Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:13][N:12]([C:14]2[C:15]3[N:16]([N:20]=[N:21][N:22]=3)[CH:17]=[CH:18][N:19]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN(C=O)C.[Br:28]N1C(=O)CCC1=O>O>[Br:28][C:17]1[N:16]2[N:20]=[N:21][N:22]=[C:15]2[C:14]([N:12]2[CH2:13][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11]2)=[N:19][CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(c2nccn3nnnc23)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(Br)n3nnnc23)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A 3 L round bottom flask was charged with tert-butyl methyl(1-(tetrazolo[1,5-a]pyrazin-8-yl)azetidin-3-yl)carbamate (200 g, 0.66 mol) and DMF (1 L). To the above was added N-bromosuccinimide (117 g, 0.66 mol) in portions at 10° C. The resulting mixture was stirred at 10° C. for 0.5 h. Work-up: the reaction mixture was poured into water (3 L). The resulting crystalline solid was collected by filtration, washed with water (500 mL), and dried to afford 200 g (79%) of the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([OH:22])[N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][C:31]([F:34])([F:33])[F:32].C(OCC)(=O)C>CS(C)=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:10][C:11]([O:22][CH2:30][C:31]([F:34])([F:33])[F:32])=[N:12]2)=[CH:15][N:16]=1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)nc2)cc1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(-c2nc(OCC(F)(F)F)nn2-c2ccc(OC)nc2)cc1
Temperature: 100 °C
Yield: 45.6 %

Procedure:
A mixture of 5-(4-methoxyphenyl)-1-(6-methoxypyridin-3-yl)-1H-1,2,4-triazol-3-ol (300 mg, 1.01 mmol), potassium carbonate (417 mg, 3.02 mmol), and 2-iodo-1,1,1-trifluoroethane (0.496 mL, 5.03 mmol) in dimethyl sulfoxide (1.5 mL) were heated at 100° C. for 1 hour. After cooling, ice water and ethyl acetate were poured into the mixture and the organic layer was separated, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (toluene-ethyl acetate 8:1) The desired product was washed with hexane to give 2-methoxy-5-(5-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazol-1-yl)pyridine (175 mg, 45.8% yield).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([O:20][CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([O:20][CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(N)n1
Yield: 47.2 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.), conc. hydrochloric acid (0.8 ml.) and methanol (13.5 ml.) was treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-butoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.4 g.), yellowish white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>>[CH:10]([C:6]1[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)[C:7]=1[O:8][CH3:9])=[O:11]
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-nitrobenzene boronic acid, gave 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[SH:26][CH2:27][CH2:28][OH:29]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][S:26][CH2:27][CH2:28][OH:29])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(OCCBr)c2ccc(Cl)cc2)cc1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: OCCSCCOC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 97.2 %

Procedure:
A solution of 2-[bis(4-chlorophenyl)methoxy]ethyl bromide (5.13 g, 14.2 mmol) in N,N-dimethylformamide (50 ml) was treated at 22° C. with powdered anhydrous potassium carbonate (3.0 g, 21.7 mmol) followed by 2-mercaptoethanol (1.25 g, 16.0 mmol). The resulting mixture was stirred at 22° for 18 h. The reaction mixture was then diluted with toluene (400 ml) washed with water, brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was chromatographed on silica gel (elution ethyl acetate 0-10% in toluene) to give 4.93 g (96%) of the title material as a clear oil.
Reaction SMILES: [CH:1]1([CH:7]([CH2:21][CH:22]=[CH2:23])[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3OCC[O:17]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>>[CH:1]1([CH:7]([CH2:21][CH:22]=[CH2:23])[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCC(C(=O)c1ccc(C2OCCO2)cc1)C1CCCCC1
Agent: Cl
Product: C=CCC(C(=O)c1ccc(C=O)cc1)C1CCCCC1
Yield: 74.5 %

Procedure:
Following the procedure of Example E, 460 mg (0.0014 moles) of the product of Example N and 3 mls of 11N HCl gave the title compound 282 mg (75% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=2)=[C:4]([F:18])[CH:3]=1.[NH2:19][OH:20]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:19][OH:20])[CH3:14])=[CH:9][CH:8]=2)=[C:4]([F:18])[CH:3]=1
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2F)cc1
Reactant: NO
Solvent: CCO
Product: CC(=NO)c1ccc(Oc2ccc(Cl)cc2F)cc1

Procedure:
A mixture of 3.4 g (12.8 mmol) of 1-[4-(4-chloro-2-fluoro-phenoxy)-phenyl]-ethanone and 3.0 mL hydroxylamine solution (50% in water) in 100 mL ethanol was refluxed for five hours. Then the mixture was evaporated to dryness, the residue was combined with approx. 15 mL water and extracted three times with 10 mL ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried and evaporated down. The product thus obtained was reacted further without any further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[C:3](=[O:6])[CH2:4][Br:5].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][N:2]([CH2:7][CH:8]1[O:12][CH2:13][CH2:14][CH2:11][CH2:10][O:9]1)[C:3](=[O:6])[CH2:4][Br:5]
Reactant: CCOC(CN(C)C(=O)CBr)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(CC1OCCCCO1)C(=O)CBr

Procedure:
N-Methyl-N-(2,2-diethoxyethyl)-α-bromoacetamide (10 grams), butandiol-1,4 (3 ml) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-methyl-N-(1,3-dioxepan-2-yl-methyl)-α-bromoacetamide.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1.C1(=O)O[CH2:18][CH2:17][O:16]1>CN(C=O)C>[CH3:3][C:4]1[N:8]([CH2:18][CH2:17][OH:16])[N:7]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=1
Reactant: O=C1OCCO1
Reactant: Cc1cc(-c2ccccc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)nn1CCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
Sodium hydride (2.5 g, 1.5 g NaH, 62 mmol, 1.1 equiv) was added over a period of 3 min to a solution of 5-methyl-3-phenyl-1H-pyrazole (9.00 g, 56.9 mmol, 1 equiv) in DMF (90 mL) cooled to 0° C. in an ice bath. After stirring 15 min, ethylene carbonate (7.6 mL, 10 g, 110 mmol, 2.0 equiv) was added. The bath was removed, and the reaction mixture was stirred for 15 h. The mixture was treated with 4 M aq K2CO3 (90 mL), heated at reflux for 5 h, and diluted with H2O (200 mL). After allowing the hot mixture to cool for 15 min, more H2O (100 mL) and then hexanes (100 mL) were added. The mixture was shaken vigorously and then allowed to separate. Crystals formed and stayed with the top organic layer. The aqueous layer was separated, and the crystals were collected by vacuum filtration and washed with hexanes (2×50 mL). The crystals were dissolved in Et2O/EtOAc (1:1; 200 mL), and the solution was dried (Na2SO4), filtered, and concentrated (75° C.) to give the title compound as an off-white crystalline solid (6.86 g, 59.6%). HRMS Calculated for C12H15N2O: m/z 203.1184. Found: 203.1168.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:23]3[C:24]4([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]4)[C:22]=3[C:21]3[CH:32]=[CH:33][C:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:35][C:20]=3[CH2:19][CH2:18][C:17]=2[CH:41]=1)(=O)C>CO>[CH2:37]([O:36][C:34]1[CH:33]=[CH:32][C:21]2[C:22]3[C:24]4([O:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][O:25]4)[C:23]=3[C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][OH:6])=[CH:41][C:17]=3[CH2:18][CH2:19][C:20]=2[CH:35]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCOC(C)=O)ccc1C1=C2C12OCC(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc2c(c1)CCc1cc(OCCOCCO)ccc1C1=C2C12OCC(C)(C)CO2
Yield: 80.2 %

Procedure:
A solution of NaOH (1.2 mL, 1.2 mmol, 1 M aqueous solution) was added to solution of acetate 10 (0.593 g, 1.11 mmol) in MeOH:THF (10:3 mL) at room temperature, and the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was partially concentrated under reduced pressure, diluted with EtOAc (approximately 25 mL) and water (approximately 10 mL), the organic layer was separated, washed with brine, and dried over anhydrous MgSO4. Solvents were evaporated under reduced pressure, and the residue was separated by chromatography (Hex:EtOAc:CH2Cl2 3:2:1+1.5% of Et3N) to provide 0.493 g (0.89 mmol, 81%) of alcohol 11 as slightly yellow oil that crystallizes on standing. 1H NMR: 7.65 (dd, J=8.4, 2.4 Hz, 2 H), 6.92-6.82 (m, 4 H), 4.18 (t, J=4.4 Hz, 2 H), 4.04 (t, J=6.4 Hz, 2 H), 3.92 (m, 4 H), 3.88 (t, J=4.4 Hz, 2 H), 3.77 (t, J=4.4 Hz, 2 H), 3.68 (t, J=4.4 Hz, 2 H), 3.24 (d, J=10.8 Hz, 2 H), 2.41 (d, J=10.8 Hz, 2 H), 1.76 (p, J=7.2 Hz, 2 H), 1.50 (sex, J=7.6 Hz, 2 H), 1.21 (s, 3 H), 1.19 (s, 3 H), 0.99 (t, J=7.2 Hz, 3 H); 13C NMR: 159.8, 159.2, 147.4, 131.84, 131.75, 131.67, 131.57, 124.4, 123.6, 119.8, 119.1, 116.3, 116.2, 112.2, 84.1, 79.4, 72.8, 69.8, 68.0, 76.7, 62.0, 37.1, 31.5, 30.8, 22.9, 19.4, 14.2.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[Cl:26][C:27]1[S:31][C:30]([S:32]([N:35]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]2)(=[O:34])=[O:33])=[CH:29][C:28]=1[N+:41]([O-])=O>>[Cl:26][C:27]1[S:31][C:30]([S:32]([N:35]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]2)(=[O:34])=[O:33])=[CH:29][C:28]=1[NH:41][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N2CCC(O)C2)sc1Cl
Product: O=C(Nc1cc(S(=O)(=O)N2CCC(O)C2)sc1Cl)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and (RS)-1-(4-amino-5-chloro-thiophene-2-sulfonyl)-pyrrolidin-3-ol (example B.18) according to general procedure II. Yellow solid. MS (ISP) 622.2 [(M+H)+]; mp 274° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[CH:8]=1.[OH-].[Na+].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1>>[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:24][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:25])[F:26])=[CH:23][CH:22]=2)[CH:8]=1
Reactant: CNCCCc1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNCCCc1cccc(Sc2ccc(C(F)(F)F)cc2)c1

Procedure:
N-Methyl-3-chloro-benzenepropanamine hydrochloride (13.14 g, 0.06 mol), 25%, by weight, sodium hydroxide solution (9.6 g of solution; 0.06 mol of sodium hydroxide), sodium hydroxide pellets (2.0 g, 0.05 mol and 4-trifluoromethylbenzenethiol (8.3 g, 0.05 mol) were reacted to provide N-methyl-3-[[4-(trifluoromethyl)phenyl]thio]benzenepropanamine as an oil. The oil was dissolved in 200 ml diethyl ether and hydrochloric acid gas was passed through the solution for about 15 minutes. The solvent was removed under reduced pressure to provide an oil which was dissolved in a 1:1:1 ethyl acetate:diethyl ether:hexane solvent mixture. The solvents were slowly removed under reduced pressure and crystals precipitated. The crystals were purified by preparing a slurry of the crystals partially dissolved in a 1:1:1 methylene chloride:ethyl acetate:diethyl ether solvent system. The mixture was chilled to 0° C. and the solids were recovered by filtration to provide 13.0 g of title compound. m.p. =125°-130° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C.CCOC(C)=O>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:12]1
Reactant: Clc1ncccn1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(c3ncccn3)C2)c(Cl)c1
Yield: 78.9 %

Procedure:
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (700 mg), 2-chloropyrimidine (283 mg) and N,N-diisopropylethylamine (1.09 ml) in DMF (20 ml) was stirred at 80-85° C. for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(2-pyrimidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (−560 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[NH2:18][C:19]1[C:28](I)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.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.[Cu]I>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[C:28]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([C:12]3[O:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[O:11])[CH:4]=2)[C:19]([NH2:18])=[N:20][CH:21]=1
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
In a 4 mL vial, N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide (0.607 g, 2.70 mmol) and methyl 6-amino-5-iodonicotinate (0.5 g, 1.80 mmol) were dissolved in DMF (6 mL). The solution was degassed by bubbling N2(g) through it for ˜30 min. To the degassed solution was added DIPEA (1.25 mL, 7.19 mmol), followed by Pd(PPh3)2Cl2 (0.126 g, 0.18 mmol) and CuI (0.068 g, 0.360 mmol). The reaction mixture was allowed to stir at 50° C. for 3 h. The reaction mixture then was taken up in EtOAc (10 mL) and was extracted with brine (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude mixture was purified via column chromatography (gradient eluant mixture of EtOAc in Hexanes: 25% to 100% EtOAc) to give the title compound as a white solid (0.554 g, 82%).
Reaction SMILES: C([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)C1C=CC=CC=1.[ClH:29]>CO.[Pd]>[ClH:29].[CH3:18][CH:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[NH:8]1
Reactant: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1
Reaction time: 16 h

Procedure:
To a solution of 2-benzyl-3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (485 mg, 1.27 mmol) in MeOH (5 mL) was added palladium, 10 wt. % on activated carbon (41 mg, 0.38 mmol). The resulting mixture was then stirred under H2 for 16 h. Then, 5 N HCl (0.2 mL) was added followed by palladium, 10 wt. % on activated carbon (41 mg, 0.38 mmol). The resulting mixture was stirred at RT under H2 (45 psi) for 30 min. The mixture was filtered through celite and the celite was washed with MeOH (2×5 mL). The combined filtrates were concentrated to give the title compound as a light yellow solid (HCl salt), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH:16]([C:18]4[CH:19]=[CH:20][C:21]([NH:24]C=O)=[N:22][CH:23]=4)[CH3:17])[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1>Cl.CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH:16]([C:18]4[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=4)[CH3:17])[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: CC(c1ccc(NC=O)nc1)n1nnc2ncc(-c3cnn(C)c3)nc21
Agent: Cl
Solvent: CO
Product: CC(c1ccc(N)nc1)n1nnc2ncc(-c3cnn(C)c3)nc21

Procedure:
A solution of compound 330-a (300 mg) in 10 mL of HCl/CH3OH was stirred overnight, then concentrated and basified with Na2CO3 solution. The resulting mixture was purified by chromatography to afford the title compound as a solid, 155 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[NH:6][C:5]2=[O:21].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[C:22]1([S:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[NH:6][C:5]3=[O:21])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1ccc(Cc2nc3ccc(N)cc3c(=O)[nH]2)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: N#Cc1ccc(Cc2nc3ccc(NS(=O)(=O)c4ccccc4)cc3c(=O)[nH]2)cc1

Procedure:
Prepared analogously to Example 1e from 4-[(6-amino-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl]-benzonitrile, benzenesulphonic acid chloride and dimethylaminopyridine in pyridine.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Br)c2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Br)cccc2-3)no1
Yield: 68 %

Procedure:
2.04 g (5 mmol) of 7-bromo-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one were stirred at room temperature for 4 hours with 1.5 g (15 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.61 g (68%) of 7-bromo-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 135°-145°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])=[CH:8][C:6]=2[N:7]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine (220 mg) in dichloromethane (7 mL) at room temperature was added triethylamine (0.174 mL) and then 3-chloropropane sulfonyl chloride (0.134 mL). The reaction mixture was stirred at room temperature for 30 min and then quenched with water (25 mL) and extracted into dichloromethane (3×25 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 3-chloro-propane-1-sulfonic acid (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amide (301 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]([N:25]=1)=[N:12][C:13]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:14][N:15]=2)=[O:5])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]([N:25]=1)=[N:12][C:13]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[CH:14][N:15]=2)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc2ncc(C=Cc3ccc(F)cc3)nc2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCNC(=O)Nc1ccc2ncc(CCc3ccc(F)cc3)nc2n1

Procedure:
108 mg of 1-ethyl-3-{3-[2-(4-fluorophenyl)vinyl]pyrido[2,3-b]pyrazin-6-yl}urea (0.32 mmol) (Example 27) were dissolved in hot ethanol. 112 mg of ammonium formate (1.78 mmol) and 110 mg of palladium (10%) on carbon were added, and the reaction mixture was heated under reflux for 7.5 h. The catalyst was filtered off from the cooled reaction mixture, and the mother liquor was freed from the solvent. The crude product was purified by column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.