Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1.O>CN(C=O)C>[CH2:17]([NH:16][C:11]1=[N:12][C:13](=[O:15])[S:14]/[C:10]/1=[CH:9]\[CH:6]1[CH2:7][CH2:8][N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=2)[CH2:4][CH2:5]1)[C:18]#[CH:19]
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (300 mg) in DMF (3 mL) were added potassium carbonate (517 mg) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.15 mL). The reaction mixture was stirred at room temperature for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (64 mg).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1.Br[CH2:19][Cl:20]>>[Cl:20][CH2:19][S:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1
Reactant: Sc1cc2ccccc2s1
Reactant: ClCBr
Solvent: CCN(CC)CC
Product: ClCSc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (20 mmol) was added to a mixture of 2-mercaptobenzo[b]thiophene [see J. Chem. Soc. (C), 2731(1970)] (20 mmol) and bromochloromethane (400 mmol). The mixture was stirred for 30 minutes at room temperature, washed with water and the dried (MgSO4) solution evaporated. Yield 4.08g (95%). 1H-NMR (CDCl3, δ): 4.88 (s, --CH2 --), 7.0-8.0 (m,5H,Ar). The product was used in Example 30 without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:3]=1[C:19]#[N:20].S(=O)(=O)(O)[OH:22].[OH-].[Na+]>>[NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:3]=1[C:19]([NH2:20])=[O:22]
Reactant: CC(C)n1nc(-c2cccc([N+](=O)[O-])c2)c(C#N)c1N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)n1nc(-c2cccc([N+](=O)[O-])c2)c(C(N)=O)c1N
Temperature: 65 °C
Yield: 85 %

Procedure:
Compound 26 (100 mg, 0.369 mmol) was added to concentrated sulfuric acid (1 mL) and heated to 65° C. for 3 hours. Afterwards, the reaction mixture was poured into ice water and the pH was brought to 14 with 10 M NaOH. The aqueous material was extracted several times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to a solid (91 mg, 85% yield): 1H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 8.21 (d, J=8.2, 1H), 7.98 (d, J=7.7, 1H), 7.69 (t, J=8.0, 1H), 6.20 (br, 2H), 4.51 (hept, 1H), 1.35 (d, J=6.5, 6H); 13C NMR (100 MHz, DMSO) δ 166.17, 149.37, 147.65, 145.50, 135.63, 134.92, 129.69, 122.79, 122.43, 95.43, 47.11, 21.50; [M+H]+ calculated for C13H15N5O3 290.1, found 290.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=12
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-Bromo-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:18])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C1CCCC(=O)O1
Solvent: c1ccccc1
Product: CC(=O)c1ccccc1NC(=O)CCCC(=O)O
Yield: 66.8 %

Procedure:
1-(2-aminophenyl)ethane-1-one (4.00 g) and glutaric anhydride (4.10 g) were dissolved in benzene (30 ml) and the solution was heated to reflux for 3.5 hours, followed by concentration of the mixture. The residue was recrystallized from ethyl acetate to obtain 4.93 g of 4-(N-(2-acetylphenyl)carbamoyl)butanoic acid as colorless plate-like crystals. Yield: 66%.
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30]([NH2:32])=[O:31])[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.[CH3:36]O>O1CCCC1>[CH2:1]([N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([C:30]([NH2:32])=[O:31])[C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[CH3:36]
Reactant: CO
Reactant: COC(=O)C(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cccc(-c2ccc(CC(C(N)=O)C(=O)O)cc2)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 46 %

Procedure:
180 mg (0.4 mmol) of methyl 2-(3′-{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-ylmethyl)malonamate (prepared in Example 16(d)) in 2 ml of methanol, 2 ml of tetrahydrofuran and 250 μl (0.5 mmol) of aqueous 2N sodium hydroxide solution are introduced [lacuna]. The reaction medium is stirred at room temperature for 36 hours, acidified to pH 3 with hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. 80 mg (46%) of the desired product, with a melting point of 117° C., are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:8])=[CH:5][N:4]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30]>>[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[CH:28]=[CH:27][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(CBr)nc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(Cc2ccc(C(N)=O)cn2)CC1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.2 mmol) was used in general procedure 5 with 1-ethylpiperazine (0.4 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(4-ethylpiperazin-1-yl)methylnicotinamide. MS (Q1) 512.2 (M)+
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Si:27]([O:34][C@H:35]1[CH2:39][N:38]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[O:41])[C@H:37]([C:53]([C:55]2[N:56]=[CH:57][N:58]3[CH:62]=[C:61]([Sn](CCCC)(CCCC)CCCC)[S:60][C:59]=23)=[O:54])[CH2:36]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>>[Si:27]([O:34][C@H:35]1[CH2:39][N:38]([C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=2)=[O:41])[C@H:37]([C:53]([C:55]2[N:56]=[CH:57][N:58]3[CH:62]=[C:61]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=4)=[O:13])[S:60][C:59]=23)=[O:54])[CH2:36]1)([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CN3C(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)[C@@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CN5C(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 49 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-[(2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (369 mg) was prepared in the same manner as in step a) of Example 1, except that 312 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 707 mg of 7-[(2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: C[CH:2]([N+:7]#[C-:8])[C:3]([O:5][CH3:6])=[O:4].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:6][O:5][C:3]([C@H:2]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:16][CH:8]=[N:7]1)=[O:4]
Reactant: O=Cc1ccccc1
Reactant: [C-]#[N+]C(C)C(=O)OC
Product: COC(=O)[C@@H]1N=CO[C@H]1c1ccccc1
Yield: 90 %

Procedure:
Methyl α-methylisocyano-acetate was reacted with benzaldehyde in the presence of the same catalyst and under the same reaction conditions of those of Example 2. After the solvent was concentrated, the reaction mixture was subjected to silica-gel column chromatography to obtain trans-4-methoxycarbonyl-5- phenyl-2-oxazoline and the corresponding cis-form in a ratio of 87/13). Total yield: 90%. The optical purity of the trans-(4S,5R) form was measured in the same manner as in Example 1, which was 93% ee.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](#[N:17])[CH:15]=[CH2:16].CO>C1(C)C=CC=CC=1>[C:14]([CH2:15][CH2:16][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)#[N:17]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CC#N
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CCCn1c2ccccc2c2ccccc21
Reaction time: 1 h
Yield: 42 %

Procedure:
Carbazole (8.0 g) was suspended in 100 ml of toluene, and 4 ml of acrylonitrile and subsequently 0.5 ml of Triton B were added to the suspension, whereby the suspension was solidified. Then, the reaction mixture was allowed to stand for one hour, and methanol was added thereto, followed by filtration to give 4.41 g (42%) of the product as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>C(#N)C>[OH:25][CH2:24][CH2:23][C@@H:22]([NH:21][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1
Reactant: Cc1ccc([C@H](N)CCO)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CCO)c4ccc(C)nc4)c3C2)c(C#N)c1
Yield: 33.3 %

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (60 mg, 0.21 mmol) and (R)-3-amino-3-(6-methylpyridin-3-yl)propan-1-ol (35 mg, 0.21 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (73 μL, 0.42 mmol) was subjected to microwave irradiation at 180° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel column (0-30% MeOH/CH2Cl2) followed by preparative HPLC (100×20.2 mm, C18 column; 20-50% CH3CN-water [10 mM Et2NH]) to yield an off-white solid (29 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:15]([C:17]1([CH2:27][CH3:28])[C:22](=[O:23])[O:21][CH2:20][C:19]([CH3:26])([CH2:24][OH:25])[NH:18]1)[CH3:16]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:27]([C:17]1([CH2:15][CH3:16])[C:22](=[O:23])[O:21][CH2:20][C:19]([CH3:26])([CH2:24][O:25][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[NH:18]1)[CH3:28]
Reactant: CCC1(CC)NC(C)(CO)COC1=O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(CC)NC(C)(COC(=O)C(C)(C)C)COC1=O
Reaction time: 20 h

Procedure:
2.4 ml (0.017 mol) of triethylamine and then 2.15 g 2 (0.018 mol) of pivaloyl chloride are added dropwise to a solution of 3.45 g (0.017 mol) of 3,3-diethyl-5-methyl-5-hydroxymethylmorpholin-2-one and 0.1 g of 4-dimethylaminopyridine in 20 ml dichloromethane at 15° C. After stirring for 20 hours, the precipitated triethylaminehydrochloride is removed by filtration and the filtrate is washed with water, dried over MgSO4 and concentrated by evaporation in a rotary evaporator. The residue is recrystallised from hexane. This gives 3.9 g (77%) of compound (217), m.p. 51-53° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C(C)(C)C.[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[NH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Br-].[Li+]>O1CCCC1.C(N(CC)CC)C>[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[N:43]1[C:6](=[O:7])[CH2:5][CH:4]([O:3][CH2:1][CH3:2])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:18]=2)=[CH:13][CH:14]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CCOC(CC(=O)O)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Temperature: -32.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-pr opionic acid (2.95 g) obtained in Example 41 and triethylamine (3.3 mL) in tetrahydrofuran (60 mL) was added dropwise a solution of pivaloyl chloride (1.265 mL) in tetrahydrofuran (5 mL) at −35° C., followed by stirring the reaction mixture at −35 to −30° C. for 30 minutes. Then, to the reaction mixture was added dropwise a solution of (R)-4-benzyl-2-oxazolidinone (1.82 g) and lithium bromide (892 mg) in tetrahydrofuran (10 mL), followed by raising the temperature up to 0° C. over 2 hours while stirring the reaction mixture. The reaction mixture was poured into ice-cold water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by mid-pressure preparative chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:5) to give (R)-4-benzyl-3-(3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionyl)oxazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.CCN(CC)CC.Cl[C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH:9][C:24](=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)NNC(=O)c1cnc(Cl)cc1NC(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 6-chloro-4-(isopropylamino)nicotinohydrazide (10) (200 mg, 0.35 mmol) in DCM (10 mL), Et3N (3.1 mmol, 3 equiv) was added and cooled to 0° C. Methyl 2-chloro-2-oxoacetate (0.42 mmol, 1.2 equiv) was added dropwise and stirred for 6 h at room temperature. The reaction mixture was quenched with aq. NaHCO3 solution and extracted in DCM. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography through silica gel and MeOH: DCM as eluent to afford methyl 2-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-2-oxoacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH2:10])=[N:7][N:6]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH:10][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:7][N:6]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1nnc(Cc2ccccc2Cl)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1nnc(Cc2ccccc2Cl)o1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 15 %

Procedure:
5-(2-Chloro-benzyl)-[1,3,4]oxadiazol-2-ylamine (21 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (21 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (6.0 mg, 0.015 mmol, 15%). ESI-MS m/z calc. 397.1. found; 398.3 (M+1)+ Retention time 2.96 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH:17]=[CH:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[O:21][CH2:22][CH:23]1[CH2:25][O:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32]>O1CCCC1>[CH3:30][N:31]([CH3:32])[CH2:25][CH:23]([OH:24])[CH2:22][O:21][C:20]1[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=1[CH:18]=[CH:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=Cc1ccccc1OCC1CO1)CCc1ccccc1OCc1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1C=CCCc1ccccc1OCc1ccccc1

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 328 mg of 2-{2-[4-(2-benzyloxyphenyl)-1-buten-1-yl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 5 ml of tetrahydrofuran was treated with 3 ml of 50% by volume aqueous dimethylamine. The crude product was purified as described in Example 1(b), to give 3-dimethylamino-1-{2-[4-(2-benzyloxyphenyl)-1-buten-1-yl]phenoxy}-2-propanol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[N:7]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:14]3[CH:13]=[CH:12][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2ncc(I)n2n1
Reactant: OB(O)c1ccc2ccccc2c1
Product: Clc1ccc2ncc(-c3ccc4ccccc4c3)n2n1

Procedure:
1.03 g of 6-chloro-3-naphthalen-2-ylimidazo[1,2-b]pyridazine were prepared from 5 3.5 g (12.52 mmol) of 6-chloro-3-iodoimidazo[1,2-b]pyridazine (Example 1.2) and 2.37 g (13.78 mmol) of 2-naphthylboronic acid (CAS No. 32316-92-0) in analogy to Example 1.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH3:28])=[O:26])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:39]=1[O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](O)=[O:46])=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH3:28])=[O:26])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:45](=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][O:40][C:39]3[CH:48]=[C:49]([F:52])[CH:50]=[CH:51][C:38]=3[CH2:37][NH:36][C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:35])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCCCCC(=O)O
Reactant: COC(=O)c1nc(N2CCNCC2)c2cccnc2c1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1nc(N2CCN(C(=O)CCCCOc3cc(F)ccc3CNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of methyl 8-(benzyloxy)-5-(piperazin-1-yl)-1,6-naphthyridine-7-carboxylate (Example 13; 1.3 mmol), 5-(2-((tert-butoxycarbonylamino)methyl)-5-fluorophenoxy)pentanoic acid (Example 17; 1.6 mmol) and diisopropyl ethylamine (3.9 mmol) in dichloromethane (10 ml) was added HBTU (2.0 mmol). The mixture was stirred overnight. The mixture was washed with saturated NaHCO3, 10% citric acid and brine and dried over Na2SO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography over SiO2 (eluent: methanol/CH2Cl2, 1:100) to afford the title compound (800 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCCCCC#Cc1ccccc1
Reactant: O=Cc1cccc(Br)c1
Product: O=Cc1cccc(C#CCCCCC#Cc2ccccc2)c1

Procedure:
Similarly, following the procedure of Example 7(b), 3-bromobenzaldehyde was reacted with 1-phenylocta-1,7-diyne to yield 3-(8-phenyl-1,7-octadiynyl)benzaldehyde which was reduced to 3-(8phenyloctyl)benzaldehyde and the latter was reacted as described in Example 35(a), (b) and (c) to give 3-(2-carboxyethylthio)-3-[3-(8phenyloctyl)phenyl]-2-hydroxypropanoic acid, dipotassium salt, hydrate as a mixture of isomers, -log KB value 6.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[N:23]=[C:22]([N:24]5[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)[CH:21]=[CH:20][CH:19]=4)[C:11]=3[CH:10]=2)=[N:6][C:7]=1[CH3:8].Cl>CO.O1CCOCC1>[N:24]1([C:22]2[N:23]=[C:18]([N:17]3[C:11]4[CH:10]=[C:9]([C:5]5[N:6]=[C:7]([CH3:8])[C:2]([NH2:1])=[N:3][CH:4]=5)[N:14]=[CH:13][C:12]=4[CH:15]=[N:16]3)[CH:19]=[CH:20][CH:21]=2)[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: Cc1nc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)cnc1N
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
To a solution of tert-butyl 4-[6-[6-(5-amino-6-methyl-pyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-1,4-diazepane-1-carboxylate (0.2293 mmol; 115 mg) in Methanol (10 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 208 as an off-white solid (4.0 mg, 4.3%). MS (ESI) m/z: 402.1 [M+H]+