Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[O:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][CH2:31][C:32]([CH:34]1[C:39](=O)[CH2:38][CH2:37][O:36][CH2:35]1)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:18]=[C:32]([CH2:31][CH2:30][CH:26]3[CH2:27][CH2:28][CH2:29][O:25]3)[C:34]3[CH2:35][O:36][CH2:37][CH2:38][C:39]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: O=C1CCOCC1C(=O)CCC1CCCO1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(CCC4CCCO4)n2)COCC3)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 1.1 %

Procedure:
A reaction mixture of 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (0.305 g, 0.83 mmol, example 7c) and potassium carbonate (0.343 g, 2.48 mmol) in ethanol (3 mL) was stirred at 50° C. for 20 minutes under argon. 3-(3-(tetrahydrofuran-2-yl)propanoyl)dihydro-2H-pyran-4(3H)-one (0.187 g, 0.83 mmol) was added dropwise (neat) over 2 hours and stirred at 50° C. overnight. The solvent was evporated and the residue was partitioned between water and dichloromethane. The water phase was extracted twice with dichloromethane. The combined organic layer was dried over MgSO4, filtered and concentrated. ¼ of the crude was purified by preparative HPLC and concentrated. The residue was partitioned between NaHCO3 (aq) and dichloromethane and the the water phase was extracted twice with dichloromethane, dried (MgSO4) and concentrated giving 4 mg of the product.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][NH2:25]>CN1CCCC1=O>[CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13]([NH:22][CH2:23][CH2:24][NH2:25])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(Cl)nc12
Reactant: NCCN
Solvent: CN1CCCC1=O
Product: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(NCCN)nc12
Yield: 56 %

Procedure:
The mixture 138 mg of 7-benzylamino-5-chloro-3-isopropylpyrazolo[4,3-d]pyrimidine (XVI), 0.62 mL of 2-aminoethylamine (20 eq.) and 0.6 mL of N-methyl-2-pyrrolidone was heated at 125° C. for 12 hours. The reaction mixture was evaporated to dryness in vacuo and then chromatographed over silica gel. The mixture of chloroform/methanol/NH4OH (91:9:1) was used as a mobile phase. Yield=56%; mp=145-147° C.; MS (ES+): 326.1 (100%, M+H+). 1H-NMR (300 MHz, CD3OD): 1.41 d (6H, J=6.9 Hz), 3.10 t (2H, J=5.8 Hz), 3.35 sept (1H, J=6.9 Hz), 3.73 t (2H, 5.8 Hz), 4.86 s (2H), 7.34 m (5H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH:34]([C@@H:36]1[CH2:41][CH2:40][C@H:39]([C:42]([O:44][CH3:45])=[O:43])[CH2:38][CH2:37]1)=O.O>C1COCC1>[C:3]1(/[CH:2]=[CH:34]/[C@@H:36]2[CH2:41][CH2:40][C@H:39]([C:42]([O:44][CH3:45])=[O:43])[CH2:38][CH2:37]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)[C@H]1CC[C@@H](C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@@H](/C=C/c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyltriphenylphosphonium bromide (2.94 g) was dissolved in THF (23.0 mL), added at −20° C. with potassium tert-butoxide (1.07 g) in small portions, and stirred for 1 hour at the same temperature. Subsequently, a THF (6.0 mL) solution of methyl cis-4-formylcyclohexane carboxylate (1.00 g) was added dropwise over 35 minutes, and stirred for 1.6 hours at the same temperature. After raising the temperature to room temperature, it was stirred after adding water and extracted with toluene. The organic layer was washed with water and saturated brine in order. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (9% ethyl acetate/hexane) to obtain the title compound (268 mg) as a colorless oil.
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)=[O:10].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH3:21][C:12]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:10])=[CH:16][CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]=1
Reactant: Sc1ccccc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)CCCC1=O
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Sc2ccccc2)CCCC1=O
Reaction time: 1.5 h

Procedure:
4.0 g (0.0134 mol) of 3-hydroxy-2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)cyclohex-2-enone (compound A2-B1) are suspended in 25 ml of oxalyl chloride, and 0.1 ml of dimethylformamide is subsequently added dropwise. After the vigorous evolution of gas has ceased, the mixture is held for 1.5 hours at a bath temperature of 45° C. and subsequently concentrated, and the residue (3-chloro-2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-cyclohex-2-enone) is dissolved in 60 ml of methylene chloride. Triethylamine (3.7 ml, 0.0268 mol), dimethylaminopyridine (160 mg, 1.34 mmol) and 1.5 ml (0.0147 mol) of thiophenol are added at a temperature of 0-5° C. After 20 hours at a temperature of 22° C., the reaction mixture is concentrated and purified on silica gel (hexane/ethyl acetate 5:1). Trituration in hexane gives pure 2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-3-phenylsulfanylcyclohex-2-enone in the form of white crystals of melting point 124-125° C. 1H-NMR (CDCl3): 1.99, m, 2H; 2.41, m 4H; 2.80, s, 3H; 2.60: 7.40-7.60, m, 6H; 7.80 ppm, d(J, 8.2 Hz), 1H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][NH:23][N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][N:23]([CH3:27])[N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccccc1Cn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccnc(-c3cn(Cc4ccccc4Cl)cn3)c2)n1
Yield: 95 %

Procedure:
The title compound was prepared in 95% yield from 2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (Example 129), MeI and potassium carbonate in DMF. 1H NMR (400 MHz, DMSO): δ 4.49 (3H, s), 5.41 (2H, s), 7.27-7.30 (1H, m), 7.38-7.40 (2H, m), 7.52-7.55 (1H, m), 7.79 (1H, d, J=5.2 Hz), 7.84 (1H, s), 7.96 (1H, s), 8.50 (1H, s), 8.67 (1H, d, J=5.1 Hz). [M+H] Calc'd for C17H14ClN7, 352. Found, 352.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9].[CH3:24][O:25][P:26]([O:29]C)[O:27][CH3:28]>>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][P:26](=[O:29])([O:27][CH3:28])[O:25][CH3:24])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:13][CH:14]3[CH2:20][CH:18]([CH2:17][CH:16]([CH2:15]3)[CH2:21]1)[CH2:19]2)=[O:9]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)OC

Procedure:
5-Bromomethyl-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (5.70 g, Example 8b) in 100 ml of trimethylphosphite was heated at reflux for 15 h. The solvent was removed by azeotropic distillation with toluene under high vacuum to afford the subtitle compound as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]3[C:35]4[C:30](=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([C:40]([F:43])([F:42])[F:41])[CH:27]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].CO.[OH-].[Na+]>C1COCC1>[F:43][C:40]([F:41])([F:42])[C:28]1[CH:27]=[C:26]([O:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:15]3[CH:14]=[CH:13][C:12]([S:9]([NH:8][CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:44])=[O:2])(=[O:11])=[O:10])=[CH:17][CH:16]=3)=[CH:19][CH:20]=2)[C:35]2[C:30](=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:32]=[CH:33][CH:34]=2)[N:29]=1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)cc1)C(=O)O
Reaction time: 72 h
Yield: 45.9 %

Procedure:
2-[4′-(2,8-Bis-trifluoromethyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester (1.026 g, 1.6 mmol, 1 equiv.) was dissolved in THF (15 mL) and MeOH (6 mL) and 1N NaOH (17.6 mL, 11 equiv.) was added. The reaction was monitored by TLC. It was complete in 3 days. Solvent was removed by rotovap and the residue was dissolved in H2O. The mixture was then acidified to pH 3 with 1N HCl. The resulting precipitate was collected by filtration and washed with cold water and dried overnight. 460 mg of white solid was obtained in 46% yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:15]=[CH:16][C:3]1=2.[OH-].[K+].O.C([OH:27])C>C(O)(=O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:27])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CCO
Reactant: CC(C(N)=O)c1ccc2c(c1)Oc1ncccc1CC2=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)Oc1ncccc1CC2=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
The mixture of 40 mg of 2-(5,6-dihydro-6-oxo benzo[b]-pyrido[3,2-f]oxepin-9-yl)-propionamide, 180 mg of potassium hydroxide, 1.5 ml of water and 5 ml of ethanol was refluxed with stirring for 5 hours. After cooling, the solvent was distilled off to obtain the residue, to this was added ice-water and the mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the oil, which was chromatographed over silica gel, eluted with chloroform-ethanol, and there was obtained 20 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-9-yl)-propionic acid as pale yellow powder.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].O.Cl>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:11][OH:12])[CH2:16][OH:17])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(C(C(=O)OCC)C(=O)OCC)CC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(C(CO)CO)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
340 cm] (1.3 mol) of a 70% NaAlH2 (OC2H4OCH3)2 in toluene with 340 cm3 of anhydrous toluene was stirred at room temperature while adding 57 g (0.2 mol) of diethyl 4-propylcyclohexylmalonate dropwise for 30 minutes, after which it was stirred for 5 hours on a hot water bath at 80°-90° C. The reactant was cooled to room temperature, and 50 cm3 of water and 1,000 cm3 of 15% HCl were dropped while stirring. The oily layer was removed, and the water layer was extracted with toluene and combined with the oily layer and washed with 10% HC1 and water. The toluene was removed, and the residue was recrystallized from hexane to obtain 18 g (0.09 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol (trans-cis form mixture).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.O[C:27]1[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: COC(=O)COc1ccc(O)cc1
Reactant: OC1CCN(c2ccncc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
Diethylazodicarboxylate (0.47 ml) was added dropwise over 30 minutes to a stirred mixture of 1-(4-pyridyl)-4-piperidinol (534 mg), methyl 4-hydroxyphenoxyacetate (546 mg), triphenylphosphine (787 mg) and dry THF (30 ml) in an atmosphere of argon and cooled to 4° C. After 1 hour at 4° C., the mixture was allowed to reach ambient temperature and stirred for 48 hours. The solvent was removed by evaporation and the residue purified by flash chromatography on silica eluting with 5% v/v methanol/dichloromethane. Recrystallisation from ethyl acetate/hexane gave the title compound, 532 mg, as a white solid: m.p. 74°-76° C.; NMR (d6DMSO) δ8.15(2H,bd), 6.89(6H,m), 4.71(2H,s), 4.50(1H,m), 3.70(2H,m), 3.69(3H,s), 3.23(2H,m), 1.96(2H,m), 1.62(2H,m); m/e 343 (M+H)+ ; calculated for C19H22N2O4 : C, 66.7; H, 6.5; N, 8.2. found: C, 66.2; H, 6.7; N, 8.2%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12]2[C:4](=[C:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]1=O.[BH4-].[Na+].CO>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:13][C:12]2[C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:10]3[C:6](=[C:5]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:4]=2[CH:3]=1)[CH2:7][CH2:8][CH2:9]3
Reactant: CC1Cc2c(c(-c3ccccc3)c3c(c2-c2ccccc2)CCC3)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1=Cc2c(c(-c3ccccc3)c3c(c2-c2ccccc2)CCC3)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
17.4 g (51 mmol) of 2-methyl-4,8-diphenyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (4b) and 3.8 g (100 mmol) of sodium borohydride in 100 ml of toluene were placed in a reaction vessel. The solution was heated to 50° C. and 22 ml of methanol was slowly added and the reaction mixture was stirred at 50° C. for 3 hours and then at room temperature overnight. During stirring solids were precipitated. 12 ml of water and 80 ml of 1 N sulfuric acid were added and the mixture was stirred at 35° C. for 30 minutes. 200 ml of methylene chloride was added and organic phase was separated and evaporated and the residue (18.0 g) was taken up in 200 ml of toluene and mixed with 100 mg of p-toluenesulfonic acid. Water was distilled off from this reaction mixture by refluxing for 1 hour on a water separator until reaction was complete. The reaction mixture was washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was dried in an oil pump vacuum. This gave 18 g of pale brawn solid. The crude product was purified by column chromatography.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:11][CH2:12]Cl)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]>O.CCOC(C)=O>[C:5]([O:11][CH2:12][N:1]=[N+:2]=[N-:3])(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
Sodium azide (1.942 g, 29.9 mmol) was added to a suspension of chloromethyl pivalate (3.00 g, 19.92 mmol) in water (5 mL) and stirred vigorously at 90° C. for 16 h. The reaction mixture was diluted with water (20 mL) and EtOAc (20 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated to afford azidomethyl pivalate as a liquid (2 g, 64% yield). 1H NMR (400 MHz, Acetone-d6): δ 5.23 (s, 2H), 1.22 (s, 9H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+]>CO>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Reactant: N=C(N)CC1(c2ccccn2)CCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a stirred solution of 2-(1-pyridin-2-yl-cyclopentyl)-acetamidine hydrochloride (435) (1 g, 3.55 mmol) and 2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (1.638 g, 5.319 mmol) in methanol (15 mL), sodium methoxide (25% in methanol) (2.3 mL, 10.638 mmol) was dropwise added at 0° C. Then reaction mixture was allowed to stir at room temperature for 16 h. Then reaction mixture was quenched with aqueous HCl (1N; 5 mL) and the methanol was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic part was dried, concentrated and the residue was purified by nor mal silica gel (100-200 mesh) column chromatography using 30% ethyl acetate in hexane as eluent to obtain 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (436) (1.2 g, 73%) as a yellow sticky liquid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[CH3:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:27]1[CH:28]=[N:23][CH:24]=[N:25][CH:26]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 3-iodo-4-methyl-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 13.1) and pyrimidin-5-ylboronic acid to afford a yellow oil. UPLC-MS (Condition 1) tR=2.62 min, m/z=374.0 [M+H]+, m/z=372.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 7.37 (d, J=8.6 Hz, 2H) 7.55 (d, J=8.1 Hz, 1H) 7.88 (d, J=9.0 Hz, 2H) 7.95 (s, 1H) 7.98 (d, J=8.1 Hz, 1H) 8.97 (s, 2H) 9.26 (s, 1H) 10.40 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C@@H:7]([O:9]CC2C=CC=CC=2)[C@H:6]([O:17]CC2C=CC=CC=2)[C@H:5]1[CH2:25][O:26]CC1C=CC=CC=1)[CH:2]=[CH2:3].Cl>[Pd].C(O)C>[OH:17][C@H:6]1[C@H:7]([OH:9])[CH2:8][N:4]([CH2:1][CH2:2][CH3:3])[C@@H:5]1[CH2:25][OH:26]
Reactant: C=CCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCN1C[C@@H](O)[C@H](O)[C@H]1CO

Procedure:
The title compound was synthesized as described for compound 9 using (2R,3R,4R)-1-allyl-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (compound 14) (0.910 g, 2.1mmol), ethanol (100 ml), 10% Pd/C (0.2 g) and excess of 1M hydrochloric acid to convert the amine to the hydrochloride salt. After evaporation of the solvent in vacuo the compound was purified on silica gel (Eluent: 2-propanol/25 % ammonium hydroxide (4: 1)) and (2R,3R,4R)-3,4-dihydroxy-2-hydrox-ymethyl-1-propylpyrrolidine was obtained as a yellow crystals (0.279 g, yield: 78%). Melting point: 79°-80° C.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[NH:8][C:7](=S)[C:6]([CH3:11])([CH3:10])[O:5][CH2:4]1.CO.[NH3:22]>>[F:1][CH:2]([F:19])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:4][O:5][C:6]([CH3:11])([CH3:10])[C:7]([NH2:22])=[N:8]1
Reactant: N
Reactant: CC1(C)OCC(c2ccccc2F)(C(F)F)NC1=S
Solvent: CO
Product: CC1(C)OCC(c2ccccc2F)(C(F)F)N=C1N
Temperature: 80 °C

Procedure:
5-Difluoromethyl-5-(2-fluoro-phenyl)-2,2-dimethyl-morpholine-3-thione (2.50 g, 8.64 mmol) was dissolved in NH3 solution 7 mol/L in methanol (40.7 mL, 285 mmol). The sealed reaction vessel was heated to 80° C. for 7 h, then the temperature was lowered to 70° C. and the reaction mixture was stirred over night. The reaction mixture was evaporated and purified on a silica gel column by eluting with CH2Cl2/1-4% EtOH:NH3 9:1 to give 2.09 g of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][C@@H:35]([OH:37])[CH3:36])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:29][CH2:30][N:31]([CH2:34][C@@H:35]([OH:37])[CH3:36])[CH2:32][CH2:33]5)[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: C[C@H](O)CN1CCN(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: C[C@H](O)CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
2-Chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 3.46 mmol) in a manner analogous to Example 68a and was isolated as a pale yellow solid (1.01 g, 95%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.03 (d, J=6.8 Hz, 1H), 8.32 (d, J=8.3 Hz, 2H), 8.14 (d, J=7.5 Hz, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.45 (t, J=7.0 Hz. 1H), 3.29 (s, 3H). MS=308 (MH)+. 142b) (S)-1-(4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and (S)-1-[4-(3-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (84.0 mg, 0.357 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (36.0 mg, 0.0658 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.085 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.6 Hz, 1H), 8.25 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.3 Hz, 1H), 7.40 (s, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.02 (t, J=7.1 Hz, 1H), 6.98-6.95 (m, 1H), 6.87 (s, 1H), 6.61-6.57 (m, 1H), 3.97-3.87 (m, 1H), 3.33-3.21 (m, 5H), 3.10 (s, 3H), 2.90-2.82 (m, 2H), 2.62-2.55 (m 2H), 2.43-2.30 (m, 2H), 1.17 (d, J=6.1 Hz, 3H). MS=507 (MH)+.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[CH2:16]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Reaction time: 1 h

Procedure:
1 g of caffeic acid was dissolved in 25 mL of pyridine. 1.14 mL of 25% aqueous sodium hydroxide solution was added while stirring. Stirring continued for 1 hr. At the end of this period a solution of 2.8 mL of phenethyl bromide was added slowly in 30 minutes. The resulting reaction mixture was stirred at room temperature for 50 hrs. Next, the reaction mixture was poured into 100 mL of 10% HCl and extracted with methylene chloride (2×50 mL). The combined organic extract was washed with water (2×50 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from toluene by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 120 mg and the purity was by TLC single spot.