Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1cccc(Br)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3cccc(Br)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 3-bromophenyl(2S)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: C([Li])CCC.[I-].[CH3:7][P+:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:27][C:28]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:29]=1[C:30](OC)=[O:31]>CCCCCC.C1COCC1>[OH:27][C:28]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:29]=1[C:30](=[O:31])[CH:7]=[P:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc(C)c1O
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
206.8 ml (330.9 mmol) of a 1.6 molar n-butyllithium solution in n-hexane are slowly added to 97.3 g (240.7 mmol) of methyltriphenylphosphonium iodide in 800 ml of absolute THF under argon. The mixture is stirred at room temperature for 3 h. Then 20.0 g (120.3 mmol) of methyl 2-hydroxy-3-methylbenzoate in 200 ml of absolute THF are added dropwise to the reaction mixture. The mixture is stirred at 60° C. for 3 h. After cooling to room temperature, the precipitated lithium iodide is filtered off. The filtrate is concentrated in vacuo, and the residue is recrystallized from methanol. 27 g (56% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[CH:32]=O)[CH:25]=[CH:24]1>ClCCCl.ClCCl>[CH2:1]([NH:4][CH2:32][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[NH:23][CH:24]=[CH:25]2)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=Cc1cccc2cc[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=CCNCc1cccc2cc[nH]c12
Temperature: 22 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
Add allylamine (2.50 mL, 33.1 mmol), acetic acid (3.4 mL), and sodium triacetoxyborohydride (5.85 g, 27.6 mmol) to a solution of indole-7-carboxaldehyde (4.00 g, 27.6 mmol) in 1,2-dichloroethane (120 mL) at 20-24° C. and stir the resulting mixture at 20-24° C. for 5 hours. Add an additional 1.5 g (7.1 mmol) of sodium triacetoxyborohydride and stir the resulting mixture overnight. Dilute the mixture with dichloromethane (300 mL), wash carefully with aqueous sodium bicarbonate (100 mL), and separate the layers. Wash the organic layer sequentially with water (100 mL) and saturated aqueous sodium chloride (100 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 10-30% ethyl acetate in hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as a light yellow oil (4.21 g, 82%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[C:19]([CH:21]1[NH:26][CH2:25][CH2:24][NH:23][CH2:22]1)#[CH:20]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:23]3[CH2:24][CH2:25][NH:26][CH:21]([C:19]#[CH:20])[CH2:22]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: C#CC1CNCCN1
Solvent: c1ccncc1
Product: C#CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1
Temperature: 100 °C
Yield: 13.2 %

Procedure:
A mixture of 1.12 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.95 g of 3-ethynylpiperazine and 15 ml of pyridine is heated at 100° C. in a pressure bottle for 3 hours, then cooled and evaporated. The residue is purified by silica gel flash chromatography, eluting with chloroform:methanol:water:triethylamine (9:0.5:0.02:0.02), giving 200 mg of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([CH3:22])=[C:13]([CH:15]=[N:16][NH:17][C:18](OC)=[O:19])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>C1(OC2C=CC=CC=2)C=CC=CC=1.CCOCC>[OH2:2].[CH3:22][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:14]2[C:13]=1[CH:15]=[N:16][NH:17][C:18]2=[O:19]
Reactant: COC(=O)NN=Cc1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1C
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(-c2ccc([N+](=O)[O-])cc2)n2c(=O)[nH]ncc12
Product: O
Reaction time: 1 h
Yield: 19.5 %

Procedure:
3-{[2-(p-nitrophenyl)-5-methyl-4-imidazolyl]methylene}carbazic acid, methyl ester (2.5 gm., 0.082 mole) is immersed in diphenyl ether (25 ml.) at 240° C. for 20 minutes, then stirred in an ice bath for 1 hour. The reaction mixture is diluted with ether and filtered to afford 2.2 gm. (0.008 mole) title product. The product is purified via an acetone soxhlet extraction to give a yellow solid, m.p. 295°-297° C.
Reaction SMILES: B(F)(F)F.[C:5]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:12]([OH:19])=[C:11]([CH:20](O)[CH:21]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:10]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:7])[CH3:6].C(=O)([O-])O.[Na+]>ClCCl>[C:5]([O:8][C:9]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][C:12]2[O:19][C:21]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:20][C:11]=2[C:10]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C(O)C(CCC(C)C)CCC(C)C)c1C(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(CCC(C)C)(CCC(C)C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
BF3 etherate (4.7 ml) was added dropwise to a solution of 4-acetoxy-3,5-di-tert-butyl-2-(2,2-diisoamyl-1-hydroxyethyl)-phenol (17.0 g) in dichloromethane under cooling with ice under a nitrogen atmosphere. After stirring the mixture overnight at room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added. After separating the organic layer, the aqueous layer was subjected to extraction with dichloromethane. The extract was combined with the organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off to afford 5-acetoxy-2,2-diisoamyl-4,6-di-tert-butyl-2,3-dihydrobenzofuran [15.5 g (yield, 95%)] as a colorless oil.
Reaction SMILES: [K].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH2:25].Cl>O1CCCC1>[OH:25][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h
Yield: 72 %

Procedure:
In a reaction container equipped with a stirring device, a thermometer and a tap funnel, 14.8 g of potassium tert-buthoxide and 50 ml of tetrahydrofuran are replaced. In nitrogen airstream, a solution in which 9.90 g of 2-hydroxy benzyl diethyl phosphonate and 5.44 g of 4-(N,N-bis(4-methylphenyl)amino)benzaldehyde are dissolved in tetrahydrofuran is slowly dropped to the reaction container at room temperature and the reaction is conducted for 2 hours. Next, while cooled down by water, water is added to the resultant and thereafter 2N hydrochloric acid is added to acidify the resultant. Furthermore, tetrahydrofuran is removed by an evaporator and the obtained coarse product is extracted by toluene. The toluene phase is washed with water, sodium hydrogen carbonate aqueous solution and saturated salt solution in this order. Magnesium sulfide is added to the resultant for dehydration. Subsequent to filtration, toluene is removed and an oily coarse product is obtained. Subsequent to column refinement by silica gel, the resultant is crystallized in hexane and 5.09 g (yield ratio: 72%) of 2-hydroxy-4′-(N,N-bis(4-methylphenyl)amino)stilbene is obtained. The melting point of the product is 136.0 to 138.0° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH3:43][S:44]([N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][C:19]2[N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]3=[C:17]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[CH:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)[N:18]=2)[CH2:29][CH2:30]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 0.17 h

Procedure:
1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolved in 2.00 mL of CH2Cl2 and charged with PS-DIEA (150.00 mg, 0.46 mmol). Methanesulfonyl chloride (10 μL, 0.47 equiv) was added in one portion. After 10 min., another 5 μL of methanesulfonyl chloride (0.24 equiv) was added. After another 10 min., another 2.1 μL of methanesulfonyl chloride (0.1 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with CH2Cl2. The crude product was purified by 5 g Jones silica gel (wetted with 100% CH2Cl2, dry loaded with silica, and eluted with 2% (7N NH3) in MeOH/CH2Cl2→5% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1 H, d, J=0.85), 8.29 (1 H, d, J=8.86), 8.20 (2 H, dd, J=1.51, J=1.12), 7.97 (2 H, m), 7.86 (1 H, dd, J=1.72, J=1.72), 7.53 (4 H, m), 7.24 (1 H, d, J=5.26), 7.08 (1 H, d, J=6.75), 3.85 (2 H, d, J=11.88), 2.98 (2 H, d, J=7.08), 2.68 (2 H, t), 2.20 (1 H, m), 1.94 (2 H, d, J=10.92), 1.50 (2 H, m); MS (ES+): m/z 513.02/514.03 (80/70) [MH+]; HPLC: tR=2.17 min (OpenLynx, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:63]1([NH:69][CH2:70][C@@H:71]2[CH2:75][CH2:74][CH2:73][NH:72]2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][C@H:71]1[CH2:70][NH:69][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3CNc3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-(phenylaminomethyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2.C([O-])([O-])=O.[Cs+].[Cs+].C(OC([N:37]1[CH2:42][CH2:41][O:40][CH:39]([CH2:43]Br)[CH2:38]1)=O)(C)(C)C>CC(N(C)C)=O.CCOCC.O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:43][CH:39]1[O:40][CH2:41][CH2:42][NH:37][CH2:38]1)[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2
Reactant: CC(C)(C)OC(=O)N1CCOC(CBr)C1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(OCC3CNCCO3)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.035 g, 0.11 mmol) in DMA (3.5 mL) was added Cs2CO3 (0.11 g, 0.33 mmol). The mixture stirred at room temperature for 1 hour before the addition of 2-bromomethylmorpholine-4-carboxylic acid tert-butyl ester (0.062 g, 0.22 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ether and water and the layers were separated. The aqueous layer was extracted with ether (3×) and the combined organic layers were washed with water and brine, and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and purified by reverse phase HPLC to afford the desired product. MS (APCI+) m/z 418 (M+1) detected; 1H NMR (400 mHz, CD3OD) δ 7.90 (s, 1H), 7.38 (s, 1H), 7.21 (s, 1H), 7.11 (m, 1H), 6.84 (m, 2H), 4.22 (m, 2H), 4.18 (d, 2H), 4.05 (m, 2H), 3.31 (m, 3H), 3.03 (m, 2H), 2.31 (m, 1H), 0.92 (d, 6H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2].F[C:23]1[CH:40]=CC(C(C2CCN(CC(O)=O)CC2)=O)=C[CH:24]=1.C1(CO)CCC1.[CH:47]1([CH2:51][O:52][C:53]2[CH:70]=[CH:69][C:56]([C:57]([CH:59]3[CH2:64][CH2:63][N:62]([CH2:65][C:66]([OH:68])=[O:67])[CH2:61][CH2:60]3)=[O:58])=[CH:55][CH:54]=2)[CH2:50][CH2:49][CH2:48]1.[NH2:71][CH2:72][C:73]1[NH:74][C:75](=[O:83])[C:76]2[CH2:82][O:81][CH2:80][CH2:79][C:77]=2[N:78]=1.C(O)(C(F)(F)F)=O>C(#N)C.O>[CH:47]1([CH2:51][O:52][C:53]2[CH:70]=[CH:69][C:56]([C:57]([CH:59]3[CH2:60][CH2:61][N:62]([CH2:65][C:66]([OH:68])=[O:67])[CH2:63][CH2:64]3)=[O:58])=[CH:55][CH:54]=2)[CH2:50][CH2:49][CH2:48]1.[CH:2]1([CH2:1][O:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:16][C:17]([NH:71][CH2:72][C:73]4[NH:74][C:75](=[O:83])[C:76]5[CH2:82][O:81][CH2:80][CH2:79][C:77]=5[N:78]=4)=[O:19])[CH2:14][CH2:15]3)=[O:9])=[CH:20][CH:21]=2)[CH2:40][CH2:23][CH2:24]1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: O=C(O)CN1CCC(C(=O)c2ccc(OCC3CCC3)cc2)CC1
Agent: OCC1CCC1
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCC(C(=O)c2ccc(OCC3CCC3)cc2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2

Procedure:
2-[4-(4-Cyclobutylmethoxy-benzoyl)-piperidin-1-yl]-acetic acid was prepared following the general procedures for the synthesis of 2-(4-(4-ethoxybenzoyl)piperidin-1-yl)acetic acid from 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid and cyclobutyl-methanol. The title compound (24.7 mg, 0.047 mmol) was prepared following the general procedure of Example 1 from 2-[4-(4-cyclobutylmethoxy-benzoyl)-piperidin-1-yl]-acetic acid and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one. MS (ESI) m/z 495.5 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.) t=1.53 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (d, J=2.53 Hz, 2H), 1.77-1.96 (m, 5H), 2.03-2.13 (m, 2H), 2.19-2.32 (m, 2H), 2.50 (br. s., 3H), 2.66-2.82 (m, 1H), 2.90-3.03 (m, 3H), 3.24-3.40 (m, 2H), 3.82 (t, J=5.56 Hz, 2H), 4.04 (d, J=6.57 Hz, 2H), 4.19 (d, J=5.56 Hz, 2H), 4.34 (s, 2H), 7.03 (d, J=9.09 Hz, 2H), 7.94 (d, J=8.59 Hz, 2H), 8.21 (t, J=5.81 Hz, 1H), 12.37 (br. s., 1H). HRMS calculated for C27H35N4O5: 495.2607 (M+H). found (ESI, [M+H]+): 495.2627.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29](Br)[CH3:30]>O1CCCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:30]
Reactant: c1cncc(Nc2cccnc2)c1
Reactant: CC(Br)c1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ccccc1Br)N(c1cccnc1)c1cccnc1
Reaction time: 0.5 h
Yield: 237.5 %

Procedure:
To a cooled solution (−78° C.) of N-pyridin-3-ylpyridin-3-amine (0.886 g, 5.23 mmol) in dry tetrahydrofuran (20 mL) was added LDA (3.8 mL of a 1.5 M solution, 5.75 mmol) to form a light yellow suspension. After stirring for 30 min, 1-bromo-2-(1-bromoethyl)benzene (3-1) (1.38 g, 5.23 mmol) was added in one portion. The reaction was stirred for 30 min at −78° C. then allowed to warmn to 0° C. and quenched with NH4Cl sat. solution (6 mL). The mixture was diluted with water and extracted with THF (2×20 mL), washed with brine and the organic layer was dried over Na2SO4. The solution was then filtered, concentrated, and dried under vacuum to give crude N-(1-(2-bromophenyl)ethyl)-N-(pyridin-3-yl)pyridin-3-amine (3-2) as a light brown solid (4.40 g): Analytical LCMS: (214 nm), 2.043 min. m/e (m+1): 356.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[O:6]C(C)C.C(Cl)(Cl)Cl.C[Si](Br)(C)C>C(O)(C)C.C1OC1C>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:6])[OH:10]
Reactant: CC(C)OP(=O)(CCCN)Cc1ccccc1
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: NCCCP(=O)(O)Cc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 5.7 g (0.0224 mol) of isopropyl 3-aminopropyl(benzyl)phosphinate in 50 ml of chloroform 9.91 ml (0.0922 mol) of trimethylsilylbromide are added raising the temperature to 44°. The reaction mixture is stirred at 50° for 4 hours and then at room temperature overnight. Removal of the chloroform and excess trimethylsilylbromide under reduced pressure yields an oil which is taken up in isopropanol and 20 ml of propylene oxide. After stirring for 10 minutes, a white solid precipitates. The solid is filtered off and dried over phosphorous pentoxide yielding 3-aminopropyl(benzyl)phosphinic acid, m.p. 278°-280°.
Reaction SMILES: Cl.[NH:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([OH:8])[CH2:3]1.[OH-].[Na+].CS(O[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:27]2[CH2:30][CH:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][CH:40]=4)=[C:33]([O:47][CH3:48])[CH:32]=3)[CH2:28]2)=[O:26])[CH:20]=1)(=O)=O.O>C(O)CC>[OH:8][C@@H:4]1[C@@H:5]([OH:7])[CH2:6][N:2]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:27]3[CH2:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]5[CH:40]=[CH:41][C:42]([CH2:45][CH3:46])=[CH:43][CH:44]=5)=[C:33]([O:47][CH3:48])[CH:32]=4)[CH2:30]3)=[O:26])[CH:20]=2)[CH2:3]1
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCN5C[C@H](O)[C@@H](O)C5)ccn4)C3)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
a solution of (3S,4S)-pyrrolidine-3,4-diol monohydrochloride (0.14 g) in 1-propanol (3.0 mL) was added aqueous 4 N NaOH (0.25 mL). The mixture was stirred at RT for 1 hr. To the mixture was added 2-(2-{3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-yloxy)ethyl methanesulfonate (0.1 g) prepared in Example 6 (1). The reaction mixture was stirred at 100° C. for 5 hr. Water was added to the reaction mixture. The precipitated solid was collected on a filter and dried to give the title compound (0.05 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[Na].[CH3:12][OH:13]>O>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:13][CH3:12])=[CH:4][N:3]=1
Reactant: COc1nc(Br)cnc1N
Reactant: CO
Agent: [Na]
Solvent: O
Product: COc1cnc(N)c(OC)n1

Procedure:
A mixture of 0.1 mole of 2-amino-3-methoxy-5-bromopyrazine and 0.1 mole of sodium in 160 ml. of anhydrous methanol is refluxed 5-10 hours and poured into water. The product is extracted with ether or chloroform and recrystallized from a suitable solvent such as ethanol to give 2-amino-3,5-dimethoxypyrazine.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29](C=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CS(CSC)=O.C[OH:41].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[O:54]1[CH2:58]C[CH2:56][CH2:55]1>O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:56][C:55]([O:54][CH3:58])=[O:41])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CO
Reactant: C1CCOC1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (3.0 g), methyl (methylsulfinyl)methyl sulfide (2.43 g), 40% benzyltrimethylammonium hydroxide methanol solution (5 mL), and tetrahydrofuran (50 mL) was heated under reflux for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the residue and 10% hydrogen chloride methanol solution (60 mL) was heated under reflux for 15 hr, and cooled to room temperature. To the reaction mixture was basified with saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.02 g, yield 64%) was obtained as a brown amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1-2:1, volume ratio). MS: 509 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[CH:31]([Mg]Cl)([CH3:33])[CH3:32]>C1COCC1>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:24][CH2:25][C:26]([OH:29])([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:28]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(C)[Mg]Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCC(=O)CC3)nncc2c1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCC(O)(C(C)C)CC3)nncc2c1
Temperature: -78 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(1-(4-oxopiperidin-1-yl)phthalazin-6-yl)benzamide (100 mg, 250 μmol) (Method A, followed by deprotection of the ketal) in 5 mL THF was stirred at −78° C. and treated with isopropylmagnesium chloride (250 μl, 499 μmol). The mixture was stirred at −78° C. warming to RT over 4 h. The mixture was quenched with 5 mL sat NH4Cl and extracted with dichloromethane (3×50 mL). The combined organics were dried over anhydrous Na2SO4, concentrated in vacuo and purified by silica gel chromatography eluting with 1-5% 2M ammonia methanol/dichloromethane to give the title compound. Found MS (ES+): 445(M+H)+.