Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.08 h
Yield: 62 %

Procedure:
To a solution of 3,17β-dihydroxyestra-1,3,5(10)-triene-2-carboxaldehyde (2a, 0.300 g, 1.0 mmol) in acetone (20 mL) was added Jones reagent (0.5 mL) at 0° C. The reaction mixture was stirred for 5 min, then quenched with 2-propanol, and extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (MgSO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:THF (4:1→3:1, v/v) to approximately 0.185 g of 5 (62% yield), m.p. 154°-157° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:16]1([N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCC1
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C2CCN(C3CCCC3)CC2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(4-Nitrophenyl)piperidine (5 g, 24 mmol) was dissolved in MeOH (240 mL). To the solution were added cyclopentanone (6.5 mL, 73 mmol) and acetic acid (3 mL). The mixture was stirred for 1 hour, and then NaBH3CN (6.1 g, 97 mmol) was added. The mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was suspended in EtOAc. The organic suspension was washed with 1N NaOH (aq), water and brine, dried, concentrated and purified by flash column chromatography (MeOH/DCM) to obtain 1-cyclopentyl-4-(4-nitrophenyl)piperidine (303) (6.5 g, 24 mmol, 100% yield).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[N:13]=1)[CH2:6][C:7]([O:9]CC)=[O:8])#[N:2].[Li+].[OH-].O.Cl>C1COCC1>[C:1]([CH2:3][CH2:4][N:5]([C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[N:13]=1)[CH2:6][C:7]([OH:9])=[O:8])#[N:2]
Reactant: CCOC(=O)CN(CCC#N)c1cc(C)nc(-n2ccnc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N(CCC#N)CC(=O)O)nc(-n2ccnc2)n1
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid, ethyl ester (4.51 g, 14.4 mmol) dissolved in THF (250 mL) was added LiOH (0.91 g, 21.7 mmol) and water (30 mL). After stirring for 18 hours, most of the solvent was removed in vacuo and 1 N HCl (21.7 mL, 21.7 mmol) was added. The solid that formed was suction filtered and collected on paper to give 3.17 g of 2-[(2-cyanoethyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]acetic acid (a compound of formula (Yc2)).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].[CH:18]1([CH2:23][C:24](OC)=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+].Cl>C(O)C>[CH:18]1([CH2:23][C:24]2[NH:17][C:15](=[O:16])[C:3]3[CH:4]=[N:5][N:6]([C:7]4[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=4[CH3:14])[C:2]=3[N:1]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cccc(C)c1-n1ncc(C(N)=O)c1N
Reactant: COC(=O)CC1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C)c1-n1ncc2c(=O)[nH]c(CC3CCCC3)nc21
Temperature: 25 °C

Procedure:
0.1 g (0.43 mmol) of 5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (Example 15A) is dissolved under argon in 6 ml of absolute ethanol and 0.24 g (1.7 mmol) of methyl cyclopentylacetate and 0.17 g (4.34 mmol) of 60% sodium hydride (suspension in mineral oil) are added. The reaction mixture is heated to reflux overnight. Cooling to room temperature is followed by acidification with concentrated hydrochloric acid. The sodium chloride precipitated thereby is filtered off. The filtrate is concentrated in vacuo, and the remaining residue is purified by preparative HPLC(YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 74 mg (53% of theory) of the product are obtained as a colourless solid.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:28]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:23])[CH2:15][O:16]C2CCCCO2)[CH2:5][C@@H:4]([OH:31])[CH2:3]1.C(O)(=O)C>O>[CH3:23][C@@H:14]([C@@H:13]1[C@:24]2([CH3:30])[C@H:10]([C@H:9]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:29])[C:6]([CH2:5][C@@H:4]([OH:31])[CH2:3][C@@H:2]2[OH:1])=[CH:7][CH2:8]3)[CH2:11][CH2:12]1)[CH2:15][OH:16]
Reactant: C[C@H](COC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
A solution of 0.69 g. of (20S)-1α,3β-dihydroxy-20-methyl-21-tetrahydropyranyloxypregna-5-ene in 6.9 ml. of acetic acid and 2.1 ml. of water was warmed to 80° and an additional 3.2 ml. of water was added. The mixture was kept at 80° for one hour, cooled and poured into water. The suspension was extracted with ethyl acetate and the organic solution was washed with saturated sodium bicarbonate solution and water. After drying and evaporation under vacuum, 0.6 g. of (20S)-20-methyl-1α,3β,21-trihydroxypregna-5-ene was obtained. Recrystallization from acetone gave 0.3 g. of colorless prisms, m.p. 208°-209°; [α]D =-29° (c=0.5, methanol).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:20]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.00 g, 3.05 mmol), isopropenyl boronic acid pinacol ester (513 mg, 3.05 mmol), saturated aqueous sodium carbonate solution (14 ml) and tetrakis(triphenylphosphine)palladium(0) (99.5 mg, 0.0861 mmol) in dimethoxyethane (17 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (680 mg, 77.0%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[OH:10]O>CC(O)=O.O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N+:3]=1[O-:10]
Reactant: Cc1cnc(C)c(C)c1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c(C)[n+]([O-])c1
Temperature: 100 °C

Procedure:
To a solution of 3,5-lutidine (42.86, 0.400 mol) in toluene (240 ml) in a three-neck flask, under N2 atmosphere, was added dropwise MeLi [0.33M in ether, 1330 ml (0.44 mol), prepared from CH3I and Li or obtained from Aldrich]. The reaction was stirred and heated at 60°-80° C. for 6 h, after which time the ether was distilled off. The remaining solution was poured into water/crushed ice (200 ml), acidified with conc. HCl and extracted with ethyl acetate (2×100 ml). The aqueous solution then was basified with aq. NaOH and extracted with CH2Cl2 (3×100 ml). The CH2Cl2 extracts were combined, washed with sat. NaCl solution (1×50 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was distilled under reduced pressure to give 2,3,5-trimethylpyridine (35.24 g, 72%) as a pale oil; bp 65°-71° C./11 mmHg. A solution of 2,3,5-trimethylpyridine (36.35 g, 0.30 mol) in AcOH (120 ml) was treated with 30% H2O (45 ml) and the mixture heated at 100° C. for 3 h. An additional aliquot of 30% H2O2 (15 ml) was added and the mixture was heated for an additional 10 h at 100° C. The reaction was cooled to rt, diluted with water (100 ml) and concentrated in vacuo. The residue again was diluted with water (200 ml), neutralized with KOH pellets and extracted with CH2Cl2 (3×100 ml). The extracts were combined, washed with sat. NaCl (1×50 ml), dried (MgSO4) and the solvent removed in vacuo to give 2,3,5-trimethylpyridine-N-oxide as a pale yellow solid, (50 g, quant.); mp 41°-42° C. (hexanes, colorless needles).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][OH:5].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])(=[O:20])[CH3:19]
Reactant: CC(=CCO)CCC=C(C)CCC(=O)C(C)C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC=C(C)CCC=C(C)CCC(=O)C(C)C
Yield: 94.7 %

Procedure:
To a solution of 3,7,11-trimethyl-2,6-dodecadien-10-on-1-ol (47.6 g) in acetic anhydride (61 g), pryidine (16 g) is added, and the resultant mixture is allowed to stand while cooling with ice for 3 hours. The reaction mixture is poured on ice and extracted with ether. The ether extract is washed with aqueous saturated solution of sodium chloride, aqueous solution of sodium hydrogen carbonate and water in order, dried over magnesium sulfate and evaporated to give 1-acetoxy-3,7,11-trimethyl-2,6-dodecadien-10-one (53 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][OH:22]>C1COCC1>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][OH:22])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: OCCC1CCCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(N2CCCCC2CCO)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 85.2 %

Procedure:
3 g (14.7 mmol) of 2-chloro-3,5-dinitropyridine, 1.0 ml of THF and 30 mmol of 2-piperidinethanol were placed in a round-bottomed flask. The mixture was maintained at 60° C. for 15 hours with stirring and was then poured into an ice-water mixture with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 3.71 g of yellow powder were obtained.
Reaction SMILES: C(S([C:5]1[N:6]=[CH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)=[N:11][C:9]=2[N:10]=1)=O)C.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>O1CCOCC1>[C:29]([N:32]1[CH2:37][CH2:36][N:35]([C:5]2[N:6]=[CH:7][C:8]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)=[N:11][C:9]=3[N:10]=2)[CH2:34][CH2:33]1)(=[O:31])[CH3:30]
Reactant: CCS(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: CC(=O)N1CCNCC1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-[2-(ethylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzaldehyde (3-1; 63 mg, 0.16 mmole) in dioxane (1 mL) was added 1-acetylpiperazine and heated to 150° C. in a microwave reactor for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% Hex. to 100% EtOAc) to give the title compound. LRMS m/z (M+H) Calcd: 438.5, found 438.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[N:16]=[C:15]([O:17][CH2:18][CH3:19])[S:14][N:13]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:13]2[C:12](=[O:11])[N:16]=[C:15]([O:17][CH2:18][CH3:19])[S:14]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1nc(O)ns1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCOc1nc(=O)n(C(=O)Nc2cccc(Cl)c2)s1
Temperature: 20 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
43 g of 3-chlorophenyl isocyanate were added to a solution of 29.4 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 300 ml of tetrahydrofuran and the mixture was stirred for 21/2 hours at 20° C. The mixture was evaporated to dryness under reduced pressure and the residue was crystallized from ethyl acetate to obtain 26 g of 2-(N-m-chlorophenylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 141° C.
Reaction SMILES: [CH:1]1([C:4]2[S:25][C:7]3[NH:8][C:9](=[O:24])[N:10](CC4C=CC(OC)=CC=4OC)[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][C:29]=1[F:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C:4]2[S:25][C:7]3[N:8]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:30][C:29]=4[F:42])[C:9](=[O:24])[NH:10][C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Reactant: COc1ccc(Cn2c(=O)[nH]c3sc(C4CC4)cc3c2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(C4CC4)sc32)c(F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A mixture of 6-cyclopropyl-3-(2,4-dimethoxybenzyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (1.8 g), potassium carbonate (1.5 g) and acetonitrile (200 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (50 mL), and the mixture was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (50 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (50 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.5 g, 64%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9](N)=[O:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[OH-:12].[Na+].[ClH:14]>>[ClH:14].[F:1][C:2]1[C:3]([C:9]([OH:10])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: [OH-]
Reactant: NC(=O)c1ncc(Br)cc1F
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ncc(Br)cc1F

Procedure:
A solution of 3-fluoro-5-bromopyridine-2-carboxamide (1.44 g, 6.5 mmol) in conc HCl (aq) (17 mL) was heated to 120° C. for 1.5 h. The reaction was cooled in an ice bath and 48% NaOH was added to slowly until the pH was 5. The solvent was removed in vacuo and toluene (25 mL) was added and then removed in vacuo. The resulting solid was extracted with 4:6 methanol/DCM (×2) and the combined extracts evaporated in vacuo to give crude 3-fluoro-5-bromopyridine carboxylic acid hydrochloride which was used directly without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:24][C:25]([F:28])([F:27])[F:26])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([S:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)(=[O:34])=[O:33])[CH2:30][CH3:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH:48][C:45]3[CH:46]=[CH:47][C:42]([CH2:41][N:38]4[CH2:37][CH2:36][N:35]([S:32]([CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:40][CH2:39]4)=[CH:43][CH:44]=3)=[CH:17][CH:16]=2)[C:12]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)OC(C)(C)C)ccc4OC(F)(F)F)cc3)cc2)CC1
Reaction time: 16 h

Procedure:
A mixture of 5′-tert-butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid (300 mg), 4-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]-phenylamine (224 mg), EDAC (144 mg), HOBT (102 mg) and N-Methylmorpholine (166 ul) in dry DMF (3 ml) was stirred for 16 hrs.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32](F)=[CH:31][C:30]=3[C:36]([F:39])([F:38])[F:37])(=[O:28])=[O:27])[CH2:23][N:22]2[C:40]2[N:41]([CH:46]3[CH2:49][CH2:48][CH2:47]3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14]>CN(C=O)C>[C:13]([C:15]1([NH:18][C:19]([C@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:31][C:30]=3[C:36]([F:37])([F:39])[F:38])(=[O:27])=[O:28])[CH2:23][N:22]2[C:40]2[N:41]([CH:46]3[CH2:49][CH2:48][CH2:47]3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
2,2,2,-Trifluoroethanol (10 ul, 137 umol; CAS Reg. No. 75-89-8 99) and cesium carbonate (45 mg, 137 umol) were added to a solution of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (37 mg, 69 umol; example 388 g) in DMF (500 ul) under an argon atmosphere. The reaction mixture was stirred for 72 h at ambient temperature and partitioned between ice water/brine 1/1 and iPrOAc. The layers were separated and the aqueous layer was extracted one more time with iPrOAc. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give a yellow foam which was purified by preparative chiral HPLC to give the title compound (6 mg, 10 umol; 14%) as colorless oil. MS (ESI): m/z=620.2 [M+H]+.
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)C>C(Cl)(Cl)Cl>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH:30]6[CH2:34][CH2:33][CH2:32][CH2:31]6)[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: CCOC(=O)C#CC1CCCC1
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Solvent: ClC(Cl)Cl
Product: O=c1cc(C2CCCC2)n2c(n1)O[C@H](COc1ccc(C3C4CCCC3CCC4)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 20) and cyclopentyl-propynoic acid ethyl ester (see Example 102) employing the procedure described in Example 95. [α]D25 −4.80 (c 0.5, CHCl3).
Reaction SMILES: ONC(=O)C=CC1C=C[C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=CC=1.C([O-])([O-])=O.[K+].[K+].[CH3:29][I:30]>CN(C=O)C>[CH3:9][NH:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:16]1[CH:21]=[CH:20][C:29]([I:30])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: CI
Reactant: O=C(C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1)NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccccc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 196.6 %

Procedure:
To compound 28 (from Example 18) (500 mg, 1.39 mmol) in DMF (10 mL) were added at room temperature K2CO3 (962 mg, 6.96 mmol), followed by methyl iodide (395 mg, 2.78 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The solvent is then removed and water was added. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were dried and concentrated. Purification by flash chromatography using hexane:ethyl acetate (8:2) afforded 510 mg (98%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=C)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=[O:16])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2nnc(C(C)C)n2n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nnc2ccc(C=O)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
The 3-isopropyl-6-vinyl-[1,2,4]triazolo[4,3-b]pyridazine (3.28 g, 17.4 mmol, Preparation #1) in 1,4-dioxane (75 mL) and water (15 mL) was treated with osmium tetroxide (3.5 mL, 0.28 mmol, 2.5 wt % in 2-methyl 1-propanol) and then sodium periodate (7.45 g, 34.9 mmol) was added. The mixture was stirred at ambient temperature for about 1 h and then diluted with 1,4-dioxane (50 mL) and filtered through Celite®. The filter cake was washed with 1,4-dioxane then EtOAc. The filtrate was concentrated under reduced pressure and then the residue was purified by flash chromatography on silica gel with DCM/MeOH (9:1) as an eluent to give the title compound (2.30 g, 69.4%) as a beige solid: 1H NMR (CDCl3) δ 1.61 (d, 6H), 3.76 (m, 1H), 7.65 (d, 1H), 8.21 (m, 1H), 10.06 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(Cl)c(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
Under argon, 3,4-dichlorophenyl 4-hydroxyphenyl ketone (154 mg) obtained in Example 121 and 4-dimethylaminopyridine (77 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 3 hours. 4-Chloro-6,7-dimethoxyquinoline (129 mg) was added, and the admixture was refluxed with heat for 21 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by thin layer chromatography on silica gel eluting with hexane/acetone (2/1) to obtain 81 mg of the title compound (yield: 31%).