Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[CH2:8][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:10][CH2:11][C:12]=1O)=[O:6])[CH3:3].[NH3:25]>O1CCOCC1>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[CH2:8][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:10][CH2:11][C:12]=1[NH2:25])=[O:6])[CH3:3].[ClH:1].[CH2:2]([O:4][C:5]([CH:7]1[C:12](=[NH:25])[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)C1=C(O)CCN(CC2=Cc3ccc(OC)cc32)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(N)CCN(CC2=Cc3ccc(OC)cc32)C1
Product: CCOC(=O)C1CNCCC1=N
Reaction time: 48 h

Procedure:
3.5 g (10 mmol) of 4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride in 50 ml of dioxan and 50 ml of 25% aqueous ammonia are heated in a bomb tube at 80° C., while stirring, for 48 hours. The reaction mixture is then extracted with trichloromethane; the extracts are washed with water, dried over sodium sulphate and concentrated under reduced pressure. The crude material is purified by chromatography, converted into the hydrochloride with hydrochloric acid and crystallised from methanol/diethyl ether. 4-amino-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride alias 1-(5-methoxybenzocyclobuten-1-yl)methyl]-4-imino-piperidine-3-carboxylic acid ethyl ester hydrochloride of m.p. 184°-184.5° is obtained
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([O:32][CH2:33][C:34]#[N:35])[CH:26]=[CH:25]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]3[NH:38][N:37]=[N:36][N:35]=3)[CH:28]=2)[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(Cc2ccccc2)c2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 97.5 °C
Yield: 102.5 %

Procedure:
To a stirred solution of the {[6-(1-benzyl-3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (87.0 g, 189.71 mmol) in DMF (900 mL) under N2 was added NaN3 (61.665 g, 948.54 mmol) and NH4Cl (50.737 g, 948.54 mmol). The reaction was heated between 95-100° C. for 1.33 h then cooled. The reaction mixture was rotovap'd to a residue and the residue partitioned between EtOAc (2000 mL) and 1 N HCl (600 mL). The layers were shaken, separated, and the organic layer washed with 1 N HCl (2×300 mL), H2O (3×300 mL), and brine (2×300 mL), dried over Na2SO4, filtered, rotovap'd and triturated with hexane to give an off-white solid (97.5 g). The product was purified by refluxing the solid in diethyl ether (2000 mL), concentrating to about a liter and cooling. The solids were collected and dried in vacuo to give the product as a white solid (77.4 g, 154.3 mmol, 81%) with dec. 111-114° C.; 1H NMR (DMSO-d6) δ 0.72 (t, J=6.9 Hz, 3H) 1.10-1.20 (m, 4H), 1.50-1.60 (m, 2H), 2.67 (t, J=7.8 Hz, 2H), 5.30 (s, 2H), 5.62 (s, 2H), 6.81 (d, J=7.3 Hz, 2H), 7.02-7.20 (m, 5H), 7.30 (dd, J=2.4, 9.0 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.44 (dd, J=1.5, 8.2 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.84-7.90 (m, 3H) 16.9 (s, 1H); IR (solid) 2920, 2850, 1610, 1390, 1200, 860, and 750, cm1; mass spectrum [ESI], m/z 502 (M+H)+;
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][CH2:31][NH:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:25]=[CH:24]4)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][CH2:31][N:32]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:33][CH:34]3[CH2:35][CH2:36]3)[CH:25]=[CH:24]4)=[N:17][CH:18]=2)=[CH:11][CH:12]=1
Reactant: O=CC1CC1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCNCC4CC4)c3)nc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCN(CC4CC4)CC4CC4)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
36 μL (0.47 mmol) cyclopropanecarbaldehyde are added to a solution of 100 mg (0.24 m mol) (2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-amine in 20 mL MeOH at RT and 15 min later 59 mg (0.94 mmol) NaBH4 and one drop of glacial acetic acid are added. The mixture is stirred for 1 h at RT, evaporated down i.vac., the residue is taken up in dilute K2CO3 solution, extracted exhaustively with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is triturated with PE, suction filtered and dried.
Reaction SMILES: [Cl-:1].[Cl-].[Ca+2].[CH2:4]([N:6]1[C:14]2[N:13]=[C:12]3[CH:15](O)[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH2:18][CH2:19][C:11]3=[CH:10][C:9]=2[CH:8]=[N:7]1)[CH3:5].Cl>C1C=CC=CC=1>[Cl:1][CH:15]1[C:12]2=[N:13][C:14]3[N:6]([CH2:4][CH3:5])[N:7]=[CH:8][C:9]=3[CH:10]=[C:11]2[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: CCn1ncc2cc3c(nc21)C(O)c1ccccc1CC3
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CCn1ncc2cc3c(nc21)C(Cl)c1ccccc1CC3
Reaction time: 8 h

Procedure:
6 g. of pulverized CaCl2 are added with stirring to a solution of 11 g. of 1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol (0.04 mol.), from example 2, in 175 ml. of dry benzene. The suspension is saturated for 15 hours with anhydrous hydrogen chloride at room temperature. After standing overnight, the mixture is filtered and the benzene is evaporated in vacuo. The residue is extracted with ether, treated with charcoal, and refrigerated to crystallize 8.3 g. of 11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]-pyridine; m.p. 107°-110° (ether).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20]CC=C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(CCCC)C([O-])=O)C.[Na+].C1(N)CCCCC1>ClCCl.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of 100 mg (0.316 mmol) of (2S,5R)-allyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate in dichloromethane (2 mL) were added a solution of 0.5M sodium 2-ethylhexanoate in ethyl acetate (1 mL) and 12 mg of tetrakis(triphenylphosphine)palladium(0), followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, followed by liquid separation with saturated aqueous sodium dihydrogen phosphate solution, the aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The residue resulting from concentration of the solvent under reduced pressure was dissolved in ethyl acetate, followed by addition of cyclohexylamine (33 mg), and the deposited solid was filtered off, and washed with ether. The resulting solid was dissolved in saturated aqueous sodium dihydrogen phosphate solution, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Subsequently, the solvent was concentrated under reduced pressure to afford 68 mg of the title compound as a colorless foamy solid (yield 75%). Instrumental data were consistent with those of the compound of Example 9.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([O:24]CC)=O)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].O1CCOCC1.[NH2:43][NH2:44]>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:43][NH2:44])=[O:24])[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:35])([F:34])[F:36])=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
To a solution of ethyl 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carboxylate (2.63 g, 5.110 mmol) in 8 mL of 1:1 PhMe:Dioxane was added hydrazine (1 mL, 31.86 mmol). The reaction was heated at 90° C. for 12 h and then cooled to room temperature. The reaction was filtered through a small amount of celite to remove a black precipitate and then concentrated and placed on the high vacuum pump. The residue was dissolved in a minimum amount of dichloromethane and slowly added to 200 mL ether with stirring. 100 mL of ether was added and the white precipitate was filtered and rinsed with ether to afford 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carbohydrazide (1.77 g, 70%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 9.21 (s, 1H), 8.16 (s, 1H), 8.14-8.13 (m, 1H), 8.03-8.00 (m, 1H), 7.92-7.89 (m, 1H), 7.85-7.89 (m, 3H), 7.74-7.64 (m, 4H), 7.36 (d, J=8.58 Hz, 2H), 4.44 (brs, 2H), 3.28 (s, 3H); MS (ES): 501.3 [M+H]+ and 523.2 [M+Na]+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].[C:8]([NH:15][C@@H:16]([CH2:18][OH:19])[CH3:17])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl>C1COCC1.O.CCOC(C)=O>[C:11]([O:10][C:8]([NH:15][C@H:16]([CH3:17])[CH2:18][O:19][CH2:4][C:5]([OH:7])=[O:6])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](COCC(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium hydride (60% w/w dispersion in mineral oil, 4.58 g, 114 mmol) was added portionwise to a solution of 2-bromoacetic acid (5.3 g, 38.1 mmol) and N-Boc-D-alaninol (10.0 g, 57.2 mmol) in THF (100 ml) at 0° C. The reaction mixture was stirred for 48 h at room temperature, diluted with water, washed 2× with EtOAc, hydrochloric acid (1M, 84 ml, 84 mmol) was added to the aqueous layer (pH 2-3) and the aqueous layer extracted 2× with DCM. The DCM layers were dried over Na2SO4 and evaporated to give the title compound as a yellow oil which crystallised on standing. (MS) ESI-MS 256.2 [M−H]−.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:11]([C:10]1[CH:19]=[CH:20][C:7]([CH2:6][O:5][CH2:4][CH2:3][NH:2][C:35]([NH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:36])=[CH:8][CH:9]=1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCOCc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCOCc1ccc(C(=O)c2ccccc2)cc1)Nc1ccccc1
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred suspension of (X) (3.49 g, 12 mmol) in dry DCM (10 ml) was added dry triethylamine (10 ml). After 0.25 h. stirring a solution of phenyl isocyanate (2.14 g, 18 mmol) in dry DCM (10 ml) was added in one portion. The mixture was stirred for a further 16 h. then quenched with water (10 ml). The organic layer was collected and washed sequentially with water, 2M HCl, and water. The organic layer was dried over MgSO4 and purified by flash chromatography on silica gel eluting with 2:1 petrol 40/60:ethyl acetate (Rf=0.1) to yield (XI) (3.01 g, 67%) as a white solid; m.p. 129-132° C.; δH (DMSO-d, 200 MHz) 3.39 (q, 2H, J=5.1 Hz, NHCH2), 3.58 (t, 2H, J=5.0 Hz, OCH2CH2), 4.65 (s, 2H, OCH2Ar), 6.32 (t, 1H, J=5.2 Hz CH2NHC(O)NHAr), 6.90 (t, 1H, J=7.3 Hz, 4″-H), 7.24 (t, 2H, J=7.4 Hz, 3″-, 5″-H), 7.44 (d, 2H, J=7.6 Hz, 2″-, 6″-H), 7.56 (m, 4H, 3-, 5-, 3′-, 5′-H), 7.70 (m, 5H, 2-, 4-, 6-, 2″-, 6″-H) 8.63 (s, 1H, CH2NHC(O)NHAr) ppm; δC (DMSO-d, 400 MHz) 39.9 (CH2CH2NH), 70.4 (CH2CH2O), 72.1 (ArCH2O), 118.4 (2″-, 6″-C), 121.9 (4″-C), 128.1 (2-, 6-, 2′-, 6′-C), 129.4 (3″-, 5″-C), 130.4, 130.6 (3-, 5-, 3′-, 5′-C), 133.5 (4′-C), 136.9, 138.0 (1-, 1″-C), 141.3 (4-C), 144.4 (1″-C), 156.1 (N(H)C(O)NH), 196.3 (Ar2C(O)) ppm; max 3431 (N—Hstr), 1724 ((R(H)N)2C═Ostr), 1658 (Ar2C═Ostr) cm−1; m/z 375 [M+H]+ (5%), 397 [M+Na]+ (10%), 433 [M+MeCN+NH4]+ (100%); found 375.1703, C23H23N2O3 requires 375.1709.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]([F:38])([F:37])[C:5]1[CH:36]=[CH:35][C:8]([O:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([CH3:34])([CH3:33])[CH2:16][CH2:17][C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]#[N:20])[CH2:11]2)=[CH:7][CH:6]=1>CC(O)(CC)CC>[F:38][C:4]([F:37])([F:3])[C:5]1[CH:6]=[CH:7][C:8]([O:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([CH3:34])([CH3:33])[CH2:16][CH2:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:19]([NH2:20])=[O:1])[CH2:11]2)=[CH:35][CH:36]=1
Reactant: [OH-]
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@@H](Oc2ccc(C(F)(F)F)cc2)C1
Agent: CCC(C)(O)CC
Agent: [K+]
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC[C@@H](Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Yield: 68 %

Procedure:
Potassium hydroxide (23 mg, 0.406 mmol) was added to a solution of example 25 (10 mg, 0.0203 mmol) in 3-methyl-3-pentanol (2 mL) and the mixture was heated under reflux for 16 hours. The solution was cooled to 25° C. and potassium hydroxide (23 mg, 0.406 mmol) was added and the solution was heated under reflux for an additional 24 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:methanol:0.88 ammonia, 95:5:0.5. to afford the title compound as a colourless gum in 68% yield, 7 mg.
Reaction SMILES: [C:1]([CH:9]([CH3:15])[CH:10]([CH3:14])C(O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:19][NH2:20])(=O)C.C(C(C)CC(O)=O)(=O)C1C=CC=CC=1.[C:35]([NH:39][NH2:40])(=O)[CH2:36][CH3:37]>>[CH2:36]([C:35]1[N:19]2[N:20]=[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]([CH3:15])=[CH:10][C:14]2=[N:40][N:39]=1)[CH3:37]
Reactant: CCC(=O)NN
Reactant: CC(C(=O)O)C(C)C(=O)c1ccccc1
Reactant: CC(=O)NN
Agent: CC(CC(=O)O)C(=O)c1ccccc1
Product: CCc1nnc2cc(C)c(-c3ccccc3)nn12

Procedure:
The general procedure of Example 4 is repeated but replacing the 3-benzoyl-2,3-dimethyl-propionic acid and N-acetylhydrazine employed in that example with 3-benzoyl-3-methyl-propionic acid and N-propionylhydrazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([OH:14])[CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2)([O-:3])=[O:2].[C:16](=O)([O-])[O-].[K+].[K+].CC(C)=O.S(OC)(OC)(=O)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14][CH3:16])[CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc([N+](=O)[O-])cc(O)c2N1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: COc1cc([N+](=O)[O-])cc2c1NC(=O)CC2
Reaction time: 4 h
Yield: 77 %

Procedure:
6-Nitro-8-hydroxy-3,4-dihydrocarbostyril (10 g) and potassium carbonate (13.3 g) were mixed with acetone (70 ml) and water (70 ml) and the mixture was refluxed with adding dropwise 12.1 g of dimethyl sulfate. After refluxing was continued for 4 hours, the reaction mixture was cooled, and crystals which precipitated were collected by filtration and washed with water to give 8.22 g of 6-nitro-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH3:25][NH:26][CH3:27]>O>[CH3:25][N:26]([CH3:27])[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Solvent: O
Product: CN(C)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 97 %

Procedure:
4-Fluoro-2-nitro-N-quinolin-8-yl-benzenesulfonamide 145 (0.13 g, 0.36 mmol) was dissolved in dimethyl amine (2M in THF; 1.77 ml, 3.59 mmol) and the mixture was heated at 90° C. in a sealed tube for 5 h. After cooling, water was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (0.13 g, 97%) which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:15][CH2:16][CH2:17][C:18](OC)=[O:19].O>S(=O)(=O)(O)O>[CH3:13][C:14]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:15][CH2:16][CH2:17][C:18]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])=[O:19]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=CCCC(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.50 g (2.8 mmol) of ascorbic acid was dissolved in concentrated sulfuric acid (14 mL). After addition of 1.0 g (2.8 mmol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate, the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][OH:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][O:19][S:61]([CH3:60])(=[O:63])=[O:62])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 141b (132 mg, 0.19 mmol) in DCM (2.0 mL) was added DIPEA (135 μL, 0.78 mmol) followed by methanesulfonyl chloride (30 μL, 4, 0.39 mmol). The reaction mixture was stirred for 2 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the subsequent step without further purification. LCMS (Method 4): Rt 3.30 min, m/z 759 [MH+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=[O:8])=[CH:2]1.[CH3:10]O>>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:2]1
Reactant: CO
Reactant: O=C(O)Cc1ccsc1
Product: COC(=O)Cc1ccsc1
Reaction time: 3 h

Procedure:
To 2-(thiophen-3-yl)acetic acid in MeOH at 0° C. was added TMS-CH2N2. The solution was stirred for 3 hours then quenched with a few drops of AcOH. The solvents were evaporated. Column chromatography (SiO2, 3-15% EtOAc/Hex) gave pure methyl 2-(thiophen-3-yl)acetate (E41).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: COCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-methoxyethylamine according to general procedure 1 providing the amino compound (432 mg, 74%) as a yellow solid; Rf=0.71 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.57 (d, J=9.7 Hz, 1H), 7.42 (s, 1H), 6.75 (d, J=9.7 Hz, 1H), 3.68 (t, J=5.4 Hz, 2H), 3.59 (t, J=5.6 Hz, 2H), 3.43 (s, 3H); ES-MS: (M+H)=271, 273 m/z.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=O)=[O:30])[CH:11]=1)=[O:9].C(N(C(C)C)CC)(C)C.[CH2:54]([NH:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)[CH3:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:54]([N:56]([CH2:57][CH2:58][N:59]1[CH2:60][CH2:61][O:62][CH2:63][CH2:64]1)[C:34](=[O:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:44])[F:1])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[O:30])[CH:32]=1)[CH3:55]
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CCNCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 25 mg of 3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoic acid 4.1e, 17 mg of diisopropylethylamine and 9 mg of N-ethyl-2-morpholinoethanamine in 1 mL of DMF was added 17 mg of HATU. The mixture was stirred at 25° C. for 1 h. The solution was injected onto a preparative reverse phase HPLC and the product was eluted with 0.5% TFA in a gradient of water and acetonitrile. The yield was 11.2 mg of product. 1H-NMR (400 MHz, DMSO-d6, ppm) δ 12.46 (s, 1H), 9.90 (s, 1H), 9.57 (t, J=6.1 Hz, 1H), 8.90 (d, J=5.1 Hz, 1H), 8.36, (s, 2H), 8.03-7.92 (m, 2H), 7.87 (dd, J=5.1, 1.3 Hz, 1H), 7.75-7.53 (m, 26H), 7.39 (s, 1H), 4.63 (d, J=5.8 Hz, 2H), 4.03 (s, 2H), 3.82 (s, 2H), 3.60 (s, 4H), 3.40 (d, J=23.1 Hz, 6H), 3.24 (s, 4H), 1.77 (s, 4H), 1.61 (s, 2H), 1.08 (t, J=6.5 Hz, 10H). MS (ES, m/z): 743 [M+H]+.