Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: BrCc1ccccc1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1ccccc1

Procedure:
The title compound, MS: m/e=308.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and benzylbromide.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[N:39][CH:40]=[N:41][CH:42]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.O1CCOCC1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[N:41][CH:40]=[N:39][CH:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cncnc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cncnc2)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyrimidin-5-yl)benzamido)-4-phenylbenzoate (1.1 g) in ethyl acetate (10 mL), methanol (20 mL), and dioxane (20 mL), 10% palladium-carbon (0.57 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 20 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 70-0% hexane/ethyl acetate] to obtain 0.73 g of tert-butyl 2-(2-hydroxy-5-(pyrimidin-5-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11].CO.[OH-:14].[K+]>COCCOCCOC>[CH2:1]([C:3](=[CH:6][CH:7]([CH2:8][CH3:9])[CH2:10][OH:11])[CH:4]=[O:5])[CH3:2].[CH2:8]([C:7]1[CH:10]([OH:14])[O:11][CH2:4][CH:3]([CH2:1][CH3:2])[CH:6]=1)[CH3:9]
Reactant: CCCC=C(C=O)CC
Reactant: [OH-]
Reactant: C=O
Agent: [K+]
Solvent: CO
Solvent: COCCOCCOC
Product: CCC(C=O)=CC(CC)CO
Product: CCC1=CC(CC)COC1O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 28.7 g of 2-ethyl-2-hexenal (purity: 99.0%, 0.225 mol), 12.5 g (0.15 mol) of 37% formalin, and 25 ml of methanol heated to 50° C. was added dropwise 3.37 g (0.015 mol) of a 25% aqueous solution of potassium hydroxide over 20 minutes. After the dropping was completed, the mixture was further stirred at 50° C. for 4 hours. The reaction mixture was analyzed by gas chromatography (the internal standard method with diethylene glycol dimethyl ether as an internal standard), and the yields of 2,4-diethyl-5-hydroxy-2-pentenal and 3,5-diethyl-5,6-dihydro-2H-2-pyranol based on the used formaldehyde and the consumed 2-ethyl-2-hexenal were found to be as follows.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:27]2[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=2)[O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:35][CH2:36][CH2:37]Br>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:27]2[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=2)[O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:35][CH2:36][CH3:37])[CH:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCBr
Reactant: Cn1cncc1C(OCc1ccc(C#N)cc1-c1ccc(=O)[nH]c1)c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(-c2cc(C#N)ccc2COC(c2ccc(C#N)cc2)c2cncn2C)ccc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of Example 91F (27.3 mg, 0.0648 mmol) in DMF (2 mL) at 0° C. was treated with NaH (60%, 3.1 mg, 0.0777 mmol), stirred for 15 minutes, and treated with n-propyl bromide (11.8 μL, 0.130 mmol). The mixture was slowly warmed to room temperature and stirred for about 18 hours. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography with 10:0.2:0.02 to 10:1:0.1 ethyl acetate/methanol/NH4OH to provide 10.5 mg (35%) of the desired product. MS (HR-FAB) m/z calculated: 464.2087 (M+H)+; observed: 464.2078 (M+H)+; 1H NMR (CDCl3) δ: 7.67 (d, 1H), 7.59 (d, 1H), 7.53 (d, 1H), 7.47-7.44 (m, 3H), 7.26-7.24 (m, 3H), 6.96 (s, 1H), 6.60-6.58 (m, 1H), 5.58 (s, 1H), 4.50 (q, 2H), 3.86 (t, 2H), 3.33 (s, 3H), 1.80-1.74 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH2:14][CH2:15][CH3:16])[C:11](=O)[CH2:10][O:9]2)=[CH:4][C:3]=1[O:18][CH3:19]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][CH2:15][CH3:16])[CH2:13]2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: CCCN1CC(c2ccc(F)c(OC)c2)OCC1=O
Agent: Cl
Product: CCCN1CCOC(c2ccc(F)c(OC)c2)C1
Yield: 92 %

Procedure:
Prepared following the same method as for example 6 starting with the morpholin-3-one from example 21 (633 mg, 2.37 mmol). After refluxing in 6M HCl (aq) the reaction mixture was cooled and extracted with diethyl ether (2×20 ml). The organic layers were discarded and the aqueous layer basified by the addition of potassium carbonate. The aqueous residue was then extracted with ethyl acetate (3×20 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (552 mg, 2.18 mmol, 92%). 1H NMR (CD3OD, 400 MHz) δ: 0.95 (t, 3H), 1.58 (m, 2H), 2.02 (t, 1H), 2.22 (dt, 1H), 2.38 (t, 2H), 2.85 (d, 1H), 2.93 (d, 1H), 3.80 (m, 1H), 3.84 (s, 3H), 4.01 (dd, 1H), 4.50 (dd, 1H), 6.88 (m, 1H), 7.02 (t, 1H), 7.09 (d, 1H). LRMS: m/z 254 (M−H+).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]1[O:13][CH2:4]1
Reactant: C[S+](C)C
Reactant: COc1ccccc1C=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: COc1ccccc1C1CO1

Procedure:
Following the procedure of Example 7, 9.7 g. of sodium hydride, 38 g. of trimethylsulfonium iodide and 25.2 g. (0.185 mol) of o-methoxybenzaldehyde are reacted to give o-methoxystyrene oxide.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1
Reactant: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: Clc1ccc2ccccc2n1
Product: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Yield: 75 %

Procedure:
Compound 1e (10.0 g, 30.4 mmol) was treated with 2-chloroquinoline using the reaction conditions described in Example 1, Step I to obtain compound 15a as a white solid (10.4 g, 75% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H18BrN5O2: 440.1 (M+H). found: 440.3.
Reaction SMILES: [Br:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:12])[NH:8][N:9]([CH3:11])[CH3:10])[C:3]1=[O:13].C1([P:20](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br-:1].[CH3:10][N:9]([CH3:11])[NH:8][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([PH3+:20])[C:3]1=[O:13])=[O:12]
Reactant: CN(C)NC(=O)N1CCC(Br)C1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)NC(=O)N1CCC([PH3+])C1=O
Product: [Br-]

Procedure:
Substantially in the same manner as in Example 39 (2), 4.25 g (17 mmol) of the thus obtained 3-bromo-1-(N-dimethylaminocarbamoyl)pyrrolidin-2-one and 4.46 g (17 mmol) of triphenylphosphine were treated to give 8.31 g of the objective crude compound as waxy residue.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)#[N:8].CC1C=CC=CC=1S(O[CH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]1)(=O)=O>O1CCCC1>[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:29][CH:30]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:31]2)=[CH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccc3ccc(C#N)cc32)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
77 mmol of potassium tert-butylate are added to a solution of 70 mmol of 6-cyanoindole in 400 ml of tetrahydrofuran. After 10 minutes' stirring at room temperature, 70 mmol of tert-butyl 3-[(methylphenyl)sulphonyloxymethyl]-1-pyrrolidinecarboxylate in 60 ml of tetrahydrofuran are added. The reaction mixture is heated at reflux for 12 hours. After cooling and dilution with water, the solvent is removed by evaporation. The residue is extracted with dichloromethane and the organic phase is washed with water, dried and concentrated to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:25])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCSc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCS(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
The product from Example 70 Step B (70 mg) was stirred in 2 mL of dichloromethane with 3-chloroperoxybenzoic acid (MCPBA) (40 mg) for 1 hour at 0° C. An additional 5 mg of MCPBA was added and the reaction stirred 30 minutes more, then diluted with EtOAc and washed with saturated NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated in vacuo to give the titled compound. ESI+ MS: 218 [MH-Boc]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[C:3]=1[CH2:11][CH3:12].[N:13]#[C:14]Br.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([CH3:10])[C:5]2[N:6]([C:14]([NH2:13])=[N:9][N:8]=2)[N:7]=1
Reactant: CCc1c(Cl)nnc(NN)c1C
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1c(Cl)nn2c(N)nnc2c1C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
(6-Chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine (W3.007; 340 mg) was dissolved in ethanol/water (10/2 ml) at RT while stirring. Thereafter, cyanogen bromide (386 mg, dissolved in 5 ml of ethanol and 1 ml of water) was cautiously added dropwise. After stirring at RT for 5 h, the mixture was left to stand overnight and then the solvent was drawn off, and the residue was admixed with water. Once the residue had been alkalized with saturated potassium carbonate solution, it was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after filtering off the desiccant, dried under reduced pressure. 385 mg of the title compound were obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12]O.[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Ni].C1(C)C(C)=CC=CC=1>[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: OCCc1ccc2ccccc2c1
Agent: [Ni]
Solvent: Cc1ccccc1C
Product: O=C(NC1CCN(CCc2ccc3ccccc3c2)CC1)c1ccccc1

Procedure:
2-(2-Naphthyl)ethanol (3.44 g., 0.02 mole), 4-benzamidopiperidine (4.08 g.,0.02 mole) and Raney Nickel (W7 ca. 5 g.) were suspended in xylene (200 ml.) and the stirred mixture boiled under reflux for 16 hours. Liberated water was removed by means of a Dean and Stark apparatus. The mixture was filtered hot and evaporated to ca. 100 ml. The resulting yellow solution was stored until crystallisation was complete. The title compound was obtained as off-white needles (3.30 g.), m.p. 189°-191° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (150 mg, 0.42 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (90 mg, 0.63 mmol) and 7-hydroxyquinoline (67 mg, 0.46 mmol) in DMF (5.0 ml) was stirred at 100° C. for 2 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue taken up in 2N. aqueous sodium hydroxide solution. The precipitate was filtered off, dried, taken up in dichloromethane and the solution filtered through phase separating paper. The filtrate was then evaporated to dryness. The resulting solid was recrystallised from acetonitrile, filtered and washed with diethyl ether to give 6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)-4-(quinolin-7-yloxy)quinazoline (122 mg, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@@H:33]1[OH:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@@H:33]1[OH:41])=[O:29]
Reactant: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)NCC2
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=C(Br)CBr
Product: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)N[C@@H]1c3ccccc3C[C@@H]1O)CC2

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: [F:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:18](Br)[C:19]#[CH:20].O>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[N:6]([CH2:20][C:19]#[CH:18])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of the compound of Step C, Example 3, (4.0 gm, 18.86 mmol) in DMF (100 mL), under N2, at 5° C. (ice-bath) was added sodium hydride (60% in mineral oil, 753.0 mg, 18.86 mmol) portionwise. When gas evolution stopped, propargyl bromide (80%, 2.24 gm, 18.86 mmol) was added dropwise. The dark solution was stirred at room temperature for 17 hours. The reaction was carefully poured into water (150 mL) and EtOAc (600 mL) was added. The organic layer was separated and evaporated to dryness. The residue was chromatographed on silica gel using 25% of ethyl acetate in hexane as eluent. Fractions of compound of interest were combined and evaporated to dryness to yield the title compound of Step D, Example 3, as a yellow solid (2.7 gm), 57%; m.p. 105°-107° C.; IR (nujol, cm-1): 1695.3 (C=O) and 2120.6 (C≡C); 1H NMR δ: 4.76-4.81 (m,4H), 6.91-6.94 (d,1H), 7.97-7.98 (d,1H), 2.35 (s,1H).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH:14]=[O:15])[CH3:13].[OH2:16]>>[C:6]([C:5]1[CH:4]=[C:3]2[C:11](=[O:16])[N:12]([C:13]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)[C:14](=[O:15])[C:2]2=[CH:10][CH:9]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN(C)C=O
Reactant: O
Product: O=C(O)c1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1
Temperature: 140 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
38.42 g of trimellitic anhydride (0.2 moles), 27.4 g of p-amino-benzoic acid (0.2 moles) and 300 cc of N,N'-dimethylformamide are fed into a glass flask of 500 cc volume fitted with a mechanical stirrer, a thermometer and a vertical condenser. The reaction mixture is heated to 140° C. and left under stirring for three hours. On termination of this reaction time, the mixture is cooled to ambient temperature and poured into 2 liters of water under stirring. The precipitate is filtered off and washed repeatedly with methanol. After drying the product at 100° C. in a vacuum oven, 46.5 g of the product of the title are obtained. Yield 75%. The product structure is confirmed by NMR spectroscopy on a sample dissolved in deuterated dimethylsulphoxide.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=N[CH:7]=1.Br[C:18]1C=CC(F)=CN=1>>[C:5]1([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:18]=1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Reactant: Fc1ccc(Br)nc1
Product: c1ccc(-n2cnc3cnccc32)cc1

Procedure:
Intermediate 2 was prepared in a manner analogous to Intermediate 1, substituting 2-bromobenzene for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C12H9N3, 197.07; m/z found 198.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:14]([CH2:15][OH:16])=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:16][CH2:15][C:14]1[C:9]([Br:8])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccnc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccnc1Br
Reaction time: 1.5 h

Procedure:
Triethylamine (8.90 mL) is added to a round bottom flask containing a solution of (2-bromopyridin-3-yl)methanol (8 g, 42.55 mmol) in dichloromethane (212 mL) at 0° C., then methanesulfonyl chloride (3.95 mL) is added and the mixture is stirred at that temperature for 1.5 h. After that time the mixture is washed with water and organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure to yield 10.4 g of the title compound used without further purification. MS (m/z): 266, 268 (M+1; M+3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:23]=[CH:22][S:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[S:21]1[CH:22]=[CH:23][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)=[CH:20]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: [O-]B([O-])Oc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccsc3)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
In toluene/ethanol/water (10/1/1) (12 ml) was dissolved methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (700 mg), and to the mixture were added 3-thienyl borate (422 mg) and potassium carbonate (0.98 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (136 mg). The mixture was stirred at 100° C. for 13 hours and cooled to room temperature, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the resulting residue was purified with silica gel column chromatography (hexane/acetone=3/1) to give methyl 7-(3-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (610 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:40])=[C:13]([C:15]23[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[CH2:19][S:18][C:17]([NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:16]3)[CH:14]=1>ClCCl>[NH3:8].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:40])=[C:13]([C:15]23[CH2:23][NH:22][CH2:21][CH:20]2[CH2:19][S:18][C:17]([NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:16]3)[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC2CSC(NC(=O)c3ccccc3)=NC2(c2cc(N)ccc2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N
Product: Nc1ccc(F)c(C23CNCC2CSC(NC(=O)c2ccccc2)=N3)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 196.2 %

Procedure:
Trifluoroacetic acid (10 mL) is added to a solution of tert-butyl 7a-(5-amino-2-fluoro-phenyl)-2-benzamido-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (2.013 g, 4.28 mmol) in dichloromethane (30 mL) and the mixture is stirred at room temperature under nitrogen for 4 hours. The solvent removed in vacuo and the crude product is purified with an SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol to give the title compound (1.555 g, 98%). ES/MS (m/e): 371 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:24][CH:25]=[O:26])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(Oc2ncccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyrimidinyloxy)benzaldehyde (prepared as described in Reference Example 9) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 227 (M+H)+.
Reaction SMILES: C([C@@:5]12[N:12]([C:13]([OH:15])=[O:14])[C@@H:9]([CH2:10][CH2:11]1)[CH2:8][CH:7](C(=O)CCC=C)[CH2:6]2)(C)(C)C.C([O-])(=O)C.[NH4+].C([N+]#[C-])(C)(C)C>FC(F)(F)CO.O>[CH:9]12[N:12]([C:13]([OH:15])=[O:14])[CH:5]([CH2:11][CH2:10]1)[CH2:6][CH2:7][CH2:8]2
Reactant: C=CCCC(=O)C1C[C@@H]2CC[C@](C(C)(C)C)(C1)N2C(=O)O
Agent: CC(=O)[O-]
Agent: [C-]#[N+]C(C)(C)C
Agent: [NH4+]
Solvent: O
Solvent: OCC(F)(F)F
Product: O=C(O)N1C2CCCC1CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 248.6 %

Procedure:
A solution (1R,5S)-tert-butyl-3-pent-4-enoyl-8-azabicyclo[3.2.1]-octane-8-carboxylic acid (1.45 g, 4.95 mmol) and ammonium acetate (3.82 g, 49.5 mmol) in 2,2,2-trifluoroethanol (4 mL) was treated with tert-butyl isocyanide (2.06 g, 2.60 mL, 24.75 mmol). After stirring at room temperature for 3 days, the reaction mixture was added to a separatory funnel, diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated aqueous sodium chloride, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 10-60% ethyl acetate in heptane) gave (1R,5S)-tert-Butyl-3(2-acetamido)-1-(tert-butylamino)-1-oxo-hex-5-en-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid as a colorless foam (1.91 g, 89%).; 1H NMR (CDCl3, 400 MHz) δ 6.90 (s, NH, 1H), 5.79 (m, 1H), 5.59 (s, NH, 1H), 4.98 (m, 2H), 4.15 (m, 2H), 2.93 (m, 2H), 2.07 (m, 1H), 2.00 (s, 3H), 1.74-1.96 (m, 3H), 1.50-1.72 (m, 6H), 1.45 (s, 9H), 1.38 (s, 9H), 1.20-1.36 (m, 1H).