Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:11][C:12]#[N:13]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]#[N:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: N#CCBr
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 1-Isopropyl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=168.1; 1HNMR(DMSO-d6) 3.70 (s, 2H), 2.70-2.40 (m, 9H), 0.95 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]([N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][N:20](C(=O)C(F)(F)F)[CH2:19][CH2:18]4)[CH2:14]3)=[O:12])[S:7][C:6]=2[CH:29]=1>CCN(CC)CC.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]([N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH2:14]3)=[O:12])[S:7][C:6]=2[CH:29]=1
Reactant: O=C(c1sc2cc(Br)ccc2c1Cl)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(c1sc2cc(Br)ccc2c1Cl)N1CC(N2CCNCC2)C1

Procedure:
A solution of compound 11b (0.3 g, 0.59 mmol) in Et3N (1 mL) and MeOH (9 mL) was stirred at room temperature for 3 days. It was then concentrated to give compound 11c, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:31])[C@@H:12]([NH:20][C:21](=[O:30])[C@H:22]([NH2:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.[O:41]=[C:42](Cl)OC(Cl)(Cl)Cl>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:31])[C@@H:12]([N:20]2[C:21](=[O:30])[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:29][C:42]2=[O:41])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](N)c2ccccc2)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)N2C(=O)N[C@H](c3ccccc3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
A solution of 2-[(S)-2-((R)-2-amino-2-phenyl-acetylamino)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid methyl ester (0.795 g, 1.82 mmol) and diisopropylethylamine (1.10 mL, 6.2 mmol) in tetrahydrofuran (20 mL) was added to a solution of diphosgene (0.151 μL, 1.27 mmol) in a mixture of toluene (20 mL) and tetrahydrofuran (20 mL) over 10 minute at 0° C. The mixture was stirred at 0° C. for 20 minute then diluted with ethyl acetate. The mixture was washed with water, brine and dried over sodium sulfate. Evaporation of the solvents and purification of the residue by chromatography over silica gel gradient eluted between 0.2 and 1.2% v/v methanol in dichloromethane followed by recrystallization of the isolated product from acetonitrile gave 2-[(S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidin-1-yl)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid methyl ester as a white crystalline solid (166 mg, 20%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:18]([NH2:20])=[O:19].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CCO.N1CCCCC1>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:18]([NH2:20])=[O:19])=[C:2]([N:1]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=3)[NH:6][N:5]=2)=[CH:13][CH:12]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1

Procedure:
5-amino-3-((4-(tert-butyl)phenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-(tert-butyl)phenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[NH2:15][C@@:16]12[CH2:23][C:22](=[CH2:24])[CH2:21][C@@H:20]1[C:19](=O)[N:18]([C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:17]2.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:15][C@@:16]12[CH2:23][C:22](=[CH2:24])[CH2:21][C@@H:20]1[CH2:19][N:18]([C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:17]2
Reactant: C=C1C[C@@H]2C(=O)N([C@H](C)c3ccccc3)C[C@]2(N)C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C1C[C@@H]2CN([C@H](C)c3ccccc3)C[C@]2(N)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
A 65% solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (0.539 ml, 1.79 mmol) was added to a solution of (1S,5S)-1-amino-7-methylene-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (115 mg, 0.449 mmol) in toluene (2.24 ml), and the mixture was stirred at room temperature for 30 minutes and at 80° C. for 30 minutes. A 5 mol/l sodium hydroxide solution (15.0 ml) was added to the reaction solution with stirring under ice-cooling, followed by extraction with toluene (30 ml×1, 20 ml×1). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 106 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[CH:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:58]([O:60][CH2:61][CH3:62])=[CH2:59])CCC>O1CCOCC1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:61]([O:60][C:58]([C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[CH:10]=2)[C:5]([F:8])=[N:6][CH:7]=1)=[CH2:59])[CH3:62]
Reactant: Cc1nc(N)cc(-c2cc(Cl)cnc2F)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: C=C(OCC)c1cnc(F)c(-c2cc(N)nc(C)n2)c1
Temperature: 120 °C
Yield: 79.8 %

Procedure:
To a 5 mL microwave reaction tube was added 6-(5-chloro-2-fluoropyridin-3-yl)-2-methylpyrimidin-4-amine (227 mg, 0.95 mmol), palladium acetate (10 mg, 0.048 mmol), X-phos (40 mg, 0.09 mmol), cesium fluoride (433 mg, 2.85 mmol) and tributyl(1-ethoxyvinyl)stannane (0.45 mL, 1.33 mmol) in 1,4-dioxane (4 mL) and DMF (1 mL). The glass tube was sealed and heated in a microwave at 120° C. for 1 h. The reaction mixture was passed through a short path of neutral alumina column, eluted with 50 mL of DCM followed by 150 mL of EtOAc and 50 mL of 5% MeOH in EtOAc. The desired fractions were collected, concentrated to give 6-(5-(1-ethoxyvinyl)-2-fluoropyridin-3-yl)-2-methylpyrimidin-4-amine (208 mg, 80% yield) as an off white crystalline solid. m/z (ESI, positive ion) 275.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=1.[OH-].[Na+]>>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:27][CH:26]=1)(=[O:32])[CH:29]([CH3:31])[CH3:30]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: CC(C)C(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)C(C)C)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 1-(4-Hydroxy-phenyl)-2-methyl-propan-1-one from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C23H28O6 [M+NH4]+: 423 [M+H]+: 401.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][CH:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:17]([CH2:18][CH:19]([OH:21])[CH3:20])[C:5]=32)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.94 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.7 g (71%) of (RS)-1-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a solid with m.p. 76°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]2[C@@H:19]([CH2:20][CH2:21][OH:22])[O:18][CH2:17][CH2:16][N:15]2[C:23]([CH:25]2[CH2:28][CH2:27][CH2:26]2)=[O:24])[CH:10]=[CH:11][C:12]=1[Cl:13].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][S:2]([O:22][CH2:21][CH2:20][C@H:19]1[O:18][CH2:17][CH2:16][N:15]([C:23]([CH:25]2[CH2:26][CH2:27][CH2:28]2)=[O:24])[CH:14]1[C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)(=[O:4])=[O:3]
Reactant: O=C(C1CCC1)N1CCO[C@H](CCO)C1c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC[C@H]1OCCN(C(=O)C2CCC2)C1c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Methanesulfonyl chloride (0.071 ml, 0.92 mmol) and 4-dimethylaminopyridine (catalytic amount) were added to a solution of 2-[(2R)-(3,4-dichlorophenyl)-4-(cyclobutanecarbonyl)morpholin-2-yl]ethanol (219 mg, 0.61 mmol), which was prepared in Example 1(a), in pyridine (2 ml) with ice-cooling under a nitrogen atmosphere. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was acidified with ice-cooled hydrochloric acid (10%) and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography using n-hexane/ethyl acetate=¼ as a developing solvent to afford the desired compound (255 mg, 96%) as a white amorphous solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[C:17]2[CH:18]=[C:19]([CH3:21])[O:20][C:16]=2[CH:15]=[CH:14][C:13]=1[OH:22])([CH3:11])([CH3:10])[CH3:9]>C([SiH](CC)CC)C>[C:8]([C:12]1[C:17]2[CH2:18][CH:19]([CH3:21])[O:20][C:16]=2[CH:15]=[CH:14][C:13]=1[OH:22])([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2c(ccc(O)c2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
Under ice-cooling, 1.4 ml of trifluoroacetic acid was added dropwise to 0.25 g of 4-t-butyl-5-hydroxy-2-methylbenzofuran in 2.8 ml of triethylsilane. After stirring at 0° C. for 15 minutes and then at room temperature for 18 hours, the mixture was poured into ice water and extracted with ethyl acetate. The extracted layers were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 20% ethyl acetate) to give 0.18 g of 4-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran as a white crystal (yield 74%).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20].C(I)C=C>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:19]([O:21][C:22]([C:24]1([CH2:7][CH:5]=[CH2:6])[CH2:29][CH2:28][CH:27]([O:30][Si:31]([C:44]([CH3:45])([CH3:47])[CH3:46])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: CC(C)NC(C)C
Agent: C=CCI
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
Diisopropylamine (3.14 g, 4.38 mL, 31 mmol) was dissolved in THF (100 mL) and cooled to −78° C. To this solution was added 2.5 M n-butyl lithium in hexane (12.4 mL, 31 mmol) and stirred for 15 min, warmed up to 0° C. and stirred for an additional min, then re-cooled to −78° C. 4-(tert-Butyl-diphenyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (10.5 g, 25.6 mmol) in THF (15 mL) was then added and the reaction mixture was allowed to stir at −78° C. for 1 h followed by the addition of a mixture of hexamethyl-phosphoramide (HMPA) (7 mL) and allyl iodide (5.59 g, 33.3.0 mmol). This mixture was stirred at −78° C. for 20 min. Then, the dry ice bath was removed and the stirring was continued to allow the reaction mixture to warm to room temperature over 1 h. The reaction mixture was poured into ice-water (100 mL) and ether (50 mL). The two layers were separated; the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to afford 11.4 g (99%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:37])=[C:5]([C:28]([O:35]C)=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:32][O:31][C:30]1[C:3](=[O:2])[C:4]([CH3:37])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])[C:28](=[O:35])[C:29]=1[O:33][CH3:34]
Reactant: COc1c(C)c(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 1397.6 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyloxy)benzoyl]piperidine (0.021 g, 0.0415 mmol) was dissolved in a mixed solution of acetonitrile (6 ml) and water (2 ml) and after adding thereto CAN (0.057 g, 0.104 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.013 g, 0.580 mmol, 66%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[C:16]([NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:27]3[CH2:26][CH2:25][CH:24]([NH:23][C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:29][CH2:28]3)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)C3CC3)cc2[N+](=O)[O-])CC1
Yield: 95 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrophenyl cyclopropyl ketone (1.0 eq), 4-(N-Boc-amino)piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 1-(4-(cyclopropanecarbonyl)-2-nitrophenyl)piperidin-4-ylcarbamate (95%). LCMS (m/z): 390.1 (MH+); LC Rt=3.25 min.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[C:9]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:7]=[C:6]([F:16])[C:5]=1[CH2:17]Br.CCN(CC)CC.[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([C@H:38]([NH2:44])[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH3:28]>CN(C=O)C>[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([C@H:38]([N:44]2[C:3](=[O:19])[C:4]3[C:5](=[C:6]([F:16])[CH:7]=[CH:8][C:9]=3[NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH2:17]2)[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH3:28]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(F)c1CBr
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(F)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 54.4 %

Procedure:
To a solution of 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-3-fluoro benzoic acid methyl ester (1 g, 3 mmol) and Et3N (1.25 ml, 9 mmol) in DMF (10 ml) was added (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (870 mg, 3.2 mmol). The mixture was heated at 90° C. for 20 hrs. The reaction mixture was cooled to room temperature and extracted with water (50 ml) and EtOAc (50 ml). The organic layer washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give (1S)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (800 mg, 55% yield): mp, 176-178° C.; 1H NMR (CDCl3) δ 0.88-0.92 (m, 2H, c-propylCH2), 1.09-1.12 (m, 2H, c-propylCH2), 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 1.64-1.68 (m, 1H, c-propylCH), 2.98 (s, 3H, CH3), 3.63-3.73 (m, 1H, CHHSO2), 3.87 (s, 3H, CH3), 4.05-4.28 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.49 (d, J=18 Hz, 1H, C), 6.85-6.92 (m, 1H, NCH), 6.86-6.93 (m, 3H, Ar), 7.04 (t, J=8 Hz, 1H, Ar), 8.45-8.55 (m, 1H, Ar), 10.32 (s, 1H, NHCO); 13C NMR (CDCl3) δ 8.26, 8.27, 14.67, 16.04, 41.50, 44.67, 51.30, 55.39, 55.96, 64.65, 111.63, 112.21, 118.95, 119.26, 119.68, 119.92, 126.43, 126.74, 128.99, 134.48, 134.53, 148.98, 149.88, 150.31, 154.22, 168.89, 172.39. Anal Calcd for C24H27FN2O6S: C, 58.76; H, 5.55; N, 5.71. Found: C, 58.60; H, 5.33; N, 5.65.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1N2CN3CN(C2)CN1C3.[C:20](O)(=[O:22])C>O>[NH:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([CH:20]=[O:22])=[CH:2]1
Reactant: CC(=O)O
Reactant: c1cnc2[nH]ccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncccc12
Temperature: 25 °C

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (94, 16.0 g, 135 mmol) in water (110 mL), were added hexamethylenetetramine (26.0 g, 185 mmol), and acetic acid (55.0 mL, 967 mmol). The reaction was refluxed for 12 hours. Water (329 mL) was added and the reaction was cooled to room temperature. The reaction was filtrated and washed with water to give the compound (95, 15.0 g, 76%). MS(ESI)[M+H+]+=147.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:24])[NH:17][C@@H:18]([CH3:23])[C:19]([NH:21][NH2:22])=[O:20])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:24])[NH:17][C@@H:18]([CH3:23])[C:19]([NH:21][NH:22][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:20])([CH3:14])([CH3:12])[CH3:13]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
4-Chlorobenzoyl chloride (0.63 mL, 4.92 mmol, 1.0 equiv) was added to a solution of (S)-tert-butyl(1-hydrazinyl-1-oxopropan-2-yl)carbamate (1.0 g, 4.92 mmol) in DCM (25 mL) at 0° C. A white precipitate formed. The mixture was stirred at 0° C. for 1 hour and the reaction mixture was then concentrated in vacuo to give crude (S)-tert-butyl(1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (1.55 g), which was used without purification. 1H NMR (400 MHz, CD3OD) δ 7.85 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 4.21 (q, J=7.0 Hz, 1H), 1.45 (s, 9H), 1.41 (d, J=7.2 Hz, 3H). MS m/z 342.1 (M+H)+; Rt-0.69 min.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([F:20])=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C>C(O)=O>[CH:6]([OH:7])=[O:5].[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][O:21][C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[N:18][C:17]=1[F:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(F)c(OCc3cccc(Cl)c3)n2)CC1
Solvent: O=CO
Product: Fc1ncc(N2CCNCC2)nc1OCc1cccc(Cl)c1

Procedure:
A solution of 6′-(3-chloro-benzyloxy)-5′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (I-3i) (50 mg, 0.12 mmol) in formic acid (96%, 0.5 ml) was stirred at room temperature for 2 h, and concentrated in vacuo. The residue was triturated three times with ether. The title compound 3-I was collected as a white solid (15 mg, 34%). MS (ES+) Calc: 322.1, Found: 323.4 (M+1).
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:35][C:34](=[O:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:35][CH:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)=[CH:22][CH:21]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1ccc(Cl)cc1)O2

Procedure:
2-(4-Chlorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 375 mg of 2-(4-chlorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.84 (s, 1H), 7.49-7.44 (m, 4H), 6.88 (d, 1H, J 2.8 Hz), 6.60 (d, 1H, J 8.6 Hz), 6.55 (dd, 1H, J 8.6, 2.8 Hz), 5.43 (bs, 1H), 5.14 (dd, 1H, J 11.9, 1.6 Hz), 4.87 (m, 1H), 2.26 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.O.NN.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: OCCc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(-c2ccc(CCO)cc2)c1

Procedure:
20 g (99 mmol) of 2-(4-bromophenyl)ethanol, 20 g (72 mmol) of sodium metaborate octahydrate and 2.0 g (2.8 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 30 ml of THF and 120 ml of water, and, after addition of 0.03 ml of hydrazine hydrate, a solution of 15.5 g (85 mmol) of 3,5-dimethoxybenzeneboronic acid in 60 ml of THF is added dropwise. The batch is heated under reflux overnight and subsequently extracted four times with dichloromethane. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is chromatographed on silica gel with heptane/ethyl acetate (2:1), giving 2-(3′,5′-dimethoxybiphenyl-4-yl)ethanol as a colourless solid.