product as a white waxy solid, mp=162.8°-163.4° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[C:21]([F:28])[CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4F)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (29 mg, 33%), MS (ISP) m/z=347.5 [(M+H)+], mp 221° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:12]=1[CH:13]=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[C:12]=1[CH:13]=[O:14]
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Reactant: Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(Oc2ccc(F)cc2Cl)cccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-chloro-4-fluoro-phenol (20.97 g, 143.10 mmol) and 2-fluoro-6-(trifluoromethyl)benzaldehyde (25 g, 130.1 mmol) in DMF (125.0 mL) was added Cs2CO3 (46.62 g, 143.1 mmol) and the reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (3×150 ml). The organics were combined, washed with water, brine (2×), dried over Na2SO4, filtered and evaporated to give a red oil which solidified after standing over night. The material was then triturated with hot hexanes and cooled to 25° C. The slurry was filtered and washed with cold hexanes to give 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (32.7 g, 79%) as an off white solid. 1H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 7.84-7.70 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 7.47 (dd, J=9.0, 5.3 Hz, 1H), 7.42-7.32 (m, 1H), 7.12 (d, J=8.3 Hz, 1H) ppm.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[N:19][C:18](N)=[N:17][CH:16]=2)=[N:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:22]C(Cl)C.N(OC(C)(C)C)=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[N:19][C:18]([Cl:22])=[N:17][CH:16]=2)=[N:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(-c2cnc(N)nn2)s1
Reactant: CC(Cl)Cl
Agent: CC(C)(C)ON=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: CC(C)(C)[Si](C)(C)OCc1cnc(-c2cnc(Cl)nn2)s1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a vial was added 6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)-1,2,4-triazin-3-amine (2.5 g, 10.7 mmol), tetrabutylammonium chloride (6.3 g, 27.7 mmol) and dichloroethane (25 mL). The mixture was heated to 75° C., followed by the addition of t-butyl nitrite (3.3 mL, 27.7 mmol). The reaction was stirred at 75° C. for 3 h, followed by cooling to rt, quenching with brine (200 mL). The reaction was extracted four times with CH2Cl2. The combined organic layers were dried over Na2SO4, concentrated, and purified using silica gel chromatography to afford the 1.1 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:6]=1.C(O)(C(F)(F)F)=O.ClC1[C:34]([Cl:35])=[CH:33][N:32]=[C:31]([NH2:36])[C:30]=1[N+:37]([O-:39])=[O:38]>C(Cl)Cl>[Cl:35][C:34]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH2:13][CH2:12]2)=[C:30]([N+:37]([O-:39])=[O:38])[C:31]([NH2:36])=[N:32][CH:33]=1
Reactant: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reaction time: 1 h
Yield: 49.1 %

Procedure:
tert-Butyl 4-((2-methylthiazol-4-yl)methyl)piperazine-1-carboxylate (0.380 g, 1.28 mmol, 1.1 eq) was dissolved in DCM (4 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (4 mL). Stirring was continued at this temperature for 1 h. Solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. 2-Methyl-4-(piperazin-1-ylmethyl)thiazole (supposedly 0.250 g, 1.28 mmol, 1.1 eq) was suspended in iPrOH (3.9 mL) and DIPEA (1 mL). To this solution, the 4,5-dichloro-3-nitropyridin-2-amine (0.240 g, 1.16 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.210 g, 44%); 1H-NMR (500 MHz, DMSO-d6): δ 2.52-2.59 (m, 4H, piperazine N(CH2)2), 2.63 (s, 3H, thiazole Me), 3.06 (m, 4H, piperazine N(CH2)2), 3.59 (s, 2H, NCH2), 6.94 (s, 2H, NH2), 7.28 (s, 1H, thiazole 5-H), 8.05 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): R=2.06 min—369/371 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (7.77 g, 25.3 mmol) in methanol (50 mL) was treated slowly with concentrated sulfuric acid (0.01 mL). The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (75 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (4×50 mL). The combined organic layers were dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid methyl ester (8.48 g, 87.5%) as yellow oil: EI-HRMS m/e calcd for C16H18F4O2 (M+) 318.1243, found 318.1240.