Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([C@H:8]1[CH2:9][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])=[CH:17][CH:16]=2)[CH2:11][CH2:12][N:13]1[C:31](=[O:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45 mg of 3-(S)-benzyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine was dissolved in dichloromethane, 1.1 equiv. of acetylchloride and 1.5 equiv. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature under nitrogen overnight. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford 51 mg of the title compound as free base. Yield 84%, Treatment with 1 equiv. of 1M HCl in dioxane gave the HCl salt. ES MS(+) m/z 453
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[Cl:11])[C:6]#[N:7].[C-:13]#[N:14].[K+]>C(O)C.O.C(OCC)(=O)C>[Cl:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:2][C:13]#[N:14]
Reactant: Cc1cc(C#N)cc(CBr)c1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(CC#N)c1Cl
Yield: 47.9 %

Procedure:
3-Bromomethyl-4-chloro-5-methyl-benzonitrile (0.9938 g, 4.06 mmol), potassium cyanide (0.529 g, 8.12 mmol) in ethanol (5.0 mL) and H2O (2.5 mL) was heated at 85° C. for 3 hr. The reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexane) to give 4-chloro-3-cyanomethyl-5-methyl-benzonitrile as a white solid (0.3707 g, 48%). 1H NMR (300 MHz, CDCl3): 7.61 (s, 1H), 7.51 (s, 1H), 3.83 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].O>CN(C=O)C.CCOC(C)=O>[C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)c1[nH]c2ccccc2c1CCSC(C)=O
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(C(=O)OC)c(CCSC(C)=O)c3ccccc32)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
To a solution of methyl 3-[2-(acetylthio)ethyl]-1H-indole-2-carboxylate (0.300 g, 1.1 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 0.048 g, 1.2 mmol) at −10° C., and the mixture was stirred at −10° C. for 15 minutes. To the mixture was added methyl 3-(bromomethyl)-benzoate (0.273 g, 1.2 mmol) at −15° C., and the reaction mixture was allowed to gradually come to room temperature and stirred overnight. To the mixture were added H2O (20 mL) and EtOAc (20 mL). The organic layer was dried over Na2SO4 and concentrated to give methyl 3-[2-(acetylthio)ethyl]-1-[[3-(methoxycarbonyl)phenyl]-methyl]-1H-indole-2-carboxylate as an oil (0.430 g). This material was used for the next reaction without further purification: 1H NMR (DMSO-d6) 2.32 (s, 3H), 3.10 (t, J=6.52 Hz, 2H), 3.31 (t, J=6.52 Hz, 2H), 3.80 (s, 3H), 3.83 (s, 3H), 5.85 (s, 2H), 7.17–7.23 (m, 2H), 7.34 (t, J=7.7 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:13]([N:21]1[CH:22]=[CH:23][CH:24]=[C:25]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CCCCCCCCn1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCn1cccc1C1=CC(=O)c2ccccc2C1=O
Yield: 32 %

Procedure:
6.32 millimol of 1,4-naphthoquinone and 3.16 millimol of N-octylpyrrole were stirred in 50 ml of chloroform in a round-bottomed flask for 5 hours at room temperature, the reaction being catalysed by addition of a few milligrams of para-toluenesulphonic acid. The reaction medium was diluted with 50 ml of chloroform and then washed four times with 50 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(1-octyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated, in the form of an oil, in a yield of 32% after purification by chromatography on a column of silica.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH2:23])[C:17]=2[N:16]=[CH:15]1.[N+](C1C2N=CSC=2C=CC=1)([O-])=O.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH:23][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:17]=2[N:16]=[CH:15]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2scnc12
Agent: CN(C)c1ccncc1
Agent: O=[N+]([O-])c1cccc2scnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2scnc12
Yield: 45.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-nitrobenzenesulfonyl chloride (1.7 g, 7.9 mmol), benzothiazol-4-ylamine (Intermediate 222) (1.0 g, 6.6 mmol), DMAP (cat), pyridine (2 ml, 24.8 mmol) and DCM (10 ml) at 0° C. for 5 h, gave the title compound (1.0 g, 45%) which was used in the next step without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>O.CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)[NH2:20])=[CH:24][CH:23]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
in said step (5) reacting the 4-(quinolin-2-ylmethoxy)phenylhydrazine product of said step (4) in H2O/methanol with p-chlorobenzyl chloride, tetrabutylammonium bromide and diisopropyl ethyl amine to yield 1-(p-chlorobenzyl)-1-[4(quinolin-2-ylmethoxy)phenyl]hydrazine.
Reaction SMILES: [CH3:1]/[C:2](/[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:17][CH:16]=1)=[CH:3]\[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1.[OH-].[K+].Cl>C(O)C.O.CCOCC>[CH3:1]/[C:2](/[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:19][CH:20]=1)=[CH:3]\[C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc(OCC=C(C)C)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)=CCOc1ccc(/C(C)=C/c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100 mg of ethyl 4-(E-2-methyl-2-(4-(3-methyl-2-butenoxy)phenyl)ethenyl)-benzoate in 3 ml of ethanol under argon is added dropwise a solution of 50 mg of potassium hydroxide in 3 ml of ethanol and 1 ml of water. The mixture is stirred at room temperature for 18 hours, cooled and acidified with 3N hydrochloric acid. The resulting precipitate is dissolved in ether, the ether solution washed with saturated aqueous sodium chloride and concentrated to give a solid which is recrystallized from aqueous methanol to give 4-(E-2-methyl-2-(4-(3-methyl-2-butenoxy) phenyl)ethenyl) benzoic acid.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]=1[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:7]2.[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].CN(C=O)C>O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:36][N:35]=[N:34][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24]=1[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC#N)ccc3c2)cnn1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)cnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
A mixture of 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (0.15 g, 0.3 mmol), prepared in the previous step, sodium azide (0.059 g, 0.9 mmol), ammonium chloride (0.048 g, 0.9 mmol) and 10 mL of DMF was stirred at 100° C. for 1.5 h. By TLC starting material remained. Additional sodium azide (0.059 g, 0.9 mmol) and ammonium chloride (0.048 g, 0.9 mmol) were added and the reaction stirred at 100° C. for 2 h. Again by TLC starting material remained. Additional sodium azide (0.059 g, 0.9 mmol) and ammonium chloride (0.048 g, 0.9 mmol) were added and the reaction stirred at 100° C. for 5 h. The reaction was diluted with water and extracted four times with ethyl acetate. The organic layers were combined and acidified with ˜3 mL 1N HCl. The mixture was swirled for one minute and then the solution was dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the resulting residue was taken up in 20 mL of water. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (0.107 g, 65%) as a tan solid, mp 219-220° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:4]=1.Cl.[N:37]1([C:42]([NH2:44])=O)C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:5]2[N:4]=[C:3]([CH2:2][NH:1][C:42]([NH2:44])=[NH:37])[CH:7]=[N:6]2)=[O:30])[N:17]=1
Reactant: NC(=O)n1cccn1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CN)n1)c1csc(N)n1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CNC(=N)N)n1)c1csc(N)n1)C(=O)O
Reaction time: 16 h
Yield: 14.7 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (60 mg, 0.089 mmol) and pyrazole-1-carboxamide hydrochloride (16 mg, 0.11 mmol) in DMF (3 mL) was added DIPEA (45 μL, 0.27 mmol). After stirring for 16 h, the solution was concentrated and washed with ether. The crude residue was purified by reverse phase prep HPLC (XBridge, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (7.5 mg, 15%) as a white solid. LCMS: m/z=571.9 (M−1); 1H NMR (400 MHz, D2O): δ 7.55 (s, 1H), 6.78 (s, 1H), 5.38 (d, J=5.2 Hz, 1H), 4.82-4.76 (m, 1H assumed; obscured by solvent residual peak), 4.76-4.72 (m, 2H assumed; obscured by solvent residual peak), 4.32 (s, 2H), 1.15 (s, 3H), 1.14 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C@@H:11]([NH2:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:22][S:23]([CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O)(=[O:25])=[O:24]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[C@@H:11]([NH:13][CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][S:23]([CH3:22])(=[O:24])=[O:25])[CH3:12])=[CH:5][CH:4]=1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: CS(=O)(=O)CC(=O)c1ccccc1
Agent: Cl
Product: C[C@H](NC(CS(C)(=O)=O)c1ccccc1)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1

Procedure:
The title compound was prepared from 3-(4-chlorophenyl)-2(S)(3-cyanophenyl)-1(S)-methyl-propylamine hydrochloride and 2-methanesulfonylacetophenone by the procedure of Example 33 as a mixture of two diastereomers. LC-MS: m/e=467 (M+1), 469 (M+3) (3.05 min and 4.05 min).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[C:17]([O:18][C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: N#Cc1cc(F)ccc1F
Reactant: Oc1cccnc1Cl
Product: N#Cc1cc(F)ccc1Oc1cccnc1Cl

Procedure:
2,5-Difluoro-benzonitrile was reacted with 2-chloropyridin-3-ol according to the method of Example 78A to provide the title compound. MS (DCI/NH3) m/z 249 (M)+, 251(M+2)+.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:19])([F:18])[CH2:15][CH2:16][OH:17].CCN(C(C)C)C(C)C.[N:29]1([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClCCl>[F:13][C:14]([F:19])([F:18])[CH2:15][CH2:16][O:17][C:2]([N:32]1[CH2:33][CH2:34][N:29]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:30][CH2:31]1)=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCC(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCCC(F)(F)F)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.1 g triphosgene and 2.3 ml 3,3,3-trifluoropropan-1-ol in 70 ml dichloromethane were added 9.0 ml DIPEA dropwise at 0° C. After 30 minutes 5.1 ml benzyl 1-piperazinecarboxylate and 34.5 ml DIPEA were added at 0° C. The reaction mixture was allowed to warm to RT overnight. Excess triphosgene was destroyed by adding a solution of 2.5 g NaOH in 200 ml water and stirring for 2 h. The layers were separated, the organic layer dried over MgSO4 and concentrated. The crude product thus obtained was purified by chromatography on silica using heptane/ethyl acetate 4/1 to 2/1 as eluent. Yield: 3.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#N.[OH-].[K+].CN(C)C=[O:17].[O:19]1[CH:21]([CH2:22][CH3:23])[CH2:20]1>O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH:4]1[CH2:20][CH:21]([CH2:22][CH3:23])[O:19][C:5]1=[O:17]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CN(C)C=O
Reactant: CCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC1CC(c2ccc(Cl)cc2Cl)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 186 g. (1 mole) of 2,4-dichlorobenzyl cyanide and 60 g. (1.1 mole) of powdered potassium hydroxide in 400 ml. of dry dimethyl formamide is added 75 g. (1 mole) of 1,2-epoxy butane dropwise at 10° C. The resulting brown reaction mixture is stirred at room temperature overnight. It is then poured into water and extracted with ether. The combined ether extracts are washed with water, 5% sodium chloride solution and dried over magnesium sulfate. Solvent is evaporated to give 228 g. of a brown oil which is assigned the iminolactone structure due to strong ir absorption at 1680 cm-1. This material is redissolved in toluene and 300 ml. 25% hydrochloric acid are added. The mixture is heated over a steam bath for two hours. The organic layer is separated and washed with water, saturated sodium chloride solution and dried over magnesium sulfate. Solvent is evaporated to give a light yellow oil which is further purified by vacuum distillation (150° C./0.2 mm) to give 200 g. of desired product.
Reaction SMILES: [Cl:1][C:2]([O:5]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[CH2:13]([O:15][CH2:16][CH2:17][OH:18])[CH3:14].N1C=CC=CC=1>O1CCCC1>[C:2]([Cl:1])(=[O:5])[O:18][CH2:17][CH2:16][O:15][CH2:13][CH3:14]
Reactant: CCOCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution (20 mL) of bis(trichloromethyl)carbonate (2.97 g) in tetrahydrofuran was dropwise added a solution (10 mL) of 2-ethoxyethanol (1.80 g) in tetrahydrofuran under ice-cooling. Then a solution (10 mL) of pyridine (2.43 mL) in tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-ethoxyethyl chlorocarbonate (1.29 g). A solution (15 mL) of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.23 g) obtained in Reference Example 1 in tetrahydrofuran was added pyridine (0.68 mL), and a solution (5 mL) of 2-ethoxyethyl chlorocarbonate obtained above in tetrahydrofuran was dropwise added to the mixture, and the mixture was stirred at room temperature for 3 days. After concentration of the reaction mixture under reduced pressure, water (50 mL) was added thereto and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:5, then 2:3). The purified product (1.60 g) was dissolved in diethyl ether (3 mL) and a 4N hydrogen chloride—ethyl acetate solution (3 mL) was added. The mixture was stirred overnight at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (0.94 g) as a white solid.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH:24]3[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:26]([CH3:40])([CH3:39])[CH2:25]3)[CH2:10][C:9]2([CH3:42])[CH3:41])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[P:44]1[O:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][O:45]1>>[CH3:50][C:47]1([CH3:51])[CH2:48][O:49][P:44]([N:23]([CH:24]2[CH2:25][C:26]([CH3:40])([CH3:39])[N:27]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:28]([CH3:30])([CH3:31])[CH2:29]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([P:44]2[O:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][O:45]2)[CH:11]2[CH2:12][C:13]([CH3:15])([CH3:14])[N:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]([CH3:42])([CH3:41])[CH2:10]2)[O:45][CH2:46]1
Reactant: CC1(C)COP(Cl)OC1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)COP(N(CCCCCCN(C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)P2OCC(C)(C)CO2)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)OC1

Procedure:
The title compound is prepared from N,N'-bis(1-cyclohexyloxy-2, 2,6,6-tetramethylpiperidin-4-yl)hexamethylenediamine and 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane according to the procedure of Example 11C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-:27]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:27])(=[O:24])=[O:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:27])(=[O:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCCCCCc1cccc(OCc2ccccc2)c1
Reactant: [F-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=S(=O)(F)CCCCCCCc1ccc(OCc2ccccc2)cc1
Product: O=S(=O)(F)CCCCCCCc1cccc(OCc2ccccc2)c1
Yield: 180.1 %

Procedure:
7-(3-Benzyloxy-phenyl)-heptanesulfonyl fluoride (13.2) was prepared as in 13.1 using 12.2 (0.149 g, 0.39 mmol) and NH4F (0.029 g, 0.78 mmol) in dry acetone (10 mL). Purification by flash column chromatography on silica gel gave the title compound (0.128 g, 91% yield) as a viscous liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=2)([C:14]2[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=2)[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=2)([C:14]2[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccc(Br)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A mixture of methyl 3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoate (865 mg, 1.34 mmol) in MeOH (10 mL)/THF (20 mL) and LiOH (2 N, 10 mL) was stirred at rt overnight. The reaction mixture was made acidic by addition of 1 N HCl to pH=1-2 and concentrated. The resulting residue was partitioned between EtOAc and sat. NaCl. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO (40 g siligel column, 0-10% MeOH/DCM over 30 min) to yield 3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoic acid as a colorless oil (650 mg, 81% yield). LCMS: RT=2.17 min [M+H] 600.88 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); HPLC: RT=4.45 min (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.2% PPA, flow rate 4 mL/min, wavelength 220 nm).