Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([O:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]3)([CH3:27])[C:25]([C:35]([F:38])([F:37])[F:36])([OH:34])[CH2:24][CH:23]4[CH2:39][CH2:40][CH2:41][CH2:42][OH:43])[CH2:20][CH2:19][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]1[CH:33]=[CH:32][C:31]2[C@@H:30]3[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]3)([CH3:27])[C:25]([OH:34])([C:35]([F:38])([F:36])[F:37])[CH2:24][CH:23]4[CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:20][CH2:19][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C(CCCCO)CC2(O)C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCCCC1CC(O)(C(F)(F)F)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Pivaloylchloride (0.50 ml; 4.10 mmol) was added dropwise to a solution of 3-Benzyloxy-15-(4-hydroxybutyl)-17-trifluoromethyl-estra-1,3,5(10)-trien-17-ol (1.65 g; 3.28 mmol) in pyridine (15 ml) at 0° C. After stirring for 2 h, the reaction mixture was poured into ice water and stirred for another h. After extraction with DCM, the combined organic phases were dried over MgSO4. After evaporation of the solvent, the residue was purified by column chromatography (SiO2, DCM) yielding the title compound (1.85 g, 96%) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(F)cc1
Reaction time: 10 h

Procedure:
A mixture of 0.1 mol 4-fluorobenzaldehyde, 0.15 mol malonic acid, and 0.1 ml piperidine in 30 ml pyridine is boiled for 10 hours, cooled, and treated with 150 ml HCl having a 10% concentration. The precipitate is filtered and crystallized with ethanol. The yield of 4-fluorocinnamic acid is 68% and the melting point is 211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:38](COCC[Si](C)(C)C)[C:37](S(C)(=O)=O)=[N:36][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:26][CH2:25][C@@H:24]([O:27]COCC[Si](C)(C)C)[CH2:23]3)=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C1(C2[O:62][C@H:61]3[CH2:63][C@@H:64]([OH:67])[CH2:65][O:66][C@@H:60]3[CH2:59][O:58]2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:38][C:37]([O:67][C@@H:64]3[CH2:63][C@H:61]([OH:62])[C@@H:60]([CH2:59][OH:58])[O:66][CH2:65]3)=[N:36][C:5]2=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: O[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Reactant: C[Si](C)(C)CCOCO[C@@H]1CCN(C(=O)c2ccc(-c3ccc(-c4nc5nc(S(C)(=O)=O)n(COCC[Si](C)(C)C)c5cc4Cl)cc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)cc1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-(4′-(6-chloro-2-(methylsulfonyl)-1-((2 (trimethylsilyl)ethoxy)-methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)(3-((2-(trimethylsilyl)-ethoxy)methoxy)pyrrolidin-1-yl)methanone (150 mg, 0.198 mmol) and (4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (100 mg, 0.423 mmol) in DMF (2 mL), was added cesium carbonate (150 mg, 0.460 mmol). The reaction mixture was stirred at room temperature for 2 h, then partitioned between water and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The chromatography of the resulting residue over silica (preparative TLC) eluting with 25% EtOAc in Hexanes afforded the title compound (Rf:0.7) LC-MS: calculated for C48H61ClN4O8Si2 912.37, observed m/e: 913.6 (M+H)+ (Rt: 3.30/4 min)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=[CH:10]1.O>CN(C)C=O>[Br:1][C:10]1[S:9][C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=1
Reactant: c1cc2c(cn1)-c1sccc1CCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cc2c(s1)-c1cnccc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
N-Bromosuccinimide (0.237 g, 1.33 mmol) in dimethylformamide (4 mL) was added dropwise to a solution of 4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (0.250 g, 1.23 mmol) in dimethylformamide (4 mL, 100 mmol) at 0° C. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was mixed with 40 ml of water and extracted with 20 ml of ethylacetate twice. Combined organic extracts were washed with water and brine, and dried over MgSO4. The solvent was evaporated affording 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (0.227 g, 63%). 1H NMR (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.26 (d, J=5.4, 1H), 6.90 (d, J=5.5, 1H), 6.88 (s, 1H), 4.36 (t, J=4.7, 2H), 3.19 (t, J=4.8, 2H). MS (ESI+) 282.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=O)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C([O:36][CH2:37][CH2:38][O:39][NH2:40])(=O)C.CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=[N:40][O:39][CH2:38][CH2:37][OH:36])[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC#CC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CC(=O)OCCON
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC#CC(=NOCCO)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
4-(3-Cloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (VII-4, 10 g) was dissolved in 300 ml of 1,4-dioxane, 1.5 equivalent of 2-(acetoxy)ethoxyamine was added, and 28 ml of 2 mol/L aqueous methanesulfonic acid solution was added, followed by stirring at 60° C. for 17 hours. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate. The residue obtained by concentrating the filtrate was recrystallized from hydrous ethanol-water, filtered, and dried to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VIII-33, 7.6 g) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([NH2:9])=[S:8])([CH3:5])[CH3:4].Br[CH2:11][C:12]([C:14]1[CH:15]=[C:16]([C:20]#[N:21])[N:17]([CH3:19])[CH:18]=1)=O>C(O)C>[OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]([C:20]#[N:21])[N:17]([CH3:19])[CH:18]=2)[N:9]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(N)=S
Reactant: Cn1cc(C(=O)CBr)cc1C#N
Solvent: CCO
Product: Cn1cc(-c2csc(NC(C)(C)CO)n2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
N-(2-Hydroxy-1,1-dimethylethyl)thiourea (0.75 g, 5 mmol), prepared in step 2 of Example 52, was added to 4-(2-bromo-acetyl)-1-methyl-1H-pyrrole-2-carbonitrile (1.15 g, 5 mmol), prepared in the previous step, in ethanol (20 mL) and the mixture was heated under reflux. After 2 h, the reaction was cooled to room temperature, the precipitate was collected, washed with ethanol, suspended in water and made basic with a 1 N sodium carbonate solution. The mixture was extracted with ethyl acetate, the organic layer was then washed with a 1 N sodium carbonate solution, water, dried (anhydrous MgSO4) and evaporated to afford 4-[2-(2-hydroxy-1,1-dimethyl-ethylamino)-thiazol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile (0.92 g, 67%), which was used without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][C:12]=2[O:19][CH2:20][CH3:21])[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:25][CH3:24])=[CH:13][C:12]=2[O:19][CH2:20][CH3:21])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CCOc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1cc(CNC)ccc1Oc1cc(Cl)ccc1C#N
Yield: 74.2 %

Procedure:
4-Chloro-2-(2-ethoxy-4-formylphenoxy)benzonitrile (0.67 g, 2.2 mmol), methylamine (2M in methanol, 3.5 mL, 7.0 mmol) and sodium cyanoborohydride (0.16 g, 2.5 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (65 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.26 g, 2.2 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[2-ethoxy-4-(methylaminomethyl)phenoxy]benzonitrile fumarate (707 mg, 74%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C@H:15]1[O:17][CH2:16]1>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C@@H:15]([OH:17])[CH2:16][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CS(C)=O
Product: Oc1ccc(CCNC[C@H](O)c2cccc(Cl)c2)cc1

Procedure:
Thus, for the preparation of the amine starting material in Example 11 hereinafter, tyramine was reacted with (R)-m-chloro-styrene oxide in DMSO while heating to give (R)-m-chloro-[[(p-hydroxyphenethyl)amino]methyl]benzyl alcohol and the latter was etherified by reaction with 2-ethoxyethylmethanesulphonate to give (R)-m-chloro-α-[[[(p-(2 -ethoxyethoxy)phenethyl]amino]methyl]benzyl alcohol, [α]20/D=-20° (c=0.5 in methanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:3]1=2.I[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>[Cu](I)I.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>[OH:17][CH:14]([C:6]1[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:3]2[C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[C:15]#[C:16][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1cc(-c2ccc(C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: Cc1ccc(-c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 81 %

Procedure:
In a similar manner to that of Example 1g, by reacting 950 mg (2.9 mmol) of 1-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)prop-2-yn-1-ol with 595 mg (2.4 mmol) of 4-iodobenzoic acid in the presence of 47 mg of copper iodide and 54 mg of bis(triphenylphosphine)dichloropalladium. The desired product is obtained in the form of white crystals (m=1 g; yield=81%; m.p.=207° C.).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]=2)[CH:5]=[C:4]([C:16](O)=[O:17])[C:3]1=[O:19].C(Cl)(=O)C([Cl:23])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]=2)[CH:5]=[C:4]([C:16]([Cl:23])=[O:17])[C:3]1=[O:19]
Reactant: Cn1c(=O)c(C(=O)O)cc2ccc(C(F)(F)F)nc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C(=O)Cl)cc2ccc(C(F)(F)F)nc21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
0.83 g (3.0 mmol) of 1-methyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 1.0 mL (12 mmol) of oxalyl chloride was added thereto. Two droplets of N,N-dimethylformamide were added to the above mixture, and the resulting mixture was stirred for 2 hours at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-methyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in acetonitrile (30 mL), and this solution was added to an acetonitrile (50 mL) solution of 0.38 g (3.4 mmol) of 1,3-cyclohexanedione and 0.51 mL (3.7 mmol) of triethylamine under ice cooling. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and was dried and concentrated. The residue was washed with diisopropyl ether, and thus 0.51 g (yield: 46%) of the title compound was obtained as brown crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15](CC2CC2)[C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]1(OC)[CH:32]=[CH:31][CH:30]=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:32]1([CH2:27][N:14]([CH2:15][C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[CH3:22])[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:30][CH2:31]1
Reactant: Cc1nc(C)c(C(CC2CC2)NC2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C)c(CN(CC2CC2)C2CCNCC2)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
4-{[Cyclopropylmethyl-(2,4-dimethyl-thiazol-5-ylmethyl)]-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.96 g, 5.18 mmol) is added to a stirred solution of dichloromethane (5 ml) and anisole (9.0 ml, 82.8 mmol). The reaction is cooled to 0° C. Trifluoroacetic acid (6.0 ml, 72.9 mmol) is then added. The reaction is stirred for 20 minutes at 0° C. and then for 5 h at room temperature. The reaction is loaded onto a pre-washed SCX-2 (10 g) column and washed with methanol (200 ml). The product is then eluted off with 2M ammonia in methanol (100 ml) and concentrated on a rotary evaporator to yield (1.25 g, 87%) of N-(cyclopropylmethyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=280.2 (M+1); 1H NMR (CDCl3): δ=3.75 (2H, s), 3.19-3.11 (2H, m), 2.81-2.73 (1H, m), 2.65-2.52 (5H, m), 2.42 (2H, d), 2.32 (3H, s), 1.76 (3H, brd), 1.50-1.38 (2H, m), 0.89-0.80 (1H, m), 0.52-0.44 (2H, m), 0.11-0.05 (2H, m).
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[C:4]([CH3:10])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.Cl.[CH3:13][N:14]1CCCC1=O>O>[F:11][C:3]1[C:4]([CH3:10])=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[C:13]#[N:14]
Reactant: Cc1c(F)c(F)cc(Br)c1F
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: O
Product: Cc1c(F)c(F)cc(C#N)c1F
Reaction time: 4.5 h

Procedure:
A mixture of 3-bromo-2,5,6-trifluorotoluene (11.0 g) and cupric cyanide (5.3 g) in N-methylpyrrolidone (15 ml) was stirred at 150° to 160° C. in a sealed tube for 4.5 hours. After cooling, to the reacting mixture was added a solution of ferric chloride (20 g) and concentrated hydrochloric acid (5 ml) in water (30 ml) and stirred at 50° to 60° C. for 20 minutes. The reacting mixture was extracted with ether, the organic layer was washed with aqueous hydrochloric acid solution, water and saturated aqueous sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (7.83 g) as pale brown oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]2)[CH:5]=1)=[O:3].[Cu](C#N)[C:26]#[N:27]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:1][C:2]([C:4]1[CH:9]=[C:8]([C:26]#[N:27])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]2)[CH:5]=1)=[O:3]
Reactant: N#C[Cu]C#N
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(Cl)n2)CC1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(C#N)n2)CC1
Temperature: 100 °C
Yield: 62.6 %

Procedure:
tert-Butyl {1-[4-(aminocarbonyl)-6-chloropyridin-2-yl]piperidin-4-yl}carbamate (Intermediate 16) (100 mg, 0.282 mmol), copper cyanide (101 mg, 1.13 mmol), Pd(dba) (103 mg, 0.11 mmol) and Dppf (250 mg, 0.45 mmol) were placed in anhydrous dioxane (5 ml) under argon. The mixture was heated at 100° C. for 5 h, then diluted with EtOAc (20 ml) and filtered through celite. The mixture was washed with sodium bicarbonate (2×20 ml), brine (20 ml), dried over sodium sulphate and concentrated in vacuo. The brown residue was purified by flash chromatography eluting with DCM and MeOH mixtures to give the title compound as a brown solid (61 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7](N)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].N([O-])=[O:19].[Na+]>OS(O)(=O)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7]([OH:19])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(N)c1Oc1cc(Cl)cc(Br)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(O)c1Oc1cc(Cl)cc(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled suspension of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-amine (11-4; 600 mg, 1.913 mmol) in 5% aqueous H2SO4 (10 mL) was added a solution of sodium nitrite (198 mg, 2.87 mmol) in water (1 mL) and stirred over ice bath for 30 minutes. After this time, this suspension was added to a solution of 5% aqueous H2SO4 (10 mL) heated to 100° C. and maintained at 100° C. for 1.5 hours. After this time, the mixture was cooled to 0° C. and treated with additional sodium nitrite (60 mg, 0.86 mmol) and then heated to 100° C. for 20 minutes. After this time, the mixture was cooled to 25° C., filtered the resulting solid and washed with water (10 mL) and dried under high vacuum to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH:9]([Br:12])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1cccc(Cl)c1
Reactant: BrBr
Product: CC(Br)C(=O)c1cccc(Cl)c1
Reaction time: 5.5 h

Procedure:
To 1 mole of m-chloropropiophenone was heated to 70±5° C., bromine was added dropwise under stirring. The reaction temperature was kept at 70±5° C. during the addition of bromine and kept for 5.5 hours after the addition. m-chloro-α-bromopropiophenone (compound of formula (II)) was obtained.
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11]Cl)[N:10]=1)[C:3]([NH2:5])=[NH:4].[SH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[OH-].[Na+]>CCO.O>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1nc(CCl)cs1
Reactant: COC(=O)CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)CCSCc1csc(NC(=N)N)n1
Reaction time: 18 h

Procedure:
To 2-guanidino-4-chloromethylthiazole hydrochloride (3.86 g.) and methyl 3-mercaptopropionate (3.0 g.) in EtOH (45 ml.) at 0° was added sodium hydroxide (1.6 g.) in water (15 ml.) over 15 minutes. The reaction mixture was allowed to attain room temperature and to stand for 18 hours. The solution was poured into water and extracted with EtOAc. The extract was washed with aqueous sodium hydroxide solution, water, dried and evaporated to give methyl 3-(2-guanidinothiazol-4-yl-methylthio)propionate as a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[N+:12]([O-])([OH:14])=[O:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1sc(C)cc1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1sc(C)c([N+](=O)[O-])c1C
Temperature: 0 °C

Procedure:
To a well stirred, chilled (0°) solution of 51.4 g (0.3 mol) of methyl 3,5-dimethylthiophene-2-carboxylate in 200 ml of glacial acetic acid are added dropwise over a period of 40 minutes, a mixture of 30 ml of fuming nitric acid (specific gravity=1.5) and 120 ml of acetic anhydride. After the addition is completed the resulting brown solution is stirred a further two hours at 5° and then poured into 3000 ml of ice water.
Reaction SMILES: [C:1]1([C@@H:7]([C@H:9]2[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10]2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:22].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[Br:22][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:9]1[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10]1
Reactant: O[C@@H](c1ccccc1)[C@@H]1CN(Cc2ccccc2)CCO1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: Br[C@H](c1ccccc1)[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 60 °C
Yield: 80.6 %

Procedure:
To a solution of 4a (4.71 g, 16.6 mmol) in anhydrous chloroform (200 ml) under nitrogen was added triphenylphosphine dibromide (14.04 g, 33.26 mmol). The reaction mixture was heated at 60° C. overnight. The mixture was allowed to cool to room temperature then washed with saturated aqueous sodium carbonate solution, dried over sodium sulphate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica (eluent: ethyl acetate/isohexane gradient 10/90 to 30/70 [v/v]) to give 5a as a white solid (4.63 g, 81%); MW 346.27; C18H20BrNO; 1H NMR (CDCl3): 7.14-7.39 (10H, m), 4.83 (1H, d, 7 Hz), 4.01 (1H, br, t, 8 Hz), 3.73 (1H, br, d, 11 Hz), 3.60-3.48 (2H, m), 3.39 (1H, d, 12 Hz), 3.20 (1H, d, 11 Hz), 2.50 (1H, d, 10 Hz), 2.07 (2H, t, 10 Hz); LCMS: (6 min method) m/z 346 [M]+ @ Rt 2.51 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([F:31])=[C:4]([C:23]([F:30])=[C:24]([F:29])[C:25]=1[N+:26]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15]CC2C=CC=CC=2)[CH:7]=1.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:3]([F:31])=[C:4]([C:23]([F:30])=[C:24]([F:29])[C:25]=1[NH2:26])[O:5][C:6]1[CH:7]=[C:8]([OH:15])[C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)c(O)c([N+](=O)[O-])c(F)c2F)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2c(F)c(O)c(N)c(F)c2F)cc1O
Reaction time: 72 h

Procedure:
43.6 g of 1-(3-hydroxy-4-nitro-2,5,6-trifluorophenoxy)-3-benzyloxy-4-nitrobenzene prepared as described in Example 13 (0.1 mol) are dissolved in 400 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 4.4 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow solution is evaporated to half in a rotary evaporator an left to stand at room temperature overnight, during which the reaction product precipitates in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at, 40° C./10 mbar in a vacuum drying cabinet.