Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][C:25]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1>>[CH2:1]([N:5]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][C:25]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:26]=3[N:27]=2)=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: Cc1ccc2oc(/C=C/c3ccc(OCCCCl)cc3)nc2c1
Product: CCCCN(CCCC)CCCOc1ccc(/C=C/c2nc3cc(C)ccc3o2)cc1
Yield: 22 %

Procedure:
Reaction of this product (2.2 g, 6.8 mmol) with dibutylamine produced 0.65 g (22% yield) of the title compound as the HCl salt, mp 143°-144° C. IR(KBr): 1600 cm-1. MS: 421(MH+). 1H NMR (CDCl3): δ 7.21-6.87 (m, 10H), 4.16 (t, J=5.6 Hz, 2H), 3.11 (m, 6H), 2.51 (s, 3H), 2.51-0.88 (m, 16H).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15]CC(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C1(CCN)CCCCC=1.C1(=O)CCCCC1.C([O:48][C:49](=[O:52])[CH2:50][CH3:51])C.Cl.CCN(C(C)C)C(C)C>>[C:23]1([CH2:22][CH2:21][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:51][CH2:50][C:49]([OH:52])=[O:48])=[CH:13][N:14]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCOC(=O)CC
Agent: Cl
Agent: NCCC1=CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C1CCCCC1
Product: O=C(O)CCSc1cnc(NC(=O)N(CCC2=CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-(1-cyclohexenyl)ethylamine hydrochloride, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction.
Reaction SMILES: [N:1]1([CH:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11](O)=[O:12])C2C=CC=CC=2N=N1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=O.CN1CCOCC1.N.C([O-])(=O)C.[NH4+]>C1COCC1.CCOC(C)=O.O.CN(C=O)C>[CH3:38][C:37]1[C:32]2[NH:31][C:11](=[O:12])[C@@H:10]([NH:14][C:15](=[O:16])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:1]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1N
Reactant: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cc1cccc2c1NC(=O)[C@@H](NC(=O)OCc1ccccc1)N=C2c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(((benzyloxy)carbonyl)amino)acetic acid (17.30 g, 53.0 mmol) in THF (128 ml) and cooled to 0° C. Oxalyl chloride (4.64 ml, 53.0 mmol) was added, followed by 50 μL DMF. The reaction mixture was stirred for 2 h at 0° C. A solution of (2-amino-3-methylphenyl)(phenyl) methanone (5.09 g, 24.09 mmol) and N-methyl morpholine (7.95 ml, 72.3 mmol) was added, and the reaction mixture was allowed to warm gradually to room temperature. After 2.5 h ammonia (7 M in MeOH) (21.29 ml, 149 mmol) was added and the reaction mixture was stirred overnight. The resulting mixture was diluted with EtOAc (250 mL), and then washed with H2O (250 mL), 1 M NaOH (250 mL), and brine (250 mL). The organic layer was concentrated and then suspended in acetic acid (48.2 ml). Ammonium acetate (9.29 g, 120 mmol) was added. After 2.5 hours, H2O was added to precipitate the product resulting in a sticky solid. The solid was collected by filtration and suspended in a minimal amount of MeOH and cooled to 0° C. The resulting white solid was collected by filtration, washed with cold MeOH and then diethyl ether. The resulting material was dried under vacuum. The mixture of enantiomers was separated using SFC to afford the desired compound: (S)-benzyl (9-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate (1.6 g, 16.63%). HPLC RT=2.773 min (CHROMOLITH® SpeedROD, 5.0 μm, 4.6 mm×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm). [M+H+]=400.4. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=8.6 Hz, 1H), 7.56-7.37 (m, 11H), 7.23-7.17 (m, 1H), 7.16-7.12 (m, 1H), 5.12-4.99 (m, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]O.N1C=CC=CC=1.P(Br)(Br)[Br:21]>C(OCC)C>[CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][Br:21]
Reactant: CC(C)=CCc1cccc(CO)c1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=CCc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
130 mg of the resulting alcohol compound was dissolved in 20 ml of ethyl ether, and 2 ml of pyridine and 270 mg of phosphorus tribromide were added. The mixture was stirred for 1 hour under ice cooling. The reaction mixture was poured into ice water, and ethyl ether was added. The mixture was worked up in a customary manner to give 109 mg (yield 62%) of the captioned compound as a pale yellow oil.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][C:23]([OH:25])=O)[C:16]=2[CH:15]=[CH:14]1.N>O1CCCC1>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][C:23]([NH2:3])=[O:25])[C:16]=2[CH:15]=[CH:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1cccc2occc12
Agent: N
Solvent: C1CCOC1
Product: NC(=O)Cc1cccc2occc12
Temperature: 20 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
Add 1,1′-carbonyldiimidazole (2.3 g, 14.2 mmol) to a solution of benzofur-4-ylacetic acid (2.5 g, 14.2 mmol) in anhydrous tetrahydrofuran (12 mL) under nitrogen and stir at 20° C. for 4 hours. Bubble anhydrous ammonia through the solution, dilute with anhydrous tetrahydrofuran (10 mL), and stir at 20° C. for 18 hours. Concentrate under reduced pressure, and wash the solid with aqueous sodium hydrogen sulfate and distilled water. Dry under vacuum to obtain 2.3 g (93%) of the title compound as a pale yellow solid. Mass spectrum (ES, m/z) (M+H)=176.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:32]1[CH2:31][CH2:30][CH2:29][CH2:28]C2.BrC1CCCC1.O>C(O)C>[CH:28]1([O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]4[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O
Agent: BrC1CCCC1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC1CCCC1

Procedure:
A 0.15 g quantity of the N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 17 and 0.5 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 4 ml of ethanol, and 0.13 g of bromocyclopentane was added thereto. The mixture was heated and refluxed for 3 hours. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. The extract was washed with water twice, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.11 g of white powdery N-[2-(3-cyclopentyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.
Reaction SMILES: Cl.[Cl:2]/[CH:3]=[CH:4]/[CH2:5][NH:6][CH2:7][CH2:8][CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[C:34]([C:38]#[CH:39])([CH3:37])([CH3:36])[CH3:35]>[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[ClH:2].[CH3:35][C:34]([CH3:37])([CH3:36])[C:38]#[C:39]/[CH:3]=[CH:4]/[CH2:5][NH:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCNC/C=C/Cl
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCCNC/C=C/C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To 7.5 ml of tetrahydrofuran were added 850 mg (5 mmol) of (E)-N-(3-chloro-2-propenyl)propylamine hydrochloride, 47.6 mg (0.25 mmol) of copper (I) iodide, 22.4 mg (0.1 mmol) of palladium acetate and 52.5 mg (0.2 mmol) of triphenylphosphine, and further, 1.48 ml (15 mmol) of n-butylamine and 0.74 ml (6 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 20 hours at room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=3/2). The desired fractions were put together and concentrated under reduced pressure. The residue was dissolved with 15 ml of 23% hydrogen chloride methanol solution, and the solvent and excess hydrogen chloride were distilled off. The resulting crystals were suspended in 3 ml of a mixture of ethyl acetate and diisopropyl ether (1/1), filtered, washed with 1 ml of the same solvent and dried to obtain 780 mg (yield: 72%) of the above identified compound as slightly yellowish brown crystalline powder.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(N(CC)CC)C.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClCCl.C1COCC1>[CH2:27]([N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1)[C:23]1[O:22][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccco1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1coc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)c1
Yield: 37.9 %

Procedure:
Following the procedure of Example 16, 0.168 g (0.897 mmol) of trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 8 ml of anhydrous dichloromethane was reacted with 0.313 ml (2.25 mmol) of triethylamine and 0.177 ml (1.80 mmol) of 2-furoyl chloride for 11/2 h, then with 2.7 ml of a 1.0M solution of lithium aluminium hydride in THF for 30 minutes at room temperature and 1 h at reflux. Chromatography on flash silica, eluting with 30-40% ethyl acetate/petroleum ether, afforded 0.091 g (38%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 214°-223° C. (dec). NMR δ(D2O) 1.55 (1H, m), 1.68 (1H, m), 1.79-1.90 (2H, m), 2.62-2.75 (2H, m), 2.91-2.99 (3 H, m), 3.23 (1H, t, J=11.8 Hz), 3.54 (1H, m), 3.72 (1H, m), 4.44 (2H, s), 6.57 (1H, d of d, J=3.3 and 1.9 Hz), 6.75 (1H, d, J=3.2 Hz), 7.21-7.28 (3H, m), 7.33-7.36 (1H, m), 7.67 (1H, d, J=1.8 Hz). m/z (CI+, NH3) 268 (M+H)+, 200 (M-C4H3O)+, 124, 96, 81.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH:17]4[CH:15]([CH:16]4[N:19](C)C)[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[NH2:19][CH:16]1[CH:17]2[CH:15]1[CH2:14][N:13]([C:11]([C:9]1[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:32][C:28]3[CH:29]=[C:30]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:22])=[CH:31]4)[CH:8]=1)=[O:12])[CH2:18]2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN(C)C1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC21
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC6C(N)C6C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (7-chloro-thieno[3,2-b]pyridin-2-yl)-(6-dimethylamino-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to example 1C. MS: 432.2 (MH+); HPLC Rf: 4.346 min.; HPLC purity: 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CC([O-])(C)C.[K+].[Cl:23][C:24]1[CH:29]=[C:28](F)[CH:27]=[CH:26][N:25]=1>CN1CCCC1=O>[Cl:23][C:24]1[CH:29]=[C:28]([O:8][C:6]2[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]([F:1])[CH:7]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
Dissolve tert-butyl N-(2-fluoro-4-hydroxy-phenyl)carbamate (10.47 g, 46.1 mmol) in N-methyl-2-pyrrolidone (NMP, 100 mL), add t-BuOK (5.67 g, 50.5 mmol) and stir at 0° C. for 30 min. Add 2-chloro-4-fluoropyridine (5.5 g, 41.9 mmol), then stir at 70° C. under N2 for 12 hrs. Quench the reaction with water, extract with EtOAc (300 mL×3), combine the organic layers, wash with brine (300 mL×2), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (11.23 g, 79.5%). MS: (M+1): 339.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C(Cl)(Cl)Cl.C(O)C>[Cl:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1Cl

Procedure:
4-Chloro-3-nitropyridine was prepared from 4-hydroxy-3-nitropyridine(25 g, 0.179M), phosphorus pentachloride(40 g, 0.192M) and 1 mL of phosphorous oxytrichloride. The mixture was heated at 120° for 1 hour. The reaction mixture was diluted with chlorform/ethanol mixture(9/1) and the precipitate was filtered to afford desired. (mp. 153-154° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=O)[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:25](=[O:28])[N:15]([CH:14]4[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1n(C2CCCCC2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Yield: 107.6 %

Procedure:
The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, Cs2CO3 (44 mg, 0.135 mmol), bromoclohexane (100 mg, 0.61 mmol) in DMF (1 mL) and by following the procedure described in Example 9. The title compound, 7,8-bis(4-chlorophenyl)-2-cyclohexyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (26 mg, 54%) was obtained as yellow lyophilate. MS M+H=439; 1H NMR (CDCl3) δ 8.17 (1H, s), 7.30-7.38 (6H, m), 7.11 (2H, d, J=5.0 Hz), 4.38-4.41 (1H, m), 1.75-2.0 (6H, m), 1.65-1.75 (1H, m), 1.35-1.50 (2H, m), 1.1-1.30 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[C:3]=1[CH:13]=O.[OH:15][C:16]1[C:17]([C:26]([NH:28][NH2:29])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[C:3]=1[CH:13]=[N:29][NH:28][C:26]([C:17]1[C:16]([OH:15])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)=[O:27]
Reactant: O=Cc1c(O)ccc2cc(O)ccc12
Reactant: NNC(=O)c1cc2ccccc2cc1O
Product: O=C(NN=Cc1c(O)ccc2cc(O)ccc12)c1cc2ccccc2cc1O
Yield: 72 %

Procedure:
Following the general procedure of Example 1, condensation of 2, 6-dihydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide yielded a yellow solid (72%): mp>280° C.; 1H NMR d 11.89 (s, 1 H), 11.75 (br s, 1 H), 10.90 (br s, 1 H), 9.14 (s, 1 H), 9.03 (s, 1 H), 8.06 (s, 1 H), 7.75 (d, 1 H, J=9.0 Hz), 7.48 (d, 1 H, J=8.4 Hz), 7.33 (d, 1 H, J=8.4 Hz), 7.28 (d, 1 H, J=9.0 Hz), 7.07 (t, 1 H, J=7.6 Hz), 6.92 (t, 1 H, J=7.4 Hz), 6.75-6.67 (m, 3 H), 6.90 (m, 2 H); 13C NMR d 163.06, 155.90, 153.93, 153.44, 147.82, 135.94, 131.34, 130.57, 129.35, 128.69, 128.34, 126.81, 125.87, 125.66, 123.88, 122.58, 119.86, 119.68, 119.04, 110.62, 110.45, 108.82; HRMS Calcd for C22H16N2O4 :372.1110, found 372.1095; Anal. (C22H16N2O4 0.4 H2O) C, H, N.
Reaction SMILES: C=CC(CCC=C(C)C)(C)O.CC1[C:17]23[CH2:25][C:24]([C:26]([CH3:28])=[O:27])=[C:23]([CH3:29])[CH:19]([C:20]([CH3:22])(C)[CH:16]2[CH2:15]C1)[CH2:18]3>>[C:20](=[C:19]1[CH:17]2[CH2:18][CH2:29][CH:23]1[CH:24]([C:26](=[O:27])[CH3:28])[CH2:25]2)([CH2:16][CH3:15])[CH3:22]
Reactant: CC(=O)C1=C(C)C2CC3(C1)C(C)CCC3C2(C)C
Agent: C=CC(C)(O)CCC=C(C)C
Product: CCC(C)=C1C2CCC1C(C(C)=O)C2

Procedure:
4 Isomers in a ratio of 1:1.5:2.9:2.8. Odor description: Woody, floral, linalool, Vertofix, ambery. 1H-NMR (CDCl3, 400 MHz): 3.01–2.44 (m, 3H), 2.15/2.11/2.10 (4s, 3H), 2.11–2.82 (m, 3H), 1.69/1.65/1.63/1.62 (4s, 3H), 1.65–1.20 (m, 5H), 1.02–0.91 (m, 3H) ppm. GC/MS (EI): (major isomer): 192 (M+, 16), 163 (9), 149 (48), 134 (41), 121 (57), 107 (54), 93 (92), 79 (52), 43 (100). IR (atr): 2960s, 2870m, 1707vs, 1453w, 1356m, 1172s, 960w cm−1.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[C:12]1([C@@H:18](O)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][C@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])=[O:4]
Reactant: C[C@H](O)c1ccccc1
Reactant: O=C(O)C(Br)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To a mixture of α-bromophenylacetic acid (10.75 g, 0.050 mol), (S)-(−)-1-phenylethanol (7.94 g, 0.065 mol) and DMAP (0.61 g, 5.0 mmol) in dry dichloromethane (100 mL) was added solid EDCI (12.46 g, 0.065 mol) all at once. The resulting solution was stirred at room temperature under Ar for 18 hours and then it was diluted with ethyl acetate, washed (H2O×2, brine), dried (Na2SO4), filtered, and concentrated to give a pale yellow oil. Flash chromatography (SiO2/hexane-ethyl acetate, 4:1) of this oil provided the title compound (11.64 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.53-7.17 (m, 10H), 5.95 (q, J=6.6 Hz, 0.5H), 5.94 (q, J=6.6 Hz, 0.5H), 5.41 (s, 0.5H), 5.39 (s, 0.5H), 1.58 (d, J=6.6 Hz, 1.5H), 1.51 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([NH2:15])=O)([O-:3])=[O:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]#[N:15])([O-:3])=[O:2]
Reactant: NC(=O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 46 %

Procedure:
5-Nitro-1H-indole-3-carboxamide (2.0 g) was suspended in dry dioxane (100 ml) containing triethylamine (7.8 g). Trifluoroacetic anhydride (8.2 g) was added dropwise with the temperature of the solution maintained at less than 5° C., the reaction was then allowed to warm to room temperature overnight. The reaction mixture was diluted with dichloromethane (200 ml), washed with water (3×100 ml), dried (MgSO4) and the solvent removed. Recrystallisation of the residue from ethyl acetate/hexane afforded the title compound (840 mg), m.p. 186°-190° C. δH (360 MHz, CDCl3) 7.58 (1H, d, J=7.2 Hz, H-7), 7.94 (1H, d, J=1.0 Hz, H-4), 8.16 (1H, dd, J=7.2, 1.0 Hz, H-6), 8.63 (1H, s, H-2); m/z 187 (M+, 100), 157 (45), 141 (95 ), 129 (30), 114 (55), 102 (10), 87 (20 ).
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[CH:19]1([CH:25]=[CH:26]B(O)O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1(/[CH:25]=[CH:26]/[C:2]2[C:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: OB(O)C=CC1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1nn2cccnc2c1Br
Product: CC(C)(C)OC(=O)Nc1nn2cccnc2c1/C=C/C1CCCCC1

Procedure:
The product from Example 148A and 2-cyclohexylethenylboronic acid were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.38 (s, 1H), 8.96 (dd, J=6.9, 1.7 Hz, 1H), 8.53 (dd, J=4.1, 1.7 Hz, 1H), 7.00 (dd, J=6.9, 4.0 Hz, 1H), 6.58 (dd, J=16.1, 6.8 Hz, 1H), 6.30 (dd, J=16.1, 1.2 Hz, 1H), 2.04-2.14 (m, 1H), 1.58-1.84 (m, 5H), 1.46 (s, 9H), 1.07-1.41 (m, 5H); MS (ESI) m/z 341 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:23]>C(Cl)Cl>[C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:6]([Cl:17])=[CH:5][N+:4]([O-:23])=[CH:3][C:2]=2[Cl:1])[CH2:9][CH2:10]1)(=[O:15])[NH2:16]
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: ClCCl
Product: NC(=O)C1CCN(c2c(Cl)c[n+]([O-])cc2Cl)CC1
Yield: 19.1 %

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (100 mg, 0.36 mmol) and hydrogen peroxide.urea complex (72 mg, 0.77 mmol) in CH2Cl2 (2 mL) cooled to 0° C. was added trifluoroacetic anhydride (0.10 mL, 0.73 mmol). After 30 min the solution was warmed to r.t., after a further 16 hours a saturated solution of Na2S2O5 (10 mL) was added. The mixture was extracted with CH2Cl2 (2×20 mL), the combined organic extracts were washed with a saturated solution of NaHCO3 (20 mL), brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 98:2) to furnish the title compound as a white solid (20 mg, 19%), m.p. 130-133° C.; umax (CHCl3)/cm−1 3026. 2855, 1724, 1452, 1273, 1107.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1>>[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NC1CCc2ccccc21
Product: Cc1ccc(C(=O)NC2CCc3ccccc32)cc1

Procedure:
The title compound was prepared from (rac)-1-aminoindan (5.0 g, 37.6 mmole) and p-toluoyl chloride (5.2 g, 33.8 mmole) as in Ex. 52; 4.8 g (19.1 mmole, 57%), mp: 140° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](I)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24].[CH3:36][C:37]1[CH:42]=[C:41](B(O)O)[CH:40]=[CH:39][N:38]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:41]4[CH:40]=[CH:39][N:38]=[C:37]([CH3:36])[CH:42]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1I
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1-c1ccnc(C)c1

Procedure:
Following the procedure described in Example 44 (Step 5) N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (114.0 mg, 180 μmol) was combined with 2-methylpyridin-4-ylboronic acid (30 mg, 216 μmol) to afford the title compound, N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide as a yellow solid. LCMS (ESI positive ion) m/z: 600.0 (M+1); 1H NMR (400 MHz, MeOH) δ ppm 2.21 (s, 3H), 2.67 (s, 3H), 6.80 (t, J=73.11 Hz, 1H), 7.35 (dd, J=8.22, 1.96 Hz, 1H), 7.47 (t, J=8.07 Hz, 1H), 7.54 (s, 1H), 7.57-7.64 (m, 1H), 7.80-7.85 (m, 1H), 7.86-7.96 (m, 2H), 8.14 (d, J=9.49 Hz, 1H), 8.57 (d, J=5.38 Hz, 1H), 8.74 (dd, J=22.45, 2.20 Hz, 2H).