Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COc1ccccc1CCl
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1CNCc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-methoxybenzyl chloride (1.50 g, 9.5 mmol) and 2-(Aminomethyl)pyridine (5.18 g, 47 mmol) were dissolved in 800 mL CH3CN. To this solution was added potassium carbonate (1.324 g, 9.5 mmol) and the mixture was stirred at room temperature for three days. The solvent was evaporated, and the residual oil was dissolved in CH2Cl2 (75 mL) and extracted with water (75 mL×3). The combined CH2Cl2 layers were reduced in volume, and the resulting yellow-orange oil was purified by silica gel chromatography eluting with CH2Cl2, followed by a 3% (NH3)MeOH/97% CH2Cl2 solution (62%). 1H NMR (CDCl3) δ 8.520 (dd, 1H, Ar), 7.600 (m, 1H, Ar), 7.335 (d, 1H, Ar), 7.27 (d, 1H, Ar), 7.211 (t, 1H, Ar), 7.113 (m, 1H, Ar), 6.895 (t, 1H, Ar), 6.832 (d, 1H, Ar), 3.921 (s, 2H, —CH2—), 3.864 (s, 2H, —CH2—), 3.800 (s, 3H, —OCH3), 3.043 (s(br), 1H, —CH—). Mass Spec.=229.13 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1
Reactant: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-{2-[2-((R)-1-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl}azetidine-1-carboxylic acid tert-butyl ester (156 mg, 0.28 mmol) in DCM (5 mL) was added TFA (2 mL) and the resulting mixture stirred at r.t. for 45 min. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (114 mg, 90%). LCMS (method A): RT 1.80 min [M+H]+ 449.4
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.[Cl-].[NH4+].CCOCC>O1CCCC1>[Br:16][C:10]1[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: Clc1cccc2cc(-c3ccco3)nn12
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1cccc2c(Br)c(-c3ccco3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
7-Chloro-2-(2-furyl)-pyrazolo[1,5-a]pyridine (0.23 g, 1.05 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0° C. N-Bromosuccinimide (0.19 g, 1.05 mmol) was added. The reaction was stirred for 1 hour. The reaction solution was poured into equal volumes (10 mL) of saturated aqueous ammonium chloride and ether. The ether layer was collected and the solvent removed in vacuo to give the crude product The product was purified by silica gel chromatography (6:1 hexane:ethyl acetate) to give 0.3 g (96%) of 3-bromo-7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine as a solid. 1H NMR (CDCl3) δ 7.63 (d, 1H), 7.51 (d, 1H), 7.29 (d, 1H), 7.21 (dd, 1H), 6.98 (d, 1H), 6.58 (dd, 1H); MS m/z 298 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[C:10]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[C:9]([N+:32]([O-:34])=[O:33])[CH:8]=1)CCC.Cl>[OH-].[Na+]>[CH2:25]([O:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][C:10]2[C:11]([S:13](=[O:15])(=[O:16])[NH2:14])=[CH:12][C:7]([C:6]([OH:35])=[O:5])=[CH:8][C:9]=2[N+:32]([O-:34])=[O:33])=[CH:23][CH:22]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCOC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(OCc3ccccc3)cc2)c(S(N)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of n-butyl-4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoate (7.3 g) in 1N sodium hydroxide (120 ml) was heated on a steam bath for 45 minutes. After cooling and acidification by addition of 4N hydrochloric acid, the precipitated 4-(4-benzyloxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. After drying, the compound was obtained with a melting point of 247° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:37]([F:40])([F:39])[F:38])=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C@@H:14]([CH2:15][O:16]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:13][CH2:12][C:11]1=[O:36])[C:5]#[N:6]>O1CCOCC1.Cl.O>[OH:16][CH2:15][C@H:14]1[CH2:13][CH2:12][C:11](=[O:36])[N:10]1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([C:37]([F:40])([F:38])[F:39])[C:2]=1[CH3:1]
Reactant: Cc1c(N2C(=O)CC[C@@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)ccc(C#N)c1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(N2C(=O)CC[C@@H]2CO)ccc(C#N)c1C(F)(F)F
Reaction time: 4 h
Yield: 79.3 %

Procedure:
To a solution of (R)-3-methyl-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (3h) (0.48 g, 0.93 mmol) in 1,4-dioxane (15 mL), 2M HCl in 1,4-dioxane (5 mL) was added at 0° C. and stirred for 4 h. After completion of reaction (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were washed with water (2×30 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound was purified by column chromatography to provide the alcohol 3i (0.22 g, 79%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[C:26]([F:28])[C:25]([OH:29])=[C:24]([F:30])[CH:23]=1)=[O:18])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:29][C:25]3[C:24]([F:30])=[CH:23][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:27][C:26]=3[F:28])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCC2)n1
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 71 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.040 g, 0.18 mmol) obtained in Step C of Preparation Example 37 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.045 g, 0.18 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.050 g, 69%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])[CH3:15]>>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:26]([NH:25][C:17]1[C:16]([CH:14]([CH3:13])[CH3:15])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:22]([CH3:24])[CH3:23])=[O:27])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCOC(=O)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1

Procedure:
In a manner similar to Example 134, phenylacetic acid, ethyl ester was condensed with 2,6-bis (1-methylethyl)phenyl isocyanate to give the title compound, mp 168°-170° C.
Reaction SMILES: [CH:1](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[C:39]([NH2:40])=[CH:38][C:37]([Br:41])=[CH:36][N:35]=2)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:34]3=[N:35][CH:36]=[C:37]([Br:41])[CH:38]=[C:39]3[N:40]=[CH:1]2)=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cc(Br)cnc1Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1cnc2c(c1)ncn2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trimethyl orthoformate (9.0 mL, 81 mmol) and p-toluenesulphonic acid (384 mg, 2.0 mmol) were added to a solution of N2-[4-(benzyloxy)phenyl]-5-bromopyridine-2,3-diamine (3 g, 8.1 mmol) in dichloromethane (40 mL) and the reaction mixture stirred at rt for 4 h. Next, the precipitated material was collected by filtration, redissolved in CH2Cl2 and the solution washed with 10% NaOH (aq) (200 mL) and brine (200 mL), then dried over MgSO4 and concentrated in vacuo to afford 3-[4-(benzyloxy)phenyl]-6-bromo-3H-imidazo[4,5-b]pyridine. 1H NMR (400 MHz, CDCl3) δ 5.14 (s, 2H), 7.16 (d, J=8.8 Hz, 2H), 7.33-7.47 (m, 5H), 7.58 (d, J=8.8 Hz, 2H), 8.25 (s, 1H), 8.28 (d, J=2 Hz, 2H) and 8.46 (d, J=2 Hz, 2H); MS (ES+): m/z 380 [Br79 MH+], 382 [Br81MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:21]1([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CCCCCC>[C:21]1([N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:15]4[C:16]([C:13]=3[CH:14]=2)=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc(N(c3ccccc3)c3ccc4c(c3)c3ccccc3n4-c3ccccc3)cc2)cc1

Procedure:
The Rf values of the objective substance, 3-bromo-9-phenyl-9H-carbazole, and N-phenyl-N-(4-phenylphenyl)amine were respectively 0.65, 0.73, and 0.54, which were obtained by silica gel thin layer chromatography (TLC) (with a developing solvent containing ethyl acetate and hexane in a 1:5 ratio).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([CH3:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+]>CN(C)C=O>[OH:18][CH:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:27][C:28]([OH:30])=[O:29])=[C:10]([CH3:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: Cc1c(O)cc2c(c1Cl)C(O)C(C)(C1CCCC1)C2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OCC(=O)O)cc2c(c1Cl)C(O)C(C)(C1CCCC1)C2

Procedure:
(1-Hydroxy-2-cyclopentyl-2,6-dimethyl-7-chloro-5-indanyloxy)acetic acid is prepared following substantially the same procedure described in Example 4, Step F, using the following substances: 2-cyclopentyl-2,6-dimethyl-7-chloroindan-1,5-diol (4.2 g., 0.015 mole); potassium carbonate (3.6 g.); ethyl bromoacetate (3.1 ml.); and dimethylformamide (35 ml.), and hydrolyzing the resultant ester with aqueous sodium hydroxide in accordance with Example 4, Step F, there is obtained (1-hydroxy-2-cyclopentyl-2,6-dimethyl-7-chloro-5-indanyloxy)acetic acid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[CH2:23][CH2:22][C@H:21]([OH:24])[C:20]2=[O:25])=[CH:16][CH:15]=1>ClCCl.O>[CH3:8][S:9]([O:24][C@H:21]1[CH2:22][CH2:23][N:19]([CH2:18][C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:27][CH:26]=2)[C:20]1=[O:25])(=[O:11])=[O:10]
Reactant: O=C1[C@@H](O)CCN1Cc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccc(Cl)cc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
Triethylamine (0.825 mL, 5.92 mmol) and methansulfonyl chloride (0.338 mL, 4.34 mmol) was added to a stirred solution of (S)-1-(4-chlorobenzyl)-3-hydroxypyrrolidin-2-one (890 mg, 3.94 mmol) in dichloromethane (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was diluted with water and the aqueous mixture was extracted with dichloromethane. The combined organic layers were washed with 10% sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel column chromatography (0-100% EtOAc). The pure fractions were combined and concentrated in vacuo to afford (S)-1-(4-chlorobenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (1.1 g, 3.62 mmol, 92% yield) as a white solid: LC-MS (M+H)+ 304.1; 1H NMR (500 MHz, chloroform-d) δ 7.38-7.33 (m, 2H), 7.22-7.17 (m, 2H), 5.25 (dd, J=8.2, 7.6 Hz, 1H), 4.52-4.41 (m, 2H), 3.40-3.31 (m, 4H), 3.25 (dt, J=10.0, 7.3 Hz, 1H), 2.58 (dddd, J=13.7, 8.4, 7.5, 3.3 Hz, 1H), 2.33-2.20 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.Cl.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:31]([NH:38][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNCc4ccccc4)cc2)CCO3)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A suspension of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g), benzylamine hydrochloride (0.5 g) and potassium carbonate (0.6 g) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-((benzylamino)methyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 117) (0.08 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[O:3]1.ClC1C=C(C=CC=1)C(OO)=[O:22]>ClCCl>[CH3:1][C:2]1([CH3:16])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:15])=[O:22])=[CH:10][CH:9]=2)[O:3]1
Reactant: CSc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(C2=CC(=O)C(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 107.7 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone (10 g) in 200 ml dichloromethane at 0° C., was added slowly dropwise 4.8 g of m-chloroperoxybenzoic acid (m-CPBA) dissolved in 50 ml dichloromethane. After the reaction mixture was stirred at 0° C. for another two hours, the reaction solution was concentrated in vacuo. The resulting residue was extracted with water and dichloromethane (50 ml×3), followed by washing with aqueous sodium carbonate. The organic layer was concentrated and the crude product was purified by column chromatography (hexane/ethylacetate) to obtain 7.5 g of 2,2-dimethyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone as a solid. mp: 108-109° C. NMR: δ1.51 (s, 6H), 2.78 (s, 3H), 6.06 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H). IR (cmu−1): 2925, 1697, 1603, 1558, 1173, 1087, 1049.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH3:21])=[O:19].Cl>O.O1CCOCC1>[CH3:21][O:20][C:18]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:19]
Reactant: CNCCCCCC(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N(C)CCCCCC(=O)O
Temperature: 25 °C
Yield: 81.3 %

Procedure:
N-methyl-caprolactam (15 g, 118 mmol) was combined with barium hydroxide (10.1 g, 72 mmol) and water (150 ml). The suspension was warmed to 110° C. for 18 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 6-(methylamino)hexanoic acid as a white solid (10.7 g). 6-(Methylamino)hexanoic acid (5 g, 34.5 mmol), and potassium carbonate (18 g, 130 mmol) were suspended in water (50 ml) and dioxane (25 ml) then cooled to 0° C. Methyl chloroformate (13 ml, 168 mmol) was added over 1 minute, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 6-[(methoxycarbonyl)(methyl)amino]hexanoic acid as a thick clear oil (5.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:69]1([CH2:75][C:76](O)=[O:77])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:76](=[O:77])[CH2:75][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2ccccc2)C2CC2)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.56 mmol) in CH2Cl2 (6 mL) are subsequently added Et3N (0.094 mL, 0.67 mmol), 1-hydroxy-benzotriazol hydrate (0.09 g, 0.67 mmol), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (0.129 g, 0.67 mmol) and phenylacetic acid (0.09 g, 0.67 mmol), followed by stirring overnight. The reaction mixture is diluted with CH2Cl2 and then washed with 1N HCl (5 mL), saturated aqueous NaHCO3 and brine, the organic layer is dried over MgSO4 and concentrated. Purification by flash chromatography (eluent: hexane/AcOEt 25:75, then AcOEt 100%) gives the title compound as colorless oil. MS (LC-MS): 652.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.80 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:12]1[C:11]([C:16]([F:17])([F:18])[F:19])=[CH:10][C:9]2[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:15]
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-ethyl-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M191) (365 mg, 0.69 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (122 mg, 43%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH2:15]1OCCOCCOCCOCCOCCOC1.CI.[H-].[Na+]>CN(C=O)C>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([CH:4]([CH3:15])[C:3]([O:2][CH3:1])=[O:14])=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 697.9 %

Procedure:
A mixture of (4-nitro-phenyl)-acetic acid methyl ester (3.0 g, 15 mmol), 18-crown-6 (396 mg, 1.5 mmol), and methyl iodide (3.74 mL, 60 mmol) were combined in DMF (50 mL) and cooled to 0° C. Sodium hydride (660 mg, 16.5 mmol) was added. The solution was stirred with warming to room temperature overnight. The solution was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 2.19 g (70%) of the title compound. MS (DCI) m/e 210 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH3:14]I>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:14])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1ccnc(Cl)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)N(C)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 600.9 %

Procedure:
A mixture of 10 g (59 mmol) N-(2-chloropyridin-4-yl)acetamide (commercially available), 9.8 g (17.6 mmol) pulverized KOH and 4.1 ml (6.4 mmol) methyl iodide in 60 ml acetone was stirred at room temperature for 2 h. After evaporation of all volatiles the residue was taken up in water and extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated to yield 7.1 g (66%) of the title compound as off-white solid. MS: (m/e): 345.2 (MH+).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].CO.ClCCl>ClCCl.C(Cl)(Cl)Cl>[CH2:25]([O:24][C:22]([N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2)CC1
Temperature: -6 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
A suspension of 4-hydroxy-4-phenylpiperidine (10 g) in dichloromethane (90 mL) was treated with triethylamine (5.71 g) and cooled to -6° C. This reaction mixture was treated with benzyl chloroformate (9.62 g) in 1 mL portions, stirred for 3 hours and diluted with chloroform (100 mL), washed with 1N HCl, and extracted with chloroform. The organic layers were washed with brine, dried and evaporated to afford the crude material. Chromatography, with methanol:dichloromethane (1:30) as the eluent, gave the benzyloxycarbonylpiperidine (9.4 g); MS: m/z=312(M+1); NMR: 1.6 (d, 2, J=10), 1.77-1.89 (m, 2), 3.91 (m, 2), 5.09 (s,2), 7.18-7.48 (m, 10).