Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH:24]([CH3:26])[N:23]([C:27](=[O:29])[CH3:28])[CH:22]([CH3:30])[CH2:21]4)[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.Cl[CH2:32][CH2:33][O:34][CH2:35][CH2:36]Cl.[I-].[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:26][CH:24]1[CH2:25][N:20]([C:16]2[CH:15]=[C:14]([N:11]3[CH:12]=[N:13][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([N:1]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:3][CH:4]=4)=[N:10]3)[CH:19]=[CH:18][N:17]=2)[CH2:21][CH:22]([CH3:30])[N:23]1[C:27](=[O:29])[CH3:28]
Reactant: ClCCOCCCl
Reactant: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(N)cc4)n3)ccn2)CC1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(N5CCOCC5)cc4)n3)ccn2)CC1C
Yield: 59.8 %

Procedure:
To a solution of 100 mg of 1-(4-{4-[3-(4-Amino-phenylamino)-[1,2,4]triazol-1-yl]-pyridin-2-yl}-2,6-dimethyl-piperazin-1-yl)-ethanone (0.246 mMol, 1.00 equiv) in 2 mL of DMF was added 100 μL of 2-chloroethyl ether, 50 mg of sodium iodide and 100 mg of K2CO3. After 3 hr at 110° C. the reaction was concentrated and purified by flash chromatography (EtOAc) to yield 70 mg of 1-(2,6-Dimethyl-4-{4-[3-(4-morpholin-4-yl-phenylamino)-[1,2,4]triazol-1-yl]-pyridin-2-yl}-piperazin-1-yl)-ethanone (0.147 mMol, 59.8% yield). 1H NMR (500 MHz, DMSO-d6) ∂ 9.26 (1H, s), 9.21 (1H, s), 8.20 (1H, d), 7.52 (2H, d), 7.21 (1H, s), 7.12 (1H, d), 6.90 (2H, d), 4.30 (2H, m), 4.05 (2H, m), 3.73 (4H, m), 3.09 (2H, m), 2.99 (4H, m), 2.51 (3H, s), 1.2 (6H, m) ppm. LC/MS: 1.78 min/477.3 (M+1).
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18](Br)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>C(Cl)Cl>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(c1ccccc1)N1c2cccc3c2C(CCC3Br)C1c1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)N1c2cccc3c2C(CCC3N2CCOCC2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A portion (600 mg) of the compound obtained in Example 132 was dissolved in anhydrous methylene chloride (10 ml) and to the solution was added morpholine (0.25 ml). The mixture was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:19-1:3) to yield 560 mg (92%) of the titled compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:23]1[C:31]2[S:30][N:29]=[CH:28][C:27]=2[CH:26]=[CH:25][C:24]=1[C:32]([OH:34])=[O:33]>C1COCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:23]3[C:31]4[S:30][N:29]=[CH:28][C:27]=4[CH:26]=[CH:25][C:24]=3[C:32]([OH:34])=[O:33])=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2cnsc2c1F
Reactant: Nc1ccc(C2CC2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cnsc2c1Nc1ccc(C2CC2)cc1F
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a solution of 4-cyclopropyl-2-fluoro-phenylamine (445 mg, 2.94 mmol) in anhydrous THF (10 mL) at −78° C. was added a 1.0 M solution of LHMDS in hexanes (4.4 mL, 4.4 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes and a suspension of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid (290 mg, 1.47 mmol) in anhydrous THF (10 mL) was added dropwise. The resultant mixture was stirred at −78° C. for 30 minutes, then allowed to reach room temperature and stirred for 18 hours before being quenched by addition of a 1M aqueous and extracted with ethyl acetate. The organic layer was separated and washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was triturated with diethyl ether to give the title compound as a brown solid (155 mg, 32%). LCMS (method B): RT=3.79 min, [M+H]+=329.
Reaction SMILES: Cl[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)Cl.[OH:22][CH2:23][CH2:24][CH2:25]/[C:26](=[CH:36]\[S:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)/[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].N1C=CN=C1>O>[Si:2]([O:22][CH2:23][CH2:24][CH2:25]/[C:26](=[CH:36]\[S:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)/[C:27]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:28])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccccc1)/C(=C/Sc1ccccc1)CCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OCCC/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
1.87 g of chloro t-butyl diphenylsilane was dropped into 10 ml of methylene chloride solution including 1.64 g of (E)-5-hydroxy-N-phenyl-2-(phenylthiomethylene)pentanamide and 0.82 g of imidazole at room temperature. After stirring at room temperature for 2 hours, the resulting solution was added with water and extracted with ethyl acetate. The organic layer was washed 3 times, then washed with brine, and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.81 g the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[ClH:15]>O>[Cl:15][C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13][C:12]=1[CH3:14]
Reactant: Cl
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Solvent: O
Product: COc1ccc(-c2nc(C)c(Cl)[nH]2)cc1
Reaction time: 8 h
Yield: 17 %

Procedure:
A suspension of 2-(p-methoxyphenyl)-4-methylimidazole, (4.5 g, 0.024 mole) in concentrated HCl (96 ml)-H2O (34 ml) was stirred vigorously while a solution of KC103 (1 g) in H2O (50 ml) was added dropwise over 1-1/4 hour. The precipitated hydrochloride salt was collected and suspended in H2O (200 ml), saturated Na2CO3 solution (50 ml). After an overnight period of stirring, the solid was collected, chromatographed on silica gel, the product eluted with 5% CH3OH-CHCl3 and crystallized from 50% CH3CN to yield 0.9 g (17%) of 38, m.p. 182°-186° C. A sample recrystallized from 50% CH3CN melted at 185°-187° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][N:6]=1)(=O)=O.O.S.[Na].C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].[F:27][C:28]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:29]=1CC(Br)C1C=CC=CC=1>CN(C=O)C.O>[F:27][C:28]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:29]=1[CH2:1][S:2][C:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][N:6]=1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: Fc1cccc(F)c1CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: S
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(SCc2c(F)cccc2F)=NO1
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 5.0 g (28.2 mmoles) of 3-methylsulfonyl-5,5-dimethyl-2-isoxazoline (present compound No. 2-1) dissolved in 50 ml of DMF were added, with ice-cooling, 4.5 g (purity: 70%, 56.1 mmoles) of sodium hydrogensulfide hydrate, 7.8 g (56.4 mmoles) of potassium carbonate and 8.7 g (56.5 mmoles) of Rongalit. The mixture was stirred for 2 hours. Thereto was added 5.8 g (28.0 mmoles) of 2,6-difluorobenzylbenzyl bromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic phase was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (solvent system=hexane-ethyl acetate) to obtain 5.8 g (yield: 80.0%) of 3-(2,6-difluorobenzylthio)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 77 to 80° C.).
Reaction SMILES: [OH-].[Na+].ClC1C=CC(C([O:10][CH2:11][C@@H:12]([N:16]([CH3:26])[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:13]([CH3:15])[CH3:14])=O)=CC=1.O.C(O)(=O)C>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([N:16]([C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:10])[CH3:26])=[O:25])=[CH:19][CH:20]=1
Reactant: CC(C)[C@@H](COC(=O)c1ccc(Cl)cc1)N(C)C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@@H](CO)N(C)C(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
NaOH (2.35 ml, 8.93 mmol) was added to (S)-2-(4-chloro-N-methylbenzamido)-3-methylbutyl 4-chlorobenzoate (Compound C2.1) (3.2 g, 8.12 mmol) in MeOH. The resultant mixture was stirred at rt for 20 min. Additional NaOH (1.07 ml, 4.06 mmol) was added and the stirring continued for 1 h. To the mixture was water (5 mol) added and the resultant mixture was stirred for 2 h. The mixture was neutralized by the addition of acetic acid. The solvent was removed and DCM (50 mL) was added. The organic phase was washed with NaHCO3 (saturated, 3×50 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (1.47 g, 71%). The obtained crude product was used without further purification. Mixture of rotamers: (600 MHz, CD3OD) δ 0.78-0.85, 0.95-0.99, 1.02-1.07, 1.78-1.86, 1.90-1.98, 2.84, 2.95, 3.35-3.40, 3.59-3.66, 3.68-3.77, 3.83-3.88, 4.28-4.34, 7.39-7.48. Total no of protons: 17. LCMS (M+H)+: 256.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:16][C:17]=2[N+:22]([O-:24])=[O:23])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinic chloride and 4-(t-butyl)-2-nitroaniline as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.30 (s, 1H), 9.03 (d, J=2.1, 1H), 8.83 (d, J=9.0, 1H), 8.29 (d, J=2.7, 1H), 8.25-8.21 (m, 1H), 7.80-7.76 (m, 1H), 7.52 (d, J=8.4, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:11]2=[CH:12][C:13]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:14][C:15]3[C:16]([CH3:22])([CH3:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:7]5[C:8]=4[N:9]([C:10]=32)[C:4]2[C:5](=[CH:34][CH:35]=[CH:36][C:3]1=2)[C:6]5([CH3:33])[CH3:32].[Br:38]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:38][C:19]1[CH:18]=[C:17]2[C:16]([CH3:21])([CH3:22])[C:15]3[CH:14]=[C:13]([B:23]4[O:24][C:25]([CH3:31])([CH3:30])[C:26]([CH3:29])([CH3:28])[O:27]4)[CH:12]=[C:11]4[C:2]([CH3:37])([CH3:1])[C:3]5[C:4]6[N:9]([C:10]=34)[C:8]2=[C:7]([C:6]([CH3:33])([CH3:32])[C:5]=6[CH:34]=[CH:35][CH:36]=5)[CH:20]=1
Reactant: CC1(C)c2cccc3c2N2c4c1cccc4C(C)(C)c1cc(B4OC(C)(C)C(C)(C)O4)cc(c12)C3(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC1(C)c2cccc3c2N2c4c1cc(Br)cc4C(C)(C)c1cc(B4OC(C)(C)C(C)(C)O4)cc(c12)C3(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 4,4,8,8,12,12-hexamethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,12-dihydro-4H-benzo[1,9]quinolizino[3,4,5,6,7-defg]acridine (2.10 g, 4.27 mmol) in CHCl3 (77 mL) at 0° C. was added N-bromosuccinimide (0.761 g, 4.27 mmol) over a period of 20 min. While warming up to room temperature, the resulting solution was stirred in the absence of light overnight. The reaction was quenched with a saturated aqueous solution of Na2S2O3. The resulting mixture was extracted with CH2Cl2 (3×) and the combined organic fractions were dried with MgSO4. After filtration and evaporation of the solvent, the residue was subjected to column chromatography (silica, n-hexane/CH2Cl2 2:3). Final recrystallization from ethanol yielded 2-bromo-4,4,8,8,12,12-hexamethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,12-dihydro-4H-benzo[1,9]quinolizino[3,4,5,6,7-defg]acridine as a white powder (1.87 g, 77%).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[CH:14]=[CH:13][C:7]2[CH:8]=[C:9]([CH:11]=O)[O:10][C:6]=2[CH:5]=1)[CH3:2].[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N+:25]1[C:34]2[C:29](=[CH:30][C:31]([S:35]([O-:38])(=[O:37])=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:39])=[CH:27][CH:26]=1)([OH:19])=[O:18].[CH3:40][N+:41]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[CH3:42]>CO.O>[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N+:25]1[C:34]2[C:29](=[CH:30][C:31]([S:35]([O-:38])(=[O:37])=[O:36])=[CH:32][CH:33]=2)[C:28](/[CH:39]=[CH:11]/[C:9]2[O:10][C:6]3[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])[CH:14]=[CH:13][C:7]=3[CH:8]=2)=[CH:27][CH:26]=1)([OH:19])=[O:18].[CH3:40][N+:41]([CH2:44][C:45]([OH:47])=[O:46])([CH3:43])[CH3:42]
Reactant: CCN(CC)c1ccc2cc(C=O)oc2c1
Reactant: Cc1cc[n+](CCCCCC(=O)O)c2ccc(S(=O)(=O)[O-])cc12
Agent: C[N+](C)(C)CC(=O)O
Solvent: O
Solvent: CO
Product: CCN(CC)c1ccc2cc(/C=C/c3cc[n+](CCCCCC(=O)O)c4ccc(S(=O)(=O)[O-])cc34)oc2c1

Procedure:
0.2 mmol 6-diethylamino-benzofuran-2-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-4-methyl-6-sulfonato-chinolinium betaine are converted according to the general directions given above. Column chromatography: SiO2 (RP18), eluent: methanol/water.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[NH2:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:17](OC(OCC)OCC)(=O)C>>[Si:1]([O:8][C:9]1[C:10]2[NH:16][CH:17]=[N:15][C:11]=2[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1N
Product: CC(C)(C)[Si](C)(C)Oc1cccc2nc[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.5 %

Procedure:
To 3-{[tert-butyl(dimethyl)silyl]oxy}benzene-1,2-diamine (4.27 g, 17.9 mmol) is added diethoxymethyl acetate (8.7 g, 53.6 mmol), and the mixture is stirred at room temperature for 5 hours. The precipitated white solid is collected by filtration, and the filtrate is further stirred at room temperature for 12 hours. The precipitated white solid is collected by filtration, and washed with a small amount of hexane. The filtrate is concentrated under reduced pressure, ant the obtained residue is purified by silica gel column chromatography (ammonic chloroform) to give the title compound as white solid (1.89 g, yield: 43%).
Reaction SMILES: I[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1>C1C=CC=CC=1.CC(N(C)C)=O.C(OCC)(=O)C.[Cu].[Zn].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>[CH:9]1([C:12](=[O:13])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CCI
Reactant: O=C(Cl)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(=O)C1CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A mixture of ethyl 3-iodopropanoate (8 g, 35 mmol) and zinc-copper (4.5 g, 70 mmol) in a mixture of benzene (80 mL) and DMA (8 mL) was heated at 60° C. for 4.5 hours under N2. Pd(PPh3)2Cl2 (1.2 g, 1.8 mmol) was added, followed by addition of cyclopropanecarbonyl chloride (3.7 g, 35 mmol). The mixture was stirred at 60° C. for another 30 minutes. The reaction mixture was diluted with ethyl acetate (300 mL), and washed with 1N HCl (50 mL), satd aq NaHCO3 (80 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated to afford the ethyl 4-cyclopropyl-4-oxobutanoate (4.2 g), which was used for next step directly without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(Cl)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(Cl)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-chlorophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (185 mg, 0.46 mmol, see step (b) Example 2) and 4-trifluoromethylbenzeneboronic acid (129 mg, 0.68 mmol). Yield 145 mg (58%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([C:10]3=[N:9][CH:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1.[H-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:31][C:32]1[N:33]=[N:34][N:35]([CH3:37])[CH:36]=1>CN(C=O)C.O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:31][C:32]4[N:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[C:14]4[C:19]([C:10]3=[N:9][CH:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1
Reactant: Cc1cc(-c2cnc3c4ccccc4c(=O)[nH]n23)no1
Reactant: Cn1cc(CCl)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnc3c4ccccc4c(OCc4cn(C)nn4)nn23)no1
Temperature: 80 °C
Yield: 61.3 %

Procedure:
3-(5-Methylisoxazol-3-yl)imidazo[2,1-a]phthalazin-6-one (100 mg, 0.375 mmol) was suspended in DMF (5 ml) and sodium hydride (60% dispersion in oil, 33 mg, 0.83 mmol) was added. After stirring at room temperature for 10 minutes potassium carbonate (50 mg, 0.36 mmol) was added, followed by 4-chloromethyl-1-methyl triazole hydrochloride (69 mg, 0.41 mmol). The solution was heated at 80° C. for 4 hours, then cooled and poured into water. The solid product was filtered off and washed with water and hexane. The solid was recrystallised from ethyl acetate/hexane to yield the title compound (83 mg, 62%), 1H NMR (360 MHz, CDCl3) 2.55 (3H, s), 4.11 (3H, s), 5.75 (2H, s), 6.72 (1H, s), 7.67 (1H, t), 7.86 (1H, t), 7.99 (1H, s), 8.17 (2H, d), 8.51 (1H, d); MS+362 [MH]+.
Reaction SMILES: C([O:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:15]=C(C2C=CC=CC=2)C2C=CC=CC=2)[O:7][CH2:6]1)(=O)C.Cl.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[NH2:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][CH:5]([OH:4])[CH2:6][O:7]2
Reactant: CC(=O)OC1COc2cccc(N=C(c3ccccc3)c3ccccc3)c2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Nc1cccc2c1CC(O)CO2
Yield: 64.5 %

Procedure:
A solution of Example 51D (504 mg, 1.36 mmol) in THF (5 mL) was stirred at room temperature, followed by addition of 6N aq HCl (3.4 mL, 6.8 mmol). After 10 min water (20 mL) and CH2Cl2 (10 mL) were added and the layers separated. The aqueous layer was washed with CH2Cl2 (5 mL). The aqueous layer was then neutralized with saturated NaHCO3 solution and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was taken up in MeOH (5 mL) and K2CO3 (938 mg, 6.78 mmol) was added. After 20 min CH2Cl2 (50 mL) was added and the mixture was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (50%-100% EtOAc/hexanes) to afford 145 mg (65%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 6.73 (t, J=8.0, 1H), 6.18 (dd, J=7.9, 1.1, 1H), 5.98 (dd, J=8.1, 1.0, 1H), 5.06 (d, J=4.2, 1H), 4.81 (bs, 2H), 4.01-3.92 (m, 2H), 3.63 (dd, J=11.0, 8.1, 1H), 2.64 (dd, J=16.9, 6.2, 1H), 2.23 (dd, J=16.1, 6.7, 1H). MS (ESI+) m/z 166 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[C:25]([C:38](O)=[O:39])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:55][C:56]([NH2:59])([CH3:58])[CH3:57].Cl>CN(C=O)C>[C:56]([NH:59][C:38]([C:25]1[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:36])([F:37])[F:35])=[CH:27][C:22]([CH2:21][N:10]2[C:11](=[O:20])[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:18])[F:16])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[CH:23][CH:24]=1)=[O:39])([CH3:58])([CH3:57])[CH3:55]
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Reactant: CC(C)(C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
30 mg (0.05 mmol) of the compound from Example 141 were initially charged in 0.75 ml of DMF, and 9 mg (0.074 mmol) of HOBt and 13 mg (0.07 mmol) of EDC were added. After 10 min of stirring at RT, 6 μl (0.06 mmol) of 2-methylpropane-2-amine were added, and the mixture was stirred at RT for 16 h. 50 μl of 1 N hydrochloric acid were then added, and the mixture was directly purified chromatographically [Method 19]. This gave 8.2 mg (24% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCC(OCc2ccccc2)C1
Solvent: CO
Product: O[C@H]1CCC[C@@H](OCc2ccccc2)C1
Yield: 36 %

Procedure:
10 g of the crude acetate/alcohol mixture from Example 29 were taken up in approx. 90 ml of methanol and approx. 70 ml of water and washed three times with in each case approx. 50 ml of n-heptane. The combined heptane phases (contain predominantly the acetate) are extracted with 50 ml of 1:1 methanol/water. The combined aqueous phases are washed again with n-heptane. After concentrating the aqueous phase, 3.6 g of the desired (1S,3R)-3-benzyloxycyclohexan-1-ol were obtained, and the concentration of the combined heptane phases gave 5.5 g of the (1R,3S)-acetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]=[C:13]=[S:14])=[C:4]([F:15])[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1)=[O:20])[CH3:17].O>C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([NH:12][C:13](=[S:14])[N:22]2[CH2:23][CH2:24][CH2:25][CH2:26][N:21]2[C:19]([O:18][CH2:16][CH3:17])=[O:20])=[C:4]([F:15])[CH:3]=1
Reactant: CCOC(=O)N1CCCCN1
Reactant: CC(C)Oc1cc(N=C=S)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCCCN1C(=S)Nc1cc(OC(C)C)c(Cl)cc1F
Yield: 43.5 %

Procedure:
4-Chloro-2-fluoro-5-(1-methylethoxy)phenyl isothiocyanate (2.8 g) was added to a solution of 2-ethoxycarbonyl-3,4,5,6-tetrahydro-(1H,2H)-pyridazine (1.8 g) and several drops of triethylamine in toluene (5 ml), and the resultant mixture was stirred at 25° C. overnight. Water was added to the mixture, which was then extracted with toluene. The toluene layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography to give 2 g of ethyl 2-(4-chloro-2-fluoro-5-(1-methylethoxy)phenylaminothioxomethyl)-3,4,5,6-tetrahydro-1(2H)pyridazine carboxylate. nD27.5 1.5534. NMR δ (ppm): 1.3 (3H, t), 1.4 (6H, d), 1.8 (4H, m), 4.35 (2H, q), 7.1 (1H, d), 8.0 (1H, d), ##STR13##