Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].[NH2:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1>O1CCOCC1>[CH2:1]([O:4][C:10]1[N:9]=[C:8]([NH2:7])[CH:13]=[N:12][CH:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: Nc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOc1cncc(N)n1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A mixture of allyl alcohol (0.21 mL, 3.08 mmol) in dioxane (4 mL) was treated with NaH (60%, 3.08 mmol), stirred for 30 minutes, treated with 2-amino-6-chloropyrazine (200 mg, 1.54 mmol), heated to 140° C. in a Smith Synthesizer for 2200 seconds, and filtered. The filtrate was concentrated and purified by flash column chromatography eluting with hexanes/ethyl acetate (2:1) to provide the desired product (133 mg, 57%). MS (DCI/NH3) m/z 152.0 (M+H)+; 1H NMR (500 MHz, CD2Cl2) δ 4.75 (m, 2H), 5.24 (m, 1H), 5.37 (m, 1H), 6.05 (m, 1H), 7.50 (s, 1H), 7.53 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.Cl.[F:11][C:12]([F:17])([F:16])[C@@H:13]([NH2:15])[CH3:14].CCN(CC)CC>O=S(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:15][C@@H:13]([CH3:14])[C:12]([F:17])([F:16])[F:11])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1nc(Br)cs1
Reactant: C[C@H](N)C(F)(F)F
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1nc(Br)cs1)C(F)(F)F
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To the mixture of 4-bromothiazole-2-carboxylic acid (80 g, 1.0 eq.) in SOCl2 (300 ml) was added DMF (10 drops). It was refluxed for 5 hours and concentrated. The residue was dissolved in DCM (300 ml) and added to the solution of (S)-1,1,1-trifluoropropan-2-amine hydrochloride (60.5 g, 1.05 eq.) with Et3N (117 g, 3.0 eq.) at 0° C. It was stirred overnight. TLC and LCMS showed the reaction was complete. It was quenched with water and extracted with DCM. The organic phase was dried, filtered and concentrated. The residue was purified by column to obtain 62 g (53% y) of (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carboxamide.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 4-fluoro-2-methyl-5-nitrophenol (0.5 g) in N,N-dimethylformamide (5 mL) were added potassium carbonate (0.44 g) and iodomethane (0.46 g), and this mixture was stirred at room temperature overnight. To this reaction mixture was added water and the precipitated solid was collected by filtration, and washed with water and n-hexane to give the title compound (0.44 g).
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:23][O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[NH:11][N:10]=1
Reactant: c1ccc(COc2cc(COc3ccc4ccccc4c3)nnc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: O=c1cc(COc2ccc3ccccc3c2)[nH]nc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.8 %

Procedure:
Under a nitrogen atmosphere, 10% palladium-barium sulfate (120 mg) was suspended in ethanol (10 ml), and 3,4-bis(benzyloxy)-6-[(2-naphthyloxy)methyl]pyridazine (120 mg) was added. Under a hydrogen atmosphere, the mixture was stirred at room temperature for 5 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was washed with diethyl ether, and the resulting solid was collected by filtration and dried under reduced pressure to give 3-hydroxy-6-[(2-naphthyloxy)methyl]pyridazin-4(1H)-one (30 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:12]=[C:11](N(C2C=CC(OC)=CC=2)C)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:23]CC1NC(=O)C2C(=CC=CC=2)N=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:23][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([CH2:2][Cl:1])[N:12]=1
Reactant: O=c1[nH]c(CCl)nc2ccccc12
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1nc(Cl)c2ccccc2n1

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A mixture of 2-chloromethyl-quinazolin-4(3H)-one (256 mg, 1.32 mmol), phosphoryl chloride (1.23 ml, 13.2 mmol) and N,N-dimethylaniline (0.34 ml, 2.64 mmol) in chloroform (10 ml) was heated under reflux for 4 h. The reaction mixture was poured onto ice and extracted by ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel with acetate and hexane (1:1) as eluent, yielding 180 mg of 4-chloro-2-chloromethyl-quinazoline. The intermediate (170 mg, 0.80 mmol) and (4-methoxy-phenyl)-methylamine (131.7 mg, 0.96 mmol) in isopropyl alcohol (5 ml) with concentrated HCl (0.05 ml) was stirred at room temperature overnight. The precipitation was formed and collected by filtration, then washed and dried to give 231 mg (92%) of the title compound. 1H NMR (CDCl3): 7.82 (d, J=8.7 Hz, 1H), 7.59-7.53 (m, 1H), 7.15-7.12 (m, 2H), 7.03-7.00 (m, 2H), 6.95-6.91 (m, 2H), 4.73 (s, 2H), 3.85 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:55]1([CH2:58][NH:59][CH2:60][C@H:61]2[CH2:65][CH2:64][CH2:63][NH:62]2)[CH2:57][CH2:56]1>CN(C=O)C.O.C([O-])(O)=O.[Na+]>[CH:55]1([CH2:58][NH:59][CH2:60][C@H:61]2[CH2:65][CH2:64][CH2:63][N:62]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:56][CH2:57]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: C1CN[C@@H](CNCC2CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H]1CNCC1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (200 mg, 0.4 mmol), EDAC (150 mg, 0.78 mmol) and HOBt (54 mg, 0.4 mmol) in DMF (4 mL) was added cyclopropylmethyl-(R)-1-pyrrolidin-2-ylmethyl-amine (100 mg, 0.65 mmol) and TEA (0.12 mL). The mixture was stirred at rt for 20 hours. The reaction was diluted with water and NaHCO3, extracted with 5% methanol in DCM. The combined extracts were concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].BrBr.[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]2[N:29]=[CH:28][O:27][N:26]=2)[CH:9]=1.O>CO>[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]2[N:29]=[CH:28][O:27][N:26]=2)[C:9]=1[S:1][C:2]#[N:3]
Reactant: N#C[S-]
Reactant: Nc1cc(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: BrBr
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CSc1c(-c2ncon2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: -78 °C
Reaction time: 0.13 h
Yield: 98.2 %

Procedure:
Potassium thiocyanate (1.45 g, 14.9 mmol) was dissolved in 20 ml of dry methanol, and then a methanol (5 ml) solution of bromine (0.28 ml, 5.44 mmol) was added dropwise with stirring at −78° C. over 8 minutes (inner temperature: not higher than −65° C.). After the completion of adding dropwise, the mixture was stirred at −78° C. for 10 minutes and a methanol (15 ml) solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1,2,4-oxadiazol-3-yl)pyrazole (1.80 g, 4.94 mmol) was added dropwise over 15 minutes. The solution was stirred at −78° C. for 2 hours, warmed to room temperature and then stirred at the same temperature for 2 hours. The reaction mixture was poured into 100 ml of iced water. After stirring for 30 minutes, the deposited crystal was filtered. The resulting crystal was washed with water and then dried under reduced pressure to obtain 2.04 g (4.85 mmol) of the title compound as a colorless crystal. Yield 98.0%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[C:15]1([C:21]2[S:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]1([C:21]2[S:25][C:24]([C:8]3[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of sodium carbonate (799 mg), tetrakis(triphenylphosphine)palladium(0) (218 mg), 3-bromopyridin-2-amine (652 mg) and 5-phenylthiophen-2-ylboronic acid (1000 mg) in water (10 mL) and 1,2-dimethoxyethane (50 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (579 mg) as a dark yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:15](C(C)C)C(C)C.N.CO.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cccc(C(=O)O)c1N
Agent: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(N)=O)c1N
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To 2-amino-3-methoxybenzoic acid (8.11 g, 48.52 mmol) in DMF (150 mL) at rt were added DIEA (13.2 mL, 58.22 mmol), 2 N ammonia in MeOH (33.96 mL, 67.92 mmol), EDCI (11.16 g, 58.22 mmol), and 1-hydroxybenzotriazole (7.87 g, 58.22 mmol). The solution was stirred at rt under argon. After 20 h the solution was diluted with water and extracted ten times with EtOAc. The EtOAc volume was reduced and washed with brine. The EtOAc fraction was concentrated and diluted with diethyl ether. The resulting tan solid was collected and dried in vacuo to give 2-amino-3-methoxybenzamide (6.08 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 6.26 (bs, 2H), 6.48 (m, 1H), 6.88 (d, J=7.9 hz, 1H), 7.12 (bs, 1H), 7.19 (dd, J=8.2, 1.0 Hz, 1H), 7.70 (bs, 1H) LC-MS (ESI) m/z 167 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=2[N+:21]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]OC(OC)N(C)C.N1CCCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[NH:21][CH:24]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cc[nH]c23)CC1
Reaction time: 6 h
Yield: 26.8 %

Procedure:
A solution of 4-(3-methyl-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (10 g, 31 mmol), N,N-dimethylformamide dimethyl acetal (13.2 mL, 100 mmol) and pyrrolidine (4 mL, 50 mmol) in 45 mL of DMF was heated under reflux for 20 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate was dried and evaporated. The residue was hydrogenated in 200 mL of THF containing 2.5 g of 10% Pd-C at 50 psi for 6 h. The mixture was filtered, concentrated in vacuo, and partitioned between ethyl acetate and aqueous HCl. The ethyl acetate was washed with brine, dried and evaporated. Silica gel chromatography (10% ethyl acetate-hexane) afforded 2.5 g of 4-(1H-Indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (19) as a white solid, m.p. 150-151° C.
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:10]C(=O)N[C:7]1=[O:12].[OH-].[Na+].[OH-].[K+].C(=O)([O-])[O-:22].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[OH-].[Ca+2].[OH-].[OH-].[Ba+2].[OH-]>>[NH2:10][CH:6]([CH2:5][CH2:4][CH2:3][C:2]([CH3:1])([N+:14]([O-:16])=[O:15])[CH3:13])[C:7]([OH:12])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CCCC1NC(=O)NC1=O)[N+](=O)[O-]
Agent: [Ba+2]
Agent: [Ca+2]
Agent: [K+]
Product: CC(C)(CCCC(N)C(=O)O)[N+](=O)[O-]

Procedure:
5-(4-Methyl-4-nitropentyl)hydantoin is hydrolyzed with alkali to give 2-amino-6-methyl-6-nitroheptanoic acid (see JP-A-11-140076). For example, 5-(4-methyl-4-nitropentyl)hydantoin is hydrolyzed in an aqueous solution preferably in the presence of 1–3 equivalents of alkali, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide, barium hydroxide and the like, relative to 5-(4-methyl-4-nitropentyl)hydantoin generally at 20–200° C., preferably 100–150° C. The reaction mixture is concentrated to dryness to give 2-amino-6-methyl-6-nitroheptanoic acid. The obtained 2-amino-6-methyl-6-nitroheptanoic acid can be isolated and/or purified by a conventional method, such as crystallization, chromatography and the like, but generally, can be used in the next step without isolation and/or purification.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])[N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: C1COCCN1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCOCC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(morpholino)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and morpholine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.[I:31]I.S([O-])([O-])(=O)=S.[Na+].[Na+].[F-].[K+]>C1COCC1.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>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]([I:31])=[CH:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1
Reactant: Clc1ccc(C#Cc2ccc(Cl)cc2Cl)cc1
Reactant: II
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: Clc1ccc(C=C(I)c2ccc(Cl)cc2Cl)cc1
Reaction time: 1 h
Yield: 83.2 %

Procedure:
Tributyltin hydride (2.7 mL, 10 mmol) was added to a mixture of 2,4-dichloro-1-(4-chloro-phenylethynyl)-benzene (2.01 g, 7.13 mmol) and PdCl2(PPh3)2 (0.45 g, 0.64 mmol) in THF (70 mL) at room temperature and stirred for 1 h. Iodine crystals (2.7 g, 11 mmol) were added to the mixture at room temperature and stirred for 30 min. The mixture was then stirred with sodium thiosulfate aqueous solution and KF aqueous solution. The mixture was filtered through CELITE. The organic layer of the filtrate was separated and concentrated in vacuo. The residue was chromatographed (SiO2, hexane) to afford 2,4-dichloro-1-[2-(4-chloro-phenyl)-1-iodo-vinyl]-benzene as a light yellow solid (2.43 g, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Si:23]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cccnc2c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-hydroxyquinoline (2.240 g, 15.43 mmol) in dry CH2Cl2 (30 mL) were added (in this order) DMAP (94 mg, 0.77 mmol), triethylamine (4.3 mL, 3.1 g, 31 mmol), and TBDMSCl (2.558 g, 16.97 mmol), and the mixture was stirred overnight at ambient temperature. Water and sat. NH4Cl sol. (10 mL each) were added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were washed with 0.25 M citric acid (2×), water, sat. NaHCO3 solution, and brine, and dried over MgSO4. EtOAc (10 mL) was added to the solution, which was then filtered through a silica gel plug (60 mL glass frit filled ≈½ with silica gel) and concentrated to give the title compound as pale yellow oil. The material thus obtained was used without further purification; 1H NMR (CDCl3, 400 MHz) δ 0.29 (s, 6H), 1.03 (s, 9H), 7.15 (dd, J=2.8, 8.8 Hz, 1H), 7.26 (dd, J=4.0, 8.0 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 8.08 (dd, J=0.8, 8.0 Hz, 1H), 8.83 (dd, J=1.6, 4.0 Hz, 1H); MS (ES+): m/z 260.2 (100) [MH+]; HPLC: tR=3.8 min (OpenLynx, polar—5 min).
Reaction SMILES: [I:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:5]([C:7](O)=[O:8])[N:6]=1.O.OC1C2N=N[NH:25]C=2C=CC=1.N.O1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:5]([C:7]([NH2:25])=[O:8])[N:6]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: COc1ccc(-c2oc(I)nc2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2oc(I)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylic acid (0.92 g, 2.7 mmol) in DCM (20 mL) and DMF (10 mL) was added hydroxybenzotriazole monohydrate (0.44 g, 2.9 mmol) followed by 0.5M ammonia in dioxane (22 mL, 11.0 mmol) and 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.77 g, 4.0 mmol) and the reaction stirred at room temperature overnight. EtOAc was then added and the mixture washed with brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using gradient of 0-50% EtOAc in DCM to afford 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxamide (0.66 g. 1.9 mmol, 70%) as a yellow solid. 1H NMR (CDCl3) 3.79 (3H, s), 5.47 (1H, br. s), 6.90 (2H, d), 6.94 (1H, br. s), 8.14 (2H, d). LCMS (1) Rt: 1.84 min; m/z (ES+) 345.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (0.18 g, 1.65 mmol) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (Starting Material 1 supra) (0.3 g, 0.82 mmol) using (Ph3P)2PdCl2 (28.8 mg) and CuI (7.8 mg) as catalyst in DMF (8 mL) and Et3N (8 mL) as solvent at 85° C. for 18 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 0.23 g, 72%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:10](C(O)=O)=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1>N1C=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:10]=[C:9]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1c(-c2ccc([N+](=O)[O-])cc2)oc2ncnc(O)c12
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2cc3c(O)ncnc3o2)cc1
Temperature: 190 °C

Procedure:
21 g of 4-hydroxy-6-(4-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylic acid are dissolved in ca. 200 ml of pyridine whilst heating, and subsequently concentrated by evaporation at 80° C. The residue is heated to 190° C. for 1 h, with a constant stream of nitrogen, in 500 ml of quinoline, which has been dried over magnesium sulfate, with 1 g of Cu2O (Aldrich, Buchs). The reaction mixture is allowed to cool and is added to 1 litre of 2.5 M hydrochloric acid, stirred and filtered by suction. The residue is washed with conc. ammonia solution and with H2O. The dark brown residue is dried in a HV: m.p.: >350° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]#[N:26].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1c(OCc2nnn[nH]2)ccc2cc(-c3csc(-c4ccccc4)n3)ccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
A mixture of {[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetonitrile (277 mg, 0.658 mmol), prepared in the previous step, sodium azide (128 mg, 1.96 mmol) and ammonium chloride (110 mg, 2.05 mmol) in 15 mL of DMF was stirred under nitrogen at 100° C. for 4 h. The reaction was filtered and then 5 mL of 1 N HCl added to the filtrate followed by the addition of 20 mL of water. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (276 mg, 82%) as an off-white solid, mp 227-231° C. Elemental Analysis for C21H14BrN5OS+0.48 C3H7NO+0.47H2O Calc'd: C, 53.07; H, 3.63; N, 15.11. Found: C, 53.08; H, 3.61; N, 14.91.