Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][C@@H:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:19](Cl)=[O:20]>C(Cl)Cl>[C:8]1([C@H:7]([NH:14][C:19]([C:18]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:16]([Br:15])[CH:17]=2)=[O:20])[CH3:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)N[C@H](C)c2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a 500 mL Erlenmeyer flask equipped with a stir bar was added 100 mL of sat. aq. NaHCO3 solution followed by 2.79 g of (R)-α-methylbenzylamine (0.023 mol) in 100 mL of CH2CH2. 3-Bromo-4-methylbenzoyl chloride in CH2Cl2 (from above) was added dropwise to the Erlenmeyer flask and the reaction mixture was continued to stir at RT for 16 hours. The organic phase was diluted with 50 mL of CH2CH2, separated from aqueous phase, dried over Na2SO4 and concentrated in vacuo. The residue was washed with 50 mL of Et2O and dried in an oven at 40 C overnight to afford light yellow solid (7.0 g, 0.022 mol, 96%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Na].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCBr
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCCSc1nc2ccccc2[nH]1
Yield: 97.5 %

Procedure:
50 g of 2-mercaptobenzimidazole are dissolved in 300 ml of ethanol, and a solution of 7.65 g of sodium in 150 ml of ethanol is added at room temperature, with stirring. The mixture is stirred for a few minutes at room temperature and 64.3 g of ethyl 4-bromobutyrate are added rapidly. The reaction mixture is refluxed for 6 hours and then cooled. The solvents are evaporated off to dryness under vacuum, the residue is taken up with water and the crystals obtained are filtered off, washed with water and then with ether and dried to give 85 g of ethyl 4-(benzimidazol-2-yl)mercaptobutanoate in the form of crystals melting at 70°-72° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5](=[O:26])[CH2:6][C:7]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)(O)[CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][CH3:19].COC(=O)CC(=O)CC(C1CCCC1)(O)CCC#CC1C=C(C)C(O)=CC=1C>>[CH:21]1([C:7]2([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18][CH3:19])[O:27][C:3](=[O:2])[CH2:4][C:5](=[O:26])[CH2:6]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)CC(=O)CC(O)(CCC#Cc1ccccc1SC)C1CCCC1
Agent: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Product: CSc1ccccc1C#CCCC1(C2CCCC2)CC(=O)CC(=O)O1

Procedure:
The desired product was prepared analogously to example F(1), substituting 5-cyclopentyl-5-hydroxy-9-(2-methylsulfanyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester (43 mg, 0.11 mmol) from Step 2 below in place of 5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester. Yield: 38 mg, 97%. 1H NMR (CDCl3) δ: 1.41-1.69 (m, 8H), 1.94-2.01 (m, 2H), 2.13-2.18 (m, 1H), 2.36 (s, 3H), 2.55 (t, J=7.45 Hz, 2H), 2.67 (d, J=16.17 Hz, 1H), 2.87 (d, J=16.17 Hz, 1H), 3.34 (d, J=8.84 Hz, 2H), 6.93-7.01 (m, 2H), 7.14-7.16 (m, 1H), 7.24 (d, J=6.32 Hz, 1H). MS (ESI): 355 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:27](Cl)[C:28]([OH:30])=[O:29]>C(O)(C)C>[CH:4]1[C:3]2[C:8]3([CH2:10][CH2:9]3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH:27]([C:28]([OH:30])=[O:29])[O:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1ccccc1C1(c2ccccc2O)CC1
Reactant: O=C(O)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)C1Oc2ccccc2C2(CC2)c2ccccc2O1
Reaction time: 24 h

Procedure:
An 18.5 g (0.082 mole) sample of unpurified 1,1-bis(2-hydroxyphenyl)cyclopropane was combined with 44.0 g (0.32 mole) of potassium carbonate, 2.0 g (0.012 mole) of potassium iodide, 8.0 ml of dichloroacetic acid, and 400 ml of isopropyl alcohol. The mixture was heated at reflux with stirring for 24 hours. Another 8 0 ml of dichloroacetic acid was added and the mixture heated at reflux with stirring for another 48 hours. The volatiles were then removed by evaporation under reduced pressure. The solid that remained was dissolved in 300 ml of water. The resulting solution was extracted with 500 ml of ether, acidified with concentrated hydrochloric acid (carefully due to foaming), and then extracted with three 500 ml portions of ether. The latter ether extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound in crude form as a solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][C@H:38]([C:41](O)=[O:42])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([NH:28][C:41]([C@H:38]2[CH2:39][CH2:40][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37]2)=[O:42])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)NC2CC2)C1
Reaction time: 3 h

Procedure:
HATU (0.97 g, 2.5 mmol) and cyclopropylamine (0.14 g, 2.5 mmol) were added to a solution of (3S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (0.50 g, 2.3 mmol) and DIPEA (0.48 mL, 2.7 mmol) in DMF (15 mL). The reaction mixture was stirred for 3 h and the solvent was concentrated. The product was recovered in EtOAc and washed with water, saturated NaHCO3 solution, water and brine. The organic layer was dried over anhydrous MgSO4 and the solvent was concentrated to provide tert-butyl (3S)-3-[(cyclopropylamino)carbonyl]pyrrolidine-1-carboxylate as white solid. The intermediate was recovered in TFA (5 mL) and stirred for 2 h. The solvent was concentrated to provide the title compound as yellow oil that was used for the next step without further purification. Yield: 0.21 g (33%).
Reaction SMILES: [Li]CCCC.Br[C-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[C-:12]1([Br:17])[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:18].[Cl-].[CH:20]1([PH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>C1COCC1.CCCCCC>[CH:27]1([P:26]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C-:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1.[Br:17][C-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:18]
Reactant: C1CCC(PC2CCCCC2)CC1
Agent: [Fe+2]
Agent: Br[c-]1cccc1
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1cc[c-](P(C2CCCCC2)C2CCCCC2)c1
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
120 ml (0.3 mol) of n-BuLi (2.5 M in hexane) are added dropwise to a solution of 103 g (0.3 mol) of 1,1′-dibromoferrocene in 300 ml of THF at a temperature of <−30° C. The mixture is stirred at this temperature for a further 1.5 hours. It is then cooled to −50° C. and 66.2 ml (0.3 mol) of dicyclohexylphosphine chloride are added dropwise at such a rate that the temperature does not exceed −45° C. After stirring the mixture for a further 10 minutes, the temperature is allowed to rise to room temperature and the mixture is stirred for another one hour. After addition of 150 ml of water, the reaction mixture is shaken with hexane. The organic phases are dried over sodium sulphate and the solvent is distilled off under reduced pressure on a rotary evaporator. The residue is crystallized in ethanol. The product A2 is obtained in a yield of 84% (yellow solid). 1H NMR (300 MHz, C6D6): δ 1.20-2.11 (m, 22H), 3.97 (m, 2H), 4.23 (m, 2H), 4.26 (m, 2H), 4.41 (m, 2H). 31P NMR (121.5 MHz, C6D6): δ −8.3 (s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33]Cl)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([NH:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.CO.C(Cl)Cl.O.CCOCC>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:39]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNCCCC
Reactant: ClCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCCCN(CCCC)CCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1

Procedure:
(+,-) cis 7-Benzyloxy-4-[4-(2-chloroethyloxy)-phenyl]-3-phenyl-chroman (235 mg, 0.5 mmol), N,N-dibutylamine (323 mg, 2.5 mmol), potassium carbonate (138 mg, 1 mmol) and potassium iodide (16 mg, 0.1 mmol) in dimethylformamide (5 ml) was stirred at 60° C. for 2 weeks. The reaction mixture was cooled and ether and water was added. The aqueous phase was extracted with ether, and the combined organic phases were washed with water and brine, dried (magnesium sulphate), and evaporated. The product was isolated by silica column chromatography using methanol-methylenechloride (1+19) as eluent.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[N:8]([CH3:22])[N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:11]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:22][N:8]1[C:7]([CH2:6][CH2:5][CH2:4][OH:3])=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[N:9]1
Reactant: CCOC(=O)CCc1cc(-c2ccc(C(F)(F)F)cc2)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCCO

Procedure:
In analogy to the procedure described for example 1 a], 3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propionic acid ethyl ester was reduced with lithium aluminium hydride in diethyl ether to give 3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propan-1-ol as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][OH:29])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxypropanamide (1.32 g) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (1.04 g).
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:70]=[CH:69][C:8]([C:9]([NH:24][C:25]2[NH:26][C:27](=[O:68])[C:28]3[N:29]=[CH:30][N:31]([C@@H:34]4[CH2:37][C@H:36]([CH2:38][O:39]C(=O)C)[C@H:35]4[CH2:43][O:44][C:45]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:54]4[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=4)[C:46]4[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=4)[C:32]=3[N:33]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.CO.C(=O)([O-])[O-].[K+].[K+].P([O-])([O-])([O-])=O>C(Cl)Cl>[N:1]#[N:2].[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:24][C:25]2[NH:26][C:27](=[O:68])[C:28]3[N:29]=[CH:30][N:31]([C@@H:34]4[CH2:37][C@H:36]([CH2:38][OH:39])[C@H:35]4[CH2:43][O:44][C:45]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:54]4[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=4)[C:46]4[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=4)[C:32]=3[N:33]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:70][CH:69]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C(Nc2nc3c(ncn3[C@@H]3C[C@H](COC(C)=O)[C@H]3COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)c(=O)[nH]2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(Nc2nc3c(ncn3[C@@H]3C[C@H](CO)[C@H]3COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)c(=O)[nH]2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
The N2 -(4,4'-dimethoxytrityl)-9-[(1R,2R,3S)-2-(4,4'-dimethoxytrity)oxymethyl-3-acetoxymethyl-1-cyclobutyl]-guanine (447 mg, 0.49 mmole) obtained above is dissolved into a mixture consisting of methanol (5 ml) and methylene chloride (1 ml), potassium carbonate (76 mg, 0.55 mmole) is added under cooling with ice, and the mixture is stirred at room temperature overnight. After adding 0.2M phosphate buffer to the reaction mixture, it is extracted with ethyl acetate. The extract solution is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (methylene chloride:methanol=30:1) to obtain N2 -(4,4'-dimethoxytrityl)-9-[(1R,2R,3S)-2-(4,4'-dimethoxytrityl)oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine (364 mg, 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C-:18]#[N:19].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:18]#[N:19])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(OCc2ccccc2)cn1
Reaction time: 0.42 h
Yield: 86.6 %

Procedure:
To a solution of 5-benzyloxy-2-chloromethyl-pyridine (2.13 g, 9.11 mmol) described in Manufacturing Example 127-1-3 in ethanol (30 mL) and water (10 mL) was added sodium cyanide (580 mg, 11.8 mmol), which was stirred for 4 hours and 25 minutes under reflux. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate=1:1) to obtain the title compound (1.77 g, 87%).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[O:5]1)[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)Cl>[CH3:10][C:6]12[O:5][CH:4]([CH:2]([CH3:3])[O:1]1)[CH2:9][CH2:8][CH:7]2[OH:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CCCC(C(C)O)O1
Solvent: ClCCl
Product: CC1OC2(C)OC1CCC2O
Temperature: 25 °C

Procedure:
A solution of 11.60 g of 16B in 25 ml of methylene chloride was added drop by drop to a stirred solution of 16.44 g of m-chloroperoxybenzoic acid in 150 ml of methylene chloride under a nitrogen atmosphere at 3° C.±10° C. The mixture was allowed to warm to room temperature and after 2 hours was washed with 800 ml of 25% aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried (MgSO4) and stripped of solvent. The residue was chromatographed (high pressure liquid) over silica gel, using in sequence one liter each of six liquids: hexane, and five mixtures of ethyl acetate and hexane, as eluents, the volume ratios of the two components in the mixtures being, respectively: 210/790; 400/600; 400/600; 560/440; 800/200. One set of fractions was collected and stripped of solvent to give 5,7-dimethyl-4-hydroxy-6,8-dioxabicyclo(3.2.1)octane (18A), as a liquid, b.p.: not determined.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]([C:12](OCC)=[O:13])[C:7](OCC)=[O:8])#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].O>C(OCC)C>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH:6]([CH2:12][OH:13])[CH2:7][OH:8]
Reactant: CCOC(=O)C(CCCC#N)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCCCC(CO)CO
Temperature: 25 °C

Procedure:
6 g of diethyl 2-(3-cyanopropyl)malonate are added dropwise, at -10° C., to a suspension of 3 g of LiAlH4 in 100 ml of dry diethyl ether under N2. The mixture is slowly warmed to room temperature and then refluxed for 3 h. After renewed cooling to -10° C., the excess hydride is decomposed with water. The precipitate is removed on a frit and washed several times with diethyl ether. The ether solution is dried over MgSO4, filtered and evaporated in a rotary evaporator. Yield 0.66 g of 2-(4-aminobutyl)-1,3-propanediol, detectable in the 1H NMR and by C and H analysis. Glassy solid, melting point 126° C. (honey-like above 60° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].CCN(C(C)C)C(C)C>>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[O:6]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Br)cccc1C(=O)NCC(F)(F)F
Yield: 81 %

Procedure:
2-Amino-3-bromo-N-(2,2,2-trifluoroethyl)benzamide (501a) (1.67 g, 81%) was prepared according to the procedures described for 720 using (2-amino-3-bromo-benzoic acid (1.5 g, 6.94 mmol, Sigma Aldrich), 2,2,2-trifluoroethylamine hydrochloride (1.1 g, 8.33 mmol, TCI), and DIEA (2.9 mL, 16.66 mmol, Sigma Aldrich) as the reagents. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (1H, t, J=6.16 Hz) 7.52-7.63 (2H, m) 6.57 (1H, t, J=7.82 Hz) 6.48 (1H, s) 4.05 (2H, qd, J=9.75, 6.36 Hz). m/z (ESI, +ve) 298.9/300.9 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[O:7][CH:6]=[CH:5][CH:4]=1.[CH2:27]([N:29]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]=O)=[CH:38][CH:37]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH3:28].[O-]CC.[Na+]>C(O)C>[CH2:27]([N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C:36]1[CH:37]=[CH:38][C:39](/[CH:42]=[CH:2]/[C:3]2[O:7][CH:6]=[CH:5][CH:4]=2)=[CH:40][CH:41]=1)[CH3:28]
Reactant: c1ccc([P+](Cc2ccco2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCN(CCCCCO)c1ccc(C=O)cc1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CCCCCO)c1ccc(/C=C/c2ccco2)cc1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
In a 200 mL flask, 1A (18.47 g, 43.6 mmol) and N-ethyl-N-(4-formyl phenyl)-5-aminopentyl alcohol 1B (10.27 g, 43.6 mmol) were dissolved in anhydrous ethanol (115 mL) under Ar at RT. In a separate flask, sodium ethoxide (2.97 g, 43.6 mmol) was dissolved in anhydrous ethanol (51 mL). The ethanolic sodium ethoxide solution was added by addition funnel to the solution containing the starting reagents. The reaction mixture was then heated to 85° C. and stirred for 4 hours. The reaction mixture was evaporated and the product was extracted into dichloromethane against water. The crude product was purified on silica gel using 1:1 hexane:ethyl acetate. Product 2 was a red viscous liquid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([OH:8])[CH:5]([OH:7])[CH3:6].[CH3:9][OH:10].CO>C1(=O)OC(C)CO1>[CH2:4]([OH:8])[CH:5]([OH:7])[CH3:6].[C:4](=[O:8])([O:10][CH3:9])[O:2][CH3:1]
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Solvent: CC(O)CO
Solvent: CC1COC(=O)O1
Product: COC(=O)OC

Procedure:
In a process as described in FIG. 1 7 t/h (tonnes per hour) propylene carbonate is fed into the upper part of a reactive distillation zone. Sodium methanolate in 0.5 t/h propylene glycol/methanol mixture as transesterification catalyst is also passed into the upper part of zone in an amount of 0.05 t/h. Twenty t/h methanol, fed into a lower part of the distillation zone, passes upward, and reacts with the propylene carbonate to form propylene glycol product and dimethyl carbonate. The propylene glycol is recovered in an amount of 5 t/h.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:37]=[CH:36][C:23]([CH2:24][N:25]5[CH2:28][CH:27]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:26]5)=[CH:22][CH:21]=4)[N:16]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>Cl.O1CCOCC1>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH2:24][N:25]5[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]5)=[CH:36][CH:37]=4)[N:16]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(CCC4(c5ccccc5)CCCCC4)n3)cc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)C1CN(Cc2ccc(-c3noc(CCC4(c5ccccc5)CCCCC4)n3)cc2)C1
Reaction time: 5 h
Yield: 21 %

Procedure:
The glassy solid tert-butyl 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate was dissolved in 3 mL of 4N HCl in dioxane, and the mixture was stirred for 5 h. The reaction was followed by LC/MS and was evaporated and dried in vacuo. The residue was purified by prep. HPLC (Phenomenex S10 30×100 mm, 40 min gradient time, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA) to give the 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (47.5 mg, yield=21%) as a white solid. LC/MS: m/e 446.17 (M+H)+. 1H NMR (400 MHz, CD3OD): δ ppm 8.1 (d, J=8.28 Hz, 2H), 7.61 (d, J=8.28 Hz, 2H), 7.40-7.46 (m, 2H), 7.32-7.39 (m, 2H), 7.14-7.21 (m, 1H), 4.49 (s, 2H), 4.36 (d, J=7.28 Hz, 4H), 3.66-3.77 (m, 1H), 2.55-2.69 (m, 2H), 2.2-2.33 (m, 2H), 2.04-2.19 (m, 2H), 1.33-1.79 (m, 8H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[C:9]1([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23]CC)=O)[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:9]1([N:15]2[CH2:16][CH2:17][CH:18]([C:21](=[O:23])[CH2:2][C:1]#[N:3])[CH2:19][CH2:20]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1CCN(c2ccccc2)CC1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCN(c2ccccc2)CC1
Yield: 23.8 %

Procedure:
To a solution of ethyl isonipecotate (8.9 g) in CH2Cl2 (500 mL) was added triphenyl bismus (25 g) and Copper(II)acetate (10.3 g) at room temperature, the mixture was stirred overnight. After filteration, the mixture was extracted with CH2Cl2. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) as colorless crystals. To a solution of acetonitrile (1.9 g) in THF (200 mL) was added n-BuLi (41 mmol) at −78° C. Further, ethyl 1-phenylpiperidine-4-carboxylate (8.6 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-phenylpiperidin-4-yl)-2-cyanoethan-1-one (2.0 g) as colorless crystals. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.2 g) and 1-(1-phenylpiperidin-4-yl)-2-cyanoethan-1-one (0.5 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.6 g) as colorless crystals.