Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si](C)(C)C)[C:2](=[CH2:4])[CH3:3].[CH2:9]([O:16][C@@H:17]1[C@@H:22]([O:23][CH2:24]C2C=CC=CC=2)[C@H:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:20]([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:19][C@:18]1([C:49]1[CH:54]=[C:53]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=2)[C:52]([Cl:64])=[CH:51][C:50]=1[O:65][CH3:66])O)C1C=CC=CC=1>C(Cl)Cl>[CH2:9]([O:16][C@@H:17]1[C@@H:22]([O:23][CH2:24][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:21]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@H:20]([CH2:39][O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:19][C@:18]1([C:49]1[CH:54]=[C:53]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=2)[C:52]([Cl:64])=[CH:51][C:50]=1[O:65][CH3:66])[CH2:1][C:2]([CH3:3])=[CH2:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C=C(C)C[Si](C)(C)C
Reactant: CCc1ccc(Cc2cc([C@]3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC)cc2Cl)cc1
Solvent: ClCCl
Product: C=C(C)C[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2OC)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a mixture of methallyltrimethylsilane (185 μL, 1.05 mmol) and 23 (0.28 g, 0.35 mmol) in anhydrous methylene chloride (10 mL) at −20° C. was added BF3 OEt2 (88 μL, 0.70 mmol) in a drop-wise manner. The resulting light orange mixture was stirred for 1 hour, during which the temperature was allowed to rise to 0° C. The reaction mixture was quenched with 10% NaHCO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered, and evaporated to yield a residue which was purified by column chromatography eluting with 0-15% EtOAc in petroleum ether to give 24 (153 mg, 52%). 1H NMR (300 MHz, CDCl3) δ 7.18-7.30 (m, 20H), 7.00-7.05 (m, 1H), 6.98 (s, 4H), 6.69 (s, 1H), 4.67 (t, J=10.8 Hz, 1H), 4.49-4.60 (m, 8H), 4.24 (d, J=11.4 Hz, 1H), 4.12 (d, J=6.0 Hz, 1H), 3.67-4.00 (m, 7H), 3.54 (s, 3H), 3.07 (d, J=16.2 Hz, 1H), 2.79 (d, J=15.9 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 1.54 (s, 3H), 1.17 (t, J=7.5 Hz, 3H). LC/MS m/z 860 (M+Na).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][C:9]1[C:10]([O:17][CH2:18][C:19](Cl)=[O:20])=[N:11][C:12]([F:16])=[C:13]([Cl:15])[CH:14]=1>O.C1C=CC=CC=1>[Cl:8][C:9]1[C:10]([O:17][CH2:18][C:19]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:20])=[N:11][C:12]([F:16])=[C:13]([Cl:15])[CH:14]=1
Reactant: O=C(Cl)COc1nc(F)c(Cl)cc1Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)CNC(=O)COc1nc(F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution was prepared by admixing 2.93 grams (0.039 mole) of glycine with 4.67 grams (0.117 mole) of sodium hydroxide in 117 milliliters of water. To this solution was added 10.0 grams of (3,5-dichloro-6-fluoro-2-pyridyloxy)acetyl chloride in 30 milliliters of benzene. The mixture was allowed to stand at a temperature of ~2°-5° C. for about 10 minutes and the mixture was warmed to room temperature and stirred for about 30 minutes. The reaction mixture was diluted with additional benzene and the aqueous layer which formed was removed and acidified. The solid which precipated was removed by filtration, dried and recrystallized from 50 percent ethanol. The N-[(3,5-dichloro-6-fluoro-2-pyridyloxy)acetyl]glycine product was recovered in a yield of 5.0 grams and melted at 155°-157° C. and upon analysis was found to have carbon, hydrogen, chlorine and nitrogen contents of 35.7, 2.1, 24.2 and 8.7 percent, respectively as compared with the theoretical contents of 36.5, 2.4, 23.9 and 9.4 percent, respectively, calculated for the above named compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[CH:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[C:13]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([CH:39]([OH:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:7][N:6]=3)[N:17]=[CH:16][N:15]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Reactant: O=Cc1ccccc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(O)c3ccccc3)cn2)cc1

Procedure:
N-[6-{2-(5-Bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide and benzaldehyde are treated in the same manner as in Example 129 to give 4-tert-butyl-N-[6-{2-(5-(α-hydroxybenzyl)primidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]-benzenesulfonamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:37]([O:38][CH3:39])=[CH:36][C:27]2[N:28]([CH2:34][CH3:35])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[C:37]([O:38][CH3:39])=[CH:36][C:27]3[N:28]([CH2:34][CH3:35])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccc(OC)cc4-n4cccn4)n3)c(OC)cc21

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (30%); 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.47 (bs, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.79 (m, 2H), 7.56 (s, 1H), 7.23 (s, 1H), 7.01-6.95 (m, 2H), 6.51 (s, 1H), 3.84 (bs, 8H), 2.36 (bs, 2H), 2.05 (bs, 2H), 1.9 (bs, 2H), 1.03 (m, 3H); MS (m/e) 534.48 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:15]=[CH:14]2.ClC1C=CC=C(Cl)C=1[CH2:33][O:34]C1C=C2C(=CC=1)N(C(C)CC#N)C=C2.[OH-].[Na+]>CN(C=O)C>[Cl:6][C:7]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:15]=[C:14]2[CH:33]=[O:34]
Reactant: N#CCCCn1ccc2cc(OCc3c(Cl)cccc3Cl)ccc21
Reactant: CC(CC#N)n1ccc2cc(OCc3c(Cl)cccc3Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCCCn1cc(C=O)c2cc(OCc3c(Cl)cccc3Cl)ccc21
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 70 %

Procedure:
A flame dried flask under argon was charged with DMF (0.43 mL, 5.57 mmol) and cooled to 0° C. Phosphorus oxychloride (0.16 mL, 1.67 mmol) was slowly added to the cooled DMF. The solution was stirred at 0° C. for 1 min and to this was added a DMF (1.5 mL) solution of a mixture of 4-[5-(2,6-dichlorobenzyloxy)indol-1-yl]butyronitrile (85%) and 3-[5-(2,6-dichlorobenzyloxy)indol-1-yl]butyronitrile (15%) (0.5 g, 1.4 mmol). The reaction mixture was stirred at room temprature for 1 h and heated at 50° C. for 4 h. The reaction solution was poured into ice water. A light yellow colored sticky solid precipated immediately. The mixture was neutralized by adding 1N NaOH until a pH of 7 was obtained. The product was extracted into ethyl acetate (3×) and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting crude yellow oil was purified by flash column chromatography (silica gel, ethyl acetate/hexane) to yield the desired aldehyde as a white solid (0.38 g, 70%) and the undesired aldehyde (0.099 g, 18%).MS(ES) m/e 387.0 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C@H:17]([N:28]([CH2:44][C:45]2[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[C:47]([C:55]([F:58])([F:57])[F:56])[CH:46]=2)[C:29]2[N:30]=[N:31][N:32]([CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)[N:33]=2)[CH2:16][C@@H:15]1[CH2:59][CH3:60])=[O:13])([CH3:10])[CH3:9].C(=O)(O)[O-].[Na+]>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([C:24]([F:27])([F:25])[F:26])=[CH:21][CH:22]=2)[C@H:17]([N:28]([C:29]2[N:30]=[N:31][N:32]([CH2:34][CH2:35][NH2:36])[N:33]=2)[CH2:44][C:45]2[CH:46]=[C:47]([C:55]([F:56])([F:57])[F:58])[CH:48]=[C:49]([C:51]([F:52])([F:53])[F:54])[CH:50]=2)[CH2:16][C@@H:15]1[CH2:59][CH3:60])=[O:13])([CH3:10])[CH3:9]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCNC(=O)OC(C)(C)C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
Add trifluoroacetic acid (1 mL) to a solution of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-[2-(2-tert-butoxycarbonylamino-ethyl)-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (61 mg, 0.079 mmol) in dichloromethane (3 mL) and stir the mixture at room temperature for 3 h. Pour the reaction mixture onto a saturated solution of sodium bicarbonate and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate, to afford the title compound (24 mg, 45%). MS (ES+): 669 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39])#[CH:30].CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:30]#[C:29][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(Cl)n1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1C#Cc1ccnc(SC)n1
Temperature: 100 °C
Yield: 100.2 %

Procedure:
A suspension of 4-chloro-2-methylthiopyrimidine (200 μL, 1.72 mmol), PdCl2(PPh3)2 (121 mg, 0.172 mmol), CuI (33.0 mg, 0.172 mmol), PPh3 (45.0 mg, 0.172 mmol), methyl 2-(2-ethynyl phenyl)acetate (K1) (359 mg, 1.08 mmol) and Et3N (0.938 mL) in THF (6 mL) was heated at 100° C. under microwave irradiation for 10 minutes. The volatiles were removed in vacuo and the resultant residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C., then Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in DCM) to give the title compound A1 as a yellow oil (323 mg, 63%); 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=5.0 Hz, 1H), 7.63 (dd, J=7.6, 1.1 Hz, 1H), 7.44-7.29 (m, 3H), 7.12 (d, J=5.0 Hz, 1H), 3.92 (s, 2H), 3.71 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([OH:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[C:32]1(O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([O:30][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Product: CCCCCCCN(CCc1ccc(CC(Oc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 50 and substituting phenol as the nucleophile to give an approximate 1:1 mixture of ethyl and methyl ester as a clear film (35 mg, 61%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 120 °C

Procedure:
To a mixture of 2-chloro-5-nitropyridine (476 mg, 3.0 mmol) and 4-piperidine acetic acid methyl ester (471 mg, 3.0 mmol) in tetrahydrofuran (10 mL) was added diisopropylethylamine (1.0 mL, 5.74 mmol). The mixture was heated in a microwave at 120° C. for 30 minutes. The mixture was evaporated to dryness and extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid methyl ester as a yellow solid. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[CH3:17][O:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[O:34][CH3:35])[C:24](=[O:36])[C:23]=2[CH:22]=[C:21]([C:37]#[N:38])[CH:20]=1.C(OCC)(=O)C>C(O)(=O)C>[CH3:17][O:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[O:34][CH3:35])[C:24](=[O:36])[C:23]=2[CH:22]=[C:21]([C:37]2[NH:16][N:15]=[N:14][N:38]=2)[CH:20]=1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(C#N)cc1C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc2c1C(=O)c1c(OC)cc(-c3nnn[nH]3)cc1C2=O
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Tri-n-butyltin azide (100 ml) was added to 9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carbonitrile (5.75 g) and heated and stirred at 150° C. for 4 hours, cooled to room temperature, poured into ethyl acetate (1000 ml). Acetic acid (10 cm3) was added and the solution allowed to stand 16 hours, the resultant precipitate was filtered to give the dimethoxyetrazole, m.p. 262°-264° C.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>CO.[OH-].[Pd+2].[OH-]>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[OH:18][CH:16]1[CH2:17][NH:14][CH2:15]1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: OC1CNC1
Reaction time: 24 h

Procedure:
1-Benzhydryl-3-hydroxyazetidine (3.0 g, 12.6 mmol) was dissolved in methanol (60 mL), and 10 mL of TFA and 10% palladium hydroxide (1.0 g) were added thereto. The mixture was stirred for 24 hours under a hydrogen stream at normal pressure. The catalyst was removed by filtration, water (100 mL) was added to the filtrate, and the mixture was washed three times with ether. The aqueous layer was concentrated under reduced pressure, and the title compound (2.33 g, 99%) was obtained as an amorphous matter.
Reaction SMILES: [Cl:1][C:2]1[C:40]([Cl:41])=[CH:39][C:5]2[NH:6][C:7]([O:9][CH:10]([C:19]3([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=5)=[CH:27][CH:26]=4)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[N:8][C:4]=2[CH:3]=1.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:42]([NH:44][C:45]([N:22]1[CH2:23][CH2:24][C:19]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)=[CH:27][CH:26]=2)([CH:10]([O:9][C:7]2[NH:8][C:4]3[CH:3]=[C:2]([Cl:1])[C:40]([Cl:41])=[CH:39][C:5]=3[N:6]=2)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:20][CH2:21]1)=[O:46])[CH3:43]
Reactant: C[Si](C)(C)CCOCC(Oc1nc2cc(Cl)c(Cl)cc2[nH]1)C1(c2ccc(-c3cccc(C#N)c3)cc2)CCNCC1
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)N1CCC(c2ccc(-c3cccc(C#N)c3)cc2)(C(COCC[Si](C)(C)C)Oc2nc3cc(Cl)c(Cl)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a solution of 0.045 g of 4′-{4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidin-4-yl}-biphenyl-3-carbonitrile (0.073 mmol, 1 eq) in 0.7 mL of dichloromethane was added ethyl isocyanate (6.5 μL, 0.088 mmol, 1.2 eq) and 15.4 μL of diisopropylethyl amine (0.088 mmol, 1.2 eq) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed by rotary evaporation to yield the crude product which was purified by preparative TLC eluting with 10% methanol in dichloromwthane to give 0.030 g of 4-(3′-cyano-biphenyl-4-yl)-4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidine-1-carboxylic acid ethylamide. This intermediate was dissolved in 2 mL of tetrahydrofuran and 0.080 g of tetrabutylammonium fluoride on silica gel (1.0-1.5 mmol/g, 2 eq) was added. The mixture was heated at 60° C. for 16 h then filtered and the resin washed with 10 mL of tetrahydrofuran. The filtrate was concentrated by rotary evaporation and the crude product was purified by flash silica gel chromatography eluting with 1% methanol in dichloromethane with 3% triethylamine to give 0.0054 g of the desired product 4-(3′-cyano-biphenyl-4-yl)-4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-piperidine-1-carboxylic acid ethylamide 58. MS (ESI): Calcd m/z for C29H27Cl2N5O2.H+=548.2; found m/z=547.8/549.8 [(M+1)+/(M+3)+].
Reaction SMILES: [O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[NH:26][CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:35](#[N:38])[CH:36]=[CH2:37]>C(O)C>[O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:37][CH2:36][C:35]#[N:38])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH:17]=[CH:16][C@@H:15]35)[Si:2]([C:5]([CH3:7])([CH3:6])[CH3:8])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)NCC[C@]314
Reactant: C=CC#N
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCC#N)CC[C@]314
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
3,6-Bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan (0.26 g, 0.52 mmol) was dissolved in absolute ethanol (3 mL) and acrylonitrile (0.07 ml, 1.0 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure to give a white solid (0.26 g, 90% yield).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[NH:12][C:11]([CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]([O:30]C(C)(C)C)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)[CH3:15])=[N:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH:1]1([CH2:7][C:8]2[NH:12][C:11]([CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:20][CH:21]=3)[CH3:15])=[N:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(Cc1ncc(CC2CCCCC2)[nH]1)c1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Cc1ncc(CC2CCCCC2)[nH]1)c1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
To a 25 mL one neck round bottom flask was added tert-butyl 4′-{2-[5-(cyclohexylmethyl)-1H-imidazol-2-yl]-1-methylethyl}biphenyl-2-carboxylate (35.7 mg), which was treated with a mixture of TFA/CH2Cl2 (1.5 mL/1.5 mL) at rt for 2 hours. Then the solvent was removed by rotary evaporation and the resulting residue was coevaporated with toluene/H2O three times. The resulting crude product was purified by PrepTLC (2000 uM, 10% MeOH/CH2Cl2) to afford 4′-[2-[5-(cyclohexylmethyl)-1H-imidazol-2-yl]-1-methylethyl]-[1,1′-biphenyl]-2-carboxylic acid. 1HNMR (CD3OD, 500 MHz, ppm): 7.52 (1H, br), 7.38 (2H, br), 7.32 (2H, br), 7.28 (1H, br), 7.10 (2H, br), 6.87 (1H, s), 3.20 (1H, br), 3.08 (1H, br), 2.99 (1H, br), 2.41 (2 h, br), 1.58-1.73 (4H, m), 1.48 (1H, m), 1.32 (3H, br), 1.14-1.22 (4H, m), 0.88 (2H, m); m/z (ES) (M+H)+=403).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][NH:7]1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C(N(CC)CC)C>[C:1]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][N:7]1[C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)=[O:21])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1CSCCN1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CSCCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
Seven grams of 3-carbethoxythiomorpholine and 6.5 g of 4-chlorophenyl isocyanate were added to 60 ml of hexanes containing 10 drops of triethylamine as a catalyst. A mild exothermic reaction took place as the reactants mixed. After the mixture cooled to room temperature, the precipitate was collected by filtration and recrystallized from a mixture of methylene chloride and ether to give 4 g of 3-carbethoxy-4-(4-chlorophenylaminocarbonyl)thiomorpholine, mp 152.5°-154.5° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[N+:13]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH2:1][CH2:2][CH3:3])[C:8]([OH:10])=[O:9])([O-:15])=[O:14]
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
9.44 g (57.5 mmol, 1.0 equiv.) of 4-propylbenzoic acid were partially dissolved in 50 mL conc. H2SO4 and chilled in an ice bath. A solution of 4.7 mL (74.7 mmol, 1.3 equiv) conc. HNO3 in 10 mL conc. H2SO4 was added dropwise over 1-2 min. After stirring 1 hour at 0° C., the reaction mixture was poured into a 1 L beaker half full with ice. After stirring 10 minutes, the white solid which formed was filtered, washed 1×H2O, and dried to give 12.01 g (100%) of the title compound: mp 106-109° C.; IR (KBr) 3200-3400, 2966, 2875, 2667, 2554, 1706, 1618, 1537, 1299, 921 cm-1 ; 1H NMR (300 MHz, DMSO-d6) d 0.90 (t, 3H, J=7.4 Hz), 1.59 (m, 2H), 2.82 (m, 2H), 7.63 (d, 1H, J=8.0 Hz), 8.12 (dd, 1H, J=1.7, 8.0 Hz), 8.33 (d, 1H, J=1.7 Hz); 13C NMR (75.5 MHz, DMSO-d6) d 14.2, 23.7, 34.2, 125.4, 130.5, 132.9, 133.6, 141.4, 149.5, 165.9; Anal. calcd for C10H11NO4.1/4H2O: C, 56.20; H, 5.42; N, 6.55. Found: C, 56.12; H, 5.31; N, 6.81.