Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:8]=1.Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1.O>CS(C)=O>[Br:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH:6]=[C:7]([NH:9][CH2:10][C:11]([F:13])([F:14])[F:12])[CH:8]=1
Reactant: Nc1cc(Br)cc(NCC(F)(F)F)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)CNc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
Aqueous HCl (1.0 M, 1.5 mL, 1.5 mmol) was added to a stirred mixture of the product of Step 2 (0.80 g, 2.97 mmol) and 2-chloro-4-trifluoromethylpyrimidine (8.0 mL, 66.2 mmol) in DMSO and the mixture was stirred at 100° C. for 2 h. The mixture was cooled, water was added and the mixture was extracted with Et2O (3×). The combined organic fractions were washed with HCl, water, aqueous copper sulfate and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (0-60% ethyl acetate in hexanes) to give 5-bromo-N-(2,2,2-trifluoroethyl)-N′-[4-(trifluoromethyl)-pyrimidin-2-yl]benzene-1,3-diamine (622 mg, 1.50 mmol, 50% yield) as a off-white solid. MS ESI: [M+H]+ m/z 416.9.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([C:16]([OH:18])=O)[CH:7]=1)[CH3:4])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:59][C:58]([CH2:82][C:83]#[N:84])([N:60]3[CH:64]=[C:63]([C:65]4[C:66]5[CH:73]=[CH:72][N:71](COCC[Si](C)(C)C)[C:67]=5[N:68]=[CH:69][N:70]=4)[CH:62]=[N:61]3)[CH2:57]2)[CH2:52][CH2:51]1>O1CCCC1>[CH2:1]([N:3]([CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[N:9]=[C:8]([C:16]([N:50]2[CH2:51][CH2:52][CH:53]([N:56]3[CH2:57][C:58]([CH2:82][C:83]#[N:84])([N:60]4[CH:64]=[C:63]([C:65]5[C:66]6[CH:73]=[CH:72][NH:71][C:67]=6[N:68]=[CH:69][N:70]=5)[CH:62]=[N:61]4)[CH2:59]3)[CH2:54][CH2:55]2)=[O:18])[CH:7]=1)[CH3:4])[CH3:2]
Reactant: CCN(C)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reaction time: 1 h

Procedure:
After prestirring a mixture of 6-{[ethyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (40.1 mg, 0.152 mmol, from Step A), triethylamine (56.6 μL, 0.406 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (54.0 mg, 0.142 mmol) in tetrahydrofuran (1.1 mL) for 30 minutes, {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (50.0 mg, 0.101 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added and the reaction stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate, filtered and concentrated. The product was deprotected by stirring first in a 1:1 mixture of DCM:TFA for 1 hour, followed by evaporation and stirring with ethylenediamine (0.2 mL) in methanol (1 mL) until deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product. Yield: 0.025 g (41%); LC-MS: 608.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.61 (d, 1H), 7.06 (d, 1H), 4.11-4.02 (m, 1H), 3.78-3.71 (m, 4H), 3.63-3.48 (m, 5H), 3.32-3.21 (m, 1H), 3.17-3.07 (m, 1H), 2.62-2.53 (m, 1H), 2.48 (q, 2H), 2.21 (s, 3H), 1.84-1.74 (m, 1H), 1.70-1.61 (m, 1H), 1.37-1.18 (m, 2H), 1.03 (t, 3H). 19F NMR (400 MHz, DMSO-d6): δ −69.45 (s, 3F).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1O)CCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OCc1ccccc1)CCC2=O

Procedure:
The mixture of 5-Hydroxy-6-methoxy-indan-1-one (2.1 g), K2CO3 (3.3 g), acetone (30 ml) and benzyl bromide was heated to reflux for 5 hours. The mixture was filtered and the filtrate was evaporated to oil. The oil was treated with diethyl ether (50 ml) and the solid was collected to give 5-Benzyloxy-6-methoxy-indan-1-one (3 g). LC-MS: m/e 269 (MH+).
Reaction SMILES: CC(C)N=C=NC(C)C.F[C@H]([C@@H](F)CCCCC)CO[C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][Si:31]([CH3:54])([CH3:53])[CH2:32][CH2:33][C:34]([F:52])([F:51])[C:35]([F:50])([F:49])[C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])=[CH:22][CH:21]=2)=[N:18][CH:19]=1.[CH2:62]([C@H:67]1[CH2:72][CH2:71][C@H:70]([C:73]([OH:75])=[O:74])[CH2:69][CH2:68]1)[CH2:63][CH2:64][CH2:65][CH3:66]>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:54][Si:31]([CH3:53])([CH2:32][CH2:33][C:34]([F:52])([F:51])[C:35]([F:49])([F:50])[C:36]([F:47])([F:48])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])[CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[N:16]=[CH:15][C:14]([O:74][C:73]([C@H:70]3[CH2:69][CH2:68][C@H:67]([CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:72][CH2:71]3)=[O:75])=[CH:19][N:18]=2)=[CH:21][CH:22]=1
Reactant: CCCCC[C@H](F)[C@@H](F)COc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2cnc(-c3ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of DIC (0.061 g, 0.48 mmol) in ethyl acetate (3.0 ml) was added dropwise to a stirred solution of compound 48 (0.261 g, 0.400 mmol), trans-4-pentylcyclohexanecarboxlic acid (0.095 g, 0.480 mmol) and DMAP (4.90 mg, 0.04 mmol) in ethyl acetate (3.0 ml). The reaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1)] to give a colorless solid, which recrystallized acetonitrile to yield colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=O)=[C:4]([OH:26])[CH:3]=1)=[O:9].O.[NH2:28][NH2:29]>C(O)C>[N:28](=[CH:24][C:5]1[C:6]2[O:17][C:16]3[C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]([O:21][CH3:22])=[C:12]([CH3:23])[C:11]=3[O:10][C:8](=[O:9])[C:7]=2[C:2]([CH3:1])=[CH:3][C:4]=1[OH:26])[NH2:29]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=NN)c1O2

Procedure:
To a stirring solution of psoromic acid (1 mmol) in ethanol (25 mL) was added hydrazine hydrate (1 mmol). The reaction was stirred for half an hour and monitored by TLC. Upon completion, all of the solvent was removed by rotary evaporation. The residue was redissolved in ethanol and dried over anhydrous magnesium sulfate, filtered, and evaporated by a rotary evaporator to yield a white solid product.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25](Cl)=[O:26])=[CH:22][C:21]=2[CH:28]=1.CO>C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:25]([C:23]1[O:24][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:28][C:21]=2[CH:22]=1)=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C(Cl)c1cc2cc(Br)ccc2o1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(c1cc2cc(Br)ccc2o1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A solution of 50 ml of toluene and 7.9 g of dibenzylamine are added dropwise with stirring at 50-60° C. in the course of 10 min. to 5.2 g of 5-bromobenzofuran-2-carbonyl chloride in 100 ml of toluene. A colourless solid is obtained. After dropwise addition is complete, the mixture is additionally stirred at 100-110° C. for a further 3 hours. After cooling to 10° C., the solid product (dibenzylammonium chloride) is filtered off with suction. The filtrate is then treated with a mixture of 150 ml of water and 10 g of sodium carbonate and thoroughly shaken. The organic phase is separated off, washed again with 100 ml of water, dried using sodium sulfate and filtered. The, filtrate is concentrated on a Rotavapor in vacuo to a residue (residue: 9.5 g). After recrystallization from 100 ml of methanol, 6.5 g of product (yield 77%) remain after isolation.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[C:17]1([Mg]Cl)[CH:22]=[CH:21]C=[CH:19][CH:18]=1.[Cl-].[NH4+].O>C1COCC1.C(OCC)C>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN(C)C(c1ccccc1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (23.56 g, 105 mmol) in abs. THF (100 ml) was added dropwise, under argon and while cooling with ice, to a 25% solution of phenylmagnesium chloride (144 ml, 262.5 mmol) in THF, and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (100 ml) and water (100 ml) were added, while cooling with ice, and extraction with diethyl ether (3×100 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=O)[CH:14]=[C:13]([O:18]CC)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].Cl.C(OCC)(=O)C>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:12][C:13](=[O:18])[CH:14]=[CH:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC1=CC(=O)CC(c2ccc(OC)c(OC)c2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C2CC=CC(=O)C2)cc1OC
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 48.2 %

Procedure:
5-(3,4-Dimethoxyphenyl)-3-ethoxy-2-cyclohexen-1-one (16.7 g) was dissolved in ethanol (260 ml), and then sodium borohydride (6.88 g) was gradually added and the mixture was stirred at 60° C. for 1.5 hours. After distilling off the reaction solvent under reduced pressure, and subsequent pouring over of ice water, extraction with ethyl acetate and drying with anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure to produce a yellow oily substance. The oily substance was dissolved in ethyl acetate (20 ml), 4 N HCl-ethyl acetate solution (50 ml) was added and the mixture was stirred at room temperature for 13 hours. The reaction solution was washed with saturated sodium bicarbonate water and saturated saline and dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure to produce a yellow oily substance which was then purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1). The resulting crystals were washed with diethyl ether to give 6.76 g of 5-(3,4-dimethoxyphenyl)-2-cyclohexen-1-one (48.1%).
Reaction SMILES: [CH:1]1([NH:4][CH:5]([C:7]2[CH:8]=[C:9]([C:15]#[C:16][CH2:17][NH:18][C:19](=[O:22])[O:20][CH3:21])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH3:6])[CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([C:36](O)=[O:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH:1]1([N:4]([CH:5]([C:7]2[CH:12]=[N:11][C:10]([O:13][CH3:14])=[C:9]([C:15]#[C:16][CH2:17][NH:18][C:19]([O:20][CH3:21])=[O:22])[CH:8]=2)[CH3:6])[C:36]([C@@H:32]2[O:33][CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31]2)=[O:37])[CH2:3][CH2:2]1
Reactant: COC(=O)NCC#Cc1cc(C(C)NC2CC2)cnc1OC
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Product: COC(=O)NCC#Cc1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cnc1OC

Procedure:
Methyl (3-{5-[1-(cyclopropylamino)ethyl]-2-methoxypyridin-3-yl}prop-2-yn-1-yl)carbamate and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid were treated in the similar manner to Example 162 to give tert-butyl (2R)-2-({cyclopropyl[1-(6-methoxy-5-{3-[(methoxycarbonyl)amino]prop-1-yn-1-yl}pyridin-3-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(296-4)] as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][CH3:39]>>[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][N:38]([C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1)[CH3:39]
Reactant: CNCCCN(C)C
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(Cl)c1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(N(C)CCCN(C)C)c1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 56% yield; Mass Spectrum: M+H+ 532.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:22]2[NH:30][C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][O:19]CC)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH2:17][CH2:18][OH:19])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[C:22]2[NH:30][C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCCS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(CCO)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-ethyl}-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 90, 680 mg, 1.6 mmol) in dichloromethane (20 mL) at 0° C. was added a solution of boron tribromide (0.76 ml, 8.0 mmol) in dichloromethane (10 ml). The mixture was stirred at 0° C. for 1 h. The reaction was quenched with a saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (2×50 mL), washed with a saturated aqueous sodium bicarbonate solution (3×20 mL) and brine (3×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded (2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzenesulfonyl}-ethanol (600 mg, 94%): LC/MS m/e calcd for C22H26N2O3S [M+H]+ 399.53, observed 399.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J=4.0 Hz, 1H), 7.85-7.93 (m, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.06 (dd, J=7.7, 4.9 Hz, 1H), 6.41 (s, 1H), 4.33 (t, J=7.8 Hz, 1H), 3.85 (t, J=6.2 Hz, 2H), 3.35-3.46 (m, 2H), 2.26-2.34 (m, 1H), 2.04-2.21 (m, 1H), 1.60-1.88 (m, 4H), 1.44-1.57 (m, 2H), 1.18-1.35 (m, 3H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10](OC)(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>CCCCCC>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13])[CH3:2]
Reactant: CCCCC(CC)CN
Reactant: C/C=C/C(=O)OC
Solvent: CCCCCC
Product: C/C=C/C(=O)NCC(CC)CCCC
Yield: 72 %

Procedure:
In a flask, 2.6 g (0.02 mol) of 2-ethylhexylamine and 1.0 g (0.01 mol) of methyl crotonate were admitted and refluxed for 6 hours. The reaction mixture was dissolved in n-hexane, washed first with diluted hydrochloric acid and then with 10% sodium hydroxide solution, and subsequently dried with sodium sulfate. The residue was recrystallized from n-hexane, obtaining 1.42 g of N-(2-ethylhexyl)-crotonamide (yield: 72.1%). Usual analysis was carried out to identify the compound. The results are shown below.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][N:28]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][N:28]=3)[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: O=C(Nc1ccccc1)c1ccnc(Br)c1
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3ccccc3)ccn1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 2-bromo-N-phenyl-isonicotinamide were converted to the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+:11]>O>[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[K+:11].[K+:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 70 °C

Procedure:
To a 500 ml 2-neck round bottom flask, equipped with a reflux condenser and a pressure equalizing addition funnel was charged 10.00 parts (0.068 eqv.) of aspartic acid. 101 ml of KOH (0.065 eqv.) was added to the addition funnel. The basic solution was added to the aspartic acid, with magnetic stirring, over about 4 minutes. The reaction mixture was then stirred at about 70° C. for an additional hour, to insure complete reaction. The water was stripped off the reaction product at about 10 mm Hg and about 70° C. The white powder was broken up and dried overnight at about 80° C. and at about 2 mm Hg. A freely flowing powder was obtained and stored in a dry, airtight container.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)C.[OH-].[Li+]>CO>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([NH:6][CH2:5][C:4]([OH:16])=[O:3])=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: CCOC(=O)CNc1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNc1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
To a solution of compound (Benzo[1,3]dioxol-5-ylamino)-acetic acid ethyl ester in methanol was added lithium hydroxide (1.2 eq.) and stirred for overnight. Reaction mixture was then concentrated and neutralized to afford (Benzo[1,3]dioxol-5-ylamino)-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[CH:3]=1.[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[C:3]=1[N:12]=[O:13]
Reactant: O=N[O-]
Reactant: CCn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(N)c(N=O)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-amino-1-ethyl-1,3-dihydropyrimidine-2,4-dione (5.0 g, 32.3 mmol) in a mixture of 50% acetic acid/water (50 ml) at 70° C. was added sodium nitrite (4.45 g, 64.5 mmol) in portions over a period of 30 minutes. The mixture was stirred at 70° C. for a further 30 minutes. The reaction mixture was cooled, and the precipitate filtered off, and washed with water, then methanol, to provide 6-amino-1-ethyl-5-nitroso-1,3-dihydropyrimidine-2,4-dione, a compound of formula (14).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7](N2CCCCC2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31]Cl>>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31][N:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:8]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=2)[CH2:9][CH2:10]1
Reactant: CCCCn1cc(N2CCCCC2)c2ccncc21
Reactant: COC(=O)c1ccccc1OCCCl
Product: CCCCn1cc(C2CCN(CCOc3ccccc3C(=O)OC)CC2)c2ccncc21
Yield: 96.2 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 1.35 g (5.25 mmol) of 1-butyl-3-piperidin yl-1H-pyrrolo[2,3-c]pyridine and 1.35 g (6.3 mmol) of 2-(2-chloroethoxy)benzoic acid methyl ester. After standard work-up and purification, 1.1 g (49% yield) of 2-{2-[4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester were obtained.
Reaction SMILES: C1(OC=O)C=CC=CC=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:18]1[CH:23]=[C:22](Cl)[CH:21]=[C:20]([C:25](OO)=O)[CH:19]=1.[Br-]>>[C:11]1([CH:10]=[CH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccccc1
Agent: O=COc1ccccc1
Agent: [Br-]
Product: C(=Cc1ccccc1)c1ccccc1

Procedure:
Formic acid phenyl ester 7 may be synthesized from the corresponding benzaldehyde via traditional oxidation methods known in the art. For example, Baeyer-Villiger oxidation using m-CPBA to form 7, followed by deformylation using a suitable base and exposure to bromide 8 affords stilbene analog 9.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Si]([O:39][S:40]([C:43](F)(F)F)(=O)=[O:41])(C)(C)C.O=O>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[O:25][S:40]([CH3:43])(=[O:41])=[O:39])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CCN(CC)CC
Product: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirring mixture of 4 (3.58 g, 8.72 mmol) and Et3N (6.1 ml, 43.6 mmol) was added Me3SiOSO2CF3 (2.56 mL, 13.0 mmol) at 0° C. under positive pressure of dry Ar. The mixture was stirred for 30 min at the same temperature, and then partitioned between CH2Cl2 and sat. aqueous NaHCO3. The organic layer was dried (Na2SO4) and evaporated. The residue was dissolved in DMSO (12 mL). To this solution was added Pd(OAc)2 (98 mg, 0.44 mmol), and the mixture was stirred for 36 h under positive pressure of O2. The mixture was partitioned between EtOAc and brine. The organic layer was dried (Na2SO4), evaporated, and chromatographed on a silica gel column (hexane/EtOAc=5/1) to give 5 (3.13 g, 88%) as a white solid.