Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[C:3]3[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Cc1cn2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn2cccc(OCc3ccc(F)cc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension under nitrogen of 15.0 g 8-hydroxy-2-methyl-imidazo[1,2-a]pyridine (from Step A) in 150 ml dimethylformamide maintained at 0°-5° C., was added 5.15 g 50% sodium hydride-oil dispersion in portions over 10 minutes. The mixturewas stirred in the cold 1/2 hr. and a brown solution resulted. 15.3 g 4-Fluorobenzyl chloride was added, and the solution was heated on a steam bath for 1/2 hr. The solution was poured into an ice bath and after 1/2 hour it became a brown solution. The solution was poured into 1.5 liters ice/water with vigorous stirring and the precipitate was separated by suction filtration, washed, and dried to give 8-(4-fluorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (m.p. 137° C.).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[C:34]=2[Cl:43])[CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=1)[CH3:6].COC(=O)CNC1C=CC=C(OCCCN(CC2C=CC=C(C(F)(F)F)C=2Cl)CC(C2C=CC=CC=2)C2C=CC=CC=2)C=1>>[ClH:43].[Cl:43][C:34]1[C:35]([C:39]([F:40])([F:41])[F:42])=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][N:17]([CH2:18][CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:16][CH2:15][CH2:14][O:13][C:9]1[CH:8]=[C:7]([N:5]([CH2:4][C:3]([OH:44])=[O:2])[CH3:6])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)CN(C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: COC(=O)CNc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Product: CN(CC(=O)O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Product: Cl

Procedure:
Following the procedure of Example 178 step (c) except [(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amino]-acetic acid methyl ester was used in step (c) instead of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}phenylamino)-acetic acid methyl ester the title compound was obtained as a solid, 65 mg (96%). MS (ES) m/e 611.2 (M+).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:25]([OH:27])=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:15]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH:43]1[CH2:47][CH2:46][C:45]2([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=3[C:49](=[O:56])[O:48]2)[CH2:44]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>[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3([C:25]([N:43]4[CH2:47][CH2:46][C@@:45]5([C:51]6[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=6[C:49](=[O:56])[O:48]5)[CH2:44]4)=[O:27])[CH2:23][CH2:24]3)=[CH:20][CH:21]=2)[N:15]=1
Reactant: Nc1nc(-c2ccc(C3(C(=O)O)CC3)cc2)cs1
Reactant: O=C1OC2(CCNC2)c2ccccc21
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)cs1
Reaction time: 5 h

Procedure:
N,N-Diisopropylethylamine (50 μL, 0.3 mmol) was added to a mixture of 1-[4-(2-amino-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxylic acid (26.0 mg, 0.1 mmol), (1S)-(+)-10-camphorsulfonic acid-3H-spiro-[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (42.1 mg, 0.01 mmol) and BOP (57.0 mg, 0.13 mmol) in DMF (0.5 mL) at room temperature, and the reaction mixture was stirred for about 5 hours (the completion of the reaction was determined by HPLC). The crude product was purified by prep-HPLC. LC-MS: 432.1 (M+H)+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:6]=1)(=[O:4])=[O:3].C1([O:26][C:27](=O)[NH:28][C:29]2[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[N:30]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([O:37][CH3:38])[N:30]=[C:29]([NH:28][C:27]([NH:1][S:2]([C:5]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:6]=2)(=[O:3])=[O:4])=[O:26])[N:34]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1cn(-c2ccccn2)nc1S(N)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)c1cn(-c2ccccn2)nc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
280 mg of Methyl 3-(aminosulfonyl)-1-(2-pyridinyl)-1H-pyrazole-4-carboxylate and phenyl(4,6-dimethoxy-2-pyrimidinyl)carbamate were dissolved in 10 mL of acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene, 0.15 mL, was added, and the reaction was stirred one hour. The solution was diluted with 30 mL of ice-water and made acidic with concentrated hydrochloric acid. The solid that separated was collected to afford 260 mg of the title compound melting 183°-188° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1.C1COCC1.[OH-].[Na+].Cl>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1
Reactant: COC(=O)Cc1ccc2nc(-c3cccnc3)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(-c3cccnc3)oc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.5 %

Procedure:
To methyl (2-(3-pyridyl)-6-benzoxazolyl)acetate (360 mg, 1.34 mmol) were added THF (8 ml) and 0.5N NaOH (8.0 ml, 4.00 mmol). The resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture were added water and 1N HCl (5.0 ml, 5 mmol) to acidify the mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give (2-(3-pyridyl)-6-benzoxazolyl)acetic acid (179 mg, 52%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH2:11].[Cl:12][CH2:13][C:14](Cl)=[O:15]>C(Cl)Cl.C(N(CC)CC)C>[Cl:12][CH2:13][C:14]([NH:11][CH:3]1[C:4]([CH3:10])([CH3:9])[CH:5]2[CH2:8][C:2]1([CH3:1])[CH2:7][CH2:6]2)=[O:15]
Reactant: CC12CCC(C1)C(C)(C)C2N
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC12CCC(C1)C(C)(C)C2NC(=O)CCl
Reaction time: 12 h

Procedure:
To a solution of 1,3,3-trimethylbicyclo[2.2.1]hept-2-ylamine (5 g, 26.3 mmol) in methylene chloride (20 ml) and triethylamine (4 ml) was added chloroacetyl chloride (2.1 ml, 26.4 mmol) dropwise. The resulting solution was stirred for 12 hours, then the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer washed with brine, and dried over magnesium sulfate. The ethyl acetate solution was absorbed onto silica gel, which was eluted with 10% ethyl acetate/hexane, to yield 2-chloro-N-(1,3,3-trimethylbicyclo[2,2,1]hept-2-yl)acetamide as a white solid. B. Preparation of a Compound of Formula (1) in which R1 is Cyclohexyl and R2 is Phenyl
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH2:11][C:12]([CH3:22])([CH3:21])[C:13]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:11][C:12]([CH3:22])([CH3:21])[C:13]([NH:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[O:14])[N:7]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(N)C(=O)NCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(Nc1ncc(C#N)c(Cl)n1)C(=O)NCC(F)(F)F
Temperature: 90 °C

Procedure:
2,4-dichloropyrimidine-5-carbonitrile (E. F. Godefroi, J. Org. Chem., 1962, 27(6), 2264-6) (0.10 g, 0.57 mmol), 2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide.1TFA (Meinke, Peter T.; Shih, Thomas L.; Fisher, Michael H., U.S. Pat. No. 6,221,894 B1) (0.171 g, 1.14 mmol) and DIPEA (0.39 mL, 2.29 mmol) were combined in anhydrous THF (5 mL) in a sealed tube and heated to 90° C. for 18 hours, before cooling to room temperature. The solvent was evaporated in vacuo and the residue purified by flash chromatography (40 g SiO2, pentane/ethyl acetate, 30-70% over 14 column volumes) to afford the title compound as a colorless waxy solid (0.036 g, 19.7%).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:44])[CH2:42][CH3:43]>C1COCC1.CS(C)=O>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:13]2)[CH2:21][CH2:20][N:19]([C:41](=[O:44])[CH2:42][CH3:43])[CH2:18][CH2:17]1)#[N:24]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Reactant: CCC(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC1
Reaction time: 18 h

Procedure:
To a suspension of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-1) (50 mg, 0.11 mmol) in THF (1 mL) was added DIPEA (0.060 mL, 0.34 mmol), followed by propanoyl chloride (0.020 mL, 0.18 mmol). The resulting mixture was allowed to stir for 18 hours before the reaction mixture was concentrated in vacuo to afford an orange oil. The residue was dissolved in DMSO (2 mL) and purified by mass-triggered reverse phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound, Example #33-1, as a colorless solid.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][CH2:12][C@H:11]([NH:27][C:28](=[O:38])[C:29]2[C:34]([OH:35])=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][N:30]=2)[C:10](=[O:39])[O:9][C@H:8]1[CH3:40])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[C:47]([O:50][CH2:51]Br)(=[O:49])[CH3:48]>CC(C)=O.C(Cl)Cl>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][CH2:12][C@H:11]([NH:27][C:28](=[O:38])[C:29]2[C:34]([O:35][CH2:51][O:50][C:47](=[O:49])[CH3:48])=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][N:30]=2)[C:10](=[O:39])[O:9][C@H:8]1[CH3:40])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(=O)OCBr
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OCOC(C)=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a mixture of (3S,6S,7R,8S)-3-(3-hydroxy-4-methoxypicolinamido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate (85 mg, 0.154 mmol) and K2CO3 (42.7 mg, 0.309 mmol) in acetone (2.0 mL) was added bromomethyl acetate (21.2 μL, 0.216 mmol), and the reaction was stirred vigorously at 50° C. under N2 for 1 h. The reaction was cooled to room temperature, diluted with CH2Cl2 (10 mL), filtered, and treated with Celite®. The solvent was removed under reduced pressure and the resulting adsorbed crude material was purified by flash chromatography (SiO2, 0→50% acetone/hexanes) to afford (3S,6S,7R,8S)-3-(3-(acetoxymethoxy)-4-methoxypicolinamido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate (70 mg, 0.112 mmol, 73% yield) as a white powder: mp 58-64° C.; 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=8.1 Hz, 1H), 8.24 (d, J=5.3 Hz, 1H), 8.02-7.94 (m, 1H), 7.89-7.81 (m, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.56-7.43 (m, 2H), 7.40 (dd, J=8.2, 7.0 Hz, 1H), 7.30 (dd, J=7.1, 1.2 Hz, 1H), 6.92 (d, J=5.4 Hz, 1H), 5.71 (d, J=6.5 Hz, 2H), 5.17-5.06 (m, 3H), 4.04 (dd, J=11.6, 7.4 Hz, 1H), 3.89 (s, 3H), 3.60 (d, J=4.2 Hz, 2H), 3.40 (dd, J=11.7, 7.1 Hz, 1H), 3.23 (dd, J=14.2, 3.1 Hz, 1H), 2.77-2.63 (m, 2H), 2.29 (ddt, J=12.2, 8.1, 3.9 Hz, 1H), 2.04 (s, 3H), 1.39 (d, J=5.6 Hz, 3H), 1.29 (dd, J=7.0, 3.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 176.38, 171.75, 170.27, 163.15, 160.19, 145.74, 143.97, 142.01, 134.75, 133.97, 131.96, 128.95, 127.78, 127.32, 125.99, 125.54, 125.38, 123.50, 109.70, 89.40, 74.18, 72.32, 71.93, 56.18, 51.77, 44.97, 34.38, 32.25, 20.85, 19.14, 19.07, 18.28; HRMS-ESI (m/z) [M+H]+ calcd for C33H39N2O10 expected, 623.2599. found, 623.2611.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].[N:20]([CH:23]1[CH2:28][CH:27]([CH3:29])[CH2:26][CH2:25][CH:24]1[C:30](Cl)=[O:31])=[N+:21]=[N-:22].CC1CCC(C(Cl)=O)=CC1.C([O-])(O)=O.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([C:30]([CH:24]1[CH2:25][CH2:26][CH:27]([CH3:29])[CH2:28][CH:23]1[N:20]=[N+:21]=[N-:22])=[O:31])[CH:11]([CH3:13])[CH3:12])=[O:4]
Reactant: CC1CCC(C(=O)Cl)C(N=[N+]=[N-])C1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Agent: CC1CC=C(C(=O)Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1N=[N+]=[N-])C(C)C
Temperature: 90 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
To a solution of 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (227 mg, 0.824 mmol) in 1,2-dichloroethane (2.5 ml) was added the 2:1 mixture of 2-Azido-4-methyl-cyclohexanecarboxylic acid chloride and 4-Methyl-cyclohex-1-enecarboxylic acid chloride (182 mg, 0.906 mmol) dissolved in 1,2-dichloroethane (0.5 ml). The resulting solution was stirred for 18 h at 90° C. and then cooled to room temperature. It was then diluted with ethyl acetate (10 ml) and a solution of saturated NaHCO3 (10 ml). The aqueous phase was separated and washed with ethyl acetate (2×10 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0% to 20% EtOAc/Hexane) to obtain 178 mg (49%) of 3-[(2-Azido-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:20][C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:10]([C:9]2[CH:8]=[N:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(-c2cccs2)nc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: O=C(c1ccc(-c2cccs2)nc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D using 6-thiophen-2-yl-nicotinic acid (CAS 179408-54-9) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine to give the title compound (58 mg). MS (ES+) 342.1 (M+H)+
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:7]([CH2:16][OH:17])[CH:6]=1)[CH3:4].[C:18]([C:22]1[C:32]([F:33])=[CH:31][C:25]([O:26][CH2:27][C:28](O)=[O:29])=[CH:24][C:23]=1[F:34])([CH3:21])([CH3:20])[CH3:19].CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:18]([C:22]1[C:23]([F:34])=[CH:24][C:25]([O:26][CH2:27][C:28]([NH:2][C@@H:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:7]([CH2:16][OH:17])[CH:6]=2)[CH3:4])=[O:29])=[CH:31][C:32]=1[F:33])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1c(F)cc(OCC(=O)O)cc1F
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(CO)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)COc1cc(F)c(C(C)(C)C)c(F)c1)c1ccc(NS(C)(=O)=O)c(CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
To a solution of N-[4-[(1R)-1-aminoethyl]-2-(hydroxymethyl)phenyl]methanesulfonamide hydrochloride (40 mg, 0.14 mmol) in N,N-dimethylformamide (DMF) (2 ml), (4-tert-butyl-3,5-difluorophenoxy)acetic acid (34 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (40 mg), and 4-dimethylaminopyridine (DMAP) (0.5 mg, 0.004 mmol) were added. The solution was stirred at room temperature for 16 hours and then partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue obtained was purified by silica gel column chromatography, eluting with methylene chloride/ethylacetate (1:1), to give 2-(4-tert-butyl-3,5-difluorophenoxy)-N-((1R)-1-{3-(hydroxymethyl)-4-[(methylsulfonyl)amino]phenyl}ethyl)acetamide (24 mg, 36%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:39][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCC2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (49%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C@H:5]([OH:36])[C@H:6]([C:8]1[C:9]([O:34][CH3:35])=[CH:10][C:11]2[CH2:12][CH2:13][N:14]3[C:20]4[C:21](=[O:33])[N:22]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:19]=4[CH:18]=[C:15]3[C:16]=2[CH:17]=1)[OH:7])[CH3:2].[C:38]1(C)[CH:43]=CC(S(O)(=O)=O)=C[CH:39]=1.C(N(CC)CC)C>CC(C)=O.COC(OC)(C)C>[C:29]([N:22]1[CH2:23][CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:19]2[CH:18]=[C:15]3[C:16]4[CH:17]=[C:8]([C@@H:6]5[O:7][C:38]([CH3:43])([CH3:39])[O:36][C@H:5]5[C:4]([O:3][CH2:1][CH3:2])=[O:37])[C:9]([O:34][CH3:35])=[CH:10][C:11]=4[CH2:12][CH2:13][N:14]3[C:20]=2[C:21]1=[O:33])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)c1cc2c(cc1OC)CCn1c-2cc2c1C(=O)N(C(C)(C)C)CCC(C)(C)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c-2cc2c1C(=O)N(C(C)(C)C)CCC(C)(C)C2
Reaction time: 0.08 h
Yield: 1722.8 %

Procedure:
A solution of 868 mg of 21c in 10 ml of acetone, 2.2 ml of 2,2-dimethoxypropane, and 17 mg of p-toluenesulfonic acid was stirred for 2 hr. The reaction was treated with 0.8 ml of triethylamine, stirred for 5 min, and then concentrated to a small volume and diluted with 30 ml of 5% NaHCO3 solution. The product was extracted with ethyl acetate and the extracts were washed with water, dried and concentrated, to provide 940 mg of product 21d, which was used as is in the next step; Rf (heptane/ethyl acetate 1/1) 0.57.
Reaction SMILES: [CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14](F)[CH:13]=1)[CH:2]=[CH2:3].[CH3:29][O-:30].[Na+]>C1COCC1.CO>[CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14]([O:30][CH3:29])[CH:13]=1)[CH:2]=[CH2:3]
Reactant: C[O-]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(F)c1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(OC)c1
Reaction time: 8 h

Procedure:
8.97 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-(4-bromo-phenyl)-methanone in 450 ml of THF are stirred with 37 ml of 5.4M sodium methanolate in methanol at room temperature for 14 hrs. and under reflux for 1 hr. The solution is evaporated and the residue is taken up in methylene chloride/10% sodium chloride solution. The organic phase is dried, dissolved in ether and stirred overnight with 2.08 g of fumaric acid. There are obtained 8.17 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-methoxy-phenyl]-(4-bromo-phenyl)-methanone.fumarate (m.p. 108°-113° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39]Br)[C:33]=2[N:32]=[CH:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>CC#N>[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39][N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH2:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[C:33]=2[N:32]=[CH:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Reactant: Cc1cccnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1cccc2c1ncn2C(=O)OC(C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure A: Reaction of 4-[(3-Methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester in dry CH3CN with 4-Bromomethyl-benzoimidazole-1-carboxylic acid tert-butyl ester, DIPEA and KI gave 4-{[(1-tert-Butoxycarbonyl-piperidin-4-yl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a white foam. Deprotection with TFA using General Procedure F gave (1H-Benzoimidazol-4-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine.