Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Br.[CH3:33][C:34]1[N:38]([CH2:39][C:40]#[CH:41])[CH:37]=[N:36][CH:35]=1.CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:41]#[C:40][CH2:39][N:38]4[C:34]([CH3:33])=[CH:35][N:36]=[CH:37]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCn1cncc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Br
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cc1cncn1CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 5-methyl-1-prop-2-ynyl-1H-imidazole hydrobromide (120.4 mg). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vacuum to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and saturated NaHCO3. The layers are separated. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluant 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 4% MeOH in CH2Cl2 (2L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractions are combined and concentrated to afford a residue. The residue is recrystallized from hot acetonitrile to afford 87.7 mg of the title compound as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[N:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Clc1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Cl)nn2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (2.0 g) synthesized in Example 4 and 3,6-dichloropyridazine (1.2 g) were dissolved in N,N-dimethylformamide (30 mL), potassium tert-butoxide (0.9 g) was added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (1.7 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>C([O-])(O)=O.[Na+].O.C1COCC1>[OH:10][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:15](=[O:16])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:13])[CH2:11][OH:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(CO)(CO)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a stirred solution of 2-(4-aminophenyl)-2-methylpropane-1,3-diol (1 g, 5.52 mmol, 1.0 eq) in sat. aq. NaHCO3 (4 mL), water (2 mL) and THF (4 mL) was added phenyl chloroformate (0.76 mL, 6.08 mmol, 1.1 eq) at 0° C. and the mixture was stirred at 0° C. for 0.5 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (10 mL) and the solvent evaporated. The crude product was purified by CC using chloroform/MeOH (95:5) as eluent to get phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)phenylcarbamate (1.1 g, 60%) as a white solid (TLC system: chloroform—MeOH; 9:1; Rf: 0.4).
Reaction SMILES: C([O-])(=O)C.Cl[N:6]1[C:11](=[O:12])[N:10](Cl)[C:9](=[O:14])[N:8](Cl)[C:7]1=[O:16]>CCCCCC>[NH:6]1[C:11](=[O:12])[NH:10][C:9](=[O:14])[NH:8][C:7]1=[O:16]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: CC(=O)[O-]
Solvent: CCCCCC
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1

Procedure:
40 g (20.4 mmol) of geranil acetate was dissolved in 100 ml of n-hexane. After adding 17.1 g (70.0 mmol) of trichloroisocyanuric acid slowly, the mixture was maintained at −10° C. to 0° C. for six hours. After the completion of the reaction, remaining trichloroisocyanuric acid and by-produced isocyanuric acid were removed out of the system by filtration. The filtrate was washed with a 5% aqueous solution of sodium hydrogencarbonate and ion-exchange water in order, and dried over anhydrous sodium sulfate. After removal of the solvent, a crude product was obtained. The crude product was subjected to silica gel column chromatography to give desired 6-chloro-3,7-dimethyl-2,7-octatrienyl acetate as pale yellow oil in a yield of 86%.
Reaction SMILES: [CH2:1]([N:5]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=1)[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:23]=[CH:22][C:21]([C:24](=[O:48])[NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[C:32]([O:39][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)[CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:28])=[O:27])=[CH:20][C:16]=2[C:17](O)=[O:18])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:58]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH2:61][C@@H:60]([CH2:68][OH:69])[NH:59]1>>[CH2:1]([N:5]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=1)[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:23]=[CH:22][C:21]([C:24](=[O:48])[NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[C:32]([O:39][CH2:40][CH2:41][N:42]5[CH2:43][CH2:44][O:45][CH2:46][CH2:47]5)[CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:28])=[O:27])=[CH:20][C:16]=2[C:17]([N:59]2[C@H:60]([CH2:68][OH:69])[CH2:61][C:62]3[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:58]2)=[O:18])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Reactant: OC[C@@H]1Cc2ccccc2CN1
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Yield: 71.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(3-(butyl(3,4-dichlorobenzyl)carbamoyl)-4-chloro-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy)naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 186B, 12 mg, 0.014 mmol) and (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (Aldrich, 9 mg, 0.056 mmol) were converted to the title compound (10 mg, 70%). 1H NMR (CD3OD, mixture of amide rotamers) δ 9.23-9.09 (m, 1H), 8.24 (dd, J=1.7, 8.0 Hz, 0.5H), 8.10-7.94 (m, 3.5H), 7.76-7.59 (m, 3H), 7.53-7.29 (m, 1.5H), 7.27-6.80 (m, 6H), 6.68 (d, J=7.5 Hz, 0.5H), 5.27-5.04 (m, 1H), 4.75-4.59 (m, 3H), 4.54-2.44 (m, 18H), 2.39-2.26 (m, 3H), 2.25-2.06 (m, 1H), 1.65-0.81 (m, 5.5H), 0.75-0.65 (m, 1H), 0.61-0.51 (m, 0.5H); MS(ESI+) m/z 1005.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:20][CH2:21][C:22]1[C:27]([N:28]2[CH2:39][CH2:38][N:37]3[C:30](=[CH:31][C:32]4[CH2:33][C:34]([CH3:41])([CH3:40])[CH2:35][C:36]=43)[C:29]2=[O:42])=[CH:26][C:25]([F:43])=[CH:24][C:23]=1B1OC(C)(C)C(C)(C)O1)(=O)C.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.C(OCC)C.O.C(OCC)(=O)C>[F:43][C:25]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:22]([CH2:21][OH:20])=[C:27]([N:28]2[CH2:39][CH2:38][N:37]3[C:30](=[CH:31][C:32]4[CH2:33][C:34]([CH3:40])([CH3:41])[CH2:35][C:36]=43)[C:29]2=[O:42])[CH:26]=1
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: Cc1cc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)n[nH]1
Temperature: 130 °C
Yield: 18.8 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 112a (150 mg, 0.5 mmol), 230a (350 mg, 0.7 mmol), 1,2-dimethoxyethane (6.4 mL) and 1M aqueous sodium carbonate (1.6 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (31 mg, 0.03 mmol) was added. The mixture was heated in microwave to 130° C. for 15 min. After this time, ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of methylene chloride-60:35:5 methylene chloride:diethyl ether:methanol to afford a 16% yield (50 mg) of 276a.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8](=[O:15])[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[Br:18]Br>C(Cl)Cl>[Br:18][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=1)[C:8](=[O:15])[C:9]([CH3:13])([CH3:14])[CH2:10][CH2:11][Cl:12]
Reactant: BrBr
Reactant: CC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
136 g (0.5 mol) of 1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-2-pentanone are dissolved in 1000 ml of methylene chloride. 79.9 g (1 mol) of bromine are added dropwise at room temperature such that the solution is always decolorized. The reaction mixture is then subsequently stirred at room temperature for 1 hour and is concentrated by distilling off the solvent. A quantitative yield, that is to say 177 g, of 1-bromo-1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-2-pentanone is obtained, and is further reacted directly. ##STR29##
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:3]([N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][N:21]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=[C:9]([Cl:8])[C:18]=3[N:19]=[CH:20]2)[CH2:25][CH2:26]1)(=[O:5])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1nc2ccccc2c2c1ncn2CCC1CCNCC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(CCn2cnc3c(Cl)nc4ccccc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 0.60 g of 4-chloro-1-[2-(4-piperidyl)ethyl]-1H-imidazo-[4,5-c]quinoline trifluoroacetate in 4 ml of pyridine, 2 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated. The residue was added with isopropanol and diisopropyl ether, and the precipitated crystals were collected by filtration, and washed with diisopropyl ether to give 0.45 g of colorless crystals. Recrystallization from a mixture of methylene chloride and diisopropyl ether gave colorless crystals having the melting point of from 183 to 186.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3C=2C[N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.[NH2:50]C1C(C(NC)=O)=NC(C2C=NN(CCCO)C=2)=CC=1>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[N:50]=[C:14]([C:15](=[O:20])[NH:16][CH3:19])[C:13]([NH:21][C:22]3[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[CH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 68 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 3-amino-6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 6C, 220.0 mg, 0.7991 mmol) to afford 337 mg of the title compound (68%). 1H NMR (400 MHz, CDCl3) δ 12.19 (s, 1H), 9.04 (d, J=9.1 Hz, 1H), 8.36-8.44 (m, 2H), 8.21 (s, 1H), 8.08 (s, 1H), 8.04 (br. s., 1H), 7.63 (d, J=8.8 Hz, 1H), 7.52 (s, 1H), 6.95 (td, J=2.3, 8 Hz, 1H), 6.86 (t, J=1.9 Hz, 1H), 4.40 (t, J=6.2 Hz, 2H), 3.97-4.11 (m, 4H), 3.91 (s, 3H), 3.65 (q, J=5.3 Hz, 2H), 3.18 (d, J=21.1 Hz, 2H), 3.09 (d, J=5.1 Hz, 3H), 2.11 (quin, J=5.9 Hz, 2H), 1.26 (t, J=7.1 Hz, 6H) [OH proton obscured]. MS (ES+): m/z 693.75 [M+H]+. UPLC: tR=1.24 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([F:29])[CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 521.4(M+H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:14][C:15]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[C:24]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([CH2:46][C:47]([O:49][CH3:50])=[O:48])=[CH:42][C:41]=3[CH2:51][CH3:52])=[CH:36][CH:35]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[CH2:13].[CH3:53]I.[Na+].[Cl-]>O1CCCC1>[CH2:11]([O:14][C:15]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:25]=[C:24]([CH2:32][O:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:45]=[CH:44][C:43]([CH:46]([C:47]([O:49][CH3:50])=[O:48])[CH3:53])=[CH:42][C:41]=3[CH2:51][CH3:52])=[CH:38][CH:39]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[CH2:13]
Reactant: C=CCOc1c(C(F)(F)F)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3CC)cc2)c1C(=O)OC(C)(C)C
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOc1c(C(F)(F)F)ccc(COc2ccc(-c3ccc(C(C)C(=O)OC)cc3CC)cc2)c1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
After lithium bis(trimethylsilyl)amide (1M n-hexane solution, 0.32 ml, 0.32 mmol) was added to a solution of tert-butyl 2-(allyloxy)-6-[({2′-ethyl-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (105 mg, 0.19 mmol) in tetrahydrofuran (2 ml) at −78° C. under nitrogen atmosphere and the mixture was stirred for 0.5 hours, methyl iodide (30 μl, 0.48 mmol) was added thereto and the mixture was stirred for 1 hour. After a saturated aqueous NaCl solution was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: hexane/ethyl acetate=5/1) to give tert-butyl 2-(allyloxy)-6-[({2′-ethyl-4′-[1-(methoxycarbonyl)ethyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate as an oil (30 mg, yield: 27%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15]>C(O)C.C(O)(=O)C>[C:18]([O:17][C:13]([NH:14][N:15]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC2=NNC(=O)OC(C)(C)C

Procedure:
A solution of 5-methoxyindan-1-one (5.46 g) and tert-butyl carbazate (4.45 g) in ethanol (100 ml) and glacial acetic acid (1 drop) was stirred and boiled under reflux for 2 hours. The volume was reduced by half under reduced pressure and the solid which crystallized was collected by filtration to give 5-methoxyindan-1-one tert-butyloxycarbonylhydrazone.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[CH3:35][NH2:36].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:35][NH:36][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])(=[O:28])=[O:29])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCOC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (25 mg, 0.055 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added methyl amine (0.15 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (13.2 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1%/o trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (9.0 mg, 36%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.CC1(C)C2C(=CC=CC=2Br)SCC1.C([Li])(C)(C)C.[C:32](=[O:34])=[O:33]>CCOCC.CCCCC>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([C:32]([OH:34])=[O:33])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2cc(Br)ccc21
Reactant: O=C=O
Agent: CC1(C)CCSc2cccc(Br)c21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC1(C)CCSc2cc(C(=O)O)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.0 g (3.9 mmol) of the 4,4-dimethyl-7-bromothiochroman and 4,4-dimethyl-5-bromothiochroman mixture in 12 ml of anhydrous ether at -78° C. was added, dropwise under nitrogen, 6.0 ml of 1.7M (10.2 mmol) tert-butyllithium in pentane. The reaction mixture was stirred at -78° C. for 1 hour and then a rapid stream of dry carbon dioxide gas was passed through it with vigorous stirring. The reaction mixture was warmed to -20° C. and then quenched with water. The mixture was warmed to room temperature and its pH adjusted to 10 with ammonium hydroxide. The basic solution was washed with 2×10 ml ether and then acidified with dilute HCl. The mixture was extracted with 3×20 ml of ether. The ether extracts were combined and washed with water and saturated NaCl solution and then dried (MgSO4). The ether solution was filtered and the solvent removed in-vacuo. The residue was recrystallized from a mixture of ethyl acetate and hexane to give the captioned compound as a white solid. PMR (CDCl3): δ1.33 (6H, s), 1.96 (2H, s), 3.04 (2H, m), 7.42 (1H, d, J~8.1 Hz), 7.66 (1H, dd, J~8.1 Hz, 1.8 Hz), 7.77 (1H, d, J~1.8 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:5]=[CH:4][N:3]=1.C(C1C(Cl)=NC=NC=1CBr)CC.FC1C(C2NC=CN=2)=NC=CC=1.O.[NH2:49][NH2:50]>CCO>[F:23][C:22]1[C:17]([C:13]2[N:12]([CH2:11][C:6]3[N:5]=[CH:4][N:3]=[C:2]([NH:49][NH2:50])[C:7]=3[CH2:8][CH2:9][CH3:10])[CH:16]=[CH:15][N:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Reactant: NN
Agent: CCCc1c(Cl)ncnc1CBr
Agent: Fc1cccnc1-c1ncc[nH]1
Solvent: O
Solvent: CCO
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Temperature: 70 °C

Procedure:
A mixture of 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (prepared from 5-propyl-6-bromomethyl-4-chloro-pyrimidine and 3-fluoro-2-(1H-imidazol-2-yl)-pyridine essentially as described in Example 1) (2.5 g, 7.5 mmol) and hydrazine monohydrate (1.37 g, 27.4 mmol) in EtOH (15 mL) is heated in a sealed tube at 70° C. overnight. The solvent is removed in vacuo and the residue is triturated with ethyl acetate and ethyl ether. Filtration gives a white solid (131) which is used in the next step without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.