Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:34][CH2:33]2)[N:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]3[CH2:33][CH2:34]3)[N:27]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C3CC3)n2)c(C(N)=O)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(C2CC2)n1
Reaction time: 6 h
Yield: 66.1 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (25 mg, 53.5 μmol) in dichloromethane (4 mL) was added TFA (370 μg, 0.25 μL, 3.24 μmol). After 6 h, the mixture was concentrated in vacuo, then purified by flash chromatography (spherical silica, 20-45 μm, 25 g, Versaflash from Supelco, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (13 mg, 10%, two steps) as a brown solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.43 (br. s., 1H) 8.17 (br. s., 1H) 8.03 (br. s., 1H) 7.44 (br. s., 1H) 7.03 (br. s., 1H) 6.80 (br. s., 1H) 6.60 (br. s., 1H) 5.76 (br. s., 1H) 5.49 (br. s., 1H) 3.82 (br. s., 1H) 3.24 (br. s., 1H) 2.03 (br. s., 1H) 1.32-1.91 (m, 8H) 1.05 (d, J=16.62 Hz, 4H). LCMS (EI/CI) m/z: 368 [M+H].
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]([N:9]([CH:16]([OH:31])[C@H:17]1[O:23][C@@:21]([CH2:24][CH2:25][CH2:26][CH3:27])([OH:22])[C@H:20]([OH:28])[C@@H:19]([OH:29])[C@@H:18]1[OH:30])[C:10](=[O:15])[NH:11][CH2:12][CH2:13][Cl:14])([CH2:7][CH3:8])[CH3:6]>C(O)(=O)C>[CH:5]([N:9]([CH:16]([OH:31])[C@H:17]1[O:23][C@@:21]([CH2:24][CH2:25][CH2:26][CH3:27])([OH:22])[C@H:20]([OH:28])[C@@H:19]([OH:29])[C@@H:18]1[OH:30])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][Cl:14])[N:1]=[O:3])([CH2:7][CH3:8])[CH3:6]
Reactant: O=N[O-]
Reactant: CCCC[C@@]1(O)O[C@H](C(O)N(C(=O)NCCCl)C(C)CC)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC[C@@]1(O)O[C@H](C(O)N(C(=O)N(CCCl)N=O)C(C)CC)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 2 h
Yield: 66 %

Procedure:
Sodium nitrite (0.85 g) was slowly added to a suspension of 3-sec-butyl-3-(n-butyl β-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (3.25 g, 8.19 mmol) in 80% aqueous acetic acid (40 ml) with thoroughly stirring at 0° to 5° C., and stirring was continued for further 2 hours at the same temperature. After confirmation by TLC that the reaction finished, 15 ml of the same ion exchange resin as mentioned above was added to the reaction mixture at 0° to 5° C., and the mixture was stirred for 30 minutes. The ion exchange resin was filtered off, and the filtrate was vacuum-concentrated at 25° C. and crystallized from methanol and water, giving 2.39 g of 3-sec-butyl-3-(n-butyl β-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 68.4%, m.p. 92°-95° C. (decomposition). [α]D20 -14.2° (C 1.0, methanol).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][C:11](=O)[C:6]2=[N:5][N:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>>[F:1][C:2]([F:14])([F:13])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][C:11](=[S:24])[C:6]2=[N:5][N:4]=1
Reactant: O=C1NCCn2c1nnc2C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: FC(F)(F)c1nnc2n1CCNC2=S
Temperature: 25 °C

Procedure:
A mixture of 173 mg (0.84 mmol) of 3-(trifluoromethyl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one, 703 mg (1.68 mmol) of Lawesson's Reagent, and 18 mL of xylenes was stirred at reflux for 4.5 h. After being cooled to room temperature, the solvent was decanted off, and the residue was washed with diethyl ether. The resulting solid was dried and purified by flash chromatography (20-50% acetone in hexanes) to give the title compound as a greenish-yellow solid. LC-MS 223 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH:12]([NH:14][C:15]3[C:16]([CH3:27])=[N:17][O:18][C:19]=3[C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)[CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[NH:14][CH:12]([CH3:13])[CH2:11][CH2:10][C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc2c(c1)OCO2
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc5c(c4)OCO5)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using (3-benzo[1,3]dioxol-5-yl-1-methyl-propyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[NH:30][C:31]([NH:33][C:34]2[CH:39]=[N:38][C:37]([CH3:40])=[CH:36][N:35]=2)=[O:32])[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:40][C:37]1[N:38]=[CH:39][C:34]([NH:33][C:31]([NH:30][C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[O:22][CH2:21][CH:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:11][CH2:12]2)=[O:32])=[N:35][CH:36]=1
Reactant: Cc1ccc(OCC2Cc3ccccc3N(C(=O)OCc3ccccc3)C2)c(NC(=O)Nc2cnc(C)cn2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(OCC2CNc3ccccc3C2)c(NC(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C

Procedure:
A stirred suspension of the crude 3-{4-Methyl-2-[3-(5-methyl-pyrazin-2-yl)-ureido]-phenoxymethyl}-3,4dihydro-2H-quinoline-1-carboxylic acid benzyl ester (6.6 mg, 12 μmol) was heated in 5 mL EtOAc on a heat gun until in solution. The clear solution was cooled to rt and treated with triethylamine (3.4 μL, 24 μmol) followed by Pearlman's catalyst (20% palladium hydroxide on carbon, 9 mg). The mixture was put through a vacuum/purge cycle three times with hydrogen gas and then held under 1 atmosphere hydrogen pressure for 1 hour. The reaction was filtered through GF/F filter paper with EtOAc and concentrated to a white solid which corresponds to the desired product (4.7 mg, 100%). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.23 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.04 (t, 1H), 6.97 (d, 1H), 6.81 (m, 2H), 6.67 (t, 1H),6.58 (d, 1H), 4.04 (m, 2H), 3.57 (d, 1H), 3.26 (t, 1H), 2.92 (ddd, 2H), 2.64 (m, 1H), 2.34 (s, 3H), 2.31 (s, 3H). LRMS (APCI, Positive) m/e 404.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:18])=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.C(O)(C)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=1[S:45]([NH2:48])(=[O:47])=[O:46]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:18])=[C:13]([C:15]([NH:48][S:45]([C:38]3[CH:39]=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:37]=3[Cl:36])(=[O:47])=[O:46])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: Cc1c(C(=O)O)nc2c(Cl)cc(C(F)(F)F)cn12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2nc3c(Cl)cc(C(F)(F)F)cn3c2C)c1
Reaction time: 0.25 h
Yield: 37.6 %

Procedure:
To the carboxylic acid prepared in Step B (200 mg, 0.72 mmol) was added a solution of 4-(dimethylamino)pyridine (262 mg, 2.15 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (344 mg, 1.79 mmol) in a 1:1 solvent mixture of t-butanol (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred for 15 minutes, 2-chloro-5-methoxybenzenesulfonamide (143 mg, 0.65 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was extracted with 1 N hydrochloric acid (3×100 mL), and the separated organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 118 mg of the title compound, a compound of the present invention, as a white solid, m.p. 222-223° C. 1H NMR (dmso-d6) δ 10.0 (br s, 1H), 8.94 (s, 1H), 7.96 (s, 1H), 7.65 (d, 1H), 7.59 (d, 1H), 7.30 (dd, 1H), 3.87 (s, 3H) 2.71 (s, 3H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH3:19])=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:1][C:16]1[CH:17]=[C:12]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[O:11])[CH:13]=[N:14][C:15]=1[NH:18][CH3:19]
Reactant: CNc1ccc(C(=O)c2ccc(Cl)cc2)cn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CNc1ncc(C(=O)c2ccc(Cl)cc2)cc1Br
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A solution of bromine (2.29 mL, 44.70 mmol) in acetic acid (30 mL) was added to a solution of compound C (11.0 g, 44.7 mmol) in acetic acid (80 mL) at RT. The mixture was stirred for 1 h, neutralized by the addition of saturated NaHCO3 solution and extracted with ethyl acetate (200 mL). The organic layer was washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified using column chromatography to obtain 9.0 g (62%) of compound D as viscous light yellow colored oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1cccc2cnccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1cccc2cnccc12)c1ccccc1
Temperature: 0 °C
Yield: 103.6 %

Procedure:
To a solution of 5-hydroxyisoquinoline (15.0 g, 103 mmol) in dichloromethane (300 ml) was added triethylamine (10.9 g, 108 mmol), and the mixture was cooled to 0° C. Under stirring, benzoyl chloride (15.2 g, 108 mmol) was added dropwise and the temperature was raised to room temperature. After stirring for 6 hours at room temperature, dichloromethane was added. The solution was washed with saturated aqueous solution of sodium hydrogencarbonate, then dried over anhydrous magnesium sulfate and solvent was distilled off, thereby affording 26.6 g of the title compound as a light brown liquid. Yield quantitative. 1H-NMR (DMSO-d6, δ): 7.68(2H, t, J=7.3 Hz), 7.75(1H, d, J=5.9 Hz), 7.79-7.85(3H, m), 8.12-8.16(1H, m), 8.28(2H, d, J=7.3 Hz), 8.55 (1H, d, J=5.9 Hz), 9.45(1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:17][CH2:18][C:13]([F:29])([F:12])[CH2:14][CH2:15]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)C2CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)C2CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=448.1, tR (minutes, Method F)=2.95
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][N:32]3C(=O)C4=CC=CC=C4C3=O)[C:6]=2[CH:43]=1.O.NN.O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][NH2:32])[C:6]=2[CH:43]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(CCN3C(=O)c4ccccc4C3=O)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Yield: 35.3 %

Procedure:
To a solution of 7-chloro-5-(2-phthalimidoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) in ethanol (50 ml) is added hydrazine monohydrate (0.19 ml), and the mixture is refluxed for 4 hours. The mixture is cooled, and thereto is added water. The mixture is extracted with dichloromethane, and the extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-aminoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1.N(C(OC(C)(C)C)=O)=NC(O[C:47](C)(C)[CH3:48])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:47][CH3:48])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(O)cc34)cc(Cl)n2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1

Procedure:
A mixture of Example 224a (80.0 mg, 0.134 mmol), di-tert-butyl azodicarboxylate (77 mg, 0.334 mmol), triphenylphosphine on solid support (3 mmol/g, 112.0 mg, 0.427 mmol) and ethanol (0.039 mL, 0.669 mmol) in THF (3 mL) was stirred at room temperature overnight. The mixture was diluted with EtOac, filtered through celite, concentrated and purified on a 12 g column using the ISCO Companion flash system eluting with hexane/EtOAc (8:2 to 6:4) to give 76.1 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([N:14]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH3:31])[C:4]=1[CH2:21]/[CH:22]=[C:23](\[CH3:30])/[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CC/C(C)=C/Cc1c(NC(=O)C(F)(F)F)c2c(c(C)c1OC)COC2=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1N(C)C(=O)C(F)(F)F)C(=O)OC2
Reaction time: 24 h

Procedure:
To a solution of 0.35 g (0.82 mmol) of methyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-(trifluoroacetylamino)-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate in 4 ml of dimethylformamide was added 0.47 g (3.40 mmol) of potassium carbonate and 0.23 ml (3.69 mmol) of iodomethane. The mixture was stirred for 24 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl (E)-6-[1,3-dihydro-6-methoxy-7-methyl-4-(N-trifluoroacetyl-N-methylamino)-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate, an oil. NMR: δ 5.22-5.17 (multiplet ("m"), 2H); 5.10-5.04 (broad triplet, 1H); 3.81 (singlet ("s"), 3H); 3.62 (s, 3H); 3.42-3.27 (m, 5H); 2.45-2.25 (m, 5H); 1.75 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:9][C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([N:9]([C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH:27]([CH3:28])[CH3:29])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:35])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N(C)[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Yield: 96.4 %

Procedure:
To a solution of (S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-propionic acid tert-butyl ester (0.24 g, 0.55 mmol) in DCE (7 mL) was added aqueous formaldehyde (4.4 mL, 55.4 mmol, 37% solution) and sodium triacetoxyborohydride (7.2 g, 34.0 mmol) portion wise over 58 h. The resulting mixture was then washed with saturated aqueous sodium carbonate and the aqueous phase extracted with further DCM. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give (S)-2-{[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methyl-amino}-propionic acid tert-butyl ester (0.24 g, 97%). LCMS: RT=3.81 min, [M+H]+=453.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[C:28]([Cl:35])[CH:27]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:34])=[C:28]([Cl:35])[CH:27]=1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in toluene for 4 days under reflux conditions to give the title compound as white solid. MS: m/e=503.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC.Cl>CN(C)C=O.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>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH2:31][CH3:32])=[CH2:29])[CH:16]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(OCC)c1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (3.5 g, 9.7 mmol) [prepared as described in Example 1 above], tributyl-(1-ethoxyvinyl)tin (4.3 ml, 12.36 mmol) and tetrakis(triphenylphosphine)palladium (1.0 g, 0.87 mmol) in dimethylformamide (25 ml) was heated at 95° C. under argon. After 16 h, the reaction mixture was cooled to room temperature and 10% aqueous hydrochloric acid (25 ml) was slowly added. After 30 min., the reaction mixture was diluted with ethyl acetate and filtered through Celite®. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 10-60% ethyl acetate/hexane) to give 5-amino-4-[3-(1-ethoxyvinyl)benzoyl]-1-(4-fluorophenyl)pyrazole which was dissolved in tetrahydrofuran (50 ml). 1 N hydrochloric acid (20 ml) was added and the reaction mixture was stirred at room temperature for 16 h. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (elution gradient: 20-50% ethyl acetate/hexane) and then was recrystallized from a mixture of ethyl acetate/hexane to give 5-amino-4-[3-acetylbenzoyl]-1-(4-fluorophenyl)pyrazole (2.0 g).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>[OH-].[Na+]>[C:1]1([S:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.5 %

Procedure:
Benzenesulphonyl chloride (7 mmol) was added to a solution of 7-aminoheptanoic acid (7 mmol) in 10% sodium hydroxide solution (10 ml). The mixture was stirred at room temperature for 3 hours. The pH was adjusted to 1 with 2NHCl and the solution was extracted with chloroform (3×100 ml). The chloroform extracts were dried over magnesium sulphate, the solvent was removed and the residue was recrystallised from methanol-water to give 7-(benzenesulphonamido)heptanoic acid (0.75 g, 38%); m.p. 75°-77° C.
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[CH2:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[CH2:11]([C:13]1[CH:18]=[C:17]2[C:16]([C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][C:6]2([CH3:9])[CH3:7])=[C:15]([OH:19])[CH:14]=1)[CH3:12]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: CCc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
Next, 2,5-dimethyl-2,5-dichlorohexane (183 g, 1 mol) is stirred with 3-ethylphenol (146.4 g, 1.2 mol) and aluminum chloride (4 g) is added. The mixture is heated at 95° C., with stirring, for 1.5 hr, after which ethylene dichloride (100 ml) is added, and then the heating continued. After 1 hr, the mixture is cooled to 20° C., and poured onto an ice water/hydrochloric acid mixture (150 ml, 10% HCl solution). The mixture is then extracted with toluene (500 ml), the organic layer separated, washed with brine (3×50 ml) and dried (Na2SO4). The solvent is removed by distillation and the residue crystallized from a hexane/benzene solvent mixture to give 7-ethyl-1,1,4,4-tetramethyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene.