Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[C:10](B(O)O)=[CH:9][CH:8]=1)=[O:5].Br[C:37]1[C:38]([CH3:44])=[N:39][CH:40]=[N:41][C:42]=1[CH3:43].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CO>[C:32]([O:31][C:29](=[O:30])[N:2]([CH:3]([CH3:28])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:37]2[C:38]([CH3:44])=[N:39][CH:40]=[N:41][C:42]=2[CH3:43])=[C:11]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[N:12]=1)=[O:5])[CH3:1])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C(=O)Nc1ccc(B(O)O)c(C#Cc2ccc3ccccc3c2)n1)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ncnc(C)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1ncnc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-(2-naphthalen-2-ylethynyl)pyridin-3-yl]boronic acid D2b (50 mg, 0.11 mmol), 5-bromo-4,6-dimethylpyrimidine (26 mg, 0.14 mmol), Dichlorobis(triphenylphosphine)-palladium(II) (8 mg, 0.01 mmol), Na2CO3 (34 mg, 0.32 mmol), dioxane (0.9 ml), MeOH (0.3 ml) and water (0.1 ml) is stirred under argon atmosphere for 2 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 12 mg (21%). HPLC-MS: M+H=536; tR=2.22 min (*Method—6).
Reaction SMILES: CC([NH:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][N:6]=1)=O>Cl>[NH2:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][N:6]=1
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Agent: Cl
Product: Nc1nnc(S(N)(=O)=O)s1
Temperature: 60 °C

Procedure:
22.2 gr of acetazolamide, was dissolved in 100 ml concentrated HCl solution (35%) and refluxed on a water bath (60° C.) for two hours.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:5][C:6](O)=[O:7].O.[NH2:19][NH2:20]>C(#N)C.C(O)(=O)C.ClCCl>[C:9]1([C:4]2[C:3]([C:2]([F:17])([F:16])[F:1])=[N:20][NH:19][C:6](=[O:7])[CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: O=C(O)C=C(C(=O)C(F)(F)F)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=c1cc(-c2ccccc2)c(C(F)(F)F)n[nH]1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
To a stirred solution of 5,5,5-trifluoro-4-oxo-3-phenyl-pent-2-enoic acid (D1) (22.6 g, 0.084 mol) in a mixture of acetonitrile (150 ml) and acetic acid (15 ml), was added hydrazine hydrate (7.75 ml, 0.148 mol). The reaction mixture was heated at reflux for 16 h, cooled to room temperature, diluted with dichloromethane and then extracted with 0.5 M hydrochloric acid (150 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo to yield D2 (20.7 g, 100%) as a mixture of isomers (75/5 ratio by LCMS). C11H7F3N2O requires 240; Found 239 (M-H)−.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[O:13]>O1CCCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:2]([Cl:4])([Cl:3])[Cl:1])=[O:13]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCCCCOC(=O)/C=C/c1ccc(OC)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)OCCCCCC[Si](Cl)(Cl)Cl)cc1OC
Reaction time: 5 h

Procedure:
5 ml of trichlorosilane are added to a solution of 0.1 g of H2PtCl6 in 20 ml of dry tetrahydrofuran while stirring. A solution of 14.8 g of hex-5-enyl (E)-3,4-dimethoxycinnamate, dissolved in 20 ml of dry tetrahydrofuran, is carefully added dropwise to this. Thereafter, stirring is carried out for 5 hours at room temperature and then for 16 hours at 50° C. The reaction mixture is concentrated in a vacuum produced by a water-jet pump and is completely freed from the remaining solvent and trichlorosilane by means of an oil pump with a cold trap under reduced pressure. This gives crude 6-trichlorosilanylhexyl (E)-3,4-dimethoxycinnamate, which is dissolved in dry tetrahydrofuran for storage.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:13][C:6]1[N:5]=[C:4]([NH:2][CH3:1])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.0 ml of a 30% ethanolic solution of methylamine were added dropwise to a mixture of 29.0 g of 2,6-dichloro-3-nitropyridine, 300 ml of ethanol and 36.6 g of sodium carbonate, whilst cooling with ice, and the resulting mixture was stirred at room temperature for 8 hours. At the end of this time, the reaction mixture was freed from ethanol by distillation. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was crystallized by trituration with ethanol, to give 22.3 g of the title compound, melting at 114° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[O:11][N:10]=[C:9]([CH2:12][O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:8]2)=[CH:14][CH:15]=1
Reactant: OCC1=NOC(Cc2ccc(F)cc2)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)OCC1=NOC(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a mixture of solution of [5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazol-3-yl]-methanol (80 mg, 0.38 mmol), TEA (57 mg, 0.57 mmol) in DCM (10 ml), methanesulfonyl chloride (43 mg, 0.38 mmol) was added slowly at 0° C. and the mixture was stirred at room temperature for 3 hrs. Aqueous NaHCO3 was added to the reaction mixture and extracted with methylene dichloride. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography to obtain Methanesulfonic acid 5-(4-fluoro-benzyl)-4,5-dihydro-isoxazol-3-ylmethyl ester (82 mg, 75%) as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH:27]=O)[CH:21]=4)[C:16]3=[O:29])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32]>N1C=CC=CC=1.CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH:27]=[N:31][OH:32])[CH:21]=4)[C:16]3=[O:29])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCOc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cc1)C2=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1c2ccc(OCC=NO)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of the above aldehyde (~23 mmol) in pyridine (20 ml) and EtOH (20 ml) is added hydroxylamine hydrochloride (3.2 g, 46 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue dissolved in EtOAc (300 ml) and 2N HCl (300 ml). The EtOAc portion is washed with saturated NaHCO3 solution (300 ml), saturated NaCl solution (300 ml), dried over MgSO4, and concentrated in vacuo. The resulting material is purified by chromatography (silica gel 1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes and 2:3 EtOAc/hexanes) yielding α-[2-(4'-fluoro-4-biphenylylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-acetaldehyde oxime.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:9]=1[C:10](OCC)=[O:11]>>[Cl:7][C:8]1[CH:18]=[C:17]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:16]=[CH:15][C:9]=1[CH2:10][OH:11]
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)cc1Cl
Product: Cc1nccn1-c1ccc(CO)c(Cl)c1

Procedure:
Prepared from 2-methylimidazole and ethyl 2-chloro-4-fluorobenzoate.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Mg+].[Br-]>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]([OH:13])[CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1sc2ccccc2c1-c1ccccc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenylbenzo[b]thiophene-2-carbaldehyde (430 mg, 1.87 mmol) in THF (10 mL) cooled to −78° C. and under a nitrogen atmosphere was added 3.0M MeMgBr in diethyl ether (1.24 mL) and stirring was continued for 30 min. The reaction mixture was quenched with a saturated solution of NH4Cl (20 mL) and slowly warmed to RT. The mixture was extracted with EtOAc (×2) and the combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo affording 1-(3-phenylbenzo[b]thiophen-2-yl)ethanol as a white solid (472 mg, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.88-7.84 (1H, m), 7.52-7.28 (8H, m), 5.21 (1H, q, J=6.35 Hz), 2.03 (1H, s), 1.59 (3H, d, J=6.63 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([NH:16][CH:17]([CH2:32][NH2:33])[C:18]([NH:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[O:19])=[O:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl.CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([NH:16][CH:17]([CH2:32][NH:33][C:43](=[O:45])[CH3:44])[C:18]([NH:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[O:19])=[O:15])=[CH:11][N:10]=[CH:9]2)=[CH:34][CH:35]=1)#[N:2]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)NC(CN)C(=O)NCc2cccc3ccccc23)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCC(NC(=O)Cc1cncn1Cc1ccc(C#N)cc1)C(=O)NCc1cccc2ccccc12
Reaction time: 18 h

Procedure:
To a solution of the product from Example 32 (37.3 mg, 69.1 mmol), and triethylamine (52 μl, 345 mmol) in CHCl3 (0.85 ml) and DMF (0.5 ml) at 0° C., was added acetyl chloride (5.0 μl 69.1 mmol). The reaction was vortexed and allowed to stand at room temperature for 18 hrs. The reaction was diluted with EtOAc and the organic layer washed with sat. aq NaHCO3, brine and dried (Na2SO4). The solvent evaporated in vacuo and the residue was purified by preparative HPLC (C-18; 95:5 to 5:95 Water:CH3CN containing 0.1% trifluoroacetic acid; gradient elution), to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Br)c4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 642.0 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].[CH:58](OC)=[O:59]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][CH:58]=[O:59])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: COC=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC=O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone(30 mg) is mixed with methyl formate (0.5 ml) and is stirred at 0° C. for 1 hr. The reaction mixture is allowed to warm to room temperature and then is stirred overnight. The excess methylformate is removed with nitrogen flow and the crude mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:33]=1)[C:18](=[O:32])[C:19]1[CH2:24][CH2:23][C:22](=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]=1[N:21]=2)=[O:12]>CN(C)C=O.C(O)(=O)C>[CH3:9][O:10][C:11]([C:13]12[CH2:2][CH:33]1[N:17]1[C:18](=[O:32])[C:19]3[CH2:24][CH2:23][C:22](=[CH:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]=3[N:21]=[C:16]1[CH:15]=[CH:14]2)=[O:12]
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)c1ccc2nc3c(c(=O)n2c1)CCC3=Cc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C12C=Cc3nc4c(c(=O)n3C1C2)CCC4=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethyl-sulphoxonium iodide (1.8 g) was reacted with 50% sodium hydride (0.39 g) in dimethyl formamide (30 ml) under stirring at room temperature for 60 minutes, then a solution of 3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 248°-250° C., (2.49 g) in dimethylformamide (30 ml) was added. The mixture was allowed to react at room temperature for 1 hour then it was diluted with ice water and neutralized with acetic acid. The precipitate was filtered and washed with water to give 2.55 g of 3-benzylidene-7,8-methylene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 185°-187° C., which was treated with 0.5% KOH in 95% ethanol solution (90 ml) at reflux temperature for 15 minutes. After cooling the reaction mixture was acidified with acetic acid and diluted with water: the precipitate was filtered, washed with water until neutral and crystallized from CH 2 Cl2 /methanol to give 1.8 g of 3-benzylidene-7,8-methylene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 230°-240° C. dec., NMR (CF3COOD) δ ppm: 1.19 (t) (1H, 7,8-methylene proton), 2.91 (d d) (1H, 7,8-methylene proton), 3.32 (br s) (4H, cyclopentane protons), 3.51 (d.d.) (1H, C-8 proton), 7.01 (d) (1H, C-5 proton), 7.45 (m) (1H, =CH--), 7.58 (br s) (5H, phenyl protons), 8.26 (d) (1H, C-6 proton).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC2CCOC2)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC2CCOC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-phenyl)-6-(tetrahydro-furan-3-ylmethoxy)-nicotinic acid (example CK) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 30% ethanol/n-heptane (−) enantiomer isolated; LC-MS (UV peak area/ESI) 100%, 483.1038 (M+H)+; αD20(MeOH)=−12.2°
Reaction SMILES: [CH:1]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[F:17][C:18]([F:28])([F:29])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][C:1]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:26][CH:27]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OC(F)(F)F)cc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a solution of triethyl methanetricarboxylate (4.55 g) in DMF (40 mL) were added 4-(trifluoromethoxy)benzyl bromide (5.00 g), potassium iodide in catalytic amount and potassium carbonate (4.07 g), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate (200 mL) and water (100 mL) were added to extract the reaction mixture. The extract was washed sequentially with water and brine, and concentrated under reduced pressure to give the title compound (7.97 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([O:15][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17])[CH3:14]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[CH2:14])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(N)nc(SC)c1C#N
Temperature: 25 °C
Yield: 48.6 %

Procedure:
To a stirred solution of 300 mg (1.22 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml dioxane under argon at room temperature were added 0.41 ml (1.22 mmol) (1-ethoxyvinyl)tributylstannane and 86 mg (0.12 mmol) bis(triphenyl-phosphine)palladium(II) chloride. The reaction mixture was heated at reflux for 16 h, then cooled to room temperature, 2 g of kieselgel added, and the mixture concentrated in vacuo. Flash chromatography (hexane then 1/1 ethyl acetate/hexane) followed by trituration in ether/hexane afforded 140 mg (48%) 2-amino-4-(1-ethoxy-vinyl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 236 (M+, 17), 221 ([M—CH3]+, 61), 207 ([M—C2H5]+, 32), 192 ([M—C3H8]+, 100).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:16])[CH2:13][CH2:14][OH:15])[CH:9]=[CH:8][C:7]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:1]([O:15][CH2:14][CH2:13][CH:12]([C:10]1[CH:9]=[CH:8][C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:6]([Cl:5])[CH:11]=1)[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(CCO)c1ccc(-c2ccccc2)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCCC(C)c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 100 °C
Yield: 80 %

Procedure:
A solution of 3.92 gm (0.05 mol) of acetyl chloride in 20 ml of absolute toluene was allowed to flow into a solution of 10.0 gm (0.038 mol) of 3-(2-chloro-4-biphenylyl)-1-butanol and 5.0 gm (0.05 mol) of triethylamine in 100 ml of absolute toluene at room temperature; the resulting mixed solution was then stirred for several hours and was subsequently heated for 1 hour at 100°C. Thereafter, the reaction mixture was allowed to cool, water was then added, the toluene phase was separated, and the aqueous phase was extracted with ether. The combined organic solutions were washed until neutral, dried and evaporated, and the residue was distilled in vacuo, yielding 9.21 gm (80% of theory) of the desired ester in the form of a colorless oil having a boiling point of 145°-152°C at 0.06 mm Hg.
Reaction SMILES: BrC1C(F)=CC2OCCN3C(C(O)C4C=CC=C(C(F)(F)F)C=4)=C(C(O)=O)N=C3C=2C=1.[Br:32][C:33]1[C:34]([F:59])=[CH:35][C:36]2[O:42][CH2:41][CH2:40][N:39]3[C:43]([CH:50]([OH:57])[C:51]4[N:52]([CH3:56])[N:53]=[CH:54][CH:55]=4)=[C:44]([C:46]([O:48]C)=[O:47])[N:45]=[C:38]3[C:37]=2[CH:58]=1.[OH-].[Li+]>>[Br:32][C:33]1[C:34]([F:59])=[CH:35][C:36]2[O:42][CH2:41][CH2:40][N:39]3[C:43]([CH:50]([OH:57])[C:51]4[N:52]([CH3:56])[N:53]=[CH:54][CH:55]=4)=[C:44]([C:46]([OH:48])=[O:47])[N:45]=[C:38]3[C:37]=2[CH:58]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C)CCOc1cc(F)c(Br)cc1-2
Agent: O=C(O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Product: Cn1nccc1C(O)c1c(C(=O)O)nc2n1CCOc1cc(F)c(Br)cc1-2
Yield: 87 %

Procedure:
10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was prepared similarly according to the procedure for the synthesis of 10-bromo-9-fluoro-3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid. methyl 10-bromo-9-fluoro-3-[hydroxy-(2-methylpyrazol-3-yl)methyl]-5,6-dihydroimidazo[1,2-d][1,4]benz oxazepine-2-carboxylate was reacted with lithium hydroxide to afford 160 mg (87% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>C(O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][CH:14]1[NH:13][CH2:7][CH:6]([OH:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: NC1CCc2ccccc2C1
Reactant: Clc1ccccc1OCC1CO1
Solvent: CCO
Product: OC(CNC1CCc2ccccc2C1)COc1ccccc1Cl
Yield: 31.7 %

Procedure:
A solution of 1-(2-chlorophenoxy)-2,3-epoxypropane (2.65 g) prepared by the method described in British Patent 767,991, and 2-aminotetralin (2.1 g) in ethanol (70 ml) is heated to the reflux temperature for 5 hours. Ethanol is then evaporated off and the thus obtained residue is chromatographed on a silica gel column eluting with ethyl acetate. The residue which is obtained upon evaporation to dryness of the combined fractions is crystallized from ethyl acetate (10 ml) yielding 1.5 g of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-chlorophenoxy)propanamine; m.p. 98°-101° C.