Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[OH:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:20][C:21]([O:23][CH3:24])=[O:22].[CH3:36][O:37][C:38]([CH3:40])=[CH2:39]>C(OCC)C>[CH3:36][O:37][C:38]([O:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH3:40])[CH3:39]
Reactant: C=C(C)OC
Reactant: CCCCCCCCCCC[C@H](O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: CCCCCCCCCCC[C@@H](CC(=O)OC)OC(C)(C)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Pyridinium p-toluenesulfonate (90 mg) was added to a solution of methyl (S)-3-hydroxytetradecanoate (VIII, 10.32 g, 40 mmol) in 2-methoxypropen (40 mL). After stirring for 20 min at room temperature the reaction mixture was diluted with diethyl ether (30 mL) and extracted first with a saturated aqueous solution of sodium hydrogen carbonate (3 mL) and then with water (2×2 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residual colorless oil (13.20 g, 99%) was used in the next step without further purification. [α]25D +10.01 (c=0.5 in hexane); 1H NMR (DMSO-D6) δ 0.86 (t, J=7 Hz, 3H), 1.24-1.27 (m, 26H), 1.44-1.46 (m, 2H), 3.09 (s, 3H), 3.58 (s, 3H), 4.03-4.05 (m, 1H); 13C NMR (DMSO-D6) δ 13.85, 22.02, 22.05, 24.26, 24.86, 28.67, 28.91, 28.97, 28.98, 29.03, 30.93, 31.27, 35.13, 40.21, 48.46, 51.15, 67.67, 100.35, 171.62. Anal. Calcd for C19H38O4 : C, 69.05; H, 11.59. Found: C, 69.00; H, 11.63.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[N:8]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[S:11][C:9]3=[N:10][C:6]=2[CH:5]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:27]>>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[N:8]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[S:11](=[O:27])[C:9]3=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1ccc2c(c1)nc1n2CC(c2ccccn2)S1
Product: CCOc1ccc2c(c1)nc1n2CC(c2ccccn2)S1=O

Procedure:
In a manner analogous to Example 4 7-ethoxy-2,3-dihydro-2-(2-pyridyl)thiazolo[3,2-a]-benzimidazole (1.65 g) was reacted with m-chloroperoxy benzoic acid (1.25) to give the title compound (0.56 g, mp 145°-147° C.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:28](=O)([O:34]C(C)(C)C)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[C:30]([O:29][C:28](=[O:34])[NH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)c1cccc(C2(N)CCC(=O)CC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCC(=O)CC1
Reaction time: 19 h

Procedure:
4-Amino-4-(3-tert-butyl-phenyl)-cyclohexanone (441 mg, 1.8 mmol) was dissolved in dry methylene chloride (10 mL), diisopropylethylamine (0.31 mL, 1.8 mmol) and di-tert-butyl carbonate (400 mg, 1.83 mmol) were added in succession at room temperature. After 19 h, the reaction was concentrated under reduced pressure, and the desired product isolated by chromatography (Rf=0.35 in 20% EtOAc/hexanes). The resulting oil was taken to the next reaction: retention time=2.57 min, method [7]; mass spec (ESI) 369 (24), 368 (100), 272 (42), 211 (24).
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:11][N:10]([C:12](=[O:29])[CH2:13][P:14]([O:26]CC)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Br[Si](C)(C)C.O>ClCCl>[CH:1]1([C@@H:7]2[CH2:11][N:10]([C:12](=[O:29])[CH2:13][P:14]([OH:26])([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:15])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1C[C@@H](C2CCCCC2)C[C@H]1C(=O)O
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H](C2CCCCC2)CN1C(=O)CP(=O)(O)CCCCc1ccccc1

Procedure:
(cis)-4-Cyclohexyl-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline, (0.83 g), bis(trimethylsilyl)acetamide (0.47 ml) and bromotrimethylsilane (0.28 ml) are stirred in 20 ml of dichloromethane for about 16 hours. A small amount of water is added and the mixture is evaporated to an oil residue (0.61 g). This material is crystallized from acetone with a recovery of 0.047 g of solid, melting point 175°-176° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]2[CH2:14][C:15]3[C:20]([CH:9]12)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:21][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[O:13]=[C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]2[C:20]3[C:15]([C:14](=[O:21])[C@@H:10]2[CH2:11]1)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3ccccc3C21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C(=O)C[C@H]2C(=O)c3ccccc3[C@H]21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester F1 (5.00 g, 18.2 mmol) in acetone (90 mL) and water (20 mL) was added KMnO4 (14.7 g, 93 mmol). The solution was stirred for 48 h at room temperature and filtered. The solution was concentrated to half the volume and sodium thiosulfate solution was added (2%, 50 mL). The solution was extracted with ethylacetate, washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (7/3) to give the desired product F26 (1.6 g, 30%). LCMS (method E): 0.81 min; ES+: 597 (2M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(N=Cc2ccccc2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 17.4 g of 5-aminopyridine-2-carboxylic acid methyl ester, 14.0 g of benzaldehyde and 100 ml of benzene is stirred and refluxed on a water separator for 6.5 hours. The resulting clear solution is evaporated, and the residue recrystallized from benzene-hexane first, then from acetonitrile-diethyl ether, to yield the 5-benzylideneaminopyridine-2-carboxylic acid methyl ester, melting at 84°-89°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16](C(=O)C)[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:2]=1.Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27].[CH2:29](O)[CH3:30]>[OH-].[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:29](=[N:24][NH:25][C:26]([NH2:28])=[O:27])[CH3:30])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1
Reactant: NNC(N)=O
Reactant: CCO
Reactant: CC(=O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=NNC(N)=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Temperature: 25 °C

Procedure:
A 2.9 g portion of 1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone was mixed with 1.23 g of semicarbazide hydrochloride in 200 ml of absolute ethanol and 1.10 ml of 10N sodium hydroxide was added. This mixture was refluxed overnight, then cooled to room temperature and the solid collected and washed with ethanol, water and ethanol. The solid was recrystallized from dimethylsulfoxide/ethanol, giving 2.9 g of the desired product, mp 256°-258° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([C:51]3[C:42](=[CH:43][C:44]4[O:49][CH2:48][CH2:47][O:46][C:45]=4[CH:50]=3)[O:41][CH2:40]2)[C:32]1=[O:52]>>[CH3:19][C:15]1([CH3:18])[O:14][C@@H:13]([CH2:12][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]3([C:51]4[C:42](=[CH:43][C:44]5[O:49][CH2:48][CH2:47][O:46][C:45]=5[CH:50]=4)[O:41][CH2:40]3)[C:32]2=[O:52])[CH2:17][O:16]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC1(C)OC[C@H](CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)O1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-t][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (98%): mp 55-57° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.30-6.99 (m, 4H), 6.47-6.20 (m, 2H), 4.88-4.84 (m, 1H), 4.63-4.59 (m, 1H), 4.48-4.40 (m, 1H), 4.17-3.77 (m, 8H), 1.35-1.28 (m, 6H); MS (ES+) m/z 410.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[CH:10]=1.[C:33](=[O:36])([O-:35])O.[Na+].FC(F)(F)C(O)=[O:41]>>[C:2]([OH:1])(=[O:41])/[CH:3]=[CH:8]/[C:33]([OH:35])=[O:36].[CH3:25][NH:24][CH2:23][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][OH:1])[N:13]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C([O-])O
Reactant: CN(Cc1cc(-c2ccccc2CO)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2CO)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl ({5-[2-(hydroxymethyl)phenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate (132 mg) was dissolved in trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→9:1) to give a free salt of the title compound as a colorless oil (yield 60.3 mg). A solution of the obtained free salt in ethyl acetate (5 mL) was added to a solution of fumaric acid (19.6 mg) in methanol (2 mL), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 48 mg, 35%).
Reaction SMILES: [CH3:1][C:2]1[N:23]([CH3:24])[C:5]2[CH:6]=[C:7]([C:20]([OH:22])=O)[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1.[NH:25]1[CH2:27][CH2:26]1.C[N:29](C)C=O>O1CCCC1>[N:25]1([NH:29][C:20]([C:7]2[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:12][C:13]=3[C:4]3[N:3]=[C:2]([CH3:1])[N:23]([CH3:24])[C:5]=3[CH:6]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: C1CN1
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)N3
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2c3c(c(C(=O)NN4CC4)cc2n1C)CCC(c1ccccc1)N3
Reaction time: 1 h
Yield: 46 %

Procedure:
To a suspension of 0.47 g (1.5 mmol) 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]quinoline-5-carboxylic acid in 10 ml tetrahydrofuran and 5 ml N,N-dimethylformamide were added 0.4 g (2.5 mmol) N,N′-carbonyldiimidazole. After 1 h at 60° C., the solution was cooled down and 0.8 g (18.6 mmol) aziridine were added in 4 portions over a period of 3 h. After complete reaction, the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate/light petroleum ether=7:3). Crystallization from diethyl ether/n-heptane yielded 0.23 g (46%) of the title compound as a colourless solid. m.p. 192-193° C.
Reaction SMILES: S(Cl)([Cl:3])=O.C(OC([NH:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]([OH:33])=O)[C:16]([NH:18][CH:19]([C:26]([O:28][CH3:29])=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=O)(C)(C)C>CO>[ClH:3].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:30][C:31](=[O:33])[N:18]([CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]([O:28][CH3:29])=[O:27])[C:16]1=[O:17]
Reactant: COC(=O)C(NC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C(c1ccccc1)N1C(=O)CN(CCN)C1=O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.9 ml (12 mmol) of thionyl chloride are added dropwise, at 0° C., to 4.1 g (10 mmol) of (1-(2-tertbutoxycarbonylaminoethyl)-3-(methoxycarbonylphenylmethyl)ureido)acetic acid in 50 ml of methanol. The mixture is allowed to warm to room temperature and then stirred further overnight, followed by filtering off with suction and drying.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:6][CH:7]=1.[CH3:22][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]#[CH:25].C(N(CC)CC)C.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH:19]1([CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:5]4[N:6]=[CH:7][C:2]([C:25]#[C:24][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:22])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH:16]=2)[CH2:21][CH2:20]1
Reactant: Brc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1
Reactant: C#C[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](C#Cc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Under an argon atmosphere, a mixture of 2-(5-bromopyridin-2-yl)-6-(cyclopropylmethoxy)-1,3-benzoxazole (200 mg), tert-butyl [(1S)-1-methylprop-2-yn-1-yl]carbamate (196 mg), dichlorobis(triphenylphosphine)palladium(II) (20.3 mg), copper(I) iodide (11.0 mg), triethylamine (0.081 mL) and DMF (5 mL) was stirred at 80° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 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 (hexane/ethyl acetate) to give the title compound as a yellow powder (150 mg).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[C:10]2[Cl:30].ClC1C2C(=CC=C(C(C3C(C)=NC(C)=CC=3)O)C=2)N=C(OC)C=1CC1C=CC(C(F)(F)F)=CC=1.[CH3:65][N:66]1[C:70]([C:71]([C:73]2[N:77]([CH3:78])[N:76]=[N:75][CH:74]=2)=[O:72])=[CH:69][N:68]=[N:67]1.C(=O)=O.CC(C)=O>C1COCC1>[Cl:30][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:71]([C:70]3[N:66]([CH3:65])[N:67]=[N:68][CH:69]=3)([C:73]3[N:77]([CH3:78])[N:76]=[N:75][CH:74]=3)[OH:72])[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1nncc1C(=O)c1cnnn1C
Agent: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
n-BuLi (1.63 M in hexane, 0.139 mL, 0.226 mmol) was added dropwise over 1 minute to a solution of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (90.1 mg, 0.209 mmol, Intermediate 12: step d in THF (2.1 mL) at ˜−70° C. under argon. After 2 additional minutes, a homogeneous solution of bis(1-methyl-1H-1,2,3-triazol-5-yl)methanone (41.4 mg, 0.215 mmol, Intermediate 13) in THF (2.1 mL) was added dropwise over 1 minute, and the resulting solution was allowed to warm to room temperature overnight as the dry ice/acetone bath expired. The resulting homogeneous yellow reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL), dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by C18 HPLC (20% to 100% CH3CN, with 0.1% TFA throughout) and the lyophilisate neutralized with 9:1 DCM/MeOH) and 2 M aqueous K2CO3. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J=2.02 Hz, 1H), 7.99 (br. s., 1H), 7.91 (d, J=8.59 Hz, 1H), 7.65 (d, J=8.08 Hz, 2H), 7.41-7.51 (m, 3H), 7.19 (s, 2H), 4.36 (s, 2H), 4.04 (s, 3H), 3.84 (s, 6H); MS m/e 544.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15]CN(CC)CC.[CH3:22][CH2:23][N:24]=[C:25]=[N:26][CH2:27][CH2:28][CH2:29]N(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:26]1[C:27]2[CH:28]=[CH:29][CH:15]=[CH:22][C:23]=2[N:24]=[C:25]1[CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CCN(CC)CC
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask charged with 4-((tert-butoxycarbonyl)amino)butanoic acid (0.5 g, 2.46 mmol) in DCM (10 mL) was added Et3N (1.03 mL, 7.36 mmol), EDCI (706 mg, 2.46 mmol), DMAP (30 mg, 0.246 mmol) and allowed to stir overnight at RT. The reaction was quenched with water (10 mL) and extracted with DCM (2×10 mL). Combined organics washed with 10% citric acid (10 mL), brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was dissolved in AcOH (7 mL) and stirred at 65° C. for 1 h. The mixture was diluted with saturated bicarbonate (15 mL) and extracted with DCM (2×15 mL), and again worked up in the above manner. The title compound was obtained as a white solid (433 mg, 64%) and used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.57 (m, 2H), 7.20 (m, 2H), (4.98 (s, 2H), 3.24 (m, 2H), 2.95 (m, 2H), 1.92 (m, 2H), 1.47 (s, 9H). ESI-LRMS: [M+H]+=276 m/z.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][CH3:24])[CH:22]=2)[O:19][C:18]([CH3:26])([CH3:25])[CH2:17][C:16]3([CH3:28])[CH3:27])=[CH:7][CH:6]=1.CO.[OH-].[Na+].O>C(#N)C>[CH2:23]([C:21]1[CH:22]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][CH:7]=2)[CH:14]=[C:15]2[C:20]=1[O:19][C:18]([CH3:25])([CH3:26])[CH2:17][C:16]2([CH3:28])[CH3:27])[CH3:24]
Reactant: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1OC(C)(C)CC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following general procedure L and using [4-(8-ethyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl) phenyl]acetic acid methyl ester (Compound 55, 0.035 g, 0.1 mmol), 5 mL of methanol and 1M sodium hydroxide solution (1 mL) followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.11 g, 25%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CN(/[CH:24]=[N:25]/[C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31](OCC)=[O:32])C.C1(O)C=CC=CC=1>C(Cl)Cl>[Br:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:10][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([CH2:2][N:1]3[C:31](=[O:32])[C:30]4[NH:29][CH:28]=[N:27][C:26]=4[N:25]=[CH:24]3)[C:4]=2[F:20])[CH:18]=1)[C:14]#[N:15]
Reactant: CCOC(=O)c1[nH]cnc1/N=C/N(C)C
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1
Yield: 38.1 %

Procedure:
The title compound was prepared in a manner similar to that described herein using 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.61 g, 1.715 mmol), ethyl 4-{[(1E)-(dimethylamino)methylidene]amino}-1H-imidazole-5-carboxylate (0.397 g, 1.887 mmol) and phenol (0.484 g, 5.15 mmol) in DCM (3 mL) to give 0.31 g (38%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (br. s., 1H), 8.45 (s, 1H), 8.17 (br. s., 1H), 7.93 (s, 1H), 7.58 (d, 2H), 7.47 (d, 1H), 7.21 (t, 1H), 5.30 (s, 2H). LCMS m/z 474.1 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10](SCC)([F:12])[F:11].Cl[C:24]1C=CC=C(C(OO)=O)[CH:25]=1.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([S:34]([CH2:24][CH3:25])(=[O:38])=[O:36])([F:12])[F:11]
Reactant: O=S([O-])([O-])=S
Reactant: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (850 mg, 2.39 mmol) in dichloromethane (100 ml), 85% m-chloroperbenzoic acid (1.4 g, 5.75 mmol) was added at room temperature, followed by stirring at room temperature for 12 hours. After the completion of the reaction, a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate were added and the resulting mixture was stirred. The dichloromethane solution was separated and after washing with water, dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether-ethyl acetate, whereby 2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (718 mg, yield: 78%) was obtained as colorless crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]1=[O:14])C.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][O:12][C:8]1[C:7](=[O:14])[N:6]([CH2:5][C:4]([NH:17][NH2:18])=[O:3])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cn1cccc(OC)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cccn(CC(=O)NN)c1=O
Yield: 83 %

Procedure:
As described for example 112a, (3-methoxy-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 16 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 83%). MS: m/e=220.1 [M+Na]+.
Reaction SMILES: ClC1C=CC=CC=1C([C:6]1[N:11]=[N:10][C:9]2[CH2:12][CH2:13][NH:14][CH2:15][C:8]=2[CH:7]=1)=O.C(O)(=O)/C=C\C(O)=O.ClC1[N:34]=[N:33]C2CCNCC=2C=1.[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>C(O)C>[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([N:14]1[CH2:13][CH2:12][C:9]2[N:10]=[N:11][C:6]([NH:33][NH2:34])=[CH:7][C:8]=2[CH2:15]1)=[O:43]
Reactant: O=C(c1cc2c(nn1)CCNC2)c1ccccc1Cl
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1Cl)C2

Procedure:
The 3-chloro-6-(o-chlorobenzoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8 (g), from 28.5 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 16.9 g of o-chlorobenzoyl chloride. M.P. 97°-99° (decomp., from 95% ethanol).