Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([O:13][C:7]2([CH3:10])[CH2:8][CH2:9][CH2:4][CH2:5][CH2:6]2)=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C(=O)OC1(C)CCCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 48 %

Procedure:
A stirred mixture of 97.5 g of 2-(p-nitrophenyl)-propionic acid [J. Med. Chem. Vol. 26, pages 222-226 (1983)], 40 ml of thionyl chloride and 500 ml of dry toluene was heated at 80° C. for 5 hours. The mixture was then allowed to cool and the solvent was evaporated under reduced pressure. The residual oil was dissolved in 400 ml of dry toluene, and 100 g of 1-methylcyclohexanol were added to the solution. The stirred mixture was heated at 80° C. for 1 hour and then at ambient temperature overnight. The solution was washed with 5% NaHCO3 solution, then water, dried over MgSO4 and finally evaporated to dryness. The crude mixture was purified over a column of 600 g of silica using CHCl3 as the eluant 34.95 g (24% yield) of 1-methyl-cyclohexyl 2-(p-nitrophenyl)-propionate as a golden yellow liquid.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:36]=[CH:35][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:34])[CH2:32][OH:33])[CH:29]=3)[C:24](O)=[O:25])=[C:18]([F:37])[CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.[CH3:38][N:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1>CN(C=O)C>[N:10]1([C:14]([C:16]2[CH:36]=[CH:35][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:34])[CH2:32][OH:33])[CH:29]=3)[C:24]([NH:44][C:41]3[CH:42]=[CH:43][N:39]([CH3:38])[N:40]=3)=[O:25])=[C:18]([F:37])[CH:17]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: Cn1ccc(N)n1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.4 %

Procedure:
DIPEA (93 mg, 0.72 mmol; 4.0 equivalents) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzoic acid (70 mg), HATU-(144 mmol; 2.1 equivalents) and 1-methyl-1-H-pyrazole-3-amine (26 mg, 0.27 mmol, 1.5 equivalents) in DMF (2 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The DMF was removed in vacuo, water was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed, eluting with 0-100% ethyl acetate in isohexane, to give desired compound (45 mg).
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH2:40][CH2:41][O:42][CH3:43])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:44])=[CH:24][N:23]=1>CN(C)C(=O)C>[Cl:44][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35](=[O:36])(=[O:37])[N:38]([CH2:40][CH2:41][O:42][CH3:43])[CH3:39])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: COCCN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CC(=O)N(C)C
Product: COCCN(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
Following a procedure similar to Example 258c, 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-(2-methoxy-ethyl)-N-methyl-benzenesulfonamide, which was prepared in a manner similar to 1141a-c, were converted to 2-[7-(5-chloro-4-{2-[2-methoxy-ethyl)-methyl-sulfamoyl]-phenylamino}-pyrimidin-2-ylamino)-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-N,N-dimethyl-acetamide (40 mg, 22%) as an off-white solid. MP: 67-76° C.; 1H-NMR (CDCl3) δ 9.22 (s, 1H), 8.47 (d, J=8.8 Hz, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.22 (t, J=8.4 Hz, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.46 (m, 2H), 3.31 (m, 2H), 3.29 (s, 2H), 3.22 (s, 3H), 3.14 (s, 3H), 2.98 (s, 3H), 2.87 (overlapped* s, 3H), 2.87 (overlapped* m, 2H), 2.70 (m, 6H); LC/MS (ESI+): 632.23 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[CH:31]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([C:35]([CH:31]3[CH2:34][CH2:33][CH2:32]3)=[O:36])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: O=C(Cl)C1CCC1
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CN(C(=O)C4CCC4)CCC3C(C)(C)OC2=C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and cyclobutanecarbonyl chloride (1 mole) with triethylamine (1 mole) in dimethylformamide, stirring 16 hours at 25°C gave the desired product.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=[O:11])[CH2:7][CH:6]=[CH:5][CH2:4]1.[C:30](Br)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([N:9]([CH:8]1[CH:3]([CH2:2][O:1][C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:4][CH:5]=[CH:6][CH2:7]1)[CH:10]=[O:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)C1CC=CCC1CO
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(C=O)C1CC=CCC1COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
[6-(Hydroxymethyl)-3-cyclohexenyl]-N-octadecylformamide obtained in Example 1 (2) is reacted with trityl bromide in acetone in the presence of potassium carbonate to obtain N-octadecyl-[6-(trityloxymethyl)-3-cyclohexenyl]formamide.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([CH3:11])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O>[NH2:9][CH2:8][C:7]1[C:2]([OH:1])=[N:3][C:4]([CH3:11])=[N:5][C:6]=1[CH3:10]
Reactant: Cc1nc(C)c(C#N)c(O)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C)c(CN)c(O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
A mixture of 4-hydroxy-2,6-dimethylpyrimidine-5-carbonitrile (2.7 g, 18.1 mmol), lithium aluminium hydride (2.1 g, 54.3 mmol), and tetrahydrofuran (80 mL) was stirred at 25° C. for 4 hours. Water (5 mL) was added to the mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 5-(aminomethyl)-2,6-dimethylpyrimidin-4-ol as a white solid (525 mg, 19%). LRMS (M+H+) m/z: calcd 153.09. found 153.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16][C:17](=[O:19])[CH3:18])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][C:12]1[C:11]([O:16][C:17](=[O:19])[CH3:18])=[CH:10][C:8]2[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[O:6][C:7]=2[C:13]=1[CH3:14]
Reactant: CC(=O)Oc1cc2cc(C(=O)CBr)oc2c(C)c1C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1cc2cc(C(=O)CN3CCOCC3)oc2c(C)c1C
Yield: 89.8 %

Procedure:
A solution of 2-bromo-1-(5-acetoxy-6,7-dimethyl-benzofuran-2-yl)-ethanone (47 mg) from Example 16, morpholine (15 mg), and potassium carbonate (25 mg) in acetone (10 mL) was stirred at room temperature for 30 min. It was then evaporated to dryness, and the residue was purified by silica gel column eluting with 5% MeOH in DCM to give 43 mg of acetic acid 6,7-dimethyl-2-(2-morpholin-4-yl-acetyl)-benzofuran-5-yl ester as an oil. Conversion into the HCl salt gave a yellow solid. 1H NMR (CDCl3, 300 MHz) δ: 7.60 (s, 1H), 7.20 (s, 1H), 3.78 (s+t, 6H), 2.64 (m, 4H), 2.50 (s, 3H), 2.40 (s, 3H), 2.20 (s, 3H) ppm. 13C NMR (CD3OD, 75 MHz) (as HCl salt) δ: 180.94, 170.31, 153.65, 150.33, 147.19, 131.94, 124.33, 122.34, 116.04, 113.59, 63.74, 60.89, 53.28, 19.64, 12.18, 12.22 ppm. M/S 332 (M+H+).
Reaction SMILES: C([Li])CCC.[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])#[CH:7].[N:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[N:14][CH:13]=1>C1COCC1.O>[N:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])([C:7]#[C:6][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH3:19])=[N:14][CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)c1ccncn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(C#C[Si](C)(C)C)c1ccncn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5M in hexane, 2.1 ml, 5.32 mmol) in THF (3 mL) at −78° C. was added dropwise ethynyl(trimethyl)silane (0.7 mL, 4.91 mmol). The reaction was stirred at −78° C. for 10 minutes and then 1-(pyrimidin-4-yl)ethanone (0.5 g, 4.09 mmol) was added in more THF (2 mL). The reaction was stirred at −78° C. to RT overnight. The mixture was diluted with water and the volatiles removed in vacuo. The product was then extracted with CHCl3:IPA (2:1 ratio, 2×25 mL). The organic phase was washed with water (20 mL), brine (20 mL); dried over Na2SO4 and the solvent removed in vacuo. Purification by column chromatography (Biotage), eluting with 0-100% EtOAc-heptane afforded 2-(pyrimidin-4-yl)-4-(trimethylsilyl)but-3-yn-2-ol; 1H NMR (500 MHz, CDCl3) delta 0.19 (9H, s), 1.78 (3H, s), 4.65 (1H, s), 7.65 (1H, dd, J=5.20, 1.10 Hz), 8.79 (1H, d, J=5.36 Hz), 9.20 (1H, s); LC-MS: m/z=+221 (M+H)+; and 2-(pyrimidin-4-yl)but-3-yn-2-ol; 1H NMR (500 MHz, CDCl3) delta 1.79 (3H, s), 2.62 (1H, s), 4.99 (1H, s), 7.67 (1H, dd, J=5.28, 0.87 Hz), 8.77 (1H, d, J=5.36 Hz), 9.19 (1H, s); LC-MS: m/z=+148.95 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-])=O)(=[O:3])[CH3:2].[ClH:18].O.NN>C(O)C.[Pd]>[ClH:18].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[NH2:15])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a suspension of 15 (0.870 g, 3.65 mmol) in ethanol (30 mL) was added Pd-C (0.87 g) and 5% HCl (0.85 mL). Hydrazine hydrate (55% hydrazine, 0.85 mL, 0.47 g, 15 mmol) dissolved in ethanol (SmL) was then added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 1/2 hour and the Pd-C was filtered. The filtrate was concentrated under vacuum to give 16 (0.500 g, 78.7% yield) as a white solid: mp 187°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1)c1c(F)cccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound LCMS (MH+): m/z=441.0, tR (minutes, Method G)=2.86. [α]D20=+17.1 (c=4.44 mg/mL,CHCl3)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].CC(C)(C)[CH2:10][NH:11][CH2:12][C:13]1[O:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1.[CH3:43][C:44](C)(C)CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:10]([N:11]([CH2:12][C:13]1[O:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH2:43][CH3:44])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CNCC(C)(C)C)c4)cc23)CC1
Reactant: CC(C)(C)CN
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)co1
Yield: 12 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2M diethylamine (102.4 mg, 1.4 mmol) for 2,2-dimethyl-1-propanamine to afford 10.1 mg of the title compound (12%).
Reaction SMILES: [CH3:1]Br.[CH:3]1([P:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)([SH:11])=[S:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>>[CH:3]1([P:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)([S:11][CH3:1])=[S:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CBr
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Product: CSP(=S)(C1CCCCC1)C1CCCCC1

Procedure:
Methyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain methyl dicyclohexylphosphinodithioate, m.p. 75°-75.5° C, which on testing lasted 1500 hours* longer than the control. The average total number of hours required to each failure was 3.4 times that of the control.
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C([O-])(=O)C.[Na+]>>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:18]=[CH:19][C:3]([CH:1]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1)#[N:15]
Reactant: O=C1CSC(=O)N1
Reactant: N#Cc1ccc(CCOc2ccc(C=O)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: N#Cc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
2.4 g (9.6 mmole) 4-[2-(4-formylphenoxy)ethyl]benzonitrile, 1.4 g (12 mmole) 2,4-thiazolidinedione and 1.96 g (24 mmole) sodium acetate was mixed and heated under vacuum to 140° C. The reaction mixture melted and was after 30 minutes removed from the heat. Water:acetone (2:1) was added and filtration followed by recrystallization in trifluoroacetic acid/acetic acid gave 1.79 g (yield 52%) of 5-(4-[2-(4-cyanophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[CH:6]=[C:5]2[CH3:15].Cl.[NH:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[NH:19].Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[NH:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][C:6]2[C:7](=[O:14])[O:8][C:9]3[C:4]([C:5]=2[CH3:15])=[CH:3][C:2]([F:1])=[C:11]([OH:12])[C:10]=3[F:13])=[O:26])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[NH:19]
Reactant: Cc1cc(=O)oc2c(F)c(O)c(F)cc12
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(OC(=O)c2ccc(NC(=N)N)cc2)c(=O)oc2c(F)c(O)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a pale yellow solution of 6,8-difluoro-7-hydroxy-4-methylcoumarin (Compound 5, 0.13 g, 0.61 mmol) in THF (5 mL) under air at room temperature is added a solution of 4-guanidinobenzoic acid hydrochloride (132 mg, 0.61 mmol) in 4 mL water, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 125 mg, 0.65 mmol). The resulting solution is stirred at room temperature overnight, followed by the addition of more EDC (100 mg). After two hours, TLC analysis indicates the starting materials are consumed. Volatiles are removed in vacuo, and a portion of the residue (0.61 g of pale yellow powder) is purified by chromatography on SEPHADEX LH-20 resin using water:dioxane (1:1) as eluant to give nonfluorescent Compound 35 as a colorless powder: Rf =0.30 (MeCN:H2O:AcOH 90:5:5). Upon treatment with ammonia vapor, a TLC spot corresponding to Compound 35 becomes blue fluorescent.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[O:20][CH3:21].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH3:19][O:18][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:20][CH3:21])=[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16]=1[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: COc1c(C)c(Br)c(OC)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(OC)c2ccccc2c1OC
Temperature: 0 °C
Yield: 88.6 %

Procedure:
n-Butyl lithium (1.6M in hexanes, 4.1 ml, 6.56 mmol) was added dropwise to 2-bromo-1,4-dimethoxy-3-methylnaphthalene (1.537 g, 5.47 mmol) in tetrahydrofuran (30 ml) at −50° C. The reaction was stirred for 30 min at −50° C. before dropwise addition of ethyl chloroformate (1 ml, 10.46 mmol). The reaction was allowed to warm to 0° C. over 18 h quenched by addition of hydrochloric acid (2N) and extracted with ethyl acetate. The extract was dried (Na2SO4) and the solvent evaporated under vacuum. The residue was purified by SPE (silica, 10 g) eluting with 10% ethyl acetate in cyclohexane to give ethyl 1,4-dimethoxy-2-methylnaphthalene-3-carboxylate (1.33 g, 89%).
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].ClC(Cl)(Cl)C(O)=[O:12].O>C(Cl)Cl>[Cl:1][C:2]([Cl:8])=[CH:3][CH:4]1[O:12][C:5]1([CH3:7])[CH3:6]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: O=C(O)C(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC1C=C(Cl)Cl
Reaction time: 15 h
Yield: 101.8 %

Procedure:
To 30.6 g (0.2 mole) of 1,1-dichloro-4-methyl-1,3-pentadiene in 400 ml methylene chloride were added 0.35 mole of technical perchloroacetic acid containing 1.0 g sodium acetate at a temperature of 10°-20° C. over a period of 20 minutes. After stirring for 15 hours, the reaction mixture was poured into 500 ml of water. The phases were separated and the aqueous phase extracted twice with 150 ml of methylene chloride. The organic phases were combined and washed with 10% aqueous sodium carbonate (2×100 ml) and saturated aqueous sodium chloride (1×100 ml), dried over Na2SO4 and the solvent evaporated. The product was distilled to give 34 g of 1,1-dichloro-3,4-epoxy-4-methyl-1-pentene (82% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:43])C(=O)C1.O>CN(C)C=O>[CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[C:10]([Br:43])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2c(Br)cn(Cc3ccccc3)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
A solution of methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (480 mg, 0.974 mmol) in N,N-Dimethylformamide (DMF) (1 mL) was treated with NBS (173 mg, 0.974 mmol) and then stirred at room temperature for 20 minutes. Water was added and then mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-50% ethyl acetate/hexanes) to afford methyl 2-(1-benzyl-3-bromo-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (450 mg, 0.787 mmol, 81% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.45-7.28 (m, 9H), 7.03-7.01 (m, 1H), 5.91-5.76 (m, 2H), 5.09 (s, 1H), 3.77 (s, 3H), 3.65 (s, 3H), 1.00 (s, 9H); LCMS (m/z) ES+=571 (M+1).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([NH2:19])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=C(O[C:27](OC2N=CC=CC=2)=[S:28])N=CC=1>ClCCl>[C:4]([Si:1]([O:8][CH:9]1[CH2:10][CH2:11][C:12]2[C:17](=[C:16]([N:19]=[C:27]=[S:28])[CH:15]=[CH:14][CH:13]=2)[CH2:18]1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N)c2C1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N=C=S)c2C1
Yield: 72 %

Procedure:
A solution of the product of Example 18B, 2-(tert-butyldimethylsilyl)-ol (1.4 g, 5.07 mmol) and di-2-pyridyl thionocarbonate (1.07 g, 4.61 mmol) in 30 mL dichloromethane was stirred at room temperature overnight. The mixture was evaporated, then the residue was taken up in 2 mL dichloromethane and filtered through silica gel, eluting with 5% ethyl acetate-hexane. Evaporation of the filtrate afforded the product as a dark red oil (1.165 g, 72%). 1H NMR (DMSO-d6) δ 7.21 (m, 3H), 4.27 (m, 1H), 2.58-3.09 (m, 4H), 1.90 (m, 1H), 1.77 (m, 1H), 0.90 (s, 9H), 0.14 (s, 6H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]([CH2:31][N:32]([S:40]([CH3:43])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)=[O:30]>>[NH2:28][C:29]([CH2:31][N:32]([C:33]1[CH:38]=[CH:37][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:35][CH:34]=1)[S:40]([CH3:43])(=[O:41])=[O:42])=[O:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CS(=O)(=O)N(CC(N)=O)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CC(N)=O)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-aminocarbonylmethyl-N-methylsulphonyl-p-phenylenediamine Rf value: 0.7 (silica gel, methylene chloride/methanol=5:1) C26H24N4O6S