Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)[CH2:2][CH3:3].[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1](=[N:20][NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH3:3])[CH:6]=1
Reactant: CCC(=O)c1cccnc1
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: CCC(=NNC(=O)c1ccccc1)c1cccnc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of 6.76 gm (0.05 mole) of 3-propionylpyridine, 6.81 gm (0.05 mole) of benzhydrazide and 100 ml of absolute ethanol is refluxed 8.5 hr. The hot solution is filtered. The filtrate is cooled to room temperature and then chilled. The crystals that separate are collected and dried to yield 10.18 gm (80%) of the title compound having a melting point of 169.4° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.O.Cl.[NH:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:7][C:8]1[CH:9]=[C:10]([S:14]([N:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCN(S(=O)(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Yield: 97 %

Procedure:
Potassium carbonate (13.96 g, 101.1 mmol) and 3-chlorobenzenesulfonyl chloride were continuously added to a two-phase solution of 4-piperidone hydrochloride hydrate (6.06 g, 39.48 mmol) in chloroform (47.4 mL) and water (47.4 mL), and the mixture was stirred at room temperature. A saturated aqueous sodium bicarbonate solution was added, and the organic layer and the aqueous layer were separated. The aqueous layer was then further extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting solid was washed with n-hexane and then collected by filtration and dried under reduced pressure to give 1-(3-chloro-benzenesulfonyl)-piperidin-4-one as a white solid (10.5 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=O)[C:11]3[CH:23]=[C:24](F)[C:25](F)=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[C:38]([F:41])([F:40])[F:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=3[C:38]([F:39])([F:40])[F:41])=[O:16])[C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 22, int. d) from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-trifluoromethylbenzonitrile. The compound was purified by preparative HPLC using a Gemini column and a gradient of acetonitrile:water (containing 0.5% formic acid). Light brown foam (42%). MS (ES+): M+H: 537.3.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=5)[CH:3]=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ncccc1-c1cccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)n1
Temperature: 80 °C
Yield: 47 %

Procedure:
N-(6-Bromopyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxamide (38 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1 mL) in a reaction tube. 2-Methoxypyridin-3-ylboronic acid (18 mg, 0.12 mmol), 0.1 mL of an aqueous 2 M sodium carbonate solution, and Pd(dppf)Cl2 (5 mg, 0.01 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was filtered and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-2,3′-bipyridin-6-yl)cyclopropane carboxamide (20 mg, 50%). ESI-MS m/z calc. 425.1, found 426.1 (M+1)+. Retention time 1.93 minutes.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:29]([C:28]4[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:24][CH2:23][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH:27]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1cccc(OCCN2CCOCC2)c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCCN4CCOCC4)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.05 g, 4.73 mmol), 3-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.67 g) and xylenes (7 ml) was heated to 160° C. overnight. Additional aldehyde (0.4 g) was added and the mixture was heated at 160° C. until the reaction was complete. The reaction mixture was cooled to room temperature and a solid formed which was collected by filtration and washed with ether. The filtrate was concentrated to dryness and the residue was combined with the solid and was purified by column chromatography on silica gel eluting with ethyl acetate/ethanol (60/40). The solid product thus obtained was washed with ether, recrystallized from ethyl acetate and then washed with ether again to afford 1-cyclopentyl-3-ethyl-6-[3-[2-(4-morpholinyl)ethoxy]phenyl]-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 173-176° C.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:13]([OH:21])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1>C(N(CC)CC)C>[C:25]([O:21][CH:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:26])[CH2:24][C:23]([CH3:22])=[O:27]
Reactant: C=C1CC(=O)O1
Reactant: OC(CN1CCCCC1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OC(CN1CCCCC1)c1ccccc1
Yield: 106.2 %

Procedure:
To 130 ml of benzene are added 14.7 g of 1-phenyl-2-piperidinoethanol, 7.1 g of diketene and 1 ml of triethylamine. The mixture is refluxed under heating for three hours. The reaction mixture is concentrated under reduced pressure to give 22 g of 1-phenyl-2-piperidinoethyl acetoacetate. A mixture of 22 of 1-phenyl-2-piperidinoethyl acetoacetate, 10.6 g of m-nitrobenzaldehyde and 12.7 g of (2-furyl)methyl β-aminocrotonate in 130 ml of isopropanol is refluxed under heating for 12 hours. The reaction mixture is concentrated under reduced pressure. To the viscous jelly-like oily substance thus obtaned is added an ethanol solution of hydrogen chloride and then the mixture is concentrated. The viscous jelly-like residue is crystallized from a mixture solvent of acetone-ether. The precipitated crystals are collected by filtration, and recrystallized from a mixture solvent of acetone-methanol to give α-diastereoisomer of 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(2-furyl)methylester-5-(1-phenyl-2-piperidinoethyl)ester in the form of hydrochloride as yellow crystals melting at 219°-221° C. (decomposition).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH3:23])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:24](Br)(C)C>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH:22]([CH3:24])[CH3:23])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(C)Br
Reactant: CCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Product: CC(C)n1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Yield: 62 %

Procedure:
This compound was prepared in the manner described above for intermediate 5b by replacing ethylbromide with isopropylbromide (10.2 g, 83 mmol) in 62% yield (6.44 g) as a white solid: mp 114.5-116° C.; MS EI m/e 324 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([F:16])([F:15])[F:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[F:14][C:13]([F:15])([F:16])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(F)(F)F
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
To a stirred solution of 338 (294 mg, 1.209 mmol) in THF (10 mL) at 0° C. under nitrogen was added sequentially NMM (159.5 μL, 1.451 mmol) neat via syringe and ethyl chloroformate (138.7 μL, 1.451 mmol) neat by syringe. After 45 min the resulting suspension was filtered through GF/F filter paper with THF and the filtrate was isolated and stirred at 0° C. under nitrogen. A solution of NaBH4 (45.74 mg, 1.209 mmol) in H2O (2 mL) was added and the cooling bath was removed. After about 15 min, the reaction was concentrated and the residue was resuspended in Et2O (30 mL) and H2O (30 mL) with stirring. After stirring for 5 min the layers were separated and the organic phase washed brine (1×30 mL). The organic phase was (MgSO4), filtered and concentrated to afford 240 mg (86%) of tert-butyl 1,1,1-trifluoro-3-hydroxypropan-2-ylcarbamate (340) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH:13](B1OB(C=C)OB(C=C)O1)=[CH2:14].C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:13]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[CH2:14]
Reactant: O=C1NCCc2ccc(Br)cc21
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 7-bromo-3,4-dihydro-1(2H)-isoquinolinone (0.679 g, 3.004 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) in 1,2-dimethoxyethane (30 ml) was stirred at room temperature for 0.5 h before addition of 2,4,6-trivinylcyclotriboroxane.pyridine complex (for a synthesis see Kerins, Fergal; O'Shea, Donal F. J. Org. Chem. (2002), 67(14), 4968) (295 mg, 1.218 mmol), K2CO3 (415 mg, 3.004 mmol) and water (10 ml). The reaction was heated at reflux for 1.5 h before cooling to room temperature and addition of water (50 ml). The mixture was extracted with 10% methanol/dichloromethane (3×100 ml), the organic layers were dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% ethyl acetate/hexane, gave the product (456 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2(C#N)[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[CH2:9][CH2:8]2)=[CH:17][CH:18]=1
Reactant: CC1(C)CCC(C#N)(Cc2ccc(Cl)cc2)C1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 140 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
A suspension of 5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone (5.0 g, 0.02 mole) in water is treated with sulfuric acid (50%, 25 ml), stirred for 5 hours at 140° C., cooled to room temperature, and extracted with toluene. The extracts are combined, washed with water, filtered through celite and concentrated in vacuo to afford the title product as a dark oil, 5.5 g (76.5% pure, 93.1% yield), identified by gas chromatography.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.Cl.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32]>>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[C:27](=[O:32])[CH2:28]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CN1CCNCC1=O
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: Cl
Product: CC(c1cc2cccnc2cc1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12

Procedure:
The title compound was prepared in analogy to Example 38 using (rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)ethyl]-7-fluoro-quinoline (Intermediate K, 50 mg, 0.153 mmol), 1-methylpiperazin-2-one hydrochloride (46.1 mg, 0.306 mmol) (tR 3.24 min (conditions 5), MH+=404, 1H-NMR in DMSO-d6: 8.83 (d, 1H); 8.28 (d, 1H); 7.84 (s, 1H); 7.81 (d, 1H); 7.72 (d, 1H); 7.56 (s, 1H); 7.43 (m, 1H); 7.11 (d, 1H); 4.88 (m, 1H); 3.98 (d, 1H); 3.83 (m, 1H); 3.25 (m, 2H); 2.77 (s, 3H); 1.78 (d, 3H)).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[H-].[Na+].Br[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CS(C)=O.C(OCC)(=O)C>[CH:11]1([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH:6]=[O:7])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc[nH]1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1cccn1C1CCCC1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (12.0 g) in DMSO (252 mL) was added sodium hydride (55% dispersion in mineral oil, 8.26 g) at 0° C., and the mixture was stirred for 30 min. To the reaction mixture was added bromocyclopentane (22.6 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (500 mL), and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (9.34 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:39])([F:38])[C:13]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:33][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)([OH:32])[C:12]([F:11])([F:39])[F:38])=[O:6]
Reactant: O=C(O)c1ccccc1F
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)[C:5]([Cl:28])=[CH:4][N:3]=1.Cl.CCOCC>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:13][CH:14]=2)[C:5]([Cl:28])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3nc(Cl)ncc3Cl)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Clc1ncc(Cl)c(Nc2ccc([C@H]3CNCCO3)cc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 198.3 %

Procedure:
(S)-tert-Butyl 2-(4-(2,5-dichloropyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (45 mg, 0.106 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4 M, 0.3 ml, 1.27 mmol) was added. The reaction mixture was stirred at 60° C. for 2 hours. After cooling, ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2,5-dichloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-4-amine hydrochloride (38 mg, 99%) as a white solid. MS (ISP): 325.1 ([{35Cl}M+H]+), 327.1 ([{37Cl}M+H]+).
Reaction SMILES: C1(C[O:8][C:9](=[O:63])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:30])[CH:26]=[C:25]([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:47])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1>[Pd].C(OCC)(=O)C.C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:30])[CH:26]=[C:25]([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:47])[CH:24]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:63])=[O:8]
Reactant: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 0.43 g of N-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.2 g of 10% palladium on carbon in 30 ml of ethyl acetate and 20 ml of THF was shaken under an initial hydrogen pressure of 51 psi for 2 hours. The catalyst was removed by filtration andthe filtrate was concentrated at reduced pressure to a solid which was recrystallized from methanol-water to give 0.28 g (82% yield, mp 84°-87°) of N-(carboxy-methyl)-N-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]glycine.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]3)[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:25])=O.[OH-].[Na+]>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:25])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: CC1CN(c2ccc3nc(N)c(C#N)c(O)c3c2)CC(C)O1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1CN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC(C)O1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
The mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6-(2,6-dimethylmorpholin-4-yl)quinoline and 3.4 ml of phosphoryl chloride is stirred at 120° C. for 4 hours. The cooled reaction mixture is poured onto 30 g of ice, the pH of the mixture is adjusted to 8 with 10% sodium hydroxide solution, and the precipitated material is filtered off. After drying 1.5 g of the title compound is obtained (MH+: 317).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:21]2[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26]2)[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(NS(C)(=O)=O)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(NS(C)(=O)=O)cc2)CC(C)(C)C1
Temperature: -2.5 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of N-{4-[(4-methoxy-phenyl)-(3,3,5,5-tetramethyl-cyclohexylidene)-methyl]-phenyl}-methanesulfonamide (180) (0.25 g, 0.585 mmol) in dry dichloromethane (20 mL) was slowly added BBr3 (1 N in dichloromethane) (1.75 mL, 1.75 mmol) at −5 to 0° C. The reaction mixture was stirred at −5 to 0° C. under nitrogen for 3 h. The reaction mixture was poured onto ice and stirred for several minutes. The quenched reaction mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc and the organic extracts were combined, washed with brine, dried over MgSO4, filtered, and concentrated to give an off white solid. The solid was triturated with hexanes followed by dichloromethane. The product was filtered, washed with methanol, and dried to give 0.174 g (72%) of compound 181 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 12H), 1.23 (s, 2H), 1.86 (s, 2H), 1.89 (s, 2H), 2.94 (s, 3H), 6.64 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 7.06 (s, 2H), 7.07 (s, 2H), 9.25 (s, 1H), 9.64 (s, 1H). HRMS (ESI) calcd for C24H30NO3S: 412.1946 (M−H)−. Found: 412.1942.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pt].CO.C1COCC1>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:3][C:2]=1[Cl:1]
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(N)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 95 %

Procedure:
A solution of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.500 g, 0.870 mmol) in 3:1 MeOH/THF (30 mL) was subjected to hydrogenation at 45 psi in the presence of 5% sulfided platinum on carbon (50 mg). After 18 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through celite and the filtrate concentrated to dryness at reduced pressure. The residue was recrystallized from hexane/EtOAc to afford the title compound (0.45 g, 95%) as an off-white solid. LCMS (m/z, ES+)=544 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:15]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[CH:34]=3)(=[O:32])=[O:31])([CH:17]3[CH2:29][C:20]4[NH:21][C:22]5[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][C:27]=5[C:19]=4[CH2:18]3)[F:16])=[N:13][N:14]=2)=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Br:39][C:35]1[CH:34]=[C:33]([S:30]([C:15]([CH:17]2[CH2:29][C:20]3[NH:21][C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][C:27]=4[C:19]=3[CH2:18]2)([F:16])[C:12]2[O:11][C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=3)=[N:14][N:13]=2)(=[O:32])=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(-c2nnc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3cccc(Br)c3)o2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(Br)c1)C(F)(c1nnc(-c2ccc(CO)cc2)o1)C1Cc2[nH]c3ccc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 12 mg (0.02 mmol) of (RS, SR) 4-[5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,3,4]oxadiazol-2-yl}-benzoic acid methyl ester in 0.5 mL of THF was treated with 3 mg (0.08 mmol) of lithium aluminiumhydride and stirred at RT for one hour. The mixture was treated with a mixture of ice cubes and water and extracted twice with dichlormothane. Drying of the combined organic phases over Na2SO4, filtration and evaporation gave 10 mg (86%) of (RS, SR) (4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,3,4]oxadiazol-2-yl}-phenyl)-methanol as a yellow solid, MS: 618 (MH+, 1Br).