Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16].C1CCCCC1.C([Li])CCC.[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>O1CCCC1>[Cl:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=1[F:28])[OH:32]
Reactant: O=Cc1ccc(F)cc1F
Reactant: Cc1nn(C)c(Br)c1-c1ccc(F)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1nn(C)c(C(O)c2ccc(F)cc2F)c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-4-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Synthesis Example 2, Step A) (0.25 g, 0.82 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL), and the mixture was cooled in a dry ice/acetone bath under a nitrogen atmosphere. A cyclohexane solution of n-butyllithium (2.0 M, 0.49 mL, 0.98 mmol) was added dropwise over 5 minutes. After 15 minutes, a solution of 2,4-difluorobenzaldehyde (0.09 mL, 0.82 mmol) in anhydrous tetrahydrofuran (3 mL) was added slowly dropwise, causing the dark red-colored solution to lighten to a yellow color. After 45 minutes, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (˜20 mL) and allowed to warm to ambient temperature. This mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous NH4Cl solution (25 mL) and with brine, dried over Na2SO4, and concentrated to leave a viscous residue. This residue was purified by column chromatography through silica gel eluted with a gradient of ethyl acetate in hexane (7% to 10%) to give the title product, a compound of the present invention, as a white semi-solid (109 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:23][N:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26]>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)[C:7](/[CH:10]=[C:30]2/[N:24]([CH3:23])[C:25](=[O:26])[NH:27][C:28]/2=[O:29])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN1CC(=O)NC1=O
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Product: CCCCc1ncc(/C=C2\C(=O)NC(=O)N2C)n1Cc1ccc(C(=O)O)cc1

Procedure:
This compound is prepared by a procedure similar to Example 1 except that the starting materials are the ester derivative, 2-butyl-1-(4-carbomethoxybenzyl)-5-formylimidazole, and 1-methylhydantoin. The crude mixed isomer products are purified and separated by silica gel column chromatography, eluting with 0.1:1.5:10 glacial acetic acid-methanol-chloroform. The "slow" moving material is the (E) isomer; tlc (0.1:2:10 acetic acid-methanol-chloroform system) 1 spot, Rf 0.5; mp 219°-221° C.; nmr (DMSO-d6), vinyl proton at δ 5.96 ppm; MS (CI) 383 (M39 +1).
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Yield: 98.6 %

Procedure:
To a mixed solution of 10 ml of 4N hydrochloric acid and 10 ml of acetic acid was added 4.10 g of ethyl 1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was stirred under reflux condition for 5 hours. After adding 20 ml of distilled water, the solution was allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 3.32 g of the title compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][NH:27]2.C(=O)(O)[O-].[Na+]>C(O)C>[CH:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][N:27]2[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1
Reactant: C1CC2CCC1CN2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2nc(N3CC4CCC3CC4)ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-6-nitroquinoline (5.0 g, 24 mmol, Example 1, Step B), 2-azabicyclo[2.2.2]octane p-toluenesulfonic acid salt (10.2 g, 36 mmol) and sodium bicarbonate (5.1 g, 60 mmol) were mixed in absolute ethanol (100 mL) and then heated at reflux for 24 h. The reaction mixture was cooled to r.t., and the solvent removed under vacuum. The solids were taken up in EtOAc (750 mL). The mixture was transferred to a separatory funnel washed with water (3×100 mL) then brine (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed under vacuum to afford the product as a yellow solid, MS: m/z 284 (MH+) which was used without further purification.
Reaction SMILES: CCCCC.C([Li])(C)(C)C.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[N:21]=[C:20]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=3)[N:19]=2)=[CH:14][CH:13]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[CH:47][CH:46]=1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:26][CH:25]=3)[N:23]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:45]4[CH:46]=[CH:47][C:48]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=5)=[CH:49][CH:50]=4)=[CH:17][CH:16]=3)[N:19]=2)=[CH:35][CH:36]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccccn2)cc1
Agent: [Pd]
Agent: [Li]C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccccn5)cc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Under a stream of argon, 3.5 ml of a pentane solution containing 5.2 mmol of tert-butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C., and 10 ml of tetrahydrofuran in which 0.61 g of 2-(4-bromophenyl)pyridine was dissolved was further added dropwise to this solution. After stirring at −78° C. for 30 minutes, 1.64 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 1.00 g portion of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine prepared in Reference Example 1 and 0.12 g of tetrakis(triphenylphosphine) palladium(0) were dissolved in 35 ml of tetrahydrofuran and added to this solution, followed by stirring under heating reflux for 13 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:dichloromethane=3:2 to 4:3) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4′-(2-pyridyl)biphenyl-4-yl]-1,3,5-triazine (1.00 g, yield 87%). Its melting point and glass transition temperature are shown in Table 4.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[O:8]=[C:9]1[NH:13][CH2:12][C@H:11]([C@H:14]([O:16][C:17]2[C:18]3[N:19]([N:35]=[CH:36][C:37]=3[C:38]#[N:39])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:22]=2)[CH3:15])[CH2:10]1.CCN(CC)CC.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:1]([N:32]1[CH2:31][CH2:30][N:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]3[N:22]=[C:17]([O:16][C@@H:14]([C@@H:11]4[CH2:10][C:9](=[O:8])[NH:13][CH2:12]4)[CH3:15])[C:18]4[N:19]([N:35]=[CH:36][C:37]=4[C:38]#[N:39])[CH:20]=3)=[CH:28][CH:27]=2)[CH2:34][CH2:33]1)(=[O:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cn2ncc(C#N)c12)[C@H]1CNC(=O)C1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(-c3cn4ncc(C#N)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Reaction time: 1.5 h

Procedure:
The crude TFA salt of 5.67 (0.107 mmol) was dissolved in DCM (2 mL) and was treated with Et3N (0.15 mL, 1.1 mmol) followed by acetic anhydride (13 μL, 0.13 mmol). After stirring for 1.5 h, the reaction mixture was partitioned between DCM and water, and the aqueous phase was extracted with DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated, and the concentrate was purified by silica gel (0-15% MeOH in DCM) to afford 6-(4-(4-acetylpiperazin-1-yl)phenyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile (5.68). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H28N7O3: 474.2; found: 474.3. 1H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.18 (s, 1H), 7.86-7.78 (m, 2H), 7.04-6.96 (m, 2H), 6.10 (s, 1H), 5.65-5.52 (m, 1H), 3.85-3.73 (m, 2H), 3.66 (dd, J=6.4, 4.0 Hz, 2H), 3.63-3.55 (m, 1H), 3.44 (dd, J=9.9, 6.7 Hz, 1H), 3.34-3.23 (m, 4H), 3.12-2.96 (m, 1H), 2.60 (dd, J=17.1, 9.2 Hz, 1H), 2.43 (dd, J=17.1, 8.0 Hz, 1H), 2.15 (s, 3H), 1.54 (d, J=6.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([C@@H:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)/[CH:13]=[CH:14]/[CH3:15])[C:9]([OH:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:29].CCCCCC>C1C=CC=CC=1>[C:1]([O:5][C:6]([C@@H:8]([C@@H:12]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=1)/[CH:13]=[CH:14]/[CH3:15])[C:9]([O:11][CH3:29])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C=C/[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](C(=O)O)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: C/C=C/[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](C(=O)OC)C(=O)OC(C)(C)C
Yield: 98 %

Procedure:
(2S,3S,E)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)hex-4-enoic acid (5.3 g, 14 mmol) was taken up in 70 mL of 3.5:1 benzene:MeOH. TMS diazomethane, 2M in hexane (7.8 mL, 16 mmol) was added slowly to the mixture. Bubbling ensued. Approximately 2 mL excess TMS diazomethane reagent was added, presumably due to loss of titer of the reagent. The bubbling was monitored, and the addition was stopped when the bubbling ceased. The solvent was removed under reduced pressure. The mixture was triturated twice with 50 mL of 10% ether:hexanes, affording (2S,3S,E)-methyl 2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)hex-4-enoate (5.4 g, 98% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (d, J=8.22 Hz, 2H) 7.34 (d, J=8.22 Hz, 2H) 5.75-5.59 (m, 2H) 4.92-4.84 (m, 1H) 4.70-4.63 (m, 1H) 3.78-3.72 (m, 1H) 3.68 (s, 3H) 1.72 (d, J=5.28 Hz, 3H) 1.37 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cu][C:16]#[N:17].CN1C(=O)CCC1>[NH4+].[OH-]>[CH:9]1([O:8][C:5]2[CH:4]=[CH:3][C:2]([C:16]#[N:17])=[N:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#C[Cu]
Reactant: Clc1ccc(OC2CCCCC2)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(OC2CCCCC2)cn1
Temperature: 180 °C
Yield: 57.1 %

Procedure:
Under a nitrogen atmosphere, add 6-chloro-3-cyclohexyloxy-pyridine (1.5 g, 7.1 mmol) and copper(I) cyanide (1.89 g, 21 mmol) to NMP (15 mL). Heat the mixture at 180° C. overnight. Cool the mixture to room temperature and add copper(I) cyanide (0.63 g, 7.1 mmol). Heat the mixture at 180° C. for 6 h. Cool the mixture to room temperature, dilute with 5N aqueous NH4OH and extract with DCM. Separate the layers and extract the aqueous phase with additional DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify the residue by chromatography on silica gel (500 g) eluting with hexane/EtOAc (20:1) to obtain the desired intermediate (820 mg, 57%). MS (ES+) m/z: 203 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[Br:14]Br>C(Cl)Cl>[Br:14][C:11]1[CH:12]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([OH:13])=[C:7]([CH:10]=1)[CH:8]=[O:9]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: BrBr
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)cc(C=O)c1O
Reaction time: 1 h

Procedure:
step 1—To a solution of 3-tert-butyl-2-hydroxybenzaldehyde (CASRN 24623-65-2, 5.00 g) DCM (20 mL) at 0° C. was added dropwise a solution of Br2 (1.45 mL) in DCM (15 mL) over a period of 30 min. After the addition was complete the reaction was stirred for 1 h before the organic volatiles were removed under reduced pressure to afford 7.23 g of 5-bromo-3-tert-butyl-2-hydroxybenzaldehyde (B-1b, R4=tert-Bu) as a light yellowish solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([C@@H:14]([NH:18][C:19]([C@H:21]([CH2:30][CH:31]=[CH2:32])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.I[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:36]([CH3:46])[CH:35]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([C@@H:14]([NH:18][C:19]([C@H:21]([CH2:30]/[CH:31]=[CH:32]/[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:36]([CH3:46])[CH:35]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cc(I)ccc1-c1ccccc1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](COC)c1ccccc1)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C/C=C/c1ccc(-c2ccccc2)c(C)c1)CC(=O)OC(C)(C)C)C(C)C)c1ccccc1
Yield: 66 %

Procedure:
According to the method of Preparation 15 a), tert-butyl (3R)-3-({[({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-(1S)-2-methyl-1-propyl]amino}carbonyl)hex-5-enoate (from c) above) (1.08 g, 2.42 mmol) was reacted with 4-iodo-2-methyl-1-phenylbenzene (Preparation 29)(1.07 g, 3.63 mmol) under palladium catalysis at reflux in acetonitrile for 18 h. After being cooled, the mixture was diluted with ethyl acetate (200 mL) and washed sequentially with 5% aqueous citric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate=30:1 to 3:1) to give tert-butyl (3R, 5E)-3-({[({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)-(1S)-2-methyl-1-propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate as a pale brown foam (980 mg, 66%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22].C(N(CC)CC)C.[OH-].[K+]>N1C=CC=CC=1.O>[CH:18]([C:3]1[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:5][C:6]2[C:11]([C:2]=1[N:26]([CH3:27])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:28])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CN(C)C1=C(C=O)C(c2ccccc2)Oc2ccccc21
Temperature: 2 °C
Reaction time: 60 h

Procedure:
A solution of 1.0 g 4-chloro-3-formyl-flav-3-ene and 0.68 g sarcosin ethyl ester hydrochloride in 10 ml pyridine is cooled at 10°-15° C. One adds 0.97 g triethylamine and warms at 55° C. for 60 hours. After cooling to 2° C., 0.74 ml 50% potassium hydroxide solution is added. After 10 minutes, one adds 37 ml water. The mixture is extracted with dichloromethane, dried over magnesium sulfate and evaporated. The residue is purified by column chromatography on silica gel using dichloromethane as eluant. The solid is crystallized in dichloromethane. Pure 3-formyl-4-(N-methyl-N-ethoxycarbonylmethylamino)flav-3-ene is obtained as yellow crystals; m.p. 158°-159° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.COCCOC>[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(-c2cccc(Br)c2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cccc(-c3ccccc3)c2)nc1
Yield: 91.6 %

Procedure:
2-(3-bromophenyl)-5-methylpyridine (14.0 g, 61 mmol), phenylboronic acid (8.8 g, 72 mmol), palladium (II) acetate (0.34 g, 1.5 mmol), triphenylphosphine (1.6 g, 6.1 mmol), and potassium carbonate (22.3 g, 162 mmol) were mixed with 120 mL of ethylene glycol dimethyl ether and 80 mL of water in a 500 mL round bottom flask equipped with a temperature probe, reflux condenser, and a magnetic stir bar. The solution was then heated at reflux under nitrogen for 16 hr. The cooled reaction mixture was placed in a separatory funnel, and 100 mL of ethyl acetate was added. The aqueous layer was discarded. The organic layer was extracted twice with a saturated solution of sodium chloride, dried over magnesium sulfate, and evaporated to dryness. After the removal of several impurities by vacuum distillation at 115° C., distillation at 190° C. gave 13.7 g of 2-biphenyl-3-yl-5-methylpyridine as a viscous light yellow liquid, which was further purified on a silica gel column with ethyl acetate/hexane to give 12.8 g (87.1% yield) of 2-biphenyl-3-yl-5-methylpyridine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34]CC4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[C:39](N)([CH2:42][CH3:43])([CH3:41])[CH3:40]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][C:39]([CH3:41])([CH3:40])[CH2:42][CH3:43])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: CCC(C)(C)N
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Product: CCC(C)(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using tert-amylamine instead of cyclopropylmethylamine. LC-MS: (M+1=545, obsd.=545).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12].[I:22]I.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.OS([O-])=O.[Na+]>O1CCOCC1.[OH-].[Na+].II.O.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[I:22][C:17]1[C:16]2[C:20](=[CH:21][C:13]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:14][CH:15]=2)[NH:19][N:18]=1
Reactant: II
Reactant: COCOc1ccc(-c2ccc3cn[nH]c3c2)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COCOc1ccc(-c2ccc3c(I)n[nH]c3c2)cc1OC
Yield: 77.6 %

Procedure:
In a 100-mL round-bottom flask under argon, 6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (1.19 g, 4.18 mmol, 1 equiv) was dissolved in dioxane (25 mL) and 3N NaOH (14 mL). This mixture was treated with iodine (117 g, 14.60 mmol, 1.10 equiv) added in ˜5 portions (˜10 min). Several (˜4) additional portions of iodine (50 mg each) were added until the reaction was complete as visualized by TLC (3:7 ethyl acetate/hexane). The mixture was acidified with 20% citric acid (25 mL) and 5% NaHSO3 (20 mL) was added. The mixture was partioned between ethyl acetate (150 mL) and water (100 mL). Te organic material was washed with saturated sodium bicarbonate (80 ml) and bine (50 mL) and were dried over sodium sulfate and concentrated under reduced pressure. Purification by crystallization from ethyl acetate (3 mL) then hexane (7 ml) gave pure 3-iodo-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole as a solid (1.33 g, 78 g): 1H NMR (CDCl3) δ 10.48 (bs, 1H), 7.62 (s, 1H), 7.57 (d, 1H, J=8.5 Hz), 7.47 (dd, 1H, J=1.3, 8.5 Hz), 7.18 (m, 3H), 5.29 (a, 2H), 3.99 (, 3H), 3.55 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:19][CH:20]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-n-Butyl-4-chloroimidazole-5-carboxaldehyde (6.34 g, 34.0 mmol, 1 eq.), 4-bromomethyl-2'-cyanobiphenyl (9.25 g, 34.0 mmol, 1 eq.), potassium carbonate (5.17 g, 37.4 mmol, 1.1 eq.) and DMF (100 mL) were mixed and stirred at 25° C. overnight. The solids were filtered and the filtrate evaporated. The residue was chromatographed over silica gel in 9:1 to 1:1 hexane/ethyl acetate and crystallized from methylcyclohexane/n-butyl chloride yielding 9.70 g of a solid; m.p. 96.0°-97.0° C. NMR (CDCl3): δ9.78 (s, 1H); 7.83-7.40 (m, 6H); 7.19 (d, 2H, J=9 Hz); 5.63 (s, 2H); 2.71 (t, 2H, J=7 Hz); 1.72 (t of t, 2H, J=7,7 Hz); 1.38 (t of q, 2H, J=7,7 Hz); 0.90 (t, 3 H, J=7 Hz). Anal. calcd. for C22H20ClN3O: C, 69.93; H, 5.34; N, 11.12. Found: C, 69.64; H, 5.37; N, 11.21.
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=2)=[S:45])=[CH:28][C:27]=1[F:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 83%).