Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH:9]([N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH3:28])[CH3:10])[CH3:7].Br[CH2:30][C:31]1[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=1)[O:34][Si](C)(C)C(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCC.C1COCC1>[CH2:6]([O:8][CH:9]([N:11]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[CH2:28][CH2:30][C:31]1[CH:32]=[C:33]([OH:34])[CH:42]=[CH:43][CH:44]=1)[CH3:10])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Reactant: CCOC(C)n1c(C)nc(-c2ccccc2)c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C)n1c(CCc2cccc(O)c2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
n-Butyllithium (3.89 g, 61mmol) in hexane (24.31 mL) was added dropwise to a stirred solution of 1-(1-ethoxyethyl)-2-methyl-4,5-diphenyl-1H-imidazole (l5.50 g, 51 mmol) in dry THF (300 mL) maintained at -78° C. under an atmosphere of nitrogen. The mixture was stirred for 45 minutes and [3-(bromomethyl)-phenoxy]dimethyl(1,1-dimethylethyl)silane (l6.77 g, 50 mmol) added dropwise. After 10 minutes, the mixture was poured onto water, extracted with CH2Cl2, the extracts combined and dried over sodium sulfate. Evaporation of the solvent left an oil which was dissolved in THF (75 mL) and a solution of tetra-n-butylammonium fluoride (l7.22 g, 66mol) in THF (65 mL) added. The solution was stirred at room temperature for 30 minutes, the solvent evaporated and the residue diluted with water. After addition of 2N HCl solution (about 20 mL) to pH=5, the mixture was extracted with CH2Cl 2 The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residual material chromatographed on a column of silica gel. Elution with a mixture of diethyl ether and hexanes (1.0 gave 3-[2-[1-(1-ethoxyethyl)-4,5-diphenyl-1H-imidazol-2-yl]ethyl]-phenol (8.l8 g, 39%), mp 165.5°-167° C. after recrystallization from a mixture of CH2Cl2 and hexanes.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].Cl[C:26]1[N:31]=[C:30]([C:32]2[CH:33]=[C:34]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:37]=2)[N:29]=[C:28]([C:50]2[CH:51]=[C:52]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH:53]=[C:54]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:55]=2)[N:27]=1>CN(C)C=O>[C:62]1([C:52]2[CH:51]=[C:50]([C:28]3[N:29]=[C:30]([C:32]4[CH:37]=[C:36]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:35]=[C:34]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:33]=4)[N:31]=[C:26]([N:13]4[C:12]5[CH:11]=[C:10]6[C:2]([CH3:22])([CH3:1])[C:3]7[C:8]([C:9]6=[CH:21][C:20]=5[C:19]5[C:14]4=[CH:15][CH:16]=[CH:17][CH:18]=5)=[CH:7][CH:6]=[CH:5][CH:4]=7)[N:27]=3)[CH:55]=[C:54]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH:53]=2)[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Reactant: Clc1nc(-c2cc(-c3ccccc3)cc(-c3ccccc3)c2)nc(-c2cc(-c3ccccc3)cc(-c3ccccc3)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4nc(-c5cc(-c6ccccc6)cc(-c6ccccc6)c5)nc(-c5cc(-c6ccccc6)cc(-c6ccccc6)c5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.3 g (40 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are dissolved in 285 ml of dimethylformamide under a protective-gas atmosphere, and 1.9 g of 60% NaH in mineral oil (19 mmol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-bis-[1,1′;3′,1″]terphenyl-5′-yl-1,3,5-triazine (25.1 g, 44 mmol) in 315 ml of dimethylformamide is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene. The yield is 23 g (28 mmol, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1c[nH]cn1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 82 %

Procedure:
As described for Example 40, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (100 mg, 0.41 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (123 mg, 82%) which was obtained as an off-white solid. MS: m/e=365.0 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:13]=[N:12][C:11]=3[NH:10][C:9]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:9]1[N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12][C:11]=2[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ncn(Cc3ccccc3)c2c(=O)n1Cc1ccccc1
Product: O=c1c2c(ncn2Cc2ccccc2)nc(Cl)n1Cc1ccccc1

Procedure:
Treat 1,7-bis(phenylmethyl)purin-2,6-dione with POCl3 in accordance with Preparative Example 4, to give the title compound, an off-white solid, EI MS: M+=350.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7](Cl)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:29][O:30][C:31]([CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH2:35][CH2:34]1)=[O:32]>CN(C=O)C>[CH3:29][O:30][C:31]([CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]([C:7]([C:6]2[C:5]([O:4][C:3]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:2]=3[Cl:1])=[N:13][CH:12]=[C:11]([F:14])[CH:10]=2)=[O:8])[CH2:35][CH2:34]1)=[O:32]
Reactant: O=C(Cl)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Reactant: COC(=O)C1CCNc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinoyl chloride (48.1 mg, 0.15 mmol, 1.0 equiv; Example 146, Step 1) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (97 mg, 128 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (31.6 mg, 0.165 mmol, 1.1 equiv; [CAS RN 68066-85-3]) and the reaction mixture stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 9.1 mg (13%) of the title compound as a light yellow solid. MS (ISP): 475.1 [M+H]+.
Reaction SMILES: [C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5].[CH2:27](O)[CH3:28]>>[CH2:27]([O:25][C:1](=[O:26])[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5])[CH3:28]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCO
Product: CCOC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
25 m mol of 5β-cholanic acid was heated in ethanol in the presence of sulfic acid, forming 23 m mol of 5β-cholanic acid ethyl ester. This product was reduced by using lithium aluminum hydride, into 20 m mol of 5β-cholane alcohol. This alcohol, 19 m mol, was subjected to tosylation and then treated with thiourea. The resultant product was treated with bromine water, whereby 10 m mol of 5β-cholanesulfonylbromide was obtained. This compound, 8 m mol, was made to react with 8.5 m mol of nitroaniline. The product of this reaction was subjected to hydrogenation, thus 6.1 m mol of preparing p-amino-5β-cholanesulfonylanilide. This anilide was reacted with cyanogen bromide, and the resultant product was treated with dichloro-dicyanobenzoquinone, thereby obtaining 1.2 m mol of N-5β-cholanesulfonyl-N'-cyano-p-quinonediimine, which is represented by the following formula: ##STR52##
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[N:33]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:31][C:32]1[N:33]=[C:34]([CH2:38][C:16]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14][N:13]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:18][CH2:17]2)[CH:35]=[CH:36][CH:37]=1
Reactant: BrCc1cccc(Br)n1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)C1(Cc2cccc(Br)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.855 ml of diisopropylamine in 15 ml of tetrahydrofuran was added 2.26 ml of a hexane solution containing 2.66 M n-butyllithium at 0° C., followed by stirring the reaction mixture at 0° C. for 30 minutes. After cooling down to −78° C., a solution of 1.54 g of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate in 5 ml of tetrahydrofuran was added to the reaction mixture, and the resultant mixture was stirred at −78° C. for 30 minutes. A solution of 1.00 g of 2-bromo-6-(bromomethyl)pyridine in 5 ml of tetrahydrofuran was added to the reaction mixture, followed by stirring the reaction mixture at −78° C. for 2 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, followed by extracting with ethyl acetate. The resulting ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1−2/1) to give the title compound as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]5[C:26]([C:49]([F:52])([F:51])[F:50])=[N:27][N:28](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:29]=5)[CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]5[C:26]([C:49]([F:52])([F:50])[F:51])=[N:27][NH:28][CH:29]=5)[CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(N1CCOCC1)N1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCOCC1)N1CCN(c2ccnc3ccc(-c4c[nH]nc4C(F)(F)F)cc23)CC1
Yield: 81.9 %

Procedure:
123 mg morpholino{4-[6-(3-trifluoromethyl-1-trityl-1H-pyrazolyl)-4-quinolyl]piperazin-1-yl}methanone obtained in Example 193 and 1.5 mL trifluoroacetic acid were reacted in the same manner as in Example 165, to give 66 mg of the title compound as a pale yellow amorphous.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].O1CCCC1.[H-].[Na+].[Cl:12][C:13]1[N:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1>O>[Cl:12][C:13]1[N:18]=[C:17]([O:4][CH2:3][CH2:2][F:1])[CH:16]=[CH:15][N:14]=1
Reactant: OCCF
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FCCOc1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
2-Fluoroethanol (0.30 mL, 4.95 mmol) was added to an anhydrous tetrahydrofuran (5 mL) solution containing sodium hydride (60% NaH, 200 mg, 4.95 mmol), and an anhydrous tetrahydrofuran (5 mL) solution having 2,4-dichloropyrimidine (104, 500 mg, 3.30 mmol) dissolved therein was slowly added. The reaction mixture was stirred for 30 minutes and water was added. Organic compounds were extracted with ethyl acetate. Then, the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give 2-chloro-4-(2-fluoroethoxy)pyrimidine (106a, 237 mg, 41%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[CH:18][C:17]=1[Cl:26])[OH:15]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][N:19]=[CH:18][C:17]=1[Cl:26])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Yield: 94.2 %

Procedure:
45 g of manganese dioxide was added to a toluene 220 ml solution of 15.9 g (40.6 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(3-chloro-5-trifluoromethyl-4-pyridyl)methanol obtained in step (b), followed by stirring under reflux by heating for 2 hours. The mixture was subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 14.9 g (yield 94%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-trifluoromethylpyridine (compound No. 102; m.p. 75-77° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:12][C:3]1[C:2]([NH:1][C:21]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Br:13])=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Nc1cc2ccccc2cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1cc2ccccc2cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 3-amino 2-hydroxy napthalene(0.320 g, 2 mmol) and 2-bromo phenyl isocyanate(0.40 g) by general Method B. It was purified by dilution of the with methylene chloride and precipitation with hexane(0.339, 47%).EI-MS m/z 357(M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[CH:36]([B-](F)(F)F)=[CH2:37].[K+].C(N(CC)CC)C>C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:36]([C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:25][CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1)=[CH2:37]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncc(Cl)n5)cc43)n2)CC1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Temperature: 105 °C
Reaction time: 20 h

Procedure:
A mixture of tert-butyl 4-[6-[6-(6-chloropyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperazine-1-carboxylate (493 mg, 1 mmol), potassium vinyltrifluoroborate (335 mg, 2.500 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride, DCM complex (55 mg, 0.07500 mmol) and triethylamine (0.63 ml, 4.500 mmol) in ethanol (9 mL) was degassed and heated in a sealed vial for 2 hours at 105° C. The mixture was left at room temperature for 20 hours. The precipitate was collected and washed with ethanol to give the crude material, 605 mg (99.8%). MS (ESI) m/z: 485.4 [M+H]+
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:18]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)([CH3:21])([CH3:20])[CH3:19]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([C:24]1[CH:29]=[CH:28][C:27]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:26][CH:25]=1)=[O:31])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Dimethyl malonate (4.24 g, 32.1 mmol), K3PO4 (18.57 g, 88.0 mmol), and tert-butyl-4-bromobenzoate (7.50 g, 29.2 mmol) were placed in a dry 500 mL flask under N2. Bis(tri-t-butylphosphine)palladium(0) (745 mg, 1.46 mmol) and toluene (100 mL) were added, and the slurry was degassed with N2 for 20 minutes. The reaction was subsequently stirred at 80° C. overnight. The slurry was cooled, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-25% EtOAc/hexanes) afforded dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.96 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 4.68 (s, 1H), 3.73 (s, 6H), 1.56 (s, 9H). MS: cal'd 331 (MNa+), exp 331 (MNa+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH:24]([CH:26]=[CH2:27])[O:23][C:10]2([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][C:34]=1[CH3:42])([CH3:31])[CH3:30].F[P-](F)(F)(F)(F)F.C[NH2+]C.C(N(CC)CC)C>C(O)C.CN(C=O)C>[CH2:1]([N:8]1[CH2:25][CH:24]([CH:26]=[CH2:27])[O:23][C:10]2([CH2:11][CH2:12][N:13]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([O:32][CH:29]([CH3:30])[CH3:31])=[C:34]([CH3:42])[CH:35]=3)=[O:39])[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: C[NH2+]C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To tert-butyl 8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (600 mg, 1.61 mmol) in ethanol (1 mL) was added HCl (4 mL of 4 M in dioxane, 16.11 mmol) and the mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo, then DMF (4 mL), 4-isopropoxy-3-methyl-benzoic acid (313 mg, 1.61 mmol) and dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (613 mg, 1.61 mmol) were added and the reaction mixture was stirred for 10 minutes. Triethylamine (898 μL, 6.44 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, diluted with DCM (5 mL), washed with 1 N aq. NaOH (2 mL) and brine (2 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0-100% EtOAc/hexane as eluent to give (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone as a pale yellow oil (715 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 7.20-7.14 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 5.83-5.74 (m, 1H), 5.34-5.26 (m, 1H), 5.15 (d, J=10.6 Hz, 1H), 4.59-4.50 (m, 1H), 4.33-4.14 (m, 2H), 3.59-3.14 (m, 7H), 2.79 (d, J=11.0 Hz, 1H), 2.56 (d, J=11.1 Hz, 1H), 2.19 (s, 3H), 1.91-1.80 (m, 2H), 1.69-1.39 (m, 2H), 1.34 (d, J=6.0 Hz, 6H); ESI-MS m/z calc. 448.6. found 449.5 (M+1)+; Retention time: 1.54 minutes (3 min run).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.I[C:12]1[N:13]=[C:14]([CH3:27])[NH:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN1C(=O)CCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:12]2[N:13]=[C:14]([CH3:27])[NH:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1nc(I)c(-c2ccc(S(C)(=O)=O)cc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1nc(Sc2ccc(Cl)cc2)c(-c2ccc(S(C)(=O)=O)cc2)[nH]1
Reaction time: 0.25 h

Procedure:
To NaH (60% in mineral oil, 0.12 g, 3.0 mmol) in NMP (10 mL) was added 4-chlorobenzenethiol (0.44 g, 3.0 mmol). After stirring for 15 min, the reaction mixture was added to the product of Step 3 (1.09 g, 3.0 mmol) and CuBr (0.65 g, 4.5 mmol) in NMP (10 mL) under argon. The resulting mixture was kept at 140° C. for 4 h. After cooling, the reaction mixture was partitioned between H2O and EtOAc. The organic layer was separated, filtered through a thin pad of silica gel, and the filtrate was dried over anhydrous Na2SO4, and concentrated. The residue was purified by chromatography on silica gel (DCM to EtOAc) to give 4-[(4-chlorophenyl)thio]-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-imidazole. LCMS: [M+1]+=379.0
Reaction SMILES: II.BrCCBr.[Mg].Br[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.[C:17]1(=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.[Cl-].[NH4+]>C(O)(=O)C.O1CCCC1>[CH3:16][C:11]1[CH:10]=[C:9]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH:18]=2)[CH:14]=[C:13]([CH3:15])[CH:12]=1
Reactant: O=C1CCc2ccccc21
Reactant: Cc1cc(C)cc(Br)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CC(=O)O
Product: Cc1cc(C)cc(C2=CCc3ccccc32)c1
Yield: 78.3 %

Procedure:
20 mg. of iodine and 0.2-0.3 ml. of 1,2-dibromoethane are added to a suspension of 5 g. (0.21 mole) of magnesium in 15 ml. of dry tetrahydrofuran stirred at 20°-25° C. under nitrogen. When the reaction commences and the color of iodine disappears, a solution of 38 g. (0.205 mole) of 1-bromo-3,5-dimethylbenzene in 150 ml. of dry tetrahydrofuran is added dropwise over a period of about 1 hour at a rate such that the reaction mixture gently refluxes, the reaction mixture is refluxed for 1 hour and cooled to 20°-25° C., a solution of 26 g. (0.197 mole) of 1-indanone in 150 ml. of dry tetrahydrofuran is added dropwise over a period of 30 minutes, and the reaction mixture is maintained at 20°-25° C. for 30 minutes, the reaction mixture being stirred under nitrogen throughout. The reaction mixture is poured into cold (0°- 5° C.) saturated ammonium chloride solution, and the mixture is extracted three times with ethyl acetate. The ethyl acetate extracts are combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a yellow oil (54 g.). The obtained oil is dissolved in 70 ml. of glacial acetic acid, and the reaction mixture is refluxed for 30 minutes and evaporated at reduced pressure to obtain a brown oil. The oil is subjected to a Kugelrohr distillation to obtain the product as a yellow oil (34 g. (79%)) (collected at a bath temperature of 115°-125° C. at 1 mm. Hg.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH:9]=[CH:13][N:14]([CH3:16])[CH3:15]
Reactant: CC(=O)c1ccccc1Cl
Reactant: COC(OC)N(C)C
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1ccccc1Cl

Procedure:
A mixture of 25 g. of o-chloroacetophenone and 25 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. Evaporation gives a thick red-brown oil which is dissolved in methylene chloride and this solution passed through a hydrous magnesium silicate column. Evaporation of solvent gives an oil which is then purified by bulb to bulb distillation.