Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Brc1cccc(-c2ccco2)c1
Temperature: 45 °C
Reaction time: 19 h

Procedure:
1-Bromo-3-iodobenzene (3.0 g), tris(dibenzylideneacetone)dipalladium(0) (1.22 g), tributyl(furan-2-yl)tin (3.34 ml), and tri(o-tolyl)phosphine (807 mg) were dissolved in dioxane (30 ml), and the solution was stirred at room temperature for 20 hours, at 35° C. for 6 hours, at 45° C. for 19 hours, and at 55° C. for 5 hours and 30 minutes. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (NH-form, hexane) to obtain the title compound (1.40 g).
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].S(C1C=CC(C)=CC=1)(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:26][C:27]([F:30])([F:29])[F:28])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCC(F)(F)F)n1cnc(C(N)=O)c1
Temperature: 130 °C
Reaction time: 13 h
Yield: 54.5 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (10 mg), 2,2,2-trifluoroethyl tosylate (27.4 mg) and potassium carbonate (14.9 mg) in N,N-dimethylformamide (1 ml) was stirred at 130° C. for 13 hours. The mixture was taken up in ethylacetate, washed three times with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (10:1) to give a pale brown powder of 1-{(2S,3R)-2-hydroxy-5-[2-(2,2,2-trifluoroethoxy)phenyl]-3-pentyl}imidazole-4-carboxamide (7) (7.0 mg).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](N)=[O:16])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>CCOCC>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: ClCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
50.6 g of dry benzyl chloride in 200 ml of dry ether was treated with 10 g of magnesium. When the reaction was complete, 15.6 g of 4-chlorobenzamide was added in portions with stirring. When the addition was complete the mixture was stirred and refluxed for 65 hours. The cooled mixture then was poured onto 400 g of ice containing 40 g of concentrated sulphuric acid. Several extractions with ether yielded the crude product as a white solid. Recrystallization from methylated spirit gave white crystals of 4-chlorodeoxybenzoin, 1A, mp: 106°-106.5° C.
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:66])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:33]([O:60][CH3:61])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:58][CH3:59])[C@@H:43]([CH3:57])[C:44]([NH:46][C@H:47]([CH3:56])[C@@H:48]([OH:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.C(OCC)C.CCCCCCC>ClCCl.C(NCC)C>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:33]([O:60][CH3:61])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:58][CH3:59])[C@@H:43]([CH3:57])[C:44]([NH:46][C@H:47]([CH3:56])[C@@H:48]([OH:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])([CH3:66])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Yield: 51 %

Procedure:
According to general procedure A, from #111 (210 mg, 0.230 mmol) in dichloromethane (5 mL, 0.05 M) and diethylamine (5 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give a mixture of an oil and solid. Diethyl ether and heptane were added and the mixture was concentrated in vacuo, producing #112 (81 mg, 51%) as a white solid. LC-MS: m/z 690.4 [M+H+], retention time=1.10 minutes; HPLC (Protocol A): m/z 690.5 [M+H+], 712.4 [M+Na+], retention time=7.229 minutes (purity >90%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [7.62 (br d, J=8 Hz), 7.88 (br d, J=8 Hz), 8.07 (br d, J=9 Hz) and 8.11 (br d, J=9 Hz), total 2H], 7.15-7.34 (m, 5H), [5.34 (d, J=4 Hz) and 5.41 (d, J=5 Hz), total 1H], 3.18, 3.21, 3.23 and 3.25 (4 s, total 6H), 2.93 and 3.08 (2 br s, total 3H), 1.15, 1.18, 1.21 and 1.25 (4 s, total 6H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCc1ccc(OC)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CCC(=O)O)cc1OC1CCCC1
Reaction time: 16 h

Procedure:
To a stirring solution of 0.38 g (1.37 mmol) of methyl 3-(3-cyclopentoxy-4-methoxyphenyl)-n-propanoate in 20 mL of methanol was added dropwise 25 mL of a 1.0 N solution of potassium hydroxide in water over a 5 minute period. The mixture precipitated immediately, but returned to a solution after a 16 hour period at which time the solution was concentrated, diluted with 20 mL of water and neutralized to pH 1.0 with concentrated hydrochloric acid. The analytically pure white solid which formed was collected, washed several times with cold water, and dried in vacuo.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@H:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylamine (1.86 g, 6.51 mmol) in THF (20 ml) was added a solution of K2CO3 (1.80 g, 13.02 mmol) in H2O (15 ml). After 10 minutes, ethyl chloroformate (0.68 ml, 7.16 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (20 ml) and a solution of borane in THF (1M) was added (26 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (100 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 1.51 g (77%) of rac-[(3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[C:12]([O:14][CH3:15])=[O:13])[C@H:3]1[OH:24].[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C.C(Cl)(=O)OCC.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:17]([O:16][C:7]1[C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[C@@H:3]([OH:24])[C@H:2]([NH:1][C:25]([O:28][CH2:29][CH3:30])=[O:27])[CH2:11][CH2:10]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Reactant: CCOC(C)=O
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N[C@@H]1CCc2c(ccc(OCc3ccccc3)c2C(=O)OC)[C@H]1O

Procedure:
To a solution of 1.0 g. of trans-2-amino-6-benzyloxy-1-hydroxy-5-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene in 20 ml. of ethyl acetate are added 5 ml. of water and 400 mg. of ethyl chlorcarbonate, and with stirring at room temperature, 1.0 g. of anhydrous potassium carbonate is added in small portions. After one-hour stirring, the organic layer is recovered, washed with water, dried and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate-n-hexane to obtain trans-6-benzyloxy-2-ethoxycarbonylamino-1-hydroxy-5-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene as colorless needles melting at 147°-148° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[NH2:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)OC>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=3[N:25]=[CH:26]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CS(=O)(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)c(N)c1
Solvent: COC(OC)OC
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(Cc2ccccc2)CC1
Yield: 629.2 %

Procedure:
The crude material from step 2 (130 g) was stirred in 300 mL trimethylorthoformate containing 4-toluenesulphonic acid (8 g) at 90° C. for one hour, and collecting the methanol distillate. The reaction was cooled and filtered to give 108 g 1-(1-benzylpiperidin-4-yl)-5-methylsulphonyl-1H-benzimidazole as a brown solid.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[CH:22]=3)[C:16]=1[CH2:40][OH:41])[CH2:8]2)(C)(C)C.C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=C[C:48]=1[N:62]1CC2C(=CC=C(N(C)C)C=2)[C:63]1=O)(=O)C>>[CH3:48][N:62]([CH3:63])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:37]=[C:31]5[CH2:32][N:33]([CH3:36])[CH2:34][CH2:35][N:30]5[N:29]=4)[C:24](=[O:38])[N:23]([CH3:39])[CH:22]=3)[C:16]=1[CH2:40][OH:41])[CH2:8]2
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(N(C)C)ccc2C1=O
Reactant: CN1CCn2nc(Nc3cc(-c4cccc(N5Cc6cc(C(C)(C)C)ccc6C5=O)c4CO)cn(C)c3=O)cc2C1
Product: CN1CCn2nc(Nc3cc(-c4cccc(N5Cc6cc(N(C)C)ccc6C5=O)c4CO)cn(C)c3=O)cc2C1
Yield: 24 %

Procedure:
Using the same general procedure as described for the preparation of 103 reaction of 123e (450 mg, 1.00 mmol) with 103l (260 mg, 0.800 mmol) followed by a hydrolysis gave a 24% yield (130 mg) of 123 as a white solid: mp 148-150° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.98 (d, 1H, J=2.0 Hz), 7.56 (d, 1H, J=8.0 Hz), 7.47 (t, 1H, J=8.0 Hz), 7.39 (dd, 1H, J=8.0, 1.5 Hz), 7.33 (dd, 1H, J=8.0, 1.5 Hz), 7.24 (d, 1H, J=2.0 Hz), 6.88-6.85 (m, 2H), 5.88 (s, 1H), 4.89 (t, 1H, J=5.0 Hz), 4.85 (s, 2H), 4.31 (d, 2H, J=5.0 Hz), 3.91 (t, 2H, J=5.5 Hz), 3.59 (s, 3H), 3.48 (s, 2H), 3.04 (s, 6H), 2.77 (t, 2H, J=5.5 Hz), 2.34 (s, 3H); MS (ESI+) m/z 540.3 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][CH2:30][OH:31].C([O-])(O)=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]3[CH2:28][CH2:29][CH2:30][O:31][C:19]=23)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: O=C(NCC1CCN(Cc2ccccc2)CC1)c1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(NCC1CCN(Cc2ccccc2)CC1)c1c2n(c3ccccc13)CCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
A stirred suspension of N-[(1-benzyl-4-piperidyl)methyl] indole-3-carboxamide (17.5g, 0.050 mole) in chloroform (250 ml) was treated with 3-bromo-1-propanol (10.1 ml, 0.11 mole) and N-chlorosuccinimde (8.7g. 0.065 mole) at room temperature and a clear solution was obtained in 15 minutes. After 1 h the reaction mixture darkened in colour from pale yellow to orange and temperature rose to 38° C. After a further 1 h the reaction mixture was treated with 10% NaHCO3 solution and the chloroform layer separated, dried (Na2SO4) and concentrated in lvacuo to leave a yellow oil, which was chromatographed on silica gel eluting with 3% methanol/chloroform. The 2-(3-bromopropoxy)indole intermediate was dissolved in acetone (400 ml), treated with anhydrous potassium carbonate (11 g, 0.80 mole) and stirred at room temperature for 20 h. The reaction mixture was concentrated in vicuo and the residue treated with water (200 ml) and extracted with chloroform (2×250 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 5% methanol/chloroform to afford the title compound (E20) as a pale yellow oil (3.1 g, 15%). This was converted to its oxalate salt and crystallised from acetone as a white solid mp 169-170° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:1][CH:2]([CH2:5][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH2:3][OH:4]
Reactant: CC(CO)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(CO)COC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
Into a 50-mL 3-necked round-bottom flask was placed 2-methylpropane-1,3-diol (20 g, 221.92 mmol, 1.00 equiv) and 4-methylbenzene-1-sulfonic acid (11 mg, 0.06 mmol). Then 3,4-dihydro-2H-pyran (5 g, 59.44 mmol, 0.27 equiv) was added at 0° C. The resulting solution was stirred for 3 h at room temperature. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). Purification afforded 6.9 g (18%) of 2-methyl-3-(oxan-2-yloxy)propan-1-ol as a light yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:42](O)(C(F)(F)F)=[O:43]>CN(C=O)C>[F:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH:42]=[O:43])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cc(F)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(C=O)CC3)cc2)cc1NCc1cc(F)ccc1F

Procedure:
Compound 4-(2,5-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 214) (70 mg, 0.15 mmol) was stirred in 4 mL DMF with DIEA (300 μL) at 120° C. in a sealed tube for two days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (46 mg). MS found for C25H25F2N5O2 as (M+H)+ 466.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.05 (1H, s), 7.97 (1H, s), 7.25 (2H, dt, J=8.8; 2.0 Hz), 7.08-6.98 (4H, m), 6.94 (1H, m), 5.74 (1H, s), 4.41 (2H, s), 4.38 (1H, m), 3.77 (1H, m), 3.17 (1H, m), 2.83 (1H, m), 2.72 (1H, m), 1.85 (2H, m), 1.53 (2H, m) ppm.
Reaction SMILES: C(N[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)(=O)C.[C:16](#[N:18])C.S(Cl)(Cl)=O.CC(O)C>C(OCC)(=O)C>[C:16]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10]1)#[N:18]
Reactant: CCOC(=O)N1CCC(NC(C)=O)CC1
Reactant: CC#N
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(C#N)CC1
Temperature: 0 °C

Procedure:
A mixture of 4-acetamido-N-ethoxycarbonylpiperidine (17.0 g) and acetonitrile (200 ml) was cooled to 0° C., and 15.5 g of thionyl chloride was added dropwise, under nitrogen, with stirring. The reaction mixture was allowed to warm to ambient temperature. To the reaction imixture was added 2-propanol (20 ml) and the mixture was heated under reflux for 1 hr. Ethyl acetate was added, the layers were separated, and the organic phase was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on a preparatory liquid chromatograph, eluting with 4:1-heptane-ethyl acetate. The appropriate fractions were collected and evaporated to give 15 g of residue. A 4-g sample of the residue was distilled to give 3.5 g (84.6%) of product, bp 130° C. (4 mm mercury).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:25]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[OH:26])[CH:14]=[CH:15][C:16]=3[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[C:1]12([C:11]3[CH:12]=[C:13]([C:25]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:26])[CH:14]=[CH:15][C:16]=3[O:17][Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:19])[CH3:20])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(O)c2cccnc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2cccnc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.17 h

Procedure:
[3-Adamantan-1-yl-4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-pyridin-3-yl-methanol (55 mg, 0.112 mmol) was dissolved in methylene chloride. The Dess Martin periodane (0.104 g, 0.224 mmol) was then added to the reaction mixture. The reaction was complete within 10 min and was then diluted with ether. The organic layer was washed with Na2S2O4 (2×30 mL) followed by NaHCO3 (2×30 mL) followed by brine (1×30 mL) The organic layers were combined, dried with Na2SO4 and then evaporated to give [3-adamantan-1-yl-4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-pyridin-3-yl-methanone, which was deprotected without further purification. The deprotection was carried out as described for Example 62, except the reaction was complete after 10 min. The product was purified by chromatography to give 17 mg of 3-adamantan-1-yl-4-hydroxy-phenyl)-pyridin-3-yl-methanone as a white solid. 1H NMR (400 MHz, methanol-d4/CDCl3): δ 8.81 (d, J=2.1 Hz, 1H), 8.68 (dd, J=5.0, 1.7 Hz, 1H), 8.07 (td, J=8.0, 2.0 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.52 (dd, J=5.0, 2.9 Hz, 1H), 7.48 (dd, J=8.6, 2.5 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 2.10 (d, J=2.9 Hz, 6H), 2.02 (s, 3H), 1.74 (t, J=2.8 Hz, 6H)
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[I:18]I>O>[I:18][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH:1]([CH3:3])[CH3:2])[C:8]([OH:10])=[O:9]
Reactant: II
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)c1ccc(C(=O)O)cc1I
Yield: 0.8 %

Procedure:
4-Isopropylbenzoic acid (4.26 g, 25.9 mmol), sulfuric acid (25 mL), and water (2 mL) was heated to 95° C. and iodine (14.42 g, 56.8 mmol) was slowly added portionwise. The reaction was maintained at this temperature for 48 h. The reaction was cooled, poured into ice and extracted with methylene chloride. The organic extracts were dried over sodium sulfate, filtered, concentrated and then purified by reverse phase HPLC (MeOH/water/TFA) to yield 3-iodo-4-isopropylbenzoic acid (60 mg).
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.Cl[C:23]1[N:28]=[C:27]([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[O:30])[C:26]([CH3:42])=[CH:25][C:24]=1[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=1.CC1(C)C(C)(C)OB([C:61]2[CH:65]=[CH:64][NH:63][N:62]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[CH3:42][C:26]1[C:27]([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[O:30])=[N:28][C:23]([C:61]2[CH:65]=[CH:64][NH:63][N:62]=2)=[C:24]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)[CH:25]=1
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cc[nH]n2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water at 120° C. to give the title compound as colorless solid. MS: 484.2 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: Cc1ccc(B(O)O)cc1
Product: COC(=O)c1c(O)c2ccc(-c3ccc(C)cc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-p-tolyl-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 4-methyl-phenylboronic acid under conditions analogous to Example 7(a). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.23 (s, 1H), 8.38 (d, J=8.7 Hz, 1H), 7.64-7.51 (m, 4H), 7.38-7.26 (m, 2H), 4.02 (s, 3H), 2.41 (s, 3H).