Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.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.CCOC(C)=O.O>[C:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:12]
Reactant: N#Cc1cc(Br)cc(C(=O)O)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Temperature: 100 °C
Yield: 56.5 %

Procedure:
To a solution of 3-Bromo-5-cyano-benzoic acid (2 g, 8.8 mmol, 1 eq) and 3-fluorophenylboronic acid (1.6 g, 11.5 mmol, 1.3 eq) in DMF (100 mL) under nitrogen were added Pd(PPh3)4 (500 mg, 0.44 mmol, 0.05 eq) and K2CO3 (3.6 g, 26.4 mmol, 3 eq). The solution was heated at 100° C. overnight, then water and EtOAc were added. The aqueous layer was acidified by addition of diluted HCl and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 25:1) to give the title compound as a white solid (1.2 g, 56%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]1>CN1C(=O)CCC1.CS(C)=O.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]2[CH2:17][CH:15]2[C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:26]3[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:14])=[CH:19][CH:20]=1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccc(F)cc3)cc(Cl)n2n1
Reactant: NC(=O)NC1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)C3CC3c3ccc(F)cc3)cc(N3CCC(NC(N)=O)CC3)n2n1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
The title compound was prepared by combining N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(4-fluorophenyl)cyclopropanecarboxamide (13B, 0.15 g, 0.435 mmol), Et3NH (0.121 ml, 0.870 mmol), and the 1-(piperidin-4-yl)urea hydrochloride (0.156 g, 0.870 mmol) in NMP (1.450 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory 45-50% HPLC ([1:1 MeCN/MeOH]/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a tan solid (85 mg, 43%). 1H NMR (DMSO-d6) δ: 10.95 (s, 1H), 7.19-7.31 (m, 3H), 7.07-7.18 (m, 3H), 6.08 (s, 2H), 4.26 (d, J=12.6 Hz, 2H), 3.66 (br. s., 1H), 3.17 (t, J=11.7 Hz, 2H), 2.41-2.49 (m, 1H), 2.35 (s, 3H), 2.24-2.31 (m, 1H), 1.90 (br. s., 2H), 1.74-1.82 (m, OH), 1.43-1.57 (m, 3H), 1.35-1.43 (m, 1H), 1.32 (ddd, J=8.3, 6.6, 4.3 Hz, 0H); ESI-MS: m/z 452.3 (M+H)+. It was noted that rotamers were present.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:9]([O:11]CC)=[O:10])=[C:4]([F:20])[CH:3]=1>CO.C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:14]([CH3:19])[C:15]([F:16])([F:18])[F:17])[C:9]([OH:11])=[O:10])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)C(c1ccc(Cl)cc1F)[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](C(C(=O)O)c1ccc(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.26 g (13.6 mmol) of ethyl (3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in a mixture of 22 ml of methanol, 22 ml of THF and 11 ml of water, and 10.9 g of 50% strength aqueous sodium hydroxide solution were added at 0° C. The reaction mixture was stirred at RT overnight. Most of the organic solvents were then removed under reduced pressure. The mixture that remained was diluted with water and extracted with diethyl ether. After phase separation, the organic phase was discarded and the aqueous phase was acidified with semiconcentrated hydrochloric acid (pH about 2) and extracted repeatedly with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulphate and concentrated under reduced pressure. This gave 3.38 g (76.7% of theory) of the target product as a mixture of diastereomers which could be used without further purification for subsequent reactions.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.Cl[Si:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH4+].[Cl-]>C1COCC1>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([Si:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
NaH (60% dispersion in oil, 1.5 g, 37 mmol) is added slowly to a cold solution (0° C.) of 3,6-dibromocarbazole (10.4 g, 31 mmol) in dry THF (1000 ml). After stirring for two hours, a solution of ClSiPh3 (18.7 g, 62 mmol) in dry THF (200 ml) is added at 0° C. The mixture is stirred overnight, and saturated NH4Cl solution is added. The resulting salt is filtered off, and the organic phase is separated from the aqueous phase. The aqueous phase is extracted with CH2Cl2. The organic phase is washed twice with water. The combined organic phases are dried over Na2SO4. Filtration through SiO2 gives the desired product (quantitative).
Reaction SMILES: O1CCCC1.[S:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[C:20]([S:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:19]([Cl:28])=[CH:18][C:17]=1[Cl:29])C#N.[F:30][C:31]([Si](C)(C)C)([F:33])[F:32].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OC(=O)C)C.CCCCCC>[F:30][C:31]([F:33])([F:32])[S:6][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[C:20]([S:22][CH2:23][C:24]([F:27])([F:25])[F:26])[C:19]([Cl:28])=[CH:18][C:17]=1[Cl:29]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#CSCCCCCCOc1cc(SCC(F)(F)F)c(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: FC(F)(F)CSc1cc(OCCCCCCSC(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To 30 ml of tetrahydrofuran were added 1.04 g (2.49 mmol) of 6-thiocyanatohexyl-[2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenyl]ether and 1.06 g (7.45 mmol) of trifluoromethyltrimethylsilane. Thereto was added 0.25 ml (concentration: 1 mol/liter, 0.25 mmol) of tetrahydrofuran solution of tetra-n-butylammonium fluoride at 0° C., and reaction mixture was stirred for 2 hours at room temperature. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane ethyl acetate=20:1), to obtain 0.73 g (yield: 64%) of an intended product.
Reaction SMILES: O[CH:2]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)(Cl)Cl>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH:22]=[CH:21]2
Reactant: COC(=O)c1ccc(C(O)c2ccc3cc(OC)ccc3c2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Cc2ccc3cc(OC)ccc3c2)cc1

Procedure:
The title compound of Example 1, Step A (0.97 g, 3 mmol) was treated with 50 mL of chloroform containing 3% each of TFA and triethylsilane for 2 h. The reaction was partitioned between aq sodium bicarbonate and EtOAc. The organic phase was concentrated and the resultant residue was purified by flash chromatography on silica gel (mobile phase=15:85 (v/v) EtOAc:hexanes) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12]Br)[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[H-].[Na+].O.[OH-].[Li+]>CN(C)C=O.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][O:14][CH2:15][C:16]2([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(=O)O)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 3-bromo-5-(bromomethyl)benzoate (2.1 g, 6.81 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.8 g, 6.2 mmol) were combined in dimethylformamide (21 mL) and cooled to 0° C. The reaction was treated with sodium hydride (298 mg, 12.4 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction was cooled to 0° C. and treated lithium hydroxide monohydrate (0.54 g, 13.6 mmol). The solution was stirred at room temperature for 16 h and the solvents evaporated. The resultant residue was diluted with water (10 mL) and the pH adjusted to ca. 1 with 1 N hydrochloric acid. The resultant white suspension was stored at 4° C. overnight and the product was collected by filtration, washed with a small amount of water, and dried in vacuo for several hours to afford 2.4 g (70%) as a white powder. LC/MS: tR=3.33 min, 506.20 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH2:16][C:17]2([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH2:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:28]([C:30]1[S:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29].C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:28]([C:30]1[S:34][C:33]([C:2]2[N:7]=[N:6][C:5]([N:8]([CH2:16][C:17]3([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:18][CH2:19][CH2:20]3)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(Cl)nn1
Reactant: N#Cc1ccc(B(O)O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ccc(C#N)s2)nn1
Temperature: 140 °C
Yield: 31.9 %

Procedure:
t-Butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (900 mg, 2.29 mmol, 1 equiv), 5-cyanothiophen-2-ylboronic acid (390 mg, 2.52 mmol, 1.1 equiv), (dppf)PdCl2 (164 mg, 0.23 mmol, 0.1 equiv), nitrogen-sparged dioxane (6.0 mL) and aq. 2 N K2CO3 (2.3 mL) were combined and heated in a microwave reactor for 30 min at 140° C. The reaction mixture was filtered through a Celite plug and the filtrate was concentrated. The resulting residue was purified on silica gel using a mixture of ethyl acetate and hexanes to provide the title compound as a yellow oil (340 mg, 32%), LRMS (M+H+) m/z 466.3.
Reaction SMILES: [CH2:1]([NH2:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[O:16]=[C:12]([CH3:11])[CH2:13][C:14]([NH:10][CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: NCC=Cc1ccccc1
Reactant: C=C1CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)NCC=Cc1ccccc1

Procedure:
3.06 g (23.0 mmol) of cinnamylamine, 2.32 ml (30.1 mmol) of ketene dimer and 0.321 ml (2.30 mmol) of triethylamine were heated at 70° C. under stirring in 23 ml of toluene for 3 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:16]([OH:18])=O)[CH2:8]2.C1(C)C=CC=CC=1.S(Cl)(Cl)=O.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>C(Cl)Cl.O>[O:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:37]=[CH:38][C:39]([NH:40][C:16]([CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]=4[O:2][CH3:1])[CH2:8]3)=[O:18])=[CH:41][CH:42]=2)[CH2:34][CH2:35]1
Reactant: COc1ccc([N+](=O)[O-])c2c1CCC(C(=O)O)C2
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1ccc([N+](=O)[O-])c2c1CCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.3 g, 5 mmol), toluene (20 mL) and thionyl chloride (1.8 mL, 25 mmol) was heated at 80° C. for 1 h. The solvents were removed in vacuo and the residue, dissolved in methylene chloride (10 mL), was added to a solution of 4-morpholinoaniline (890 mg, 5 mmol) and triethylanmine (1.0 g, 10 mmol) in methylene chloride (20 mL) at 0° C. The mixture was stirred at 20° C. for 2 h, water was added and the precipitate was filtered to yield 1.9 g (90%) of the title product as crystals: mp 251-253° C.; EIMS (70 eV) m/z (relative intensity) 411 (100, M+).
Reaction SMILES: [S:1]([O-])(=O)(=O)[CH3:2].S[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>C(#N)C>[N:10]1[CH:11]=[CH:12][CH:7]=[CH:8][C:9]=1[S:1][C:2]1[CH:12]=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Sc1ccncc1
Reactant: CS(=O)(=O)[O-]
Solvent: CC#N
Product: c1ccc(Sc2ccccn2)nc1
Yield: 22.8 %

Procedure:
This product (4) is treated with 4-mercaptopyridine (129 mg; 1.4 equivalents) in acetonitrile (2 ml) at 0° C. for 1 hour to give pyridylthioylide (7) as in Example F-3. This is heated in toluene (35 ml) at 110° C. for 1 hour as in Example E-8 to give 6α-(1-hydroxyethyl)-1-ethyl-2-(4-pyridylthio)methyl-1-carbapen-2-em-3-carboxylic acid p-methoxybenzyl ester (b) {86 mg; IR (CHCl3)ν: 3680, 3604, 1772, 1712, 1612, 1586 cm-1, Yield: 22.8%} and two other products.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].I[CH2:28][CH:29]([OH:32])[CH2:30][OH:31].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: OCC(O)CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A solution of 7.34 g. of 4-(8-cyclohexyloctylamino)-benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[NH:7][C:6]=2[CH:24]=1.C(N(C(C)C)CC)(C)C.[CH3:34][Si:35]([CH3:42])([CH3:41])[CH2:36][CH2:37][O:38][CH2:39]Cl.O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[N:7]([CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:42])([CH3:41])[CH3:34])[C:6]=2[CH:24]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc(Cn2nc(-c3nc4ccc(Br)cc4[nH]3)cc2C)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(-c3nc4ccc(Br)cc4n3COCC[Si](C)(C)C)cc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 6-bromo-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1H-benzimidazole (Example 37, 600 mg, 1.57 mmol) in dichloromethane (20 mL) were added diisopropylethylamine (0.82 mL, 4.72 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.36 mL, 2.36 mmol) and the resulting mixture was stirred at rt for 16 h. Water was then added and the mixture was extracted with dichloromethane (1×50 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was then purified with an ISCO CombiFlash Companion using gradient elution from 0% to 30% EtOAc in hexanes to afford the title compound as a white solid (560 mg, 70%, mixture of two regioisomers): Isomer 1 (less polar): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 1H), 7.78 (d, 1H), 7.60-7.63 (dd, 1H), 7.31-7.36 (m, 4H), 6.95 (s, 1H), 6.34 (s, 2H), 5.57 (s, 2H), 3.61 (t, 2H), 2.50 (s, 3H), 2.46 (s, 3H), 0.91 (t, 2H), 0.00 (s, 9H); ES-MS m/z 512.21, HPLC RT (Method C) 4.05 min. Isomer 2 (more polar): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 1H), 7.79 (d, 1H), 7.59-7.62 (dd, 1H), 7.31-7.34 (m, 4H), 6.94 (s, 1H), 6.35 (s, 2H), 5.57 (s, 2H), 3.61 (t, 2H), 2.50 (s, 3H), 2.47 (s, 3H), 0.92 (t, 2H), 0.00 (s, 9H); ES-MS m/z 512.11, HPLC RT (Method B) 4.03 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][C:14](=O)[CH2:13][C:12]=3[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[N:9]=2)=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.[BH3-]C#N.[Na+].Cl>CO.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH:14]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:13][C:12]=3[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)n1)CCC(=O)C2
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)n1)CCC(N1CCCC1)C2
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step F (0.128 g) in MeOH (4 mL) was added of bromocresol green (0.003 g), pyrrolidine (0.06 mL), and NaBH3CN (0.20 g). To this mixture was added 1 M HCl in MeOH until a persistent color change to yellow was observed. After 30 min, the mixture was quenched with 1 M NaOH and poured into water (50 mL). The mixture was extracted with CH2Cl2, dried and concentrated. Chromatography on SiO2 (0 to 5% 2 M NH3 in MeOH/CH2Cl2) afforded 0.015 g of the desired compound. MS (ESI): exact mass calcd. for C21H26FN3, 339.21; m/z found, 340.4 [M+H]+. 1H NMR (CDCl3): 7.59-7.54 (m, 2H), 7.18-7.13 (m, 2H), 3.76-3.68 (m, 1H), 3.50-3.44 (m, 1H), 3.41-3.35 (m, 1H), 3.28-3.14 (m, 2H), 3.0-2.93 (m, 1H), 2.88-2.70 (m, 4H), 2.36-2.23 (m, 3H), 2.19-2.09 (m, 1H), 1.98-1.87 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O.O>O1CCCC1>[Br:23][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)c1ccc(-c2cccn2-c2ccc(F)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2ccc(Br)n2-c2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 71 %

Procedure:
0.32 g (1.0 mmol) of 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 33) was dissolved in 10 ml of anhydrous tetrahydrofuran, and 0.18 g (1.0 mmol) of N-bromosuccinimide was added to the resulting solution, whilst ice-cooling. The mixture was then stirred, whilst ice-cooling for 1 hour and then at room temperature for a further 1 hour. At the end of this time, water was added to the mixture, and the resulting mixture was extracted with methylene chloride. The organic extract was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The resulting residue was applied to a silica gel chromatography column and eluted with a 1:3 by volume mixture of ethyl acetate and hexane, to give 0.28 g of the title compound as a white powder (yield 70%), melting at 174-176° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[NH:5][CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:3]1.O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:3]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1cccnc1)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 4,4-dimethyl-2-(2-(pyridine-3-sulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous Sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 4,4-dimethyl-2-[2-(pyridine-3-sulfonylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 438.20.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:30])[N:9]([CH2:22][CH2:23][S:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH:10]1[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.O1CCCC1>[C:3]([O:7][C:8](=[O:30])[N:9]([CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1)[CH2:22][CH2:23][S:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(CCSc1cccs1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCSc1cccs1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 1 mL of a methanol solution containing 66 mg of tert-butyl(2-(2-thienylthio)ethyl)(1-(trifluoroacetyl) piperidin-4-yl)carbamate, 0.2 mL of water was added, and 32 mg of potassium carbonate was added under cooling with ice, and the mixture was stirred at a room temperature for 20 minutes. Thereto was added 0.5 mL of methanol, and the mixture was stirred at room temperature for 1 hour and 10 minutes. The reaction mixture was added with 0.6 mL of tetrahydrofuran, and stirred for 10 minutes, and the solvent was removed under reduced pressure. The residue thus obtained was added with ethyl acetate and water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 43 mg of a colorless oily substance, tert-butyl(piperidin-4-yl)(2-(2-thienylthio)ethyl)carbamate.