Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1([N+:8]([O-:10])=[O:9])[CH2:7][NH:6][CH2:5]1)([O-:3])=[O:2].[N+](N1CC([N+]([O-])=O)([N+]([O-])=O)C1)([O-])=O.[N+:24]([O-:27])([O-:26])=[O:25].[NH4+]>>[N+:24]([O-:27])([O-:26])=[O:25].[N+:1]([C:4]1([N+:8]([O-:10])=[O:9])[CH2:7][NH2+:6][CH2:5]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C1([N+](=O)[O-])CNC1
Agent: O=[N+]([O-])N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C1([N+](=O)[O-])C[NH2+]C1

Procedure:
In another embodiment of the present invention, 3,3-dinitroazetidine can serve as a starting material for the preparation of 1,3,3-trinitroazetidine. After preparation of 3,3-dinitroazetidine, the material can be admixed with, e.g., ammonium nitrate to form the energetic salt, 3,3-dinitroazetidinium nitrate. This material can then be dehydrated to form the product 1,3,3-trinitroazetidine. This process is high yielding and produces a minimum of byproducts.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[C:6]([OH:16])[C:7]3[C:12]([C:13]=2[OH:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.C1C2C(C(=O)C3C(C2=O)=CC=CC=3)CC=C1>>[CH2:4]1[CH:5]2[CH:14]([C:13](=[O:15])[C:12]3[C:7]([C:6]2=[O:16])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:1][CH2:2][CH2:3]1
Reactant: Oc1c2c(c(O)c3ccccc13)CCCC2
Agent: O=C1c2ccccc2C(=O)C2CC=CCC12
Product: O=C1c2ccccc2C(=O)C2CCCCC12

Procedure:
A process for the preparation of 1,2,3,4-tetrahydro-9,10-anthracene-diol, in which catalytic hydrogenation of 1,4,4a,9a-tetrahydro-anthraquinone is carried out in the liquid phase to give 1,2,3,4,4a,9a-hexahydro-9,10-anthracene-dione followed by isomerization of the latter in the presence of an acid to give 1,2,3,4-tetrahydro-9,10-anthracene-diol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][CH2:7][CH:6]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:5]2>C(O)C.[Pd]>[CH2:19]([N:15]([CH2:16][CH2:17][CH3:18])[CH:6]1[CH2:5][C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=[CH:2][CH:3]=2)[NH:8][CH2:7]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCC)C1CNc2c(N)cccc2C1
Reaction time: 18 h
Yield: 101.3 %

Procedure:
A mixture of 6-bromo-1,2,3,4-tetrahydro-8-nitro-N,N-dipropyl-3-quinolinamine (2.7 g) and 10% palladium charcoal (0.5 g) in ethanol (150 mL) was hydrogenated for 18 hours. The solution was filtered and the ethanol evaporated to give 1.9 g of 1,2,3,4-tetrahydro-N3,N3 -dipropyl-3,8-quinolinediamine as an oil.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([CH3:30])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.C(N)C1C=CC=CC=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][C:12]=1[O:19][CH3:20].[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=2)[C:25](Cl)=[N:24][N:23]=1.C1CCN2C(=NCCC2)CC1>CN1CCCC1=O>[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=2)[C:25]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[C:12]([O:19][CH3:20])[CH:13]=2)=[N:24][N:23]=1
Reactant: COc1cc(CN)ccc1Cl
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: NCc1ccccc1
Product: COc1cc(CNc2nnc(Cl)c3ccc(C#N)cc23)ccc1Cl

Procedure:
4-Chloro-3-methoxybenzylamine benzylamine hydrochloride synthesized according to the method described in WO9518097 and 1,4-dichlorophthalazine-6-carbonitrile were stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, whereby 1-chloro-4-[(4-chloro-3-methoxybenzyl)amino]-6-phthalazine carbonitrile was obtained as a less polar product.
Reaction SMILES: NC1C=CC(OC2C=CN=C3C=C(C4N=CC(CN(CCOC)C(=O)OC(C)(C)C)=CC=4)SC=23)=C(F)C=1.[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[C:43]1[CH:44]=[CH:45][C:46]([C:49]2[S:57][C:56]3[C:51](=[N:52][CH:53]=[CH:54][C:55]=3[O:58][C:59]3[CH:64]=[CH:63][C:62]([N+:65]([O-])=O)=[CH:61][C:60]=3[F:68])[CH:50]=2)=[N:47][CH:48]=1>>[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[C:43]1[CH:44]=[CH:45][C:46]([C:49]2[S:57][C:56]3[C:51](=[N:52][CH:53]=[CH:54][C:55]=3[O:58][C:59]3[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][C:60]=3[F:68])[CH:50]=2)=[N:47][CH:48]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Agent: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Yield: 95 %

Procedure:
Following the procedure described above for the synthesis of compound 126 (Scheme 6) but substituting compound 125 for compound 138, title compound 139 was obtained in 95% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, J=1.8 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.36 (s, 1H), 8.29 (d, J=8.2 Hz, 1H), 7.96 (dd, J=8.2, 2.0 Hz, 1H), 7.11 (t, J=9.0 Hz, 1H), 6.60 (d, J=5.3 Hz, 1H), 6.53 (dd, J=13.1, 2.5 Hz, 1H), 6.44 (dd, J=8.7, 1.9 Hz, 1H), 5.87 (s, 1H), 5.55 (s, 2H), 4.11-4.07 (m, 2H), 4.00-3.97 (m, 2H). MS (m/z): 410.2 (M+H).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:33]([O:40][C:41]([CH:43]1[CH2:51][CH:50]2[CH:45]([CH2:46][CH2:47][CH2:48][CH2:49]2)[NH:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:33]([O:40][C:41]([CH:43]1[CH2:51][CH:50]2[CH:45]([CH2:46][CH2:47][CH2:48][CH2:49]2)[N:44]1[C:4](=[O:6])[C@H:2]([CH3:3])[NH:1][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(OCc1ccccc1)C1CC2CCCCC2N1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(C(=O)OCc2ccccc2)CC2CCCCC21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
19 g of Boc-Ala-OH are dissolved in 100 ml of dimethylformamide, and 13 ml of N-ethylmorpholine, 13.5 g of HOBt and 29.6 g of octahydroindole-2-carboxylic acid benzyl ester hydrochloride are added to the solution. The mixture is cooled in an ice bath, 21 g of dicyclohexylcarbodiimide are added to it, and it is stirred for 15 hours at room temperature. The precipitated urea is filtered off under suction, and the filtrate is concentrated in vacuo and taken up in ethyl acetate. The solution is extracted 3 times in each case with aqueous KHSO4 solution, KHCO3 solution and saturated NaCl solution and the organic phase is concentrated in vacuo.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:6][C:7]=1[CH2:8]O.C(N(CC)CC)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:8][C:7]1[S:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][C:3]=1[CH:2]([F:18])[F:1]
Reactant: COc1ccc(-c2nc(C(F)F)c(CO)s2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(C(F)F)c(CCl)s2)cc1
Temperature: 25 °C

Procedure:
2.70 g [4-Difluoromethyl-2-(4-methoxy-phenyl)-thiazol-5-yl]-methanol were dissolved in 15 ml dichloromethane and cooled in an ice bath. 2.07 ml triethylamine were added, followed by the addition of 0.92 ml methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. Then 2.07 ml triethylamine and 0.92 ml methanesulfonylchloride were added again and the reaction mixture stirred at room temperature for additional four hours. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 3.0 g crude 5-chloromethyl-4-difluoromethyl-2-(4-methoxy-phenyl)-thiazole as an oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[O:17][CH2:16][CH2:15]C[O:13]2)[CH:6]=[C:7](I)[C:8]=1[O:9][CH3:10].[Cu](C#N)[C:19]#[N:20]>CN(C=O)C>[C:19]([C:7]1[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH:12]2[O:13][CH2:15][CH2:16][O:17]2)[CH:6]=1)#[N:20]
Reactant: COc1cc(C2OCCCO2)cc(I)c1OC
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: COc1cc(C2OCCO2)cc(C#N)c1OC
Temperature: 25 °C
Yield: 78.2 %

Procedure:
2-(3,4-dimethoxy-5-iodophenyl)-1,3-dioxolane (42) (FIG. 22) (2.80 g, 8.0 mmole), copper cyanide (5.7 g, 32.0 mmole) and dry DMF (50 ml) were stirred under an argon atmosphere for 24 hours at 140° C. The reaction was cooled to room temperature, filtered through celite, and the filtrate concentrated to an oil in vacuo. The dark brown oil was purified through a short flash silica column using 2:1 hexane/ethyl acetate as eluent to yield 1.471 g (74%) of a white solid. The product can be recrystallized from hexane/ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[CH:23]=[O:24])[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][OH:24])[CH:21]=4)[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C=O)c3)C2=O)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(CO)c3)C2=O)cn1

Procedure:
3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzaldehyde (example 10-24) (131 mg, 0.3 mmol) was dissolved in 2 mL ethanol. The solution was passed through the H-Cube instrument at room temperature using 10% Pd/C catalyst at a flow rate of 1 ml/minute. The collected fraction was concentrated, redissolved in 2 mL ethanol and purified by HPLC (10-95% Acetonitrile/Water, 25 minutes). The purified fractions were combined and concentrated to give the title compound. 1H NMR (DMSO, 400 MHz): δ2.123 (s, 3H), 2.388 (s, 3H), 3.978 (s, 2H), 4.516 (s, 2H), 5.182 (s, 2H), 7.242 (m, 4H), 7.779 (s, 1H), 8.172 (s, 1H), 8.505 (s, 1H). MS M+H calculated 396.1. found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.3 uM. Yield: 24 mg, 18%.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCCCCC.C(OCC)(=O)C>CC(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc2ccccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCOc1ccc2ccccc2c1F
Yield: 65 %

Procedure:
To a solution of 1-fluoronaphthalen-2-ol (0.162 g, 1.0 mmol) and K2CO3 (0.300 g, 2.0 mmol) in acetone was added tert-butyl (2-bromoethyl)carbamate (0.336 g, 1.5 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 6:4) showed the disappearance of 1-fluoronaphthalen-2-ol, solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (10 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {2-[(1-fluoronaphthalen-2-yl)oxy]ethyl}carbamate as a white solid (65% yield) which was used without further purification.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([F:34])([F:33])[F:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (92 mg, 84%), MS (ISP) m/z=439.4 [(M+H)+], mp 197° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3,3,3-trifluoropropanoic acid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:4]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27].C(=O)=O.CC#N.[B]1OC2C(=CC=CC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.CCOC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:18])([F:17])[F:19])(=[O:14])=[O:15])=[C:4]([C@H:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27]
Reactant: CCOC(=O)C(=O)c1c(C)c(Br)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](O)c1c(C)c(Br)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A solution of ethyl 2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.18 g, 2.52 mmol) in PhMe (20 mL) was cooled to −40° C. (dry ice/CH3CN). (R) —CBS catalyst (140 mg, 0.504 mmol) was introduced, followed by distilled catecholborane (neat, 402 μL, 3.77 mmol) over a 5 min period. After 30 min, the reaction was warmed to ˜−20° C. EtOAc (20 mL) was added. Then 15% Na2CO3 (10 mL) was added. The reaction was stirred vigorously as it was warmed to 23° C. overnight. The next day, the organic phase was washed (with vigorous stirring) with more 15% Na2CO3 (10 mL portions for 30 min each) until the washes were colorless. After the fifth wash, the organic phase was washed once with saturated NH4Cl (10 mL) for 10 min, then dried (MgSO4), filtered, and concentrated. The residue was dissolved in hexane and re-concentrated. The residue was treated with benzene, filtered, and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (886 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=8.2 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.71 (dd, J=8.6, 8.2 Hz, 1H), 7.66 (dd, J=8.6, 8.6 Hz, 1H), 5.84 (d, J=2.4 Hz, 1H), 4.34-4.20 (m, 2H), 3.41 (d, J=2.4 Hz, 1H), 2.63 (s, 3H), 1.22 (t, J=7.0 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−73.0 (s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.C([Li])(C)(C)C.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C1COCC1.CCCCC.C(OCC)C>[CH3:14][Sn:15]([CH3:17])([CH3:16])[SH:1]1[CH:5]=[C:4]([Sn:15]([CH3:17])([CH3:16])[CH3:14])[C:3]2[S:6][CH:7]=[CH:8][C:2]1=2
Reactant: C[Sn](C)(C)Cl
Reactant: c1cc2sccc2s1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)C1=C[SH]([Sn](C)(C)C)c2ccsc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
1 g (7.1 mmol) thieno[3,2-b]thiophene are dissolved in 40 ml anhydrous THF under argon and cooled to −78° C. 11 ml (17.6 mmol) of a 1.6 M tert-butyllithium solution in pentane are added slowly. The mixture is stirred for 2 hours at −78° C., then 4 g (20 mmol) trimethyltin chloride are added as solid. The solution is warmed to room temperature and, stirred for one hour. The solution is diluted with 100 ml diethylether, extracted with aqueous sodium bicarbonate solution, dried and evaporated. The residue is crystallized from acetonitrile at −20° C. to yield 1.9 g (58%) of colorless crystals. Mp=130° C., MS (FD, 8 kV) m/z=465.4 g/mol—calculated: 465.9 g/mol for C12H20S2Sn2; 1H-NMR (300 MHz, CD2 Cl2, RT): δ 7.28 (s, 2H), δ 0.41 (s, 2H); 13C-NMR (75 MHz, CD2Cl2, RT): δ 148.0, 142.0, 16.6, −8.0; elemental analysis: found 30.91%, 4,48% H, 13.61% S—calculated: 30.94% C, 4.33% H, 13.77% S.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N.CCN(CC)CC>C(O)C>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 33.6 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (674 mg, 2.0 mmol) in ethanol (200 mL) were added 2-chlorophenylhydrazine hydrochloride (538 mg, 3.0 mmol) and Et3N (0.56 mL, 4.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(2-chlorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (280 mg, 34%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:14]([CH2:28][O:29][CH2:30][CH3:31])=[N:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1>C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:14]([CH2:28][O:29][CH2:30][CH3:31])=[N:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCN
Temperature: 25 °C
Yield: 93.9 %

Procedure:
Concentrated hydrochloric acid (15.6 mL, 0.194 mol) was added to a solution of tert-butyl [4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (23.2 g, 48 mmol) in ethanol, and the reaction was heated at reflux for 20 minutes. A precipitate formed, and the reaction was allowed to cool to ambient temperature overnight. The solid was isolated by filtration, washed with ethanol, and dissolved in water. The solution was washed with dichloromethane and then made basic with the addition of 50% aqueous sodium hydroxide. The basic solution was extracted with dichloromethane (3×300 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 17 g of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[C:8]=1[C:9]([NH2:11])=[O:10].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:29]([S:31]([NH:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[C:8]=1[C:9]([NH2:11])=[O:10])(=[O:33])=[O:32])[CH3:30]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1c(Nc2ccc(I)cc2F)cc(F)cc1OCc1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(COc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
In analogy to GP 6b, 89 mg of 2-(3-Amino-benzyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Intermediate 3.2; 0.18 mmol, 1 eq.) were dissolved in 0.75 mL pyridine, treated with 34 μL ethylsulfonyl chloride (0.36 mmol, 2 eq.). and stirred at rt for two days. the resulting mixture diluted with ethyl acetate, washed with water and the organic layers dried. Concentration in vacuo was followed by trituration to provide 84 mg of the desired compound (80% yield) with a melting point of 170° C.
Reaction SMILES: CO.[NH:3](C(OCC1C=CC=CC=1)=O)[C@H:4]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H][H]>[Pd].C(O)(=O)C>[NH2:3][C@H:4]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
300 ml of absolute methanol, 2 ml of acetic acid, and palladium black were added to 9.68 g (20.26 mmol) of Z-Lys(Boc)-Pro-OH, and hydrogenation was performed in the stream of dry hydrogen at room temperature under 1 atm for 8 hours. Then, the catalyst was filtered off and washed on the filter with methanol. Pooled filtrate was evaporated to dryness. The residue was precipitated with ether from the absolute methanol. Then, it was dried under vacuum, while desiccant was changed several times.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@@H:28]([CH2:32][NH2:33])[C:29]([OH:31])=[O:30])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>C1COCC1.[OH-].[Na+]>[CH:19]1[C:20]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@@H:28]([CH2:32][NH:33][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:29]([OH:31])=[O:30])=[O:26])[C:22]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CNC(=O)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl chloride (86 mg, 0.613 mmol) and NaOH (0.735 mL, 0.735 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid (200 mg, 0.613 mmol) in THF (1.5 mL) and NaOH (1N, 0.8 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (149 mg, 52%).