Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][CH:9]1[C:16]([O-:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([NH2+]C(C1C=CC=CC=1)C)C1C=CC=CC=1.Cl.[Na+].[Cl-]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:12][CH2:13]2)[CH2:10][CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C(=O)[O-]
Agent: CC([NH2+]Cc1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C(=O)O
Temperature: 0 °C
Yield: 81.6 %

Procedure:
To a suspension of N-benzyl-1-phenylethanaminium 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylate (single unknown enantiomer) (D2) (10 g, 24 mmol) in EtOAc (100 mL) stirred at 0° C. was slowly added aqueous HCl 0.5N (100 ml) saturated with NaCl. After addition was completed, dissolution was observed. The organic layer was decanted, washed with saturated NaCl, dried (Na2SO4) and evaporated in vacuo to afford 5 g of acid which was recrystallized from petroleum ether/EtOAc (60 ml/20 ml) to afford the tile compound (D3) (2.8 g) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]2[C:29]3[C:28](=[O:30])[CH2:27][CH:26]([CH2:31][CH2:32][CH3:33])[CH2:25][C:24]=3[NH:23][C:22]([CH3:34])=[C:21]2[C:35]#[N:36])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl.C(OCC)(=O)C>[Br:19][C:6]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[C:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])[CH:3]=[C:4]([CH:20]2[C:29]3[C:28](=[O:30])[CH2:27][CH:26]([CH2:31][CH2:32][CH3:33])[CH2:25][C:24]=3[NH:23][C:22]([CH3:34])=[C:21]2[C:35]#[N:36])[CH:5]=1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(OCc2cccc([N+](=O)[O-])c2)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc([N+](=O)[O-])c2)c(NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
A solution of 4-[3-amino-5-bromo-4-(3-nitro-benzyloxy)-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (1.15 g) and triethylamine (740 μl) in dichloromethane (20 ml) was treated with methanesulfonyl chloride (203 μl). After stirring for 18 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude N,N-bis-methanesulfonyl-aniline derivative was dissolved in THF (20 ml) and treated with 2N NaOH (3 ml). After 2 h, the mixture was quenched with sat. aq. NH4Cl and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20](Br)=[CH:19][N:18]=1.O>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:19][N:18]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cccnc2)cc1[N+](=O)[O-]

Procedure:
0.21 g of dichlorobis(tricyclohexylphosphine)palladium, 0.66 g of 3-pyridyl-boronic acid and 14 ml of a 2N sodium carbonate solution are added to a solution of 1.02 g of 2-amino-5-bromo-3-nitropyridine in 40 ml of degassed dioxane. The mixture is heated to reflux under N2 for 28 hours and, after cooling and addition of water, extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is crystallized from ethyl acetate. This gives 0.58 g of the title compound of m.p. 226–228° C. The mass spectrum shows the molecular peak MH+ at 217.2 Da.
Reaction SMILES: [CH:1]1([C@:4]2([C:27]#[N:28])[CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]4[CH:17]=[N:18][N:19]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[CH:20]=4)[N:10]=3)[C:5]2=[O:26])[CH2:3][CH2:2]1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:28][CH2:27][C@@:4]1([CH:1]2[CH2:3][CH2:2]2)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[N:18][N:19]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[CH:20]=3)[N:10]=2)[C:5]1=[O:26]
Reactant: CC(C)(CO)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Agent: Cl[Co]Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC(C)(CO)n1cc(Nc2nccc(N3CC[C@@](CN)(C4CC4)C3=O)n2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.8 %

Procedure:
To a solution of (3S)-3-cyclopropyl-1-(2-((1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (400 mg) obtained in Step I of Example 103 and cobalt(II) chloride hexahydrate (1.0 g) in methanol (6.0 mL) was added sodium borohydride (400 mg), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution in an ice bath, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (84 mg).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[C:37]([O:44][CH3:45])[CH:36]=1.C(=O)(O)[O-].[Cs+]>COCCOC.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[CH2:32]([N:30]1[N:29]=[N:28][C:27]([CH2:26][N:5]2[C:4]3[CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([F:34])=[CH:36][C:37]=4[O:44][CH3:45])[S:10][C:9]=3[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]3)[C:6]2=[O:25])=[N:31]1)[CH3:33]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])O
Solvent: COCCOC
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1

Procedure:
Tert-butyl 4-{6-bromo-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (405 mg, compound B101), (4-fluoro-2-methoxyphenyl)boronic acid (140 mg), dichlorobis(tricyclohexylphosphine)palladium (55 mg) and aqueous cesium bicarbonate solution (0.563 ml, 2.0 M) in DME (10 ml) are reacted according to the procedure described in example B55 to afford the title compound after purification by flash column chromatography [silica gel, elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 to 30/70 (v/v)] as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>ClCCl.O>[N+:27]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:17]=1[NH:1][CH2:2][C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH:25][CH:24]=[CH:23][CH:22]=2)([O-:29])=[O:28]
Reactant: NCC1(O)CCCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCCC1
Yield: 65.1 %

Procedure:
To a solution of 1-(aminomethyl)cyclopentanol (approximately 55.2 mmol, prepared as described above) in dichloromethane (280 mL) was added triethylamine (7.76 mL, 55.7 mmol) and 4-chloro-3-nitroquinoline (9.22 g, 44.3 mmol). The mixture was allowed to stand at rt over the weekend. A solid formed that was isolated by filtration. Two more crops of solid were isolated from the mother liquor. The yellow solid was stirred in water and filtered. The solid was washed with water multiple times and was dried under vacuum with heat to give 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopentanol as yellow crystals (8.29 g, 52%).
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.N1C=CC=CC=1.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl>[C:37]([O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Reaction time: 20 h

Procedure:
To a solution of dehydro-aripiprazole (1.2 g, 2.7 mmol) in dichloromethane (30 mL) was added pyridine (1 mL), followed by pivaloyl chloride (0.66 mL, 5.4 mmol). The reaction mixture was stirred for 20 hours, then washed with water and dried over MgSO4. After evaporation the residue was co-evaporated with toluene and then further purified on silica eluting with ethyl acetate. After evaporation of the product containing fraction, Compound-316 (0.53 g) was obtained as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:17]([N:20](C)[C:21](=O)[O-])=[N:18][CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:21][NH:20][C:17]1[N:18]=[CH:19][C:14]([C:5]2[N:4]=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:15][CH:16]=1
Reactant: CN(C(=O)[O-])c1ccc(-c2nnc(N)nc2-c2ccccc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(-c2nnc(N)nc2-c2ccccc2)cn1
Yield: 71.4 %

Procedure:
6-(6-(Methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (49.5 mg, 0.177 mmol, 71.4%) was prepared from 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-2-yl(methyl)carbamate (vide supra), by BOC deprotection with trifluoroacetic acid (0.4 mL) in dichloromethane (1.6 mL) for 1 hour at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=O)[CH:9]=1.[BH4-].[Na+].O.[CH3:18][NH2:19]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH2:13][NH:19][CH3:18])[CH:9]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CNCc1c[nH]c(-c2ccccc2F)c1
Reaction time: 1 h

Procedure:
5-(2-Fluorophenyl)-1H-pyrrol-3-carboxaldehyde 1d (1.89 g, 10 mmol, prepared by a known method disclosed in “Journal of Medicinal Chemistry”, 2012, 55(9), 4446-4456) was dissolved in 20 mL of methylamine, and the reaction solution was stirred for 1 h. Sodium borohydride (1.14 g, 30 mmol) was added and continuously stirred for 1 h. 10 mL of water were added to the reaction solution, and the reaction solution was concentrated under reduced pressure to obtain the title product 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine 1e (2.0 g, a yellow oil), which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.Br[CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22].S.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[N:5]([CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)[nH]c1cc(Br)ccc12
Reactant: CCCCC(CC)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: S
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCC(CC)Cn1c2cc(Br)ccc2c2ccc(Br)cc21

Procedure:
A mixture of 2,7-dibromocarbazole (3.0 g, 8.95 mmol), 1-bromo-2-ethylhexane (2.70 g, 13.4 mmol), tetra-n-butylammonium hydrogen sulfide (0.1 g), and NaOH (0.54 g, 13.5 mmol) in acetone (30 mL) was refluxed for 9 h. After the reaction, the acetone was removed under vacuum and the residue was extracted with toluene. The combined organic layer was washed with a saturated NaCl aqueous solution, and dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel using hexane as the eluent to afford 2,7-dibromo-9-(2-ethylhexyl)-carbazole as a white powder. Yield: 2.46 g (62.9%). M.P.: 95-97° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[C:23]([C:30]5[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])=[N:24][O:25][C:26]=4[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=3[CH3:38])=[CH:11][CH:12]=2)[N:7]([CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:6]=1)=[O:4].CO.[OH-].[Na+]>C1COCC1>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[C:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:10]3[CH:9]=[C:8]4[C:13]([C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]4[CH2:39][CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:12][CH:11]=3)=[C:15]([CH3:38])[CH:16]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[O:25][N:24]=1
Reactant: COC(=O)c1cn(CCS(C)(=O)=O)c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc2c(C(=O)O)cn(CCS(C)(=O)=O)c2c1
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A mixture of 6-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-1-(2-methanesulfonyl-ethyl)-1H-indole-3-carboxylic acid methyl ester (235 mg, 0.358 mmol), methanol (17 mL), THF (8 mL), and 5 N sodium hydroxide (1.29 mL) is heated at reflux for two days. The mixture is allowed to cool and is concentrated under reduced pressure to near dryness. Approximately 10 mL of water is added and the mixture is stirred for two hours. The mixture is filtered and the solid is washed with water and dried to provide the title compound (187 mg, 81%). LCMS (ES+): (641.0).
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[C:3]([CH:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].C1(C(CCC)(CCC)C(C(C(OCC)=O)C(OCC)=O)=O)C=CC=CC=1>>[OH:13][C:11]1[C:18]2[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:2]([CH3:16])([CH3:1])[C:3](=[O:4])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1
Agent: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Product: CCOC(=O)C1=C(O)c2ccccc2C(C)(C)C1=O

Procedure:
The title compound was prepared according to the procedure of Example 1F, substituting the product of Example 9D for the product of Example 1E. 1H NMR (300 MHz, CDCl3): δ 15.16, 15.03 (two s, 1 H), 8.18 (m, 1 H), 7.52 (m, 3 H), 4.47 (m, 2 H), 1.66 (s, 3H), 1.51 (s, 3 H), 1.45 (t, J=6.62 Hz, 3 H).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[OH:9])=[N+:2]=[N-:3].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:9][C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[N:1]=[N+:2]=[N-:3])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1Oc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Trans-1-azidocyclopentan-2-ol 1.27 g was dissolved in DMF and treated with sodium hydride (400 mg. 60%) at room temperature for 1 h. 4-Fluoronitrobenzene (1.41 g) was added and the mixture stirred at 50° C. for 4 h and then left at room temperature overnight. The reaction was quenched with water and extracted with ether. The organic solution was washed with water, dried (MgSO4) and evaporated. Purification by flash chromatography (SiO2-20% DCM/hexane) gave trans-2-(4-nitrophenoxy)cyclopentylazide. 1H nmr (CDCl3) 8.22 (2H, d); 6.98 (2H, d); 5.63 (1H, m); 4.07 (1H, m); 2.20 (2H, m); 1.87 (4H, m).
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1C(Cl)=O.CO.S(=O)(=O)(O)O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:4]([CH2:6][C:7]([O:9][CH3:2])=[O:8])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC(=O)c1c(F)cccc1F

Procedure:
To 3.6 g (25 mmole, 1 eq) of Meldrum's acid and 6.1 g of 4-dimethylamino-pyridine in 60 ml of methylenechloride was added with stirring, 4.4 g (25 mmole) of 2,6-difluorobenzoylchloride. The temperature was maintained at 0° throughout the addition period and for three additional hours of stirring under argon atmosphere. Most of the methylene chloride was then removed by distillation at 25° or less using a water aspirator to maintain reduced pressure. There was then added 60 ml of anhydrous methanol containing 25 mmole of conc. sulfuric acid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[CH:21][CH:20]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:25](/[CH:24]=[CH:23]/[C:22]3[CH:28]=[CH:29][C:19]([O:18][CH2:17][O:16][CH3:15])=[CH:20][CH:21]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COCOc1ccc(C=CC(=O)O)cc1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)cc3)nc2n(CC)c1=O
Yield: 64.2 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 4.00 g (20.2 mmol) of 5,6-diamino-1,3-diethyluracil and 4.62 g (22.2 mmol) of 4-methoxymethoxy-cinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 4.80 g (yield 64%) of Compound 145 as pale yellow needles.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C@H:12]3[NH:23][CH2:22][CH2:21][C@@:18]4([C:19]=2[CH:20]=1)[C@H:13]3[CH2:14][CH2:15][CH2:16][CH2:17]4)(=[O:5])=[O:4].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>C(Cl)Cl>[CH:28]1([CH2:27][N:23]2[CH2:22][CH2:21][C@@:18]34[C:19]5[CH:20]=[C:7]([O:6][S:3]([C:2]([F:1])([F:24])[F:25])(=[O:5])=[O:4])[CH:8]=[CH:9][C:10]=5[CH2:11][C@@H:12]2[C@@H:13]3[CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:30][CH2:29]1
Reactant: BrCC1CC1
Reactant: O=S(=O)(Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CC1CC1)CC3)C(F)(F)F
Reaction time: 5 h
Yield: 77 %

Procedure:
To a solution of compound 38 (50 mg, 0.13 mmol) and TEA (74 μL, 0.53 mmol) in dry CH2Cl2 (2 mL) was slowly added (bromomethyl)cyclopropane (25 μL, 0.26 mmol) at 0° C. and the mixture stirred for 5 h. Solvent was removed under reduced pressure. The crude product was purified on a silica gel column chromatography (95:5 CH2Cl2/MeOH) to give a white solid (43 mg, 77% yield): 1H NMR (300 MHz, CDCl3) 0.19˜2.10 (m, 17H); 2.31 (d, J=13.8 Hz, 1H); 2.47˜2.59 (m, 2H); 2.78˜2.88 (m, 2H); 3.30 (s, 1H); 7.02˜7.06 (m, 1H); 7.13˜7.20 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[OH:9].[OH-].[K+].[CH2:18](Br)[CH:19]=[CH2:20].[Na+].[Cl-]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH2:20][CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COC(=O)CCc1ccc(O)c(OC)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CCC(=O)OC)cc1OC
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
13.1 g methyl 3-(3-methoxy-4-hydroxyphenyl)propionate (62.4 mmol) is dissolved in 150 ml dry N,N-dimethylformamide (DMF). After addition of 4.0 g 88% KOH (62.7 mmol) to this solution, the whole is stirred for 30 minutes, after which 7.55 g allyl bromide (62.4 mmol) in 120 ml dry DMF is added dropwise over a 30-minute period. After stirring for 11/2 hours at room temperature, the reaction mixture is poured out into 1700 ml saturated NaCl solution. Extraction with ethyl acetate, evaporation to dryness and chromatography on 150 g silica gel with tolueneethyl acetate (95:5) as eluent gives 12.4 g methyl 3-(3-methoxy-4-allyloxyphenyl)propionate as an oil. Rf in toluene:ethyl-acetate (85.15)=0.5 on SiO2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH2:21][CH2:22][N:23]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:29])[F:30])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)nc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.3 %

Procedure:
1-(2-Chloro-phenyl)-5-[6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-3-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 356, methanesulfonyl chloride (6.0 uL, 0.08 mmol), and triethylamine (38.0 uL, 0.28 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH:8]([CH3:10])[CH3:9].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[CH3:11][C:12]1[N:17]=[C:16]([S:18][CH2:2][C:3]2[S:7][CH:6]=[N:5][C:4]=2[CH:8]([CH3:10])[CH3:9])[N:15]=[C:14]([OH:19])[CH:13]=1
Reactant: CC(C)c1ncsc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2scnc2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of 5-(bromomethyl)-4-(propan-2-yl)-1,3-thiazole (5.1 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (510 mg, 3.6 mmol), and triethylamine (2.2 mL, 15.8 mmol) in absolute ethanol (30 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness and then co-evaporated with EtOAc (20 mL). The residue was treated with water (100 mL). The solid material was recovered by filtration and washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL). The solid material was dried in vacuo, affording the title compound (565 mg, 56% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, 6H, J=6.8 Hz), 2.24 (s, 3H), 3.27 (m, 1H), 4.61 (s, 2H), 6.03 (s, 1H), 8.84 (s, 1H); M+ 282.