Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([Cl:21])[CH:16]=[C:17]([C:18](O)=[O:19])[C:12]=2[O:11][C:10]([CH3:23])([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:38][CH:39]1[CH:44]2[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]2)[CH2:40]1>C(OCC)(=O)C>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([Cl:21])[CH:16]=[C:17]([C:18]([NH:38][CH:39]3[CH:44]4[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]4)[CH2:40]3)=[O:19])[C:12]=2[O:11][C:10]([CH3:22])([CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CN2CCC1CC2
Reactant: CC1(C)CN(Cc2ccccc2)c2cc(Cl)cc(C(=O)O)c2O1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(Cc2ccccc2)c2cc(Cl)cc(C(=O)NC3CN4CCC3CC4)c2O1
Temperature: 25 °C

Procedure:
To a solution of 1.5 g of 4-benzyl-6-chloro-2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.2 ml of triethylamine, and 0.55 g of pivaloyl chloride was added dropwise thereto at -10° to -5° C. under cooling. After stirring for 15 minutes at the same temperature, 0.57 g of 3-aminoquinuclidine was added at -10° to -5° C. and the mixture was stirred at room temperature for an hour. The resultant mixture was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of isopropyl ether and ethanol to give 4-benzyl-6-chloro-2,2-dimethyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide as white crystals, melting at 174°-175° C.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=O)[CH3:2].[OH-].[K+].Br[CH:20](C(OCC)=O)[C:21]([O:23]CC)=[O:22]>CCO.Cl.C(O)(=O)C>[CH3:2][C:1]1[C:4]2[C:5](=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)[C:6](=[O:7])[O:8][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(C(=O)O)oc(=O)c2cc(C(F)(F)F)ccc12
Temperature: 90 °C
Yield: 41.7 %

Procedure:
To a solution of 1.12 g (4.8 mol) 2-acetyl-5-(trifluoromethyl)benzoic acid in EtOH (30 ml) were succesively added 270 mg (4.8 mmol) KOH and 1.15 g (4.8 mmol) diethyl 2-bromo-malonate at RT. The resulting mixture was heated at 90° C. for 6 h. After cooling to RT, the RS was concentrated in vacuo. The residue was taken up with water (30 ml) and extracted with EtOAc. The organic layer was washed with water (40 ml) and brine (30 ml), dried over Na2SO4 and concentrated in vacuo. This residue obtained was diluted with hydrochloric acid (10 ml) and acetic acid (6 ml) and the RS was heated at 90° C. for 2 h. After cooling to RT, the RS was poured into ice-water and the precipitate was filtered off to yield 540 mg (2.0 mmol, 41%) 4-methyl-1-oxo-7-(trifluoromethyl)-1H-isochromene-3-carboxylic acid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:34]2[CH:38]=[CH:37][N:36]([CH2:39][CH2:40][NH2:41])[N:35]=2)[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32].C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:34]2[CH:38]=[CH:37][N:36]([CH2:39][CH2:40][NH:41][C:7]([C:5]3[CH:6]=[C:2]([CH3:1])[NH:3][N:4]=3)=[O:9])[N:35]=2)[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]
Reactant: Cc1cc(C(=O)O)[nH]n1
Reactant: COc1cc(-c2ccn(CCN)n2)ccc1[N+](=O)[O-]
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2ccn(CCNC(=O)c3cc(C)[nH]n3)n2)ccc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
3-Methylpyrazole-5-carboxylic acid (70.0 mg, 0.555 mmol), HOBt (85 mg, 0.629 mmol) and PS-carbodiimide (672 mg) were weighed in a glass vial. DCM (4 ml) and DMF (0.4 ml) were added. The mixture was stirred for 10 minutes. 2-(3-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethanamine (97 mg, 0.370 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off. PS-Trisamine (616 mg, 1.849 mmol) was added to the filtrate. The mixture was stirred for 2 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 46 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 2.35 (s, 3H), 3.92, (m, 2H), 4.05, (s, 3H), 4.40, (t, 2H), 6.57 (s, 1H), 6.61 (d, 1H), 7.31 (s, 1H), 7.40-7.43 (m, 1H), 7.47 (d, 1H), 7.62 (d, 1H), 7.96 (d, 1H), 9.94 (s, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>>[O:25]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]4[N:21]=[C:22]([NH:24][C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(Br)cc1
Reactant: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Product: COc1ccc(Nc2nc3cccc(-c4ccc(CN5CCS(=O)(=O)CC5)cc4)n3n2)cc1
Yield: 43.1 %

Procedure:
5-{-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (50 mg, 0.140 mmol) and 1-bromo-4-methoxy benzene (29 mg, 0.154 mmol) were combined in a manner analogous to Example 77 to yield 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-N-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine (28 mg, 42%) as a beige solid. The material was purified via trituration with methanol. MP=241° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.03 (d, J=8.1 Hz, 2H), 7.51-7.67 (m, 6H), 7.17 (d, J=6.4 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 3.80 (s, 2H), 3.69 (s, 3H), 3.15 (br s, 4H), 2.92 (br s, 4H). MS=464 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=O.O.[NH2:13][NH2:14]>C(O)CCC>[NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([NH:13][NH2:14])=[O:10]
Reactant: NN
Reactant: COC(=O)c1scc(C)c1N
Solvent: O
Solvent: CCCCO
Product: Cc1csc(C(=O)NN)c1N

Procedure:
A solution of methyl 3-amino-4-methyl-2-thenoate (25 g) and hydrazine hydrate (20 ml) in butanol (150 ml) was heated under reflux for 18 hours. On cooling the solvent was removed and teh residue was recrystallised from toluene to give the title product, m.p. 141-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:43]([O:45][C:46](=[O:66])[C@@H:47]([CH3:65])[CH2:48][CH:49]([NH2:64])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([Cl:63])[CH:58]=2)=[CH:53][CH:52]=1)[CH3:44]>CN(C=O)C>[CH2:43]([O:45][C:46](=[O:66])[C@@H:47]([CH3:65])[CH2:48][CH:49]([NH:64][C:13]([C:10]1[N:11]=[N:12][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[N:9]=1)=[O:15])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([Cl:63])[CH:58]=2)=[CH:53][CH:52]=1)[CH3:44]
Reactant: COc1ccc(Cn2nnc(C(=O)O)n2)cc1
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid (Intermediate 32) (149 mg, 0.636 mmol) in DMF (2 mL) is added HATU. The mixture is stirred at room temperature for 15 minutes then (S)-4-amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 31) (200 mg, 0.578 mmol) is added and the mixture is stirred at room temperature for 2 hours. Any insoluble material is filtered and the filtrate is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to give (S)-5-(3′-chloro-biphenyl-4-yl)-4-{[2-(4-methoxy-benzyl)-2H-tetrazole-5-carbonyl]-amino}-2-methyl-pentanoic acid ethyl ester; HPLC Retention time 1.79 minutes (condition C): MS 562.4 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:16]=[C:17]([C:23]5[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=5)[S:18][C:19]=4[CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:8]=[N:7]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:28]([N:24]1[C:23]([C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:13]4[CH:12]=[C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][CH2:4][OH:3])[CH:10]=5)[CH:32]=[CH:31][C:14]=4[C:15]=3[N:16]=2)=[N:27][CH:26]=[N:25]1)([CH3:30])[CH3:29]
Reactant: CCOC(=O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCO)c3)ccc1-2
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of {4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-acetic acid ethyl ester in THF (200 mL) was cooled to 0° C. and treated dropwise with a solution of 1M LiAlH4 (in THF, 23 mL, 23 mmol, 2.5 eq). After 1 h, LCMS indicated consumption of starting material. A solution of saturated sodium sulfate was added slowly until H2 evolution ceased. ˜30 g of solid magnesium sulfate was added and the whole was stirred for 20 min. Filtration over celite (EtOAc and DCM) followed by concentration of the filtrant gave a crude residue that was purified by reverse-phase HPLC to give 1.4 g of 105 (43%). LCMS: 423.1. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.43 (dd, J=8.3, 1.6 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 5.84 (dt, J=13.2, 6.6 Hz, 1H), 4.91 (t, J=5.3 Hz, 1H), 4.39 (t, J=4.9 Hz, 2H), 4.16 (t, J=5.6 Hz, 2H), 3.77 (q, J=5.5 Hz, 2H), 3.44 (t, J=4.9 Hz, 2H), 1.56 (d, J=6.6 Hz, 6H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br-].[CH3:13][C:14]([CH3:16])=[O:15].Cl>CCOCC>[OH:15][C:14]([CH3:16])([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: CC(C)=O
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a mixture of magnesium turnings 13.16 g (0.541 mol) in 200 ml of anhydrous Et2O was added 100.0 g (0.492 mol) of 1-bromo-3-phenyl propane as a solution in 100 ml of Et2O. After of 5-10 ml of the solution had been added, the addition was stopped until the formation of the Grignard reagent was in progress. The remaining bromide was then added over 1 hour. The Grignard reagent was stirred for 20 minutes at 35° C. and then 31.64 g (0.541 mol) of acetone was added over a 45 minute period. The reaction was stirred overnight at room temperature before being cooled to 0° C. and acidified by the careful addition of 20% HCl. The aqueous layer was extracted with Et2O (3×200 ml) and the combined organic layers washed with water, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvent under reduced pressure and distillation of the residue afforded 63.0 g (72%) of the product as a pale-yellow oil, bp 99°-102° C./0.5 mm Hg. 1H NMR (CDCl3): δ 7.28-7.18 (5H, m), 2.63 (2H, t, J=7.5 Hz), 1.68 (2H, m), 1.52 (2H, m), 1.20 (6H, s).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:5][C@H:4]1[OH:22].[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH2:2][C@H:3]3[CH2:7][N:6]([CH2:8][CH2:9][C:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=5)[N:13]=[CH:12][CH:11]=4)[CH2:5][C@H:4]3[OH:22])[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2nccc(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(CCN3C[C@H](CNCc4cc5c(cn4)OCCO5)[C@H](O)C3)c2n1
Reaction time: 24 h
Yield: 26.6 %

Procedure:
To a stirred solution of (3S,4S)-4-(aminomethyl)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.30 g, 1.0 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.165 g, 1.0 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.32 g, 1.5 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.12 g, 27%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.67 (d, J=4.5 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.68 (d, J=4.5 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 7.02 (s, 1H), 4.61 (m, 1H), 4.38 (m, 4H), 4.20 (s, 2H), 4.15 (s, 3H), 3.60 (m, 8H), 3.42 (m, 1H), 3.25 (m, 1H), 2.82 (m, 1H). LC-MS (ES) m/e 452 (M+H)+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][CH2:23][CH2:24][OH:25])[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([O:25][CH2:24][CH2:23][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:12]1[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:10][CH:11]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccccc1OCc1coc(/C=C/c2ccccc2)n1
Product: CS(=O)(=O)OCCCc1ccccc1OCc1coc(/C=C/c2ccccc2)n1
Yield: 95 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with methanesulfonyl chloride to give 3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The yield was 95%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 93-94° C.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20]C)[C:17]([O:22]C)=[C:16]([O:24]C)[CH:15]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([OH:20])[C:17]([OH:22])=[C:16]([OH:24])[CH:15]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1cc(O)c(O)c(O)c1)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
(2-Phenyl-thiazol-4-yl)-(3,4,5-trihydroxy-phenyl)-methanone (11f) was synthesized beginning with compound 8f. To a solution of compound 8f (123 mg, 0.35 mmol) in 5 mL anh. CH2Cl2 was added BBr3 (1M solution in CH2Cl2, 1.75 mL, 5 mmol) under −78° C. The mixture was stirred for 2 h and a solution of amide 7 (1.14 mmol) in 3 mL THE was charged. The mixture was allowed to warm to room temperature slowly and stirred overnight. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl acetate, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound as red crystalline solid. Yield: 50.9%. M.p. 175-176° C. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, 1H), 8.07-8.04 (m, 2H), 7.57-7.55 (m, 3H), 7.33 (s, 2H). MS (ESI) m/z 336.1 [M+Na]+. Anal. (C6H11NO4S) C, H, N.
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](O)=[O:16])[CH:10]=[C:11]([Cl:13])[CH:12]=1>C1COCC1>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][OH:16])[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: O=C(O)Cc1cc(Cl)cc(CBr)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1cc(Cl)cc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of borane dimethyl sulfide complex (2M in THF, 2.8 mL) was added portionwise over 5 minutes to a solution of 2-(3-(bromomethyl)-5-chlorophenyl)acetic acid [Aromatic Intermediate 8, step a] (0.73 g) in dry THF (10 mL) at room temperature. The resulting effervescing solution was stirred for 1 hour, then cooled in ice-water and quenched by the portionwise addition of methanol (3 mL) over 5 minutes. The solution was stirred at room temperature for a further 20 minutes and then concentrated in vacuo. The residue was purified by flash chromatography on silica eluted with 25% ethyl acetate in isohexane to afford the crude subtitled compound as a white solid. Yield 0.46 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]([O-])=[O:19])[S:17][C:10]=12.[Li+]>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[Cl:8])[CH:15]=2)=[O:19])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(Nc1ccncc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 4-aminopyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 290/292 (MH+); HPLC Rf: 4.63 min.; HPLC purity: 99%.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:41][CH:42]1[CH2:44][CH2:43]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl>O1CCCC1>[CH:42]1([CH2:41][N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]3([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:15]=2)=[O:13])[CH2:44][CH2:43]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a stirred solution 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (446) (200 mg, 0.325 mmol) of in tetrahydrofuran (10 mL) was added (1N) aqueous HCl (2 mL). The mixture was stirred for 1 h at room temperature. After completion of the reaction, volatiles were removed, the residue diluted with water (10 mL) and pH was adjusted to 8 using NaHCO3. The mixture was extracted with ethyl acetate (2×30 mL), and the organic part was dried and concentrated. The resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 50-60% ethyl acetate in hexane as gradient polarity mobile phase to get 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropylmethyl-(2-hydroxyethyl)-amide (447) (123 mg, 75%) as a colorless gummy liquid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH3:10][C:11]1[S:12][C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=1>O1CCCC1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:17]([C:13]1[S:12][C:11]([CH3:10])=[N:15][C:14]=1[CH3:16])=[O:18]
Reactant: c1c[nH]cn1
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)c2ncc[nH]2)s1
Reaction time: 0.5 h

Procedure:
To a solution of imidazole (2.72 g; 40 mmol) in dry tetrahydrofuran (60 ml) was added dropwise thionyl chloride (1.20 g; 10 mmol) under ice-cooling while stirring. After the resultant mixture was turned to room temperature, 2,4-dimethyl-5-thiazolecarboxylic acid (1.57 g; 10 mmol) was added thereto at once, and stirring was continued for 30 minutes, whereby 5-imidazolylcarbonyl-2,4-dimethylthiazole was produced. To the mixture was added dropwise a solution of 2-(2-furyl)aminoacetonitrile (1.46 g; 12 mmol) in dry tetrahydrofuran under ice-cooling, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, tetrahydrofuran was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude crystals. Recrystallization from ethanol gave 2.0 g of 2-(2,4-dimethylthiazole-5-carboxamido)-2-(2-furyl)acetonitrile as colorless crystals. m.p., 108° -109° C. Yield, 74%.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[N:5]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(=O)[nH]1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1

Procedure:
The title compound was prepared from 6-methyl-4-(6-trifluoromethyl-pyridin-3-yl)-1H-pyrimidin-2-one (2.0 g, 7.84 mmol) and phosphoroxychloride (12 ml) according to the general procedure I. Obtained as an orange solid (1.33 g, 62%). MS (ISP) 274.1 [(M+H)+]; mp 123.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 75.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (62 mg, 75.2%) as an orange solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:19](=[O:25])[CH:18]([CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:17]2.C(Br)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:17][CH:18]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:11][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:29][CH2:28]3)[C:19](=[O:25])[C:20]2=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCNCC1)C2
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Yield: 95.3 %

Procedure:
0.18 g of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one p-toluenesulfonic acid salt were dissolved in 10 mL of dry N,N′-dimethylformamide. 0.073 g of benzyl bromide and 0.3 g of potassium carbonate were added thereto. The resulted mixture was stirred until the reaction completed. Then 60 mL of water were added and the solution was extracted with 4×30 mL of ethyl acetate. The extracts were combined, washed with 15 mL of Na2CO3 solution and with 15 mL NaCl solution, and dried over anhydrous MgSO4. Drying agent was then filtered off. The solvent was removed in vacuo yielding 0.141 g of product, 96% yield. 1H NMR (CDCl3), 7.15-7.35 (m, 5H), 7.09 (s, 1H), 6.78 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.48 (s, 2H), 3.17 (dd, 1H, J=8.0 Hz, J=17.6 Hz), 2.82-2.92 (m, 2H), 2.58-2.74 (m, 2H), 1.80-2.03 (m, 3H), 1.57-1.76 (m, 2H), 1.40-1.56 (m, 1H), 1.18-1.40 (m, 3H).