Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:17][C:5]2[CH2:6][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=O.O=[C:28]([CH3:39])[CH2:29][CH:30]([CH2:36][CH2:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl[Si](C)(C)C>CN(C=O)C>[CH2:10]([N:7]1[CH2:6][C:5]2[S:17][C:2]3[N:1]=[C:28]([CH3:39])[C:29]([CH:30]([CH2:36][CH2:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[C:3]=3[C:4]=2[CH2:9][CH2:8]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCN(Cc2ccccc2)C3)cc1
Reactant: CCCC(CC(C)=O)C(=O)OCC
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(Cc1ccccc1)C3
Temperature: 100 °C

Procedure:
To a solution of (2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone (0.286 g; 1 mmol) and ethyl 4-oxo-2-propylpentanoate (0.204 g; 1.1 mmol) in dry DMF (4 mL) under nitrogen atmosphere was added chlorotrimethylsilane (0.511 mL; 4 mmol) dropwise. The mixture was stirred in a sealed tube and heated at 100° C. for 24 h. An extra volume of chlorotrimethylsilane was added (0.100 mL) and the reaction mixture was stirred at 100° C. for 48 h. After cooling, the volatiles were removed under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (1-20%) in dichloromethane furnished the title compound as a dark oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH2:29]=O>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([CH3:29])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C)C3)cc1

Procedure:
Method as example 26 using 1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and formaldehyde as starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:13].I[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]>O.C(O)(C)C>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1.[Na+:13]
Reactant: CC(C)CCI
Reactant: O=S(=O)(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)CCOc1ccc(S(=O)(=O)[O-])cc1

Procedure:
A solution of 4-hydroxybenzenesulfonic acid (10.0 grams, 43.1 mmole) and sodium hydroxide (3.3 grams, 83 mmole) in water (40 mL) was mixed with a solution of 1-iodo-3-methylbutane (11.3 mL, 86.4 mmole) in isopropanol (60 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vacuum. The title compound, 10.0 grams (87%), was collected by filtration and washed with isopropanol.
Reaction SMILES: [N+:1]([CH:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)[CH:7]=[CH:6][NH:5]1)([O-])=O>CO.N.CO>[NH2:1][CH:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)[CH:7]=[CH:6][NH:5]1
Reactant: Cc1cc(N2C=CNC2[N+](=O)[O-])ccn1
Agent: N
Solvent: CO
Product: Cc1cc(N2C=CNC2N)ccn1
Yield: 58.5 %

Procedure:
A stirred solution of 2-nitro-3-(2-methyl-4-pyridinyl)-1H-imidazole (3.40 g, 16.6 mmol) in 7N methanol/NH3 (70 ml) and methanol (70 ml) was hydrogenated at room temperature on Raney Nickel (2.9 g) for 2 h. The catalyst was removed by filtration and the solution evaporated. The crude product was purified by column chromatography on silica gel (dichloromethane/methanol/NH4OH 40:10:1) to yield 2-amino-3-(2-methyl-4-pyridinyl)-1H-imidazole (1.71 g, 59%) as a green solid. MS (ISP) 175.1 [(M+H)+]; mp 167° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]([O:26]C(=O)C)([CH3:25])[CH3:24])=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>CO.O.C1COCC1>[CH2:35]([O:34][C:32]1[CH:31]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:33]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]([OH:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1)=[O:13])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C(=O)Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.2 %

Procedure:
To a stirred suspension of N-{6-[(3,5-dibenzyloxybenzoyl)amino]-pyridin-3-yl}-2-acetoxy-2-methyl-propionamide (158 mg) in methanol (10 ml) was added a solution of LiOH.H2O (30 mg) in water (1 ml) and THF (3 ml). The mixture was stirred at ambient temperature for 20 hours. Volatile material was removed by evaporation. To the residue was added water (10 ml). Made acidic with 2M hydrochloric acid. Precipitate filtered off, washed with ethyl acetate, and dried under high vacuum to give the title compound (120 mg) as a solid, 1H NMR δ (d6-DMSO): 1.35 (s, 6H), 5.18 (s,4H), 6.88 (s,1H), 7.28 to 7.48 (m, 12H), 8.08 (d, 1H), 8.22 (d, 1H), 8.82 (s,1H), 9.90 (s, 1H), 10.96 (s, 1H). MS ES+512.16 (M+H)+.
Reaction SMILES: O1C2C=CC=CC=2N=C1O[CH2:11][C:12]1[C:13](=[O:22])[N:14]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:15]=[CH:16][CH:17]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[CH2:18]([N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][Cl:25])[C:13]1=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCn1cccc(COc2nc3ccccc3o2)c1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCn1cccc(CCl)c1=O
Reaction time: 1 h

Procedure:
To a solution of 3-(benzoxazol-2-yloxymethyl)-1-butyl-2-pyridone (7-008-03) (169 mg) in methylene chloride (4.0 mL) was added thionyl chloride (122 mg) at room temperature. After stirring for 1 h, the solvent was removed to 1-butyl-3-chloromethyl-2-pyridone (7-008-04) as an oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:33](I)[C:34]([CH3:37])([CH3:36])[CH3:35]>C(OCC)(=O)C.O>[Br:20][C:17]1[CH:18]=[C:19]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([O:21][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:8]=3)[O:13][C:14]2=[N:15][CH:16]=1
Reactant: CC(C)(C)CI
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)cnc1O2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A 350 mL sealable flask was charged with (R)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (12.10 g, 34.8 mmol) and DMF (99 mL, 34.8 mmol). To this solution was added cesium carbonate (28.3 g, 87 mmol). The resulting brown slurry was stirred at rt for 3 minutes before neopentyl iodide (9.21 mL, 69.5 mmol) was added in one portion. The reaction vessel was sealed and heated at 100° C. After heating for 4 hours another 1 mL of neopentyl iodide was added and heating at 100° C. was continued for another 1 hour at which point the reaction was allowed to cool to room temperature. The reaction was diluted with ethyl acetate (500 mL) and poured into water (2000 mL) before being transferred into a separatory funnel containing ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water and then brine. The aqeuous layer was combined with the above brined wash and was then extracted with DCM (2×500 mL). The organic layers were washed with water and then brine. All of the organigs were combined, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown foam that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (330 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (R)-3-bromo-7-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a light yellow solid.
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][CH2:38][C:39](=[O:41])[NH2:40])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C.O>[ClH:7].[ClH:7].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:32]2[CH:31]=[CH:30][C:29]3[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=3)[C:33]=2[CH2:37][CH2:38][C:39](=[O:41])[NH2:40])=[O:19])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(NC2=NCCN2)cc1
Reactant: N=C(N)c1ccc2c(CCC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: N=C(N)c1ccc2c(CCC(N)=O)c(OC(=O)c3ccc(NC4=NCCN4)cc3)ccc2c1
Reaction time: 2 h
Yield: 17.1 %

Procedure:
45 Milliliters of 20% hydrous pyridine was added to 2.71 g of 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid.hydrochloride, 3.0 g of 6-amidino-1-(2-carbamoylethyl)-2-naphthol.hydrochloride, 2.52 g of DCC and 124.6 mg of DMAP, followed by stirring for 2 hours under cooling with ice and 6 days under cooling with water. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of DMF, and a small amount of insoluble matter was filtered off. The filtrate was added dropwise to 400 ml of acetone, followed by stirring for 1 hour under cooling with ice and 24 hours under cooling with water. The supernatant was decanted, and to the residue was added 15 ml of methanol, followed by stirring for 1 hour under cooling with ice. The precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using a mixed liquid of methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent solvent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml of DMF and 200 μl of concentrated hydrochloric acid, and the solution was added dropwise to 200 ml of acetone. After stirring for 1 hour under cooling with ice and then 24 hours under cooling with water, the precipitate was collected by filtration to obtain 495.4 mg of the desired product.
Reaction SMILES: [F:1][C@H:2]1[CH2:18][C@@H:17]2[C@:9]([F:25])([C@@H:10]([OH:24])[CH2:11][C@@:12]3([CH3:23])[C@H:16]2[CH2:15][CH:14]=[C:13]3[C:19](=[O:22])[CH2:20][OH:21])[C@:8]2([CH3:26])[C:3]1=[CH:4][C:5](=[O:27])[CH:6]=[CH:7]2.[CH2:28]([N:35]([CH2:39][Si](C)(C)C)[CH2:36]OC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C(C)=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)Cl.CCOC(C)=O>[CH2:28]([N:35]1[CH2:39][C@:13]2([C:19](=[O:22])[CH2:20][OH:21])[C@@H:14]([CH2:15][C@H:16]3[C@H:17]4[C@@:9]([F:25])([C@:8]5([CH3:26])[C:3]([C@@H:2]([F:1])[CH2:18]4)=[CH:4][C:5](=[O:27])[CH:6]=[CH:7]5)[C@@H:10]([OH:24])[CH2:11][C@@:12]32[CH3:23])[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3CC=C(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 140 °C
Yield: 55.1 %

Procedure:
A mixture of intermediate 6 (95 mg, 0.185 mmol), N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (500 mg) and then Xylene (5 ml) containing 0.01% of TFA is placed in a closed vessel and heated at 140° C. for 1 hour. The solvent is removed under vacuum, and the residue is purified by silica gel cartridge eluting with DCM to DCM:AcOEt 6:4 leading to the title compound (52 mg, 0.102 mmol, 54.9% yield).
Reaction SMILES: Cl[Si:2]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].[Li].[CH3:11][C:12]1[CH-:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2>C(OCC)C>[CH3:11][C:12]1[CH:13]([Si:2]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: Cc1cc2ccccc2[cH-]1
Reactant: CC(C)(C)N[Si](C)(C)Cl
Agent: [Li]
Solvent: CCOCC
Product: CC1=Cc2ccccc2C1[Si](C)(C)NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
Chloro(t-butylamino)dimethylsilane (9.57 g, 0.058 moles) was stirred in diethylether (150 mL) at 0° C. as lithium-2-methylindenide (7.68 g, 0.058 moles) was added as a solid over a 15 minute period of time. The mixture was then allowed to stir for 16 hours at room temperature. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the volatiles resulted in the isolation of the desired product as a pale yellow oil (9.99 g, 67.5 percent).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:10])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[C:5]([CH3:10])=[N:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cccnc1C
Agent: O=S(=O)(O)O
Product: CCOc1ccc([N+](=O)[O-])nc1C
Temperature: 25 °C

Procedure:
3-Ethoxy-2-methylpyridine (132.5 g) was added dropwise to concentrated sulphuric acid (530 ml) with stirring and cooling to keep the mixture below 10° C. A mixture of concentrated nitric acid (81 ml) and concentrated sulphuric acid (97 ml) was added dropwise over 4 hours, keeping the temperature below 5° C. The reaction mixture was allowed to warm up slowly to ambient temperature and then added in portions to ice/water (2.5 l). The solid was collected by filtration, washed with water and dried under vacuum at 50° C. to give 3-ethoxy-2-methyl-6-nitropyridine, m.p. 82°-84° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17]C(=O)OC(C)(C)C)[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH2:17])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1)=[O:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCC3)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](N)C1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
A mixture of tert-butyl [(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (15 mg, 0.045 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (19 mg, 0.054 mmol), HATU (43 mg, 0.11 mmol) and DIPEA (24 μL, 0.14 mmol) in dry DMF (0.11 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give an intermediate, which was treated with TFA (0.070 mL, 0.90 mmol). The resulting reaction mixture was stirred at room temperature for 1 h then concentrated under reduced pressure. The residue was diluted with MeOH and neutralized with small amount of NH4OH. The mixture was filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 1.5% NH4OH) to give the title compound as a white powder (7.5 mg, 35%). LCMS calc. for C23H25F2N6OS (M+H)+: m/z=471.2. Found: 471.1. 1H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.61 (s, 2H), 7.57-7.45 (m, 1H), 7.36-7.17 (m, 2H), 3.12-2.96 (m, 3H), 2.91 (t, J=9.8 Hz, 1H), 2.88-2.70 (m, 4H), 2.66-2.55 (m, 1H), 2.07-1.99 (m, 2H), 1.86-1.56 (m, 3H), 1.18-1.01 (m, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]3[CH2:14][CH:10](N3C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.C12CC([O:27]1)CNC2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]3[CH2:14][CH:10]([O:27]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C1NCC2CC1O2
Reactant: CC(C)(C)OC(=O)N1C2CC1CN(c1ccc(Br)cc1)C2
Product: Brc1ccc(N2CC3CC(C2)O3)cc1
Yield: 61 %

Procedure:
Prepared by the procedure, previously described for the synthesis of tert-butyl 3-(4-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate, using instead 6-oxa-3-azabicyclo[3.1.1]heptane as a starting material to afford 570.0 mg (61%) of 3-(4-bromophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24]2[S:25][CH:26]=[C:27]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[N:28]=2)[CH:17]=1)=[O:14])C.O1CCCCC1.CO.O.[OH-].[Li+]>O>[CH:29]1([C:27]2[N:28]=[C:24](/[CH:23]=[CH:22]/[C:18]3[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[C:4]([OH:33])=[O:3])[CH:21]=[CH:20][CH:19]=3)[S:25][CH:26]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccccc1CCC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOCC1
Solvent: O
Solvent: CO
Product: O=C(CCc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A solution composed of 0.457 g of (E)-2-[3-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-3-oxopropyl]benzoic acid ethyl ester, 25 ml of tetrahydropyran, 8 ml of methanol, 8 ml of water and 0.282 g of lithium hydroxide monohydrate was allowed to stand at room temperature for 20 hr. The solvents were removed by rotary evaporation and the residual materials were taken up in 30 ml of water. Addition of excess acetic acid caused the precipitation of 0.42 g of (E)-2-[3-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-3-oxopropyl]benzoic acid; m.p. 238°-239° C.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.C1(C(C2C=CC=CC=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[NH2:18][CH:19]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([F:10])[F:1])[CH:4]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: FC(F)c1cccc(Br)c1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(N)c1cccc(C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Quantities of 1.0 g (4.83 mmol) of 3-(difluoromethyl)phenyl bromide, 1.42 g (5.31 mmol) of ethyl N-(diphenylmethylene)glycinate, 0.19 ml (0.193 mmol) of a 1M solution of tri-tert-butylphosphane in toluene, 55 mg (0.10 mmol) of bis(dibenzylideneacetone)palladium(0), 3.08 g (14.49 mmol) of potassium phosphate and 6.04 ml (18.11 mmol) of 3M hydrochloric acid were heated under argon to 100° C. in 20 ml of degassed toluene, and stirred at this temperature overnight. A further 0.19 ml (0.193 mmol) of tri-tert-butylphosphane (1M solution in toluene) and 55 mg (0.10 mmol) of bis(dibenzylideneacetone)palladium(0) were added and the mixture was stirred at 100° C. for a further 24 h. The mixture was cooled to RT and filtered over celite. The celite was washed with a little toluene and the filtrate was freed from the solvent under reduced pressure. For elimination of the protecting group, the residue was taken up in 50 ml of acetonitrile and admixed with 15 ml of 3M hydrochloric acid. After 2 h, the acetonitrile fraction was removed on a rotary evaporator. The aqueous residue was diluted with water to a volume of approximately 150 ml and washed three times with diethyl ether. The aqueous phase was adjusted to a pH of 9 using 2M aqueous sodium carbonate solution and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 265 mg (6.46% of theory) of the title compound, in a purity of about 27%, which was reacted further without additional purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]1([N:7]2[C:11]([NH2:12])=[C:10]([C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=3)[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCCC1
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccc1
Product: Nc1c(C2=CCCCC2)c(-c2ccccc2)nn1-c1ccccc1

Procedure:
It is obtained by essentially following the procedure of example 1, reacting 1,3-diphenyl-5-pyrazolamine (1 mole) with cyclohexanone (1.1 mole) at a temperature of about 80° C. for about 4 hours. M.p. 115°-117° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Na].N.[Cl-].[NH4+].[NH2:18]C1C=CC(CCCC)=CN=1>C(OCC)C>[NH2:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: CCCCc1ccc(N)nc1
Reactant: Clc1ccc(-c2ccccc2)cn1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Nc1ccc(-c2ccccc2)cn1
Yield: 36 %

Procedure:
A solution of 2-chloro-5-phenylpyridine (4.0 g., 0.021 mole) in dry diethyl ether (160 ml.) was added dropwise to a solution of sodium (3.39 g., 0.15 g-atom) in liquid ammonia (160 ml.) containing ferrous nitrate hexahydrate (0.095 g.). The resulting suspension was allowed to reflux for 4 hours. Ammonium chloride was added and the ammonia allowed to evaporate. The residue was treated with 5% aqueous sodium hydroxide (5 ml.). The mixture was filtered. The aqueous layer was extracted with ether (2 × 100 ml.). The combined ethereal layers were washed with brine and dried over sodium sulfate. The solution was concentrated and the residue recrystallized from methylcyclohexane. The product was triturated with chloroform (100 ml.). The mixture was filtered and the filtrate evaporated to give 2-amino-5-phenylpyridine (1.3 g., 36%), m.p. 133°-135° (lit. m.p. 133° in Chem. Ber., 91, 247 (1958).