Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][C:18]3=[S:21])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32].N1C=CC=CC=1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:31]([NH:30][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=2[Cl:22])=[O:32])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][C:18]3=[S:21])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=S)NCC3)n1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(=S)NCC3)n1
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A suspension of 7-(3-t-butyl-5-amino-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-1(2H)-thione (0.150 g, 0.499 mmol) in THF (3 mL) was added to a solution of 2,3-dichlorophenyl isocyanate (0.141 g, 0.749 mmol), pyridine (0.061 mL, 0.059 g, 0.749 mmol) and THF (3 mL). The flask which contained the starting material was again rinsed with THF (4 mL) and the solution was added to the reaction flask. The resulting yellow suspension was briefly heated with a heat gun, causing the reaction mixture to become clear. After 18 h, the solution was concentrated and the residue was purified by column chromatography to yield 1-[3-t-butyl-1-(1-thioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea as a yellow solid (203 mg, 83% yield). 1H NMR (400 MHz, acetone-d6): δ 9.60 (brs, 1H), 8.66 (d, J=2.0 Hz, 1H), 8.61 (brs, 1H), 8.26 (dd, J=8.4, and 2.0 Hz, 1H), 8.17 (brs, 1H), 7.68 (dd, J=8.0, and 2.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.30 (t, J=8.2 Hz, 1H), 7.23 (dd, J=7.6, and 1.2 Hz, 1H), 6.48 (s, 1H), 3.62-3.58 (m, 2H), 3.07 (t, J=6.6 Hz, 2H), 1.33 (s, 9H); MS (ESI) m/z: 488.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)(=[O:9])=[O:8]>[Ni].CO>[NH2:17][C:13]1[CH:12]=[C:11]([CH2:10][S:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:9])=[O:8])[CH:16]=[CH:15][CH:14]=1
Reactant: COCCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: COCCCNS(=O)(=O)Cc1cccc(N)c1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
N-(3-Methoxy-propyl)-C-(3-nitro-phenyl)-methanesulfonamide (0.31 g, 1.08 mmol) was hydrogenated over Raney nickel (0.05 g) in methanol at 50° C. and 70 psi for 4 h. Then, the catalyst was filtered off, washed with warm methanol, and the combined filtrates were evaporated to give 0.14 g (50%) of C-(3-amino-phenyl)-N-(3-methoxy-propyl)-methanesulfonamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH2:25])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1.[CH:33]1([N:38]2[CH:42]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:40]=[N:39]2)[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([N:38]2[CH:42]=[C:41]([C:2]3[CH:3]=[C:4]4[N:10]=[CH:9][N:8]([C:11]5[CH:12]=[C:13]([NH:25][S:29]([CH:26]6[CH2:28][CH2:27]6)(=[O:31])=[O:30])[CH:14]=[C:15]([C:17]6[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=6[F:24])[CH:16]=5)[C:5]4=[N:6][CH:7]=3)[CH:40]=[N:39]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Reactant: CC1(C)OB(c2cnn(C3CCCC3)c2)OC1(C)C
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(C5CCCC5)c4)cnc32)c1)C1CC1
Yield: 27.86 %

Procedure:
The compound was prepared using the procedures of Example 334 starting from 5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (133 mg, 0.33 mmol) and using cyclopropanesulfonyl chloride (20 mg, 0.66 mmol, 2.0 eq.) and 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.115 g, 0.43 mmol, 2.0 eq.) to give the crude residue which was purified by preparative HPLC to give the product in 27.86% yield (34 mg). 1H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 8.96 (s, 1H), 8.76-8.75 (d, 1H), 8.45-8.42 (t, 2H), 8.06 (s, 1H), 8.00-7.99 (d, 1H), 7.78-7.70 (m, 2H), 7.49-7.43 (m, 2H), 7.31-7.26 (t, 1H), 4.74-4.70 (t, 1H), 2.84 (m, 1H), 2.14-2.08 (m, 2H), 2.00-1.96 (m, 2H), 1.84-1.81 (m, 2H), 1.69-1.65 (m, 2H), 1.09-1.02 (m, 4H); LC-MS (ESI): Calculated mass: 560.18; Observed mass: 561.2 [M+H]+ (rt: 1.70 min).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][C@@H:6]([OH:39])[C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:22]([CH3:38])[CH2:23][CH:24]=[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3]1.[C:40](OC(=O)C)(=[O:42])[CH3:41].[CH3:47][CH2:48][O:49]CC>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.O>[C:40]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][C@@H:6]([O:39][C:48](=[O:49])[CH3:47])[C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:22]([CH3:38])[CH2:23][CH:24]=[C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3]1)(=[O:42])[CH3:41]
Reactant: CCOCC
Reactant: CC(=O)OC(C)=O
Reactant: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](OC(C)=O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H](C(C)CC=C(c3ccccc3)c3ccccc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3α,7α,12α-trihydroxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-5β-androstane (2.65 g), acetic anhydride (2.4 ml), and 4-dimethylaminopyridine (0.061 g) in toluene (10 ml) is stirred at room temperature for about 30 minutes, diluted with ether and water and the layers are separated. The organic solution is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: [OH:1][C:2]([C:32]([F:35])([F:34])[F:33])([CH2:15][C:16]([C:19]1[CH:24]=[C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:22]=[CH:21][C:20]=1[O:30]C)([CH3:18])[CH3:17])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[CH:6]=[CH:5]1.B(Br)(Br)Br>C(Cl)Cl>[OH:1][C:2]([C:32]([F:35])([F:34])[F:33])([CH2:15][C:16]([C:19]1[CH:24]=[C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:22]=[CH:21][C:20]=1[OH:30])([CH3:18])[CH3:17])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[CH:6]=[CH:5]1
Reactant: COc1ccc(-c2ccsc2)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cc(-c2ccsc2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a solution of 1-[2-hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (32 mg, 0.06 mmol) in methylene chloride (1 mL) at 0° C. under an argon atmosphere was added BBr3 (0.06 mL, 0.6 mmol). The mixture was warmed to room temperature, stirred 3 hours, cooled to 0° C., stirred 2 days, and quenched with methanol (5 mL). The volatiles were removed in vacuo and the residue diluted with ethyl acetate (10 mL), washed with saturated aqueous sodium bicarbonate (5 mL), and brine (5 mL), and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue purified by reverse phase HPLC to afford 1-[2-hydroxy-4-(2-hydroxy-5-thiophen3-ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (20 mg, 68%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[C:29](OC(=O)C)(=[O:31])[CH3:30].[OH-].[Na+].Cl>O1CCCC1.O.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][O:23][C:29](=[O:31])[CH3:30])=[C:20]([Cl:24])[N:19]=[C:18]3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)O)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(COC(C)=O)n1Cc1ccc(-c2cccc(C(=O)O)c2)cc1

Procedure:
A solution of 0.10 g of 1-[(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5hydroxymethylimidazole, 5 mg of N,N-dimethylaminopyridine, 0.10 mL of acetic anhydride, and 0.14 mL of triethylamine in 8 mL of tetrahydrofuran was stirred for 4.5 hours at 25°. The reaction mixture was poured into water, and dilute aqueous sodium hydroxide was added until the pH of the solution remained in the range of pH 8-9. The solution was then acidified to pH 3.5 using 10% aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography on silica gel (elution: 0.5% i-propanol/chloroform) furnished 0.065 g of 1-[(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-acetoxymethylimidazole, m.p. 172°-173°; NMR (200 MHz, DMSO-d6): δ 8.17 (s, 1H); 7.93 (t, 1H); 7.61 (t, 1 H); 7.43 (A2M2, 4H); 5.32 (s, 1H); 4.99 (s, 1H); 2.60 (t, 2H); 1.76 (s, 3H); 1.53 (quint., 2H); 1.28 (sext., 2H); 0.82 (t, 3H).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1O)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Temperature: 100 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Ethyl 4-hydroxy-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-carboxylate (Preparation 3, 150 g, 515 mmol) was added portionwise to phosphorus oxychloride (450 mL, 4.92 mol) and the resulting mixture stirred at 100° C. for 1 hour and then cooled to room temperature. The volatiles were removed in vacuo, and the residue was carefully poured into a vigorously stirred ice/water mixture. Ethyl acetate (500 mL) was added to the mixture. The mixture was adjusted to pH 8, by addition of 10M aqueous sodium hydroxide solution. The layers were separated and the aqueous layer was further extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting oil was poured into a crystallisation dish, where it solidified on standing to give the title compound, 140.69 g, in an 88% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, 3 H), 1.86-1.89 (m, 4 H), 2.59 (s, 3 H), 2.82-2.84 (m, 2 H), 3.08-3.11 (m, 2 H), 4.46 (q, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:13][C:8]2([S:12][CH2:11][CH2:10][S:9]2)[CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[O:4].C(OCC)C.[BrH:29]>C(O)(=O)C>[BrH:29].[CH3:1][O:2][C:3]([C@@H:5]1[CH2:13][C:8]2([S:9][CH2:10][CH2:11][S:12]2)[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)SCCS2
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC2(CN1)SCCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 3.0 g of 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid methyl ester (3.0 g) in 20 ml of 20% hydrobromic acid in glacial acetic acid and stir the mixture at room temperature for two hours. Add the mixture dropwise to diethyl ether at 0°-5° to give 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid methyl ester hydrobromide, a brown solid m.g. 156°-158°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[CH2:16]=O.[Cl-:18].[CH3:19][NH2+:20][CH3:21]>Cl.C(O)C>[Cl-:18].[CH3:19][NH+:20]([CH2:16][CH2:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:21]
Reactant: C[NH2+]C
Reactant: C=O
Reactant: CC(=O)c1ccccc1-c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: C[NH+](C)CCC(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 10.1 g. of 2-acetyl-1,1'-biphenyl in 100 ml. of ethanol containing 7.6 g. of paraformaldehyde, 9.7 g. of dimethylaminium chloride and one drop of concentrated hydrochloric acid was heated to reflux and stirred for sixteen hours. After cooling the reaction mixture to room temperature, the solvent was removed by evaporation. The residue thus formed was crystallized from ethanol and diethyl ether to give 3.6 g of N,N-dimethyl-3-oxo-3-(1,1'-biphenyl-2-yl)propylaminium chloride. M.P. 130°-131° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](=O)[C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][NH:7][CH:6]=1)=[O:4].CN(C=O)C.S(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:10]([Cl:23])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)c1c[nH]cc(C(=O)OC)c1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(C(=O)OC)c1Cl
Yield: 41 %

Procedure:
A mixture of 16.38 g (77.6 mmol) of 4-oxo-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester (prepared according to the method described in S. Zupancic, Helerocycles; 2000; 2033-2042) and 0.5 ml of DMF in 150 ml of thionyl chloride is heated at reflux for 2 hours. Excess thionyl chloride is removed under vacuum and the residue is added to aqueous NaHCO3. and extracted in ethyl acetate. The phases are separated and the organic layer is dried and evaporated. The residue is washed with aqueous K2CO3 and water, and dried. There is obtained 7.35 g (41% yield) of white solid (M+1=230).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C[O:32][C:33]1[CH:38]=[N:37][CH:36]=[C:35]([Sn](CCCC)(CCCC)CCCC)[N:34]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:35]3[CH:36]=[N:37][CH:38]=[C:33]([OH:32])[N:34]=3)[C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(OC)n1
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(O)n2)c2c(N)ncnc21
Yield: 22.2 %

Procedure:
The title compound was made in a similar way as that of the compound of example 89 from 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 120 mg, 0.236 mmol) and 2-methoxy-6-(tributylstannyl)pyrazine (188 mg, 0.471 mmol) to give the title compound (25 mg, 36.8%) as a white powder.
Reaction SMILES: [ClH:1].[O:2]([CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:14]([O:16]CCCCC)=O>C(O)(=O)C>[Cl:1][C:11]([CH3:13])([CH:10]([N:14]=[O:16])[CH2:9][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:12]
Reactant: CCCCCON=O
Reactant: Cl
Reactant: CC(C)=CCOc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(Cl)C(COc1ccccc1)N=O
Reaction time: 1 h
Yield: 22 %

Procedure:
Concentrated hydrochloric acid (8.1 ml) was added dropwise over 10 minutes to a mixture of 1-(p-methoxy)phenoxy-3-methylbut-2-ene (VI ; R = CH2OC6H4 .OCH3, R1 = R2 = CH3) (16.05 g) and amyl nitrite (12.1 ml) in glacial acetic acid (16.2 ml) at -5° to 0° (ice-salt bath). After a further 1 hour at -5° to 0°, the mixture was filtered. The solid so obtained was washed with acetone and recrystallised from acetone to give the nitrosochloride (V) (4.87 g, yield 22%) as pale yellow crystals, m.p. 123° (decomp.).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:30]2[CH:29]=[N:28][CH:27]=[N:32][CH:31]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(-c2cncnc2)c1
Yield: 70.6 %

Procedure:
To the solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromopyridine (670 mg, 1.88 mmol) in toluene (10 mL) was added tetrekis(triphenylphosphine)palladium (70 mg, 1%) and tributyl(pyrimidinyl)tin (0.84 g, 2.26 mmol). The mixture was stirred and heated under reflux for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 2:1) to afford an oil (473 mg, 71%): 1H NMR (CDCl3, 300 MHz) δ 1.44 (s, 9H), 1.88-2.00 (m, 2H), 2.05 (m, 1H), 3.30-3.48 (m, 2H), 4.04 (m, 1H), 4.10-4.22 (m, 2H), 4.30 (m, H), 7.64 (s, 1H), 8.42 (d, 1H, J=2.5 Hz), 8.45 (s, 1H), 8.98 (br s, 1H), 9.01 (s, 1H), 9.27 (s, 1H); MS (CI/NH3) m/z 357 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1(c2ccc(O)cc2)CC1)OCc1ccccc1
Reactant: ClCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(NC1(c2ccc(OCCCN3CCCCC3)cc2)CC1)OCc1ccccc1

Procedure:
{1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-cyclopropyl}-carbamic acid benzyl ester is prepared from [1-(4-Hydroxy-phenyl)-cyclopropyl]-carbamic acid benzyl ester (1.21 g, 4.28 mmol), Cs2CO3 (2.78 g, 8.55 mmol), KI (71 mg, 0.43 mmol), and N-(3-chloropropyl)piperidine (0.86 g, 5.34 mmol) in dioxane (50 mL) in a manner substantially analogous to Procedure A to give the product((1.16 g, 66%). MS (ES+) 409.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH:16]([OH:18])[CH3:17])=[CH:10][CH:9]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([OH:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC(O)/C=C/c1ccc(-c2ccccc2F)cc1
Solvent: CCOC(C)=O
Product: CC(O)CCc1ccc(-c2ccccc2F)cc1

Procedure:
24.5 Gm (0.101 mol) of (E)-4-(2'-fluoro-4-biphenylyl)-3-butene-2-ol, dissolved in 300 ml of ethyl acetate, were hydrogenated at room temperature at a hydrogen pressure of 3 atmospheres in the presence of 8.5 gm of Raney-nickel until hydrogen absorption was complete. The catalyst was filtered off, the filtrate was evaporated in vacuo, and the residue was recrystallized twice from cyclohexane/petroleum ether (ratio by volume: 1:1). Yield: 15.0 gm (61% of theory) of colorless crystals, m.p. 59°-60°C.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[N:45]1([CH2:50][C:51]2[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1.N[C:59]1C=CC=C[CH:60]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:55][C:54]5[CH:56]=[CH:57][C:51]([CH2:50][N:45]6[CH2:49][CH2:48][CH2:47][CH2:46]6)=[CH:52][CH:53]=5)=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:59][CH2:60]1)[CH2:5][O:12][CH2:9]2
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccccc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4ccc(CN5CCCC5)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(pyrrolidin-1-ylmethyl)aniline as the aniline component. (52%, MS=553.5 (M+H))
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([Cl:9])Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([Mg]Cl)([CH3:18])[CH3:17]>C1COCC1>[C:10]1([Si:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:16]([CH3:18])[CH3:17])[Cl:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[Mg]Cl
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)[Si](Cl)(c1ccccc1)c1ccccc1

Procedure:
Into 200 ml of dry THF was dissolved 160 g (0.63 mole) of diphenyldichlorosilane. To this was added dropwise 450 ml (0.90 mole) of a 2.0 M solution of isopropylmagnesium chloride in THF at a room temperature over 20 minutes. A mildly ethothermic reaction was observed. After the conclusion of the dropwise addition, the reaction mixture was refluxed for 3 days. The formed salt and the solvent were removed from the reaction mixture. The residue was distilled under a reduced pressure to give 130 g of a colorless clear liquid (b.p. 116° to 118° C./0.22 Torr).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH:4]=[CH:3]1.[C:18](Cl)(=[O:22])[C:19]([Cl:21])=[O:20].C(Cl)Cl>CCOCC>[F:16][C:13]([F:14])([F:15])[C:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:18](=[O:22])[C:19]([Cl:21])=[O:20])=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)=[O:17]
Reactant: Cn1ccc2ccc(NC(=O)C(F)(F)F)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(NC(=O)C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
200 mg of 1-methyl-6-trifluoroacetylaminoindole was taken into 5 mL ether and cooled to 0° C. It was treated with 0.485 mL 2.0 M oxalyl chloride/methylene dichloride and stirred at 0° C. for 2 h. The yellow crystals were collected and washed with ether and dried in vacuo to yield 240 mg of (6-trifluoroacetylamino-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[CH3:39][C:40]1[O:44][C:43]([CH2:45][NH2:46])=[N:42][N:41]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:31])[F:30])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:46][CH2:45][C:43]1[O:44][C:40]([CH3:39])=[N:41][N:42]=1)=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1nnc(CN)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)o1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 35 mg, 0.081 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.054 mL, 0.487 mmol), (5-methyl-1,3,4-oxadiazol-2-yl)methanamine (16.52 mg, 0.146 mmol), and BOP (64.6 mg, 0.146 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.5 min) to give single enantiomer 2-hydroxy-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15.1 mg, 0.027 mmol, 33.7% yield): LCMS=527.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.24 (2 H, m), 7.66-7.78 (4 H, m), 7.54-7.66 (3 H, m), 5.21 (1 H, s), 4.63 (2 H, d, J=3.30 Hz), 2.49 (3 H, s). HPLC Peak RT=9.2 min (Analytical Method C).