Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][C:64]([O:92][CH3:93])=[C:65]([O:87][CH2:88][CH2:89][O:90][CH3:91])[CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH3:93][O:92][C:64]1[CH:63]=[C:62]2[C:67]([C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)=[N:69][C:60]([C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([NH:53][C:8](=[O:10])[CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:55]=3)=[N:61]2)=[CH:66][C:65]=1[O:87][CH2:88][CH2:89][O:90][CH3:91]
Reactant: O=C(O)CN1CCOCC1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(N)c3)nc2cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-morpholinoacetic acid (0.034 g, 0.24 mmol), DIEA (0.165 mL, 0.94 mmol) and PyBOP® (0.125 g, 0.24 mmol) in CH2Cl2 (1 mL) was stirred at RT for 10 minutes, upon which it was added to a solution of tert-Butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.260 g, 0.47 mmol) in CH2Cl2 (10 mL). the subsequent was stirred at RT for 1 hr upon which further aliquots of 2-morpholinoacetic acid (0.034 g, 0.24 mmol) and PyBOP® (0.125 g, 0.24 mmol) were added. The resulting mixture was stirred at RT overnight upon which the mixture was concentrated in vacuo and taken directly to the next step. HPLC retention time 5.35 mins.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[NH3:18]>C(O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH2:18])[N:3]=1
Reactant: Nc1nc(Cl)cnc1-c1cc(Cl)cc(Cl)c1Cl
Reactant: N
Solvent: CCO
Product: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Temperature: 180 °C

Procedure:
A suspension of 2-amino-6-chloro-3-(2,3,5-trichlorophenyl)pyrazine (0.3 g, 9.71×10−4 mole) in absolute ethanol (4 ml) and 0.880 aqueous ammonia (8.24 ml) was stirred and heated in an autoclave at 180° C. for 44 hrs. The cooled mixture was evaporated in vacuo, and the residue extracted with chloroform (3×30 ml). The combined chloroform extracts were dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was purified by ‘flash chromatography’ using chloroform to 98:2 chloroform:methanol as the eluent. The product was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 0.155 g (56%), M.p. 178-180° C.
Reaction SMILES: C(N[CH:9]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:10]1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.C[OH:28]>>[CH2:20]([NH:19][C@@H:10]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:28])[OH:14])[OH:12])[CH:9]=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OC[C@H]1OC(NCc2ccccc2)[C@@H](NCc2ccccc2)[C@@H](O)[C@@H]1O
Reactant: CO
Product: O=C[C@@H](NCc1ccccc1)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 40 °C

Procedure:
From compound of example 1: to a suspension of N,N′-dibenzyl-1,2-diamino-1,2-dideoxy-D-mannopyranose (10 g) in methanol (30 ml) conc. HCl-solution (4 ml) was gradually added and the mixture was heated to 40° C. for 2-3 hours. The solvent was carefully evaporated, the residue was taken up in methanol and evaporated again 3-4 times. The resulting solid was suspended in ethanol and heated to reflux, the insoluble material was removed by hot filtration, and the filtrate was evaporated to dryness to yield the hydrochloride salt of N-benzyl-2-amino-2-deoxy-D-mannose.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1CSC1C=CC=C2C=1N=CC=C2.[Li+].[OH-]>CO.O>[C:3]([OH:22])(=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccccc1CSc1cccc2cccnc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1.0 eq of ester 41 and 3.0 eq. of LiOH in methanol and water was heated to 65° C. for a time sufficient for completion of the hydrolysis. The mixture was cooled to room temperature and concentrated, then diluted with H2O. The pH of the aqueous mixture was adjusted to 4.5 and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to give the intermediate benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:17][C:18]([CH3:23])([CH3:22])[C:19](O)=O>O>[CH3:22][C:18]([CH3:23])([C:19]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[OH:17]
Reactant: CC(C)(O)C(=O)O
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Solvent: O
Product: CC(C)Cn1c(C(C)(C)O)nc2cnc3ccccc3c21
Temperature: 160 °C
Yield: 22.8 %

Procedure:
3-Amino-4-(2-methylpropyl amino)quinoline (28.7 g; 0.133 mol) and 2-hydroxyisobutyric acid (27.8 g; 0.267 mol) were mixed and the mixture was heated at 160° C. for 5 hrs. Water was added to the dark mixture and a green oil formed. The oil was extracted with ether to yield 8.6 g of an oil which contained two products. The mixture was purified by silica gel column chromatography to yield 3.2 g of the intended product. A small amount was recrystallized from ethyl acetate for analysis and characterization. m.p. 156-164° C. Analysis: Calculated: C, 72.1; H, 7.5; N, 14.8. Found: C, 7-1.9; H, 7.4; N, 14.6.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.CN(C)C=O.[NH2-].[Na+].[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>O>[N+:17]([C:13]1[CH:12]=[C:11]([N:10]2[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3](=[O:20])[N:31]([CH2:28][CH2:29][CH3:30])[C:32]2=[O:33])[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: COC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCCN=C=O
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 2.9 g of 2-(m-nitroanilino)benzoic acid methyl ester and 20ml of dry dimethylformamide was added 0.43 g of sodium amide, and the whole was stirred for 30 minutes. To this was added dropwise under cooling 2.6 g of propyl isocyanate. This mixture was allowed to stand for one hour at room temperature and for additional one hour at 60° C, and then reacted for 4 hours at 120° C. The solvent was distilled off from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. This product was recrystallized from methanol to produce 2.4 g of 1-(m-nitrophenyl)-3-propylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][N:11]([CH:18]([CH3:22])[C:19](O)=[O:20])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH:15]([F:16])[F:17])=[CH:12][N:11]([CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:20])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1cc(OC(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
270 mg (purity 63%, 0.46 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 98 mg (0.51 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 100 mg (40% of theory)
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].[Mn]([O-])(=O)(=O)=O.[K+]>>[O:1]=[CH:2][CH:3]([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(CO)CCC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CC(C=O)CCC(=O)O

Procedure:
1.00 g. (7.57 mmol) of 5-hydroxy isocaproic acid was oxidized with 0.82 g. (5.22 mmol) of potassium permanganate in an aqueous base according to the procedure of Carson, et al., Org. Syn. Col. Vol. 1, 241 (1941). The oily product contaminated with a minor amount of starting material was characterized by NMR and used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([CH:26]1[CH2:30][CH2:29][N:28]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: c1ccc(CC2CCNC2)cc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(Cc2ccccc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-benzylpyrrolidine (9.7 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.3 mg). Calcd for C22H19F3N2O2: 400.1399, found 400.1402.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7](Cl)=[O:8].[Cl:23][C:24]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:25]=1[NH2:26].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7]([NH:26][C:25]1[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:24]=1[Cl:23])=[O:8]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)Cl)c2)c1
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(NC(=O)COc2cc(Cl)cc(Oc3cc(Cl)cc(C#N)c3)c2)c(Cl)c1

Procedure:
A DMF solution (0.5 mL) of 29 mg (0.081 mmol) of [3-chloro-5-(3-chloro-5-cyanophenoxy)phenoxy]acetyl chloride (5-4), 33 mg (0.163 mmol) of 2-chloro-4-methylsulfonylaniline (5-5) and 21 mg (0.163 mmol) of DIEA were stirred at 25° C. until the reaction would not proceed any further. This solution was loaded directly onto a CombiFlash silica gel column eluted with EtOAc:hexanes (3:97 to 100:0). Clean fractions were combined and concentrated in vacuo to give the desired product 5-6 as a white solid. Rf=0.8 (DCM:MeOH:NH4OH 98:2:0.2). HRMS (M+Na): measured 542.0066; theoretical 542.0105. 1H NMR(CDCl3): 3.07 (s, 3H), 4.69 (s, 2H), 6.61 (m, 1H), 6.74 (m, 1H), 6.89 (m, 1H), 7.15 (m, 1H), 7.25 (m, 1H), 7.42 (m, 1H), 6.94 (dd, 1H), 8.02 (m, 1H), 8.74 (d, 1H), 9.11 (s, 1H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[O:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)C=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1>N1C=CC=CC=1>[O:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:3]=[CH:2][C:1]([OH:7])=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
62.4 g of malonic acid are dissolved in 100 ml of pyridine. After termination of the exothermal reaction, 99 g of 3-phenoxybenzaldehyde and 5 g of piperidine are added, the batch is refluxed for 3 hours, cooled to 25° C. and poured onto ice/concentrated hydrochloric acid in order to wash out pyridine and piperidine, while the acid precipitates in the form of crystals. After drying, 113.7 g (95% of theory) of 3-phenoxycinnamic acid, m.p. 107°-109° C., are obtained. 18 g (0.15 mol) of thionyl chloride are added to a suspension of 24 g (0.1 mol) of 3-phenoxycinnamic acid in 100 ml of toluene, and stirred for 3 hours at 30° C. After removal of the solvent in vacuo, distillation is carried out. 24.6 g (95% of theory) of 3-(2-phenoxyphenyl)-2-propenic acid chloride, b.p. 155°-158° C./0.2 mm Hg, are obtained.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:23])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C)=[CH:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2].O1CCCC1.N.[Li]>C(O)(C)(C)C>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:23])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Agent: N
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.0 g. of 16β-ethyl-3-methoxy-1,3,5(10)-estratrien-17β-ol in 40 ml. of tetrahydrofuran and 4 ml. of tert.-butanol is added dropwise at -40° C. to 80 ml. of ammonia. After the incremental introduction of 1.2 g. of lithium, the mixture is stirred for 2 hours at -40° C.; then the ammonia is allowed to evaporate, the residue is poured into about 200 ml. of water, and the mixture is extracted with ethyl acetate. The crude product is taken up in 40 ml. of methanol and 4 ml. of 4 N hydrochloric acid and agitated for 15 minutes at 50° C. Thereafter, the mixture is poured into water and extracted with methylene chloride. After recrystallizing the crude product from ethyl acetate/ether, 1.7 g. of 16β-ethyl-17β-hydroxy-4-estren-3-one is produced, m.p. 150°-152° C.
Reaction SMILES: C(O)C.[CH2:4]([C:14]1[CH:24]=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O.[NH2:26][NH2:27]>O>[CH2:4]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([NH:26][NH2:27])=[O:19])=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCc1ccc(C(=O)OCC)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCc1ccc(C(=O)NN)cc1
Yield: 72.9 %

Procedure:
18 ml of ethanol was added to 10.0 g of ethyl 4-decylbenzoate, and then 20 g of 80%-hydrazine hydrate was added thereto, followed by refluxing for 16 hours. After the reaction, the reaction mixture was poured into 200 ml of iced water to precipitate a crystal. The crystal was recovered by filtration and recrystallized from ethanol to obtain 6.93 g of 4-decylbenzohydrazide (Yield: 72.9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]1[CH2:12][CH:6]([CH2:7]1)[C:5]2=[N:13]O.S(Cl)(Cl)=[O:16]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]3[CH2:12][CH:6]([NH:13][C:5]2=[O:16])[CH2:7]3)=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: ON=C1c2cc(Br)ccc2C2CC1C2
Solvent: C1COCCO1
Product: O=C1NC2CC(C2)c2ccc(Br)cc21
Temperature: 25 °C
Yield: 221.6 %

Procedure:
Into a 20-L 4-necked round-bottom flask was placed 6-Bromo-2,3-dihydro-1H-1,3-methano-naphthalen-4-one oxime (790 g, 3.13 mol, 1.00 equiv), 1,4-dioxane (7.5 L), followed by the addition of a solution of thionyl chloride (12000 g, 32.00 equiv) in 1,4-dioxane (7.5 L) dropwise with stirring at 25° C. The resulting solution was stirred at 65° C. for 6 h. This reaction was repeated for 2 more times. The resulting mixture was concentrated under vacuum, diluted with 10 L of DCM and then quenched by the addition of 8 L of water. The resulting solution was extracted with 2×10 L of dichloromethane and the organic layers were combined. The pH value of the solution was adjusted to 7 with sodium bicarbonate (sat.). The organic layer was dried over anhydrous sodium sulfated and concentrated under vacuum. The residue was diluted with 4 L of EA and stirred at reflux for 0.5 h. The solids were collected by filtration and washed with 2×500 mL, of EA. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column eluting with PE:EA (5:1-3:1). This solid was combined with the previous solids to afford 1749 g (74%) of 5-Bromo-9-aza-tricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one as an off-white solid.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:25])[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>>[CH3:24][N:22]([CH3:23])[CH2:21][CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][N:14]([CH3:13])[CH3:25])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCCNCCCN(C)C
Product: CCCCCCC/C=C/C(=O)N(CCCN(C)C)CCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N-(3-(dimethylamino)propyl)-N′,N′-dimethylpropane-1,3-diamine as starting materials to give the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]1([C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1>>[C:10]1([C:16]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:8][C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[N:1]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: Nc1ncccc1C=O
Solvent: C1CCNCC1
Product: c1ccc(-c2cc3cccnc3nc2-c2ccccc2)cc1
Temperature: 120 °C

Procedure:
A suspension comprising 2-amino-pyridine-3-carbaldehyde (5 g, 40.9 mmol) and deoxybenzoin (8.03 g, 40.9 mmol) in piperidine (4.46 ml, 45.0 mmol) was heated at 120° C. overnight. The resulting solution was partitioned between DCM (200 ml) and water (200 ml). The organic layer was separated and washed with water (2×150 ml), brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title product as a yellow solid;
Reaction SMILES: [BrH:1].[CH2:2]([O:4][C:5]([C:7]1[S:8][C:9](N)=[N:10][N:11]=1)=[O:6])[CH3:3].N([O-])=O.[Na+]>C(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[CH2:2]([O:4][C:5]([C:7]1[S:8][C:9]([Br:1])=[N:10][N:11]=1)=[O:6])[CH3:3]
Reactant: Br
Reactant: CCOC(=O)c1nnc(N)s1
Agent: O=N[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1nnc(Br)s1
Temperature: 3 °C
Yield: 71 %

Procedure:
A 500 mL (three neck) round-bottom flask with a stir bar, needle inlet, and a gas outlet to a trap containing a 10% solution of Na2S2O3 was charged with CuBr (1.24 g, 8.67 mmol, 0.1 equiv.) and HBr (48% aqueous solution, 108 mL). The purple solution was cooled to 3° C. (internal, ice bath), to which was added portion-wise a solid mixture of 5-amino-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (15.0 g, 86.6 mmol) and sodium nitrite (27.0 g, 391.3 mmol, 4.5 equiv.) over the course of 30 min. The reaction mixture was allowed to warm to room temperature for 2 h 15 min. The reaction mixture was diluted with CH2Cl2 and 10% aqueous Na2S2O3 and the layers were separated. The aqueous layer was extracted 3 times with CH2Cl2. The combined organic layers were washed with Brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (ISCO XL, 330 g SiO2 column, 20-25% EtOAc/Hexanes) to provide an off-white solid that was triturated with 5% EtOAc/Hexanes. Filtration provided 5-bromo-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (14.5 g, 71%) as white needles. Concentration and trituration of the mother liquor provided an additional product (2.3 g, 11%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH:17]1([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](I)[CH:23]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.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>[CH:17]1([NH:20][C:21]([C:22]2[CH:27]=[C:26]([C:6]3[CH:5]=[CH:4][C:3]([C:9](=[O:10])[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:2]([NH2:1])[CH:7]=3)[C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:30])[CH2:18][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1I
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
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: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)c2ccccc2)c(N)c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 48.6 %

Procedure:
To a solution the (2-Amino-4-bromo-phenyl)-phenyl-methanone (276 mg, 1.0 mmol) and N-Cyclopropyl-3-iodo-4-methyl-benzamide (301 mg, 1.0 mmol) in 5 mL of methyl sulfoxide was added potassium carbonate (276 mg, 2.0 mmol) and followed by Pd(PPh3)4 (58 mg, 0.05 mmol). After the reaction mixture was stirred at 95° C. for 4 hours, the reaction mixture was allowed to cool to room temperature and 10 mL of water was added to the mixture. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers washed with water (10 mL) and brine (10 mL), dried over MgSO4, and the solvents were evaporated. The residue was purified by chromatography (hexanes:ethyl acetate=1:1) to give the desired compound as a colorless solid (180 mg, 49%).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][C:15]=1[F:16]>O1CCCC1.C(OCC)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH2:18][C:3]([O:6][CH3:7])=[O:8])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(F)c(Br)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a suspension of sodium hydride (1.1 g of 60% suspension in mineral oil, hexane-washed, 27.6 mmol) in 50 mL of tetrahydrofuran was added dimethyl carbonate (2.3 mL, 27.6 inmol) and 3'-bromo-4'-fluoroacetophenone (3.0 g, 13.8 mmol). The resulting suspension was stirred at 65° C. for 1 h and then was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexane/ethyl acetate) to afford 1.0 g (26%) of the title compound. 1H NMR (CDCl3) (data for keto tautomer) δ8.15 (dd, 1H), 7.87 (m, 1H), 7.2 (m, 1H), 3.95 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl:15][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[Cl:15][C:16]1[O:20][C:19]([CH:21]([OH:22])[C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=Cc1ccc(Cl)o1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2ccc(Cl)o2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 117.6 %

Procedure:
To a solution of THF (40 mL) and 4-iodobenzonitrile (2.0 g) was added isopropylmagnesium chloride (2M, 6.1 mL) dropwise at −78° C. under a nitrogen atmosphere, which was stirred for 1 hour and 10 minutes at 0° C. After cooling to 78° C., 5-chloro-2-furaldehyde (1.4 g) was added dropwise thereto, which was stirred for 15 minutes at room temperature. A saturated aqueous ammonium chloride solution was added at room temperature, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (2.4 g).