Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)CCC.NO.Cl.[CH:9]#[C:10][CH2:11][C@@H:12]([OH:22])[C@H:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Br[C:24]#[C:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27]>C(Cl)Cl.[Cu]Cl>[C:28]1([C@@H:26]([OH:27])[C:25]#[C:24][C:9]#[C:10][CH2:11][C@@H:12]([OH:22])[C@H:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O[C@@H](C#CBr)c1ccccc1
Reactant: C#CC[C@@H](O)[C@H](O)CCCCCCC
Agent: Cl[Cu]
Agent: Cl
Agent: NO
Solvent: CCCCN
Solvent: ClCCl
Product: CCCCCCC[C@@H](O)[C@H](O)CC#CC#C[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
Copper(I) chloride (6.4 mg, 64.6 μmol, 20 mol %) was added to a stirred solution of n-BuNH2 (0.32 mL) and distilled water (0.74 mL) at 0° C., which resulted in a deep blue solution. A few crystals of NH2OH.HCl were added to get a colorless solution which is indicative of the presence of the required Cu(I) salt. At the same temperature was added (4R,5R)-1-dodecyne-4,5-diol (64.1 mg, 0.323 mmol) by cannula as a solution in CH2Cl2 (0.6 mL). Then a freshly prepared solution of (R)-3-bromo-1-phenyl-2-propyn-1-ol (75.0 mg, 0.355 mmol, 1.1 equiv) in CH2Cl2 (2.4 mL) was slowly added over 60 min by help of syringe pump under a flow of argon in order to prevent the solution from turning to green or blue (NH2OH.HCl can be added as necessary throughout the reaction). The reaction mixture was allowed to warm up to room temperature. After stiffing for 10˜20 minutes, the brownish orange colored solution was extracted three times with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated. The reaction procedure in Cho, E. J.; Kim, M.; Lee, D. Org. Lett. 2006, 8, 5413-54169 and supporting information, both of which are incorporated herein by reference in their entireties, can also be followed. Purification of the crude mixture by gradient flash chromatography on silica gel (hexanes/EtOAc=2.5:1→2:1→1.5:1→1:1) afforded the title compound (83.2 mg, 78%) as a white solid: 1H-NMR (CDCl3, 500 MHz) δ 7.51-7.38 (m, 2H), 7.40-7.32 (m, 3H), 5.50 (s, 1H), 3.63-3.60 (m, 2H), 2.62-2.53 (m, 3H), 2.17 (br s, 1H), 1.68 (br s, 1H), 1.50-1.28 (m, 12H), 0.88 (t, J=7.0 Hz, 3H); 13C-NMR (CDCl3, 75 MHz) δ 139.68, 128.71, 128.62, 126.60, 78.40, 75.64, 73.07, 72.11, 71.23, 66.52, 64.86, 33.49, 31.78, 29.52, 29.20, 25.55, 24.92, 22.62, 14.09.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:2].C1CCCCC=1.B(Br)(Br)Br>ClCCl>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[C:8]([C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:25]([C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH3:2]
Reactant: CCC1c2ccccc2-c2cc(-c3cccc(OC)c3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CCC1c2ccccc2-c2cc(-c3cccc(O)c3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A stirred and cooled solution of 4-{[6-ethyl-2-(3-methoxyphenyl)phenanthridin-5(6H)-yl]sulfonyl}phenol (0.645 g, 1.36 mmol) and cyclohexene (1.1 mL, 10.9 mmol) in dichloromethane (5 mL) was treated drop-wise under nitrogen at −30° C. with boron tribromide (1.03 mL, 10.9 mmol). After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for four hours. The reaction was cooled to −30° C. and quenched with methanol (1 mL). The solvent was removed in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:3); to yield the title compound (0.473 g, 1.03 mmol, 76%), which was characterized by LCMS (ES+, FA, CV=20 or 5), m.p. 105° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([C:21]2[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH:18]4[CH2:19][CH2:20]4)=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(C2CC2)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C4CC4)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyclopropyl-pyridine-2-carboxylic acid (CAS 1174322-66-7; WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=387.3 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:36][C:37]1[C:38]([F:46])=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41]>C(Cl)(Cl)Cl>[Cl:36][C:37]1[C:38]([F:46])=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(Cl)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 19.4 g of 1-Boc-piperazine, 24.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 19.1 g of 1-hydroxybenzotriazole, 20.0 g of 3-chloro-2-fluorobenzoic acid and 200 ml of chloroform was stirred at room temperature for 4 hours. The resulting mixture was diluted with chloroform, and an insoluble matter was filtered off using Celite. Then, the filtrate was washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 1/1) to give title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH3:24])[CH2:22]OS1(=O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].[NH4+].[Cl-]>CN(C=O)C>[C:12]([O:16][C:17](=[O:18])[NH:19][C@@H:23]([CH3:22])[CH2:24][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Oc1ccc2ccccc2c1
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc2ccccc2c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
β-Naphthol (721 mg) was dissolved in DMF (25 mL) and cooled to 0° C. Potassium-tert-butylate (1M in THF, 6.0 mL) was added drop by drop over a periode of 15 minutes and the mixture was stirred for 30 min. (S)-4-Methyl-2,2-dioxo-[[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (IV, 1.42 g) was added in one portion and stirring was continued for 3 hours. The reaction mixture was poured into 1M NH4Cl and extracted with ether. The organic phase was washed with 1M NH4Cl and brine, dried over Na2SO4 and evaporated to yield a yellow solid. The crude product was purified by flash chromatography (ethyl acetate/hexanes 1:9) to give the desired product as a colorless solid (1.5 g).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:28]#[N:29].N(OCCC(C)C)=O.[ClH:38]>C(#N)C.[Cu](Cl)Cl>[Cl:38][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:28]#[N:29]
Reactant: Cl
Reactant: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CNC(=O)c1cc(CSc2nc(Cl)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1.42 g (3.55 mmol) of the compound from Example 24A are initially charged in 30 ml of acetonitrile, 0.96 ml (7.10 mmol) of isopentyl nitrite and 0.95 g (7.10 mmol) of copper(II) chloride are added and the mixture is stirred at 60° C. for 5 hours. Once more, the same amount of copper(II) chloride is added and the mixture is stirred at 60° C. overnight. 7 ml of 1N hydrochloric acid are added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue is purified by preparative HPLC (with 0.1% TFA added).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]1[N:19]3[CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:18]3=[N:17][C:10]=1[CH:11]=[N:12]2.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([N:23]1[CH2:22][CH2:21][CH2:20][N:19]2[C:9]3[C:8]4[C:13](=[CH:14][CH:15]=[CH:16][CH:7]=4)[N:12]=[CH:11][C:10]=3[N:17]=[C:18]2[CH2:24]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc2c(c1)ncc1nc3n(c12)CCCNC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
Methanesulfonyl chloride (2.54 mL, 32.6 g) was added to a solution of 9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline hydrochloride (7.47 g, 27.2 mmol) and triethylamine (22.73 mL, 163.1 mmol) in DMF (50 mL). The reaction was stirred overnight at ambient temperature and then concentrated under reduced pressure to provide 3.065 g of 9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([C:35]([OH:39])([CH3:38])[CH2:36][OH:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[OH:39][C:35]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:38])[CH2:36][O:37][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: CC(O)(CO)c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCC(C)(O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 17, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-propane-1,2-diol.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]2)[CH2:10][CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:25][C:26]([CH3:31])([CH3:30])[C:27](Br)=[O:28]>C(Cl)Cl>[Br:25][C:26]([CH3:31])([CH3:30])[C:27]([C:4]1[CH:3]=[CH:2][C:1]([C:7]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]2)[CH2:10][CH2:9][CH2:8]3)=[CH:6][CH:5]=1)=[O:28]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)CC12CCCC(c3ccccc3)(CC1)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC12CCCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 25.6 %

Procedure:
To an ice water cooled solution of methyl (5-phenylbicyclo[3.2.2]non-1-yl)acetate (Intermediate 23; 229 mg, 0.79 mmol) in DCM (10 mL) was added aluminium chloride (318 mg, 2.38 mmol) followed by the dropwise addition of 2-bromoisobutyryl bromide (0.10 mL, 0.79 mmol). The reaction mixture was allowed to stir at 0° C. for 40 mins then poured onto ice-water (100 mL). The organic phase was separated and the aqueous phase washed with DCM (3×50 mL), the organic washings were combined, dried (MgSO4) and concentrated to leave a yellow gum. This was purified on a 12 g Crawford silicyle cartridge, loading in DCM and eluting with 0-10%-20% isohexane-EtOAc to provide the title compound (85 mg, 0.202 mmol, 26%) as a pale yellow gum; 1H NMR (CDCl3) δ 1.09 (d, 3H), 1.50-1.57 (m, 3H), 1.67-1.74 (m, 3H), 1.82-1.86 (m, 6H), 2.03 (s, 6H), 2.27 (q, 1H), 3.67 (s, 3H), 7.37 (d, 2H), 8.11 (d, 2H); GC-MS CI m/e MH+ 421.
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH2:34][C:35](=[O:41])[NH:36]2.N1CCCCC1>C(O)C>[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:35](=[O:41])[NH:36]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 73 %

Procedure:
(R)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde if (50 mg, 0.156 mmol), 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 3d (34.3 mg, 0.14 mmol) and piperidine (7.7 μL, 0.078 mmol) were dissolved in 0.3 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound 2-[(Z)-4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-[(R)-2-hydroxy-3-morpholin-4-yl-propyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 3 (56 mg, yield 73%) as a yellow solid.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)C(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)c1ccc(CBr)cc1

Procedure:
To a suspension of 28.5 g. (1.17 g. atoms) magnesium turnings in 150 ml. tetrahydrofuran under a nitrogen atmosphere there is added 10 ml. of 4-bromo toluene (1.17 mole) in 650 ml. dry tetrahydrofuran; the reaction is started and the remainder of the bromo toluene solution is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for an additional 11/2 hours. The resulting Grignard solution is added dropwise to a cold solution of 128.0 g. pivaloyl chloride (1.06 mole) in 500 ml. dry tetrahydrofuran at a rate that maintains the temperature at 0° to -5° C. The solution is stirred for an additional 11/2 hours at 0° C. and then at room temperature for 18 hours. The mixture is then cooled to 0° C. and hydrolyzed by the addition of 100 ml. 2N hydrochloric acid. The layers are separated and 200 ml. of ether is added to the organic phases which is then washed respectively with 100 ml. 2N hydrochloric acid, 100 ml. 10% sodium bicarbonate solution, and 100 ml. saturated sodium chloride. The resulting layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo to give p-pivaloyl toluene (b.p. 80° to 84° C./0.7 mm, nC21 1.5108). A mixture of 156.3 g. (0.886 mole) of the resulting p-pivaloyl toluene is then added to 157.8 g. (0.886 mole) N-bromosuccinimide, 4.0 g. (0.016 mole) benzoyl peroxide and 150 ml. carbon tetrachloride and heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting oil is distilled in vacuo to give α-bromo-p-pivaloyl toluene (b.p. 124°-132° C/0.7 mm, nD22 1.5546-V.P.C. 96% monobromo 4%-dibromo).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:10]([NH:20][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)C=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c1

Procedure:
A solution of 20.0 g. of bis(4-chlorophenyl)acryloyl chloride in 150 ml. of dichloromethane is added to a stirred solution of 10.3 g. of methyl 3-aminobenzoate and 12.2 ml. of triethylamine in 150 ml. of dichloromethane. This solution is stirred under reflux for 3 hours and then at room temperature overnight and evaporated. The residue is stirred with 300 ml. of boiling acetone, filtered white hot, and the filtrate is chilled. The resulting solid is collected and dried in vacuo, giving 13.8 g. of the desired product as a white solid, m.p. 155°-159° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:25][CH:26]=1>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:25][CH:26]=1)[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2csc(-c3ccccc3)n2)c1)C(=O)O
Yield: 64 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-phenyl-thiazole, the title compound was obtained in 64% yield as a brown oil. MS: (M+H)+ 407.3.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](Cl)=[O:12].Cl>C(Cl)Cl>[CH2:1]([NH:5][C:11]([C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccco1
Reactant: CCCCN
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)c1ccco1
Temperature: 0 °C
Yield: 88.5 %

Procedure:
To a solution of n-butylamine (99 mL, 1.0 mol) in CH2Cl2 (300 mL) was added 2-furoyl chloride (33.0 mL, 0.335 mol) dropwise at 0-5° C. with stirring. The reaction mixture was stirred for additional 2 h at 0-5° C. and overnight at room temperature. The solution was poured into a mixture of wet-ice (200 g) and 37% HCl (50 mL). After separation, the organic layer was washed with 2×200 mL water, dried over Na2SO4 and filtered. Removal of solvent provided the title compound (49.59 g, 88.6% yield) as a white solid, m.p.=43.8° C. (Rf=0.53 on a silica gel plate using EtOAc as an eluant). This product was used without further purification.
Reaction SMILES: [C-:1]#[N:2].[K+].CO.Cl.CN([CH2:10][CH:11]1[CH2:16][S:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[C:12]1=[O:20])C>O>[O:20]=[C:12]1[CH:11]([CH2:10][C:1]#[N:2])[CH2:16][S:15][C:14]2[S:17][CH:18]=[CH:19][C:13]1=2
Reactant: CN(C)CC1CSc2sccc2C1=O
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CCC1CSc2sccc2C1=O
Yield: 86.1 %

Procedure:
To a solution of 25.3 g of potassium cyanide in 100 ml of water is added 400 ml of methanol and to the solution is added 41 g of 5-dimethylaminomethyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one hydrochloride with stirring. The mixture is stirred for 3 hours at 45°-50° C. and then concentrated under reduced pressure. To the residue is added water and the mixture is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and the chloroform is distilled off. The residue is subjected to chromatography on silica gel and eluted with chloroform to give 28 g of 4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetonitrile as pale brown oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:11]([CH2:25][CH2:24][O:23][CH3:22])[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)n[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a solution of 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (0.122 g, 0.48 mmol) in DMF (3 ml) was added NaH (19 mg, 0.48 mmol) and the suspension was stirred for 20 minutes under nitrogen. Methoxyethylbromide (45 μL, 0.48 mmol) was then added and the reaction mixture was heated to 100° C. under nitrogen for 18 hours. The solvent was removed in vacuo and the residue was purified by radial chromatography (2 mm plate, eluting with EtOAc) to give the title compound as a clear oil (90 mg, 60%). 1H NMR (400 MHz, DICHLOROMETHANE-D2) δ ppm 8.54 (d, 2 H), 7.61 (d, 2 H), 7.18-7.24 (m, 2 H), 7.03 (t, 2 H), 6.32 (s, 1 H), 4.19 (t, 2 H), 4.05 (s, 2 H), 3.72 (t, 2 H), 3.28 (s, 3 H); m/z (APCI+) for C18H18N3FO 312.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[N:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:17]=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 87.5 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (440 mg; 2.2 mmol), 6-chloro-2-methyl-3-nitro-pyridine (346 mg; 2.0 mmol), and triethylamine (420 μL; 3.0 mL) is dissolved in dimethylformamide (6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 14 hours at 100° C. The reaction mixture is treated by aq. sat. ammonium chloride (5 mL), the precipitate formed is filtered, then rinsed with water (2 mL) and dried under high vacuum to afford the desired product (590 mg; 1.75 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH3:44])[CH:39]=[CH:38]3)[C:28]([NH:31][C:32](=[O:34])[CH3:33])=[N:29][N:30]=1)C1C=CC=CC=1.O1CCCC1>[Pd].[OH-].[Pd+2].[OH-].CO>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH3:44])[CH:39]=[CH:38]3)[C:28]([NH:31][C:32](=[O:34])[CH3:33])=[N:29][N:30]=1
Reactant: CC(=O)Nc1nnc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)n1-c1ccc2c(ccn2C)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1nnc(-c2cc(C(C)C)c(O)cc2O)n1-c1ccc2c(ccn2C)c1
Reaction time: 16 h

Procedure:
A flask was charged with N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide, tetrahydrofuran (10 mL), methanol (10 mL), 10% palladium on carbon (50 mg.) (in some cases palladium hydroxide was used). The reaction was stirred under an atmosphere of hydrogen for 16 hours, filtered through celite, and evaporated to give N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide. 1H-NMR (CDCl3): 8.60 (br, 1H); 7.60 (d, 1H); 7.49 (d, 1H); 7.29 (br, 1H); 7.23 (d, 1H); 7.14 (dd, 1H); 6.55 (d, 1H); 6.40 (s, 1H); 6.38 (s, 1H); 3.94 (s, 3H); 2.82 (q, 1H); 2.20 (s, 3H); 0.47 (d, 6H). MS: expected ion=406.2; observed ion=406.3.