Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:19][CH:6]2[CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:4]([C:5]=32)[CH2:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[NH2:1][CH:2]1[CH2:19][C:6]2=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:4]([C:5]=32)[CH2:3]1
Reactant: NC1Cc2cccc3c2C(C1)C(c1ccccc1)N3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: NC1Cc2cccc3[nH]c(-c4ccccc4)c(c23)C1
Yield: 29.2 %

Procedure:
A portion (0.83 g) of the compound obtained in Example 166 was dissolved in methylene chloride (80 ml) and to the solution was added active manganese dioxide (1.66 g). The mixture was heated to reflux for 28 hours. The manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=7:1) to yield 240 mg (29%) of the titled compound.
Reaction SMILES: C(O[C:4]1[CH:5]=C(C=C[C:11]=1C)C=O)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18].C(Br)C=C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])[CH:4]=[CH2:11]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: C=CCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate E10) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with allylbromide in DMF using K2CO3 as base (see also A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan and B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).
Reaction SMILES: [CH2:1]([C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]1)[CH3:2].Br[C:32]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[C:39]([Cl:47])[CH:38]=2)[S:34][N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(O)=O.O.C(O)(C)C>[Cl:47][C:39]1[CH:38]=[C:37]([C:35]2[S:34][N:33]=[C:32]([C:8]3[C:3]([CH2:1][CH3:2])=[C:4]([CH:18]4[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:22][CH2:23]4)[CH:5]=[CH:6][CH:7]=3)[N:36]=2)[CH:42]=[CH:41][C:40]=1[O:43][CH:44]([CH3:45])[CH3:46]
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Reactant: CCOC(=O)CCN1CCC(c2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCc1c(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)cccc1C1CCN(CCC(=O)O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
To a solution of ethyl 3-{4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperidinyl}propanoate (D123) (200 mg, 0.481 mmol), 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (161 mg, 0.481 mmol) and Pd(Ph3P)4 (55.6 mg, 0.048 mmol) was added tripotassium phosphate (307 mg, 1.444 mmol) under nitrogen. The solution was sealed for Biotage microwave irradiation at 120° C. for 20 min. To the resulted solution, Isopropanol (10 mL) and water (2 mL) and then sodium hydroxide (0.5 mL, 3.05 mmol) was added. This solution was stirred at 50° C. for 2 hr. The solution was neutralized with AcOH, dried, dissolved in DMF and purified by Mass Directed AutoPrep to afford 3-{4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]-1-piperidinyl}propanoic acid (E100) (40 mg).
Reaction SMILES: C([CH:3]([O-:19])[CH2:4][CH2:5][C:6]([C:17]#[N:18])([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]#[N:16])[CH:7]([CH3:9])[CH3:8])C.[BH4-].[Li+].Cl>C1COCC1>[C:17]([C:6]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]#[N:16])([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:4][CH2:3][OH:19])#[N:18]
Reactant: CCC([O-])CCC(C#N)(c1sccc1C#N)C(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCCO)c1sccc1C#N
Reaction time: 0.33 h
Yield: 57 %

Procedure:
500 mg (1.72 mmol) of ethyl 4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexanolate was dissolved in 10 ml of THF, 37.5 mg (1.72 mmol) of lithium borohydride was added, and the mixture was heated under reflux. After one hour 20 minutes, heating was stopped, and 2N HCl was added under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was successively washed with brine and water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to obtain a crude product. The crude product was subjected to silica gel (eluted with ethyl acetate:hexane=35:65), to give 244 mg (0.98 mmol, 57.1%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[CH3:19])[C:8](=[O:9])[C:7]2[C:6](=[CH:23][CH:22]=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=2)[N:5]=1
Reactant: COc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c(C)c1
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(-n2c(CF)nc3ccc([N+](=O)[O-])cc3c2=O)c(C)c1
Yield: 86.8 %

Procedure:
4.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-methoxyaniline, 3.5 g of boron trifluoride etherate and 30 ml of acetic acid are treated in the same manner as described in Example 1-(2)l, whereby 3.3 g of 2-fluoromethyl-3-(2-methyl-4-methoxyphenyl)-6-nitro-4(3H)-quinazolinone are obtained as yellow prisms.
Reaction SMILES: Cl[C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(Cl)nc3cc21
Reactant: NCc1ccccc1
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NCc4ccccc4)nc3cc21
Temperature: 200 °C
Reaction time: 0.13 h
Yield: 10.6 %

Procedure:
A mixture of F1 (100 mg) and benzylamine (1.5 ml; 13.6 mmol) is stirred in a microwave apparatus at 200° C. for 8 min. After re-cooling the mixture is concentrated in vacuo and purified by RP-MPLC (Polygoprep 100-50 C18) eluting with a water/MeCN gradient to give the desired compound (13 mg).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH2:4]([O:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Br)[CH:17]=2)[C@H:12]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:11][C@@H:10]1[CH3:43])=[O:8])[CH3:5].O>CN(C)C=O>[CH2:4]([O:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][S:2][CH3:1])[CH:17]=2)[C@H:12]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:11][C@@H:10]1[CH3:43])=[O:8])[CH3:5]
Reactant: CCOC(=O)N1c2cc(CBr)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1c2cc(CSC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
To a suspension of sodium thiomethoxide (11 mg, 0.156 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-bromomethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 90) (100 mg, 0.156 mmol), and the reaction was stirred for 6 h. The reaction mixture was then poured into water and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The excess N,N-dimethylformamide was azeotroped off with heptanes. Purification by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent afforded the title product (0.040 g, 42%): 1H NMR (CDCl3) δ 1.1 (d, 3H), 2.1 (s, 3H), 3.8 (m, 6H), 6.4 (s, 1H), 7.3 (s, 1H), 7.7 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([N:31]=[C:32]=[O:33])[CH:24]=[CH:25][C:26]=1[O:27][CH:28]([F:30])[F:29]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=[O:33])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH:28]([F:30])[F:29]
Reactant: O=C=Nc1ccc(OC(F)F)c(Cl)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(OC(F)F)c(Cl)c2)cc1

Procedure:
93 mg of pale yellow solid 3-{4-[3-(3-chloro-4-difluoromethoxyphenyl)-ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3-chloro-4-difluoromethoxyphenyl isocyanate.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.O>O1CCCC1>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:18]1([OH:21])[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(O)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
46 ml of 2.4 M n-butyllithium are added over a 15 minute span to a mixture cooled to -70° C. of 17.5 g of 2-bromofluorobenzene and 50 ml of tetrahydrofuran. After total addition, the reaction mixture is stirred at between -60° to -70° C. for 15 minutes to enable complete lithiation, which results in a tan colored solution. A mixture of 11.3 g of 1-methyl-4-piperidone in 20 ml of tetrahydrofuran is added to the solution at a rate to maintain the reaction medium's temperature below -60° C. After total addition, the reaction mixture is stirred at the same low temperature for one hour before being permitted to warm to ambient temperature. Water is added and the biphasic mixture is permitted to separate into its organic and aqueous phases. The organic phase is collected and the aqueous phase is extracted thrice with ether and the ether extracts are combined with the organic phase. The combined organic solution is extracted with an excess of 2 N hydrochloric acid and then discarded. The acidic solution is basified with ammonium hydroxide, producing a heavy oil which is dissolved in a 1:1 ethyl acetate ether mixture. This solution is dried and then concentrated to dryness, leaving a viscous oil which crystallizes with cooling. The solid product is recrystallized from a benzene-hexane mixture to give prisms, mp 127°-129° C. of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[O:5][C:6]1[C:11]([F:12])=[C:10]([O:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=2[O:25][CH3:26])[C:9]([F:27])=[C:8]([O:28][C:29]2[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:30]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:7]=1.[N:48]#[C:49][NH2:50].Cl>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[O:5][C:6]1[C:11]([F:12])=[C:10]([O:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=2[O:25][CH3:26])[C:9]([F:27])=[C:8]([O:28][C:29]2[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:30]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:7]=1)[C:49]([NH2:50])=[NH:48]
Reactant: CCOC(=O)c1ccc(Oc2c(F)c(Oc3cccc(N)c3)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)c(OC)c1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(Oc2c(F)c(Oc3cccc(NC(=N)N)c3)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)c(OC)c1
Reaction time: 4 h

Procedure:
To ethanol (15 mL) was added 4-[[2-(3-aminophenoxy)-6-(5-cyano-2-phenylmethoxyphenoxy)-3,5-difluoropyridin-4-yl]oxy]-3-methoxybenzoic acid, ethyl ester (0.50 g, 0.80 mmol), cyanamide (0.60 g, 14 mmol), and 6 M hydrochloric acid (0.7 mL). After refluxing for 19 hours, cyanamide (0.60 g, 14 mmol) and 6 M hydrochloric acid (0.7 mL) was added and refluxing was continued for 4 hours. The reaction mixture was concentrated in vacuo and purified by HPLC to give 4-[[2-[3-(guanidino)phenoxy]-6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-pyridin-4-yl]oxy]-3-methoxybenzoic acid, ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1.[B:16]1([OH:26])[C:20]2[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=2[CH2:18][O:17]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C>[OH:26][B:16]1[C:20]2[CH:21]=[CH:22][C:23]([O:25][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=3)=[CH:24][C:19]=2[CH2:18][O:17]1
Reactant: OB1OCc2cc(O)ccc21
Reactant: N#Cc1ccc(Cl)nc1OCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1OCC(F)(F)F
Temperature: 80 °C
Yield: 40.7 %

Procedure:
To a solution of 6-chloro-2-(2,2,2-trifluoro-ethoxy)-nicotinonitrile (4, 1.26 g, 5.33 mmol) in DMF (anhydrous, 30 mL) were added 3H-benzo[c][1,2]oxaborole-1,5-diol (400 mg, 2.67 mmol) and Cs2CO3 (1.91 g, 5.87 mmol). The reaction was heated at 80° C. for 2 h by microwave. After the reaction cooled to room temperature, HCl (1 M, 20 mL) was added. The volatiles were removed in vacuo. Purification was accomplished by preparative HPLC, eluting with 5%-90% ACN/water gradient, to afford 380 mg (41% yield) of the title compound as a white solid.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH2:54][C@@H:55]([CH3:74])[CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][P:66](=[O:73])([O:70]CC)[O:67]CC>>[NH2:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:54][C@@H:55]([CH3:74])[CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][P:66](=[O:67])([OH:73])[OH:70]
Reactant: CCOP(=O)(CCOCCOCCOC[C@H](C)N)OCC
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCC
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)N[C@@H](C)COCCOCCOCCP(=O)(O)O)OCCCCCCCCCCCC

Procedure:
The title product was prepared from (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2,3-bis(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 20, step 5) and (S)-diethyl (2-(2-(2-(2-aminopropoxy)ethoxy)ethoxy)ethyl)phosphonate (1.2 eq, from example 28, step 2) by following the procedure described for example 28, step 3-5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.[C:21](=[O:23])=[O:22]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:21]([OH:23])=[O:22])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: OCCc1csc(-c2ccc(Cl)cc2)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccc(Cl)cc2)nc1CCO
Temperature: -75 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Dissolve 2-[2-(4-chloro-phenyl)-thiazol-4-yl]-ethanol (107 g gross, 91 g net, 380 mmol) in THF (1210 mL) and cool to about −75° C. Evacuate the chilled solution under vacuum and fill with nitrogen three times. Slowly add n-BuLi (1.6 M in hexanes, 530 mL, 848 mmol) over approximately 4 h, keeping the temperature<−70° C. Slowly add the red-purple solution via cannula over 3.5 h to a flask containing −75° C. THF that has been saturated with CO2 gas (approximately 390 g) keeping the temperature<−60° C. Charge the resulting brown slurry with additional CO2 gas (approximately 355 g) and then allow the slurry to come to room temperature while stirring mechanically overnight. Quench the reaction with 1 N HCl (3000 mL), cool to 16° C., and collect the precipitate by filtration. Rinse the solid with hexanes (1400 mL) and dry under vacuum to give 81.3 g (75%) of the title compound. ES/MS m/z (35Cl) 284.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.Cl>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reaction time: 4 h
Yield: 54.7 %

Procedure:
The a solution of 1-[1(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.3 g, 0.90 mmol) in 10 mL of ethanol purged with argon was added 10% Palladium on carbon (0.060 g). The hydrogenation was finished under 30 psi after 4 h. The mixture was passed through Celite to a flask containing HCl in ethanol. Concentration of the filtrate gave the final product (0.15 g, 88% yield). MS/ES+: m/z=334.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].ClCC1NC2C=CC=CC=2N=1.[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][N:30]=[C:31]=[S:32]>>[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][NH:30][C:31]([NH:14][CH2:13][CH2:12][NH:11][CH2:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:32]
Reactant: NCCNCc1nc2ccccc2[nH]1
Reactant: CN(C)CCN=C=S
Agent: ClCc1nc2ccccc2[nH]1
Product: CN(C)CCNC(=S)NCCNCc1nc2ccccc2[nH]1

Procedure:
N-(2-Benzimidazolylmethyl)ethylenediamine, prepared by reacting ethylenediamino with 2-chloromethylbenzimidazole by the procedure of Example 40, is reacted with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15]C(C(Cl)Cl)=O)[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([OH:21])[C@H:12]([NH2:15])[CH2:13][F:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Temperature: 110 °C
Yield: 100 %

Procedure:
A solution of florfenicol (0.090 g, 0.25 mmol) in acetic acid (3.0 mL) was treated with sulfuric acid (10%, 15 mL) and heated to 110° C. for 12 h. The reaction mixture was cooled to room temperature, treated with 10 M aqueous sodium hydroxide to adjust the pH to 14, extracted with dichloromethane (3×30 mL), dried (Na2SO4), and evaporated to provide florfenicol amine 60 (65 mg, 0.25 mmol) as a yellow oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH:6]1[OH:12])=O.C1(C)C=C(C)C=C(C)C=1>>[OH:12][CH:6]1[CH2:7][CH:8]2[CH2:9][CH2:10][CH:5]1[C:3](=[O:2])[NH:11]2
Reactant: COC(=O)C1CCC(N)CC1O
Solvent: Cc1cc(C)cc(C)c1
Product: O=C1NC2CCC1C(O)C2
Temperature: 25 °C

Procedure:
Reaction of compound (3) with mesitylene at elevated temperature (e.g., 165° C.) followed by cooling to rt yields 5-hydroxy-2-aza-bicyclo[2.2.2]octan-3-one (4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[C:16]=1[F:25]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([F:14])=[C:16]([F:25])[C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2sc(F)c(F)c21
Product: CC1c2c(sc(F)c2F)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,3-difluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S.[S:34](=O)(=O)(O)O>C(Cl)Cl>[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[S:34])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)CCCNC(=O)OCc1ccccc1
Reactant: O=S(=O)(O)O
Agent: CC(C)COC(=O)Cl
Agent: S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCC(O)=S)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 g (20 mmol) of triethylamine and a solution of 1.4 ml (10 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise, in succession, to a solution, cooled to -10°, of 2.37 g (10 mmol) of 4-benzyloxycarbonylaminobutyric acid in 50 ml of dry methylene chloride. The reaction mixture is stirred for one hour at -10° and then a strong current of hydrogen sulphide is passed through for 11/2 hours. After warming to room temperature, the mixture is cooled again and acidified with 2N sulphuric acid. The organic phase is separated, dried and concentrated in vacuo. The 4-benzyloxycarbonylaminothiobutyric acid obtained can be used without further purification.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(C4C=CC(C5NC(C6CCCN6C(=O)C(N)C6C=CC=CC=6)=NC=5)=CC=4)C=3)C=2)=CN=1)=O)C(C)C.[CH3:58][O:59][C:60](=[O:123])[NH:61][CH:62]([C:66]([N:68]1[CH2:72][CH2:71][CH2:70][CH:69]1[C:73]1[NH:77][C:76]2[C:78]3[C:83]([CH2:84][CH2:85][C:75]=2[N:74]=1)=[CH:82][C:81]([C:86]1[CH:95]=[CH:94][C:93]2[C:88](=[CH:89][CH:90]=[C:91]([C:96]4[NH:97][C:98]([CH:101]5[CH2:105][CH2:104][CH2:103][N:102]5[C:106](=[O:122])[CH:107]([NH:114]C(OC(C)(C)C)=O)[C:108]5[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=5)=[N:99][CH:100]=4)[CH:92]=2)[CH:87]=1)=[CH:80][CH:79]=3)=[O:67])[CH:63]([CH3:65])[CH3:64]>>[CH3:58][O:59][C:60](=[O:123])[NH:61][CH:62]([C:66]([N:68]1[CH2:72][CH2:71][CH2:70][CH:69]1[C:73]1[NH:77][C:76]2[C:78]3[C:83]([CH2:84][CH2:85][C:75]=2[N:74]=1)=[CH:82][C:81]([C:86]1[CH:95]=[CH:94][C:93]2[C:88](=[CH:89][CH:90]=[C:91]([C:96]4[NH:97][C:98]([CH:101]5[CH2:105][CH2:104][CH2:103][N:102]5[C:106](=[O:122])[CH:107]([NH2:114])[C:108]5[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=5)=[N:99][CH:100]=4)[CH:92]=2)[CH:87]=1)=[CH:80][CH:79]=3)=[O:67])[CH:63]([CH3:65])[CH3:64]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C(C)C
Agent: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C(C)C
Yield: 99 %

Procedure:
This compound was synthesized using the procedure used to make [1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (1-{2-[7-(6-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.180 g, 0.202 mmol) to give the title compound (0.160, >99% yield). LCMS-ESI+: calc'd for C47H50N8O4: 790.40 (M+); Found: 791.39 (M+H+).