Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([OH:15])=O)=[CH:8][C:7]=2[CH:16]=1.S(Cl)(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1.C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([N:32]3[CH2:31][CH2:30][N:29]([CH2:28][C:27]4[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:25]([O:24][CH3:23])[CH:26]=4)[CH2:34][CH2:33]3)=[O:15])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)OCCC(C(=O)O)=C2
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)OCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1)=C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 7,8-dimethoxy-2,3-dihydro-1-benzoxepin-4-carboxylic acid (0.5 g) dissolved in toluene (10 ml) is added thionyl chloride (1.5 ml), followed by stirring for one hour at 100° C. The reaction mixture is concentrated under reduced pressure to give a crude acid chloride, which is dissolved in methylene chloride (8 ml). The solution is added dropwise, while stirring under ice-cooling, to a solution of 1-(3,4,5-trimethoxybenzyl)piperazine (0.78 g) in a mixture of methylene chloride (20 ml) and triethylamine (1.6 ml), followed by stirring for 3 hours. The reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (eluent: hexane-acetone-ethanol=10:8:1) to afford 1-(7,8-dimethoxy-2,3-dihydro-1-benzoxepin-4-carbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine as a colorless oily product (0.9 g). This product is converted into its hydrochloride, followed by recrystallization from ethanol-ether to give colorless needles, m.p. 208°-210° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH:12]=O)=[C:10]([O:14][Si:15]([CH3:23])([CH3:22])[C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])[CH:9]=[C:8]([O:24][CH3:25])[C:7]=1[Cl:26])[CH:2]=[CH2:3].[I-:28].[Na+].C[Si](C)(C)Cl.C[SiH2]O[Si](C)(C)C>C(#N)C>[CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH2:12][I:28])=[C:10]([O:14][Si:15]([CH3:23])([CH3:22])[C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])[CH:9]=[C:8]([O:24][CH3:25])[C:7]=1[Cl:26])[CH:2]=[CH2:3]
Reactant: [I-]
Reactant: C=CCOC(=O)c1c(Cl)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Agent: C[SiH2]O[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Product: C=CCOC(=O)c1c(Cl)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CI
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
To a solution of 3.3 g of 2-chloro-5-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-6-formyl-3-methoxy-benzoic acid allyl ester in 4 ml of acetonitrile were added 1.8 g of sodium iodide and 1.6 ml of trimethyl-chlorosilane. A white precipitate occurred. The mixture was stirred for 5 min at 20° C. The suspension was cooled to 0° C. and 1.48 ml of tetramethyldisiloxane were added. The mixture was stirred for hours at 0° C. and then partitioned between 20 ml of ethyl acetate and 20 ml of water. The aqueous phase was extracted twice with 20 ml of ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was chromatographed on silica gel using diethyl ether/hexane (3:1, v/v) as eluent to afford 3.39 g of 2-chloro-5-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-6-iodomethyl-3-methoxy-benzoic acid allyl ester as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[I:12].[OH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[I:12][C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:2][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: ClCc1nc2ccccn2c1I
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCc1nc2ccccn2c1I
Yield: 45.7 %

Procedure:
4 g (13.68 mmol) of 2-(chloromethyl)-3-iodoimidazo[1,2-a]pyridine were dissolved in dimethylformamide with magnetic stirring and then 2.71 ml (20.51 mmol) of methyl 2-hydroxybenzoate and 6.68 g (20.51 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 2 h before being poured into 200 ml of water. The aqueous phase was extracted with 2×100 ml of ethyl acetate. The combined organic phases were washed with 100 ml of a saturated NaHCO3 aqueous solution, 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was triturated in 50 ml of diisopropyl ether, the obtained solid was isolated by filtration. 2.55 g of expected product were isolated. On the other hand, an aqueous phase suspension was isolated by filtration and washed with 2×30 ml of water. The analyses confirmed that this was also the expected product. Both batches were therefore collected and 5.58 g (yield=76%) of methyl 2-((3-iodoimidazo[1,2-a]pyridin-2-yl) methoxy)benzoate were obtained as a white powder. LC-MS: m/z=409 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.33 (d, J=6.9 Hz, 1H), 7.69-7.44 (m, 3H), 7.45-7.28 (m, 2H), 7.16-6.93 (m, 2H), 5.23 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:5]1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[O:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:41](=[O:43])[CH3:42])[CH2:16][CH2:15]3)[N:10]=2)[N:6]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[O:21])[CH2:5]1
Reactant: CON=C1C[C@@H](c2nc(C3CCNCC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C1C[C@@H](c2nc(C3CCN(C(C)=O)CC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
(3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[3-(4-piperidinyl)-1,2,4-oxadiazol-5-yl]-3-pyrrolidinone O-methyloxime (Example 12) was dissolved in dry DCM at 0° C. in presence of 1.5 equivalent of triethyl amine and treated with 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes and then hydrolyzed with ice. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. It was then dried with magnesium sulfate and solvent removal afforded a residue which was purified by flash-chromatography using cyclohexane/ethylacetate (1/1) as eluent to give (3EZ,5S)-5-[3-(1-acetyl-4-piperidinyl)-1,2,4-oxadiazol-5-yl]-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers in 95% yield (100% purity by HPLC).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[N:3][C:4]2[C:9](=[CH:8][C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=2)[N:10]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cc2nc(N)c(OC)nc2cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.9 %

Procedure:
2-Amino-3,6,7-trimethoxyquinoxaline (2.60 g, 11.0 mmol) and ethyl chloroformate (2.40 g, 22.1 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (1.75 g, 22.1 mmol) was added. The mixture was stirred at room temperature for 22 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 3.04 g of the titled compound (yield, 90%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[CH3:12][O:13][C:14](=[O:18])[C:15]#[C:16][CH3:17].CCN(CC)CC>CCOCC>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:16]=1[CH3:17])=[O:18]
Reactant: CC#CC(=O)OC
Reactant: ON=C(Cl)c1ccccc1F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2F)noc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.2 %

Procedure:
To a solution (0° C., N2) of 2-fluorobenzoylchloride oxime (0.50 g, 2.9 mmol) and methyl-2-butynoate (0.57 g, 5.8 mmol) in Et2O (15 ml) was added a solution of Et3N (0.52 ml) in Et2O (2 ml) over a period of 1 h followed by warming to room temperature while stirring overnight (17 h). The reaction was diluted with Et2O, washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, hexanes/EtOAc gradient) gave the title compound (0.39 g, 58%).
Reaction SMILES: [C:1]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([O:31][CH3:32])=[O:30])[CH:27]=2)[NH:22][CH:21]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[CH2:1]([CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([O:31][CH3:32])=[O:30])[CH:27]=2)[NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1c[nH]c2ccc(C(=O)OC)cc12
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCC1CNc2ccc(C(=O)OC)cc21

Procedure:
Methyl 3-(n-octadecanoyl)indole-5-carboxylate (17.30 g) was suspended in glacial acetic acid (400 ml), containing perchloric acid (11 ml, 70% w/v), and was hydrogenated over palladium on charcoal (5% w/w, 15 g) at atmospheric pressure and at a temperature of 80°-90° C. The mixture was then hot filtered through diatomaceous earth and was poured into water (150 ml) to give an off-white solid. The solid was collected, washed with water (2×100 ml) and was dissolved in ethyl acetate (1000 ml). The ethyl acetate solution was washed with an aqueous solution of sodium carbonate (of strength 2N, 150 ml) and the organic layer was separated and was dried over magnesium sulfate. The organic solvent was removed in vacuo to give (RS)-methyl 3-(n-octadecyl)indoline-5-carboxylate in the form of an off-white solid, which was used without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([N+:19]([O-])=O)[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>[Ni].CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:12]=[C:11]([NH2:19])[C:10]=1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1c(N)cc(C(C)(C)C)cc1OCc1ccccc1

Procedure:
This is obtained, by reducing 2-methyl-3-nitro-5-tert.-butylphenyl benzyl ether with hydrazine hydrate and Raney nickel in methanol, in the form of a pale brown oil.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([N:11]=[CH:12][C:13](=[O:38])[N:14]2[CH2:17][CH2:18][CH2:19][C:20]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>O>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([N:11]=[CH:12][C:13](=[O:38])[N:14]2[CH2:17][CH2:18][CH2:19][C:20]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)cnc3ccc(OC)cc32)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)cnc3ccc(OC)cc32)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3.0 mL of a chloroform solution containing 0.60 g of 1-tert-butyl 4-ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinoxalin-1-yl)propyl)piperidine-1,4-dicarboxylate, 1.5 mL of trifluoroacetic acid was added under cooling with ice, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Thereto were added ethyl acetate and water. The aqueous layer was separated, ethyl acetate was added thereto, and the resultant solution was adjusted to pH 11.0 with a 20% aqueous saturated sodium hydroxide solution. The organic layer was separated, and washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.21 g of a pale yellow oily substance, ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinoxalin-1-yl)propyl)piperidine-4-carboxylate.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C:3]([CH:1]=[O:2])=[CH:4]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Product: COC(=O)c1ccc2c(C=O)cn(C(C)=O)c2c1

Procedure:
A suspension of methyl 3-formylindole-6-carboxylate (1 g, 4.93 mmol) in acetic anhydride (10 ml) was refluxed for 2 h.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][N:6]2[CH:14]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][N:6]3[CH:14]=2)[CH2:27][CH2:28]1
Reactant: CCOc1ccc2nc(CCl)cn2c1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccc2nc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)cn2c1
Temperature: 75 °C
Yield: 23.8 %

Procedure:
A mixture of 2-(chloromethyl)-6-ethoxyimidazo[1,2-α]pyridine (0.204 g), 1-(2,4-dichlorophenyl) piperazine (Example 31, Step 1; 0.2283 g), triethylamine (Aldrich; 0.15 mL), and THF (1.3 mL) is stirred at 75° C. until the reaction is judged complete by thin layer chromatography. The cooled mixture is concentrated under reduced pressure and partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (2/98) and crystallized from ethyl acetate/ether to give 0.0936 g of the title compound; mp 171-172° C.; MS m/z 404, 406; IR (mineral oil) 1478, 1189, 797, 1508, 1273 cm-1 ; 1H NMR (CDCl3) δ1.45, 2.77, 3.08, 3.77, 3.98, 6.94, 7.17, 7.34, 7.45, 7.47, 7.60.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]([CH:12]([F:14])[F:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C.O>[F:13][CH:12]([F:14])[C:5]1[C:4]([C:15]([O:17][CH3:18])=[O:16])=[C:3]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:2]([N:1]2[CH:25]=[CH:29][CH:28]=[CH:27]2)=[C:7]([C:8]([F:10])([F:11])[F:9])[N:6]=1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(N)c1C1CCC1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(-n2cccc2)c1C1CCC1

Procedure:
A solution of 1.62 g (5 mmol) of methyl 5-amino-2-(difluoromethyl)-4-cyclobutyl-6-(trifluoromethyl)-3-pyridinecarboxylate (example A-2 of U.S. Pat. No. 5,114,465) and 0.8 g (6 mmol) of 2,5-dimethoxytetrahydrofuran in 10 ml of acetic acid as heated at 70° C. for 2.5 h. The reaction mixture was then diluted with 100 ml of water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate (3×100ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10% EtOAc in hexane) to give the product, mp 70-71° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:12][C@H:13]1[C@@H:17]([C:18]2[N:22]3[C:23]4[CH:29]=[CH:28][N:27]([S:30]([C:33]5[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=5)(=[O:32])=[O:31])[C:24]=4[N:25]=[CH:26][C:21]3=[N:20][N:19]=2)[CH2:16][C@@H:15]([NH2:40])[CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CC#N.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][C@H:13]1[C@@H:17]([C:18]2[N:22]3[C:23]4[CH:29]=[CH:28][N:27]([S:30]([C:33]5[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=5)(=[O:32])=[O:31])[C:24]=4[N:25]=[CH:26][C:21]3=[N:20][N:19]=2)[CH2:16][C@@H:15]([NH:40][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:14]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@H]4C[C@@H](N)C[C@H]4C)n23)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@H]4C[C@@H](Nc5cccc(C#N)c5)C[C@H]4C)n23)cc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 65.2 %

Procedure:
To a solution of 3-cyanophenylboronic acid (0.143 g, 0.974 mmol) in DCM (4 mL) was added copper (II) acetate monohydrate (0.013 g, 0.122 mmol) and 4 Å molecular sieves. The reaction mixture was purged 3 times with oxygen. A solution of (1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]-triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.20 g, 0.48 mmol, Preparation #19.2) and DIEA (0.085 mL, 0.487 mmol) in MeCN (1 mL) was added and the reaction mixture was heated at about 45° C. for about 18 h. Additional copper (II) acetate monohydrate (0.013 g, 0.122 mmol) was added and the reaction mixture was stirred for about 4 h. The reaction mixture was filtered through a pad of Celite® and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-60% EtOAc in DCM to give 3-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)benzonitrile (0.16 g, 48%) as a dark brown solid: LC/MS (Table 1, Method c) Rt=1.54 min; MS m/z: 512 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=2[N:10]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:12]=1)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][OH:36])=[CH:29][CH:28]=1>>[CH:13]1([C:11]2[N:12]=[C:7]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][OH:36])=[CH:31][CH:32]=3)[C:8]3[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][CH2:18][C:9]=3[N:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=S1(=O)CCCc2nc(C3CCCC3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: Nc1ccc(CCCO)cc1
Product: O=S1(=O)CCCc2nc(C3CCCC3)nc(Nc3ccc(CCCO)cc3)c21
Yield: 17.2 %

Procedure:
Following general procedure H, 2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.215 g, crude) was reacted with 3-(4-aminophenyl)propan-1-ol (0.040 g, 0.26 mmol) to afford the title compound (0.018 g, 17%) as a white solid. MW=401.52. 1H NMR (DMSO-d6, 500 MHz) δ 8.56 (s, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 4.44 (t, J=5.5 Hz, 1H), 3.70-3.65 (m, 2H), 3.45-3.38 (m, 2H), 3.09 (quin, J=8.0 Hz, 1H), 2.93 (t, J=6.5 Hz, 2H), 2.63-2.57 (m, 2H), 2.36-2.28 (m, 2H), 1.99-1.90 (m, 2H), 1.83-1.55 (m, 8H); APCI MS m/z 402 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[C:10]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[CH:11][C:12]([F:25])=[C:13]([CH:24]=1)[C:14](OC1C=CC(C)=CC=1)=[O:15].O>CC1CCCO1>[Cl:8][C:9]1[C:10]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:35])[F:36])[CH:28]=2)=[CH:11][C:12]([F:25])=[C:13]([CH:24]=1)[C:14]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:15]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 65 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a suspension of sodium hydride (7.39 g, 184.66 mmol) in 2-methyltetrahydrofuran (400 mL) at 0-5° C. was added methanesulphonamide (16.47 g, 173.12 mmol) and the mixture stirred for 1 hour and allowed to reach room temperature. 4-Methylphenyl 5-chloro-4-[4-chloro-3-(trifluoromethyl)phenoxy]-2-fluorobenzoate (Preparation 163, 53 g, 115.41 mmol) in 2-methyltetrahydrofuran (100 mL) was added and the reaction mixture heated at 65° C. for 6 hours and cooled. Water (250 mL) was charged to the stirred reaction mixture and the layers separated. The organic layer was further washed with 1M citric acid solution (200 mL) and concentrated under reduced pressure at 45° C. The resulting solid was stirred in tert butyl methyl ether (250 mL) at 50° C. for 1 hour, cooled to 0-5° C., filtered and dried to give the title compound as an off-white solid (27.5 g, 53%).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][CH2:20][N:21]([C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:33]([O:32][C:30]([N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:19][CH2:18][S:17][C:9]1[N:8]([CH2:7][C:6]([OH:37])=[O:5])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)=[O:31])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCOC(=O)N(CCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C)CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)N(CCCSc1nc2ccccc2n1CC(=O)O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A solution of tert-butyl{2-[3-(butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor K-01b, 200 mg, 0.38 mmol) is dissolved in TFA/dichloromethane (1:1, 3 ml). The resulting solution is allowed to stir at rt overnight. The solvent is evaporated under reduced pressure and the crude product is triturated in Et2O (2 ml) until a solid forms. It is filtered, washed thoroughly with Et2O and dried under high vacuum, yielding quantitatively the title compound (179 mg) as a white powder: tR=6.82 min (LC-1), ESI-MS (neg.): m/z 470.19 [M−H]+, ESI-MS (neg.): m/z 468.32 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 0.82 (t, 3H, CH2CH3), 1.29 (m, 2H, CH2CH3), 1.48 (quint., 2H, OCH2CH2), 1.71 (m; 2H, SCH2CH2), 2.67 (bs, 2H, PhCH2), 3.12 (m, 4H), 3.26 (bs, 2H, PhCH2CH2N), 3.94 (bs, 2H, OCH2), 4.77 (s, 2H, CH2CO2), 7.05 (s, 2Harom), 7.08-7.18 (m, 6Harom), 7.53 (m, 1Harom).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:21][N:22]([CH:24](N(C)C)N(C)C)[CH3:23]>C1(C)C=CC=CC=1>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:17])[CH:16]=[CH:21][N:22]([CH3:24])[CH3:23])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2cccc(C(C)=O)c2C1
Reactant: CN(C)C(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(C(=O)C=CN(C)C)c2C1
Reaction time: 2 h
Yield: 107.9 %

Procedure:
A solution of 2-di-n-propylamino-8-acetyl-1,2,3,4-tetrahydronaphthalene (0.3 g, 1.1 mmol), prepared as in Part A hereof, and tris(dimethylamino)-methane (0.32 g, 2.2 mmol) in toluene was heated to reflux for 5 hours and at 60° for 18 hours. An additional aliquot of tris(dimethylamino)methane (0.16 g, 1.1. mmol) was added and the reaction stirred at 60° for an additional 2 hours. The reaction was concentrated to give 2-di-n-propylamino-8-(1-oxo-3-(dimethylamino)-prop-2-enyl)-1,2,3,4-tetrahydronaphthalene (0.39 g) as a viscous, orange oil.