Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][C:9](=[O:22])[C:10]([OH:21])([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:3]1.[Br:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[Br-:23].[OH:21][C:10]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[C:9]([O:8][C@@H:4]1[CH2:5][CH2:6][CH2:7][N@@+:2]([CH3:1])([CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:3]1)=[O:22]
Reactant: BrCCCc1ccccc1
Reactant: CN1CCC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Solvent: CC#N
Product: C[N@@+]1(CCCc2ccccc2)CCC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Product: [Br-]
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Hydroxy-di-thiophen-2-yl-acetic acid (R)-1-methyl-piperidin-3-yl ester (2.1 g, 0.00623 mol) is dissolved in acetonitrile (5 ml) at 60° C. and 1-bromo-3-phenylpropane (1.43 ml, 0.00934 mol) is added dropwise. After 18 hours stirring at 60° C., the white solid is broken up and stirring continued for another 8 hours at this temperature. The suspension is cooled to room temperature and the solid filtered off. The solid is recrystallised from 3 ml of acetonitrile containing 2 drops of water to yield (1R,3R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-methyl-1-(3-phenyl-propyl)-piperidinium bromide (96a) as a white solid. The reaction mixture mother liquid is evaporated to dryness and the residue is purified by flash chromatography over C18 silica gel (70 g) using a gradient of water/acetonitrile 10010 to 0/100 over 25 minutes at 20 ml/min. The product containing fractions are combined and evaporated to dryness to yield (1S,3R)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-methyl-1-(3-phenyl-propyl)-piperidinium bromide (96b) as a white amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:26]([O:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A cooled solution of (R)-2-(tert-butoxycarbonylamino)-3-phenyl-1-propanol (92) (1 g, 4 mmol) in CH2Cl2 (20 ml) at 0° C. was treated with triethylamine (1.12 m, 8 mmol), pivaloyl chloride (0.74 ml, 6 mmol) followed by 4-(dimethylamino)pyridine (50 mg 0.4 mmol) and stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (1:4) as an eluant to give compound 94.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1)=[O:18])=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4].[NH:35]1[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1>>[Cl:27][C:9]1[CH:8]=[C:7]2[C:12]([C:13](=[O:26])[C:14]([CH2:15][NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:35]4[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]4)=[N:21][CH:20]=3)=[O:18])=[C:5]([C:3](=[O:4])[N:2]([CH3:34])[CH3:1])[N:6]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11][CH:10]=1
Reactant: OCCC1CCNCC1
Reactant: CN(C)C(=O)c1c(CNC(=O)c2ccc(Cl)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(N3CCC(CCO)CC3)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
4-(2-Hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carboxylic acid (7-chloro 2-dimethylcarbamoyl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared according to the procedure described for example 3-11, starting from the intermediate 7-chloro-3-{[(6-chloro-pyridine-3-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide and 2-(piperidin-4-yl)ethanol. MS calcd. for C32H34ClN5O4 [(M+H)+] 588.2, obsd. 588.3.
Reaction SMILES: [CH2:1]=[O:2].[CH2:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:12]>ClC(Cl)CCl>[Cl:12][CH2:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=O
Reactant: Cl
Reactant: CCCCCCCCO
Solvent: ClCC(Cl)Cl
Product: CCCCCCCCOCCl

Procedure:
75 g (2.5 mole) of paraformaldehyde were stirred in 250 ml 1,1,2-trichloroethane with 268 ml (2.5 mole) 1-octanol at 0°-5° C. HCl gas was passed for one hour. The product chloromethyloctyl ether can be isolated by evaporation of the excess solvent. Alternatively, a stock solution of 3M concentration is made in 1,1,2-trichloroethane and used as such, or kept refrigerated. Chloromethyloctylether may be distilled, b.p. 63°-64° C. (0.7 torr).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.N>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: Fc1ccc(I)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole (yield: 245 mg, 54%). mp 195-197° C. 1H NMR (300 MHz, CDCl3) δ 3.08 (s, 3H), 7.19 (m, 4H), 7.25 (m, 2H), 7.41 (d, J=9 Hz, 2H), 7.70 (m, 2H), 7.95 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 455 (M+H)+, 472 (M+NH4)+. Anal. calc. for C23H16ClFN2O3S: C, 60.78; H, 3.52; N, 6.17. Found: C, 60.81; H, 3.53; N, 5.93.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:7])[C:5]#[CH:6].Br[CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[CH2:9][O:7][CH:4]([CH3:3])[C:5]#[CH:6]
Reactant: C#CC(C)O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: C#CC(C)OCC(=O)OC

Procedure:
Sodium hydride (60% dispersion in mineral oil, 10 g, 0.25 mol), (±)-3-butyn-2-ol (21 g, 0.30 mol), and methyl bromoacetate were processed as described in Example 43A to provide the title compound. 1H NMR (CDCl3) δ 1.51 (d, 3H), 2.46 (d, 1H), 3.76 (s, 3H), 4.25 (AB q, 2H), 4.39 (dq, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pt](=O)=O.C(O)C>[NH2:14][C:5]1[C:6]2[CH2:7][CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][C:12]=2[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: [H][H]
Reactant: CN1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: CN1CCc2c(N)ccc(Cl)c2CC1

Procedure:
A suspension of 12.0 g. (0.05 mole) of 6-chloro-3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine, 100 ml. of ethanol and 0.2 g. of platinum dioxide is hydrogenated on a Parr apparatus at 25° C. and an initial hydrogen pressure of 60 p.s.i. After the rapid hydrogen uptake is completed, the mixture is filtered and the filtrate is concentrated in vacuo to give 9-amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: CC(C)C(=O)Cl
Product: CCc1noc(-c2sc(NC(=O)C(C)C)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and isobutyryl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1

Procedure:
Bromo-4-methyl-benzene of general formula H-1, where B, R1, R2, R3 and R4 are as defined above is reacted with copper cyanide in a polar solvent as dimethylformamide at elevated temperature to obtain the 4-methyl-benzonitrile of general formula H-2. The 4-methyl-benzonitrile of general formula H-2 is brominated by the treatment with N-bromosuccinimide in refluxing tetrachloromethane in the presence of a radical initiator like AIBN to obtain the 4-Bromomethyl-benzonitrile of general formula H-3.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][CH2:14][C@H:15]1[C:19](=[O:20])[O:18][CH2:17][C@@H:16]1[CH2:21][C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.Cl>CCCCCC.O1CCCC1>[CH3:13][CH2:14][C@@H:15]1[C:19](=[O:20])[O:18][CH2:17][C@@H:16]1[CH2:21][C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1
Reactant: CC[C@H]1C(=O)OC[C@@H]1Cc1cncn1C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@@H]1C(=O)OC[C@@H]1Cc1cncn1C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
0.97 ml of a 15% solution of n-butyllithium in hexane is added at 0° C. to a solution of 0.21 ml of diisopropylamine in tetrahydrofuran. After stirring for 15 minutes and cooling to -78° C., 100 mg of (+)-isopilocarpine dissolved in 1 ml of tetrahydrofuran are added, and the mixture is stirred at -78° C. for 10 hours. After the addition of 1 g of 2,6-di-tert.-butyl-4-methylphenol, warming to room temperature and addition of 15 ml of hydrochloric acid (0.5 N), the layers are separated. The aqueous layer is washed twice with 25 ml of chloroform. Concentration of the organic layer and preparative separation on an HPLC column gives optically pure (+)-pilocarpine which is converted into the pilocarpine nitrate, m.p. 174° C., αD =+81° (c=1.618, water) with nitric acid (65%) in ethanol. Reference1 : R. S. Compagnone, H. Rapoport, J. Org. Chem. 51, 1713-1719 (1986)
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[C:9]1([CH2:15][CH2:16][CH2:17][Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([OH:8])[CH2:17][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1sccc1Br
Reactant: Br[Mg]CCCc1ccccc1
Product: OC(CCCc1ccccc1)c1sccc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 3-bromo-thiophene-2-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([S:19][C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(S)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Sc2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-fluorobenzotrifluoride (9.85 g) and 4-aminothiophenol (7.51 g) in DMSO (60 mL), cooled in an ice bath, was added in one portion potassium t-butoxide (6.73 g). The resulting mixture was stirred at 0° C. for 10 minutes, then at 60° C. overnight. After cooling, the mixture was poured into water (600 mL) and the resulting mixture extracted with ether (2×200 mL). The organic phase was washed with 2N sodium hydroxide (50 mL), then with water (50 mL). After drying (MgSO4), the solvent was evaporated to give a brown solid. Recrystallization from hexane gave the title aniline as a yellow solid, m.p. 97-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[C:10]2[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:4][CH:3]=1.[CH2:18]1[CH2:24][S:21](=[O:23])(=[O:22])[O:20][CH2:19]1>C(O)C>[OH-:20].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[C:10]2[CH:15]3[CH2:14][CH2:13][N+:12]([CH2:19][CH2:18][CH2:24][S:21]([OH:23])(=[O:22])=[O:20])([CH2:17][CH2:16]3)[CH2:11]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CC=C2CN3CCC2CC3)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CCO
Product: O=S(=O)(O)CCC[N+]12CCC(CC1)C(=CCc1ccc(Cl)cc1)C2
Product: [OH-]
Temperature: -10 °C

Procedure:
Combine 7.43 g (0.03 mole) of 3-[2-(4-chlorophenyl)ethylidene]-1-azabicyclo[2.2.2]octane and 5.49 g (0.045 mole) of 1,3-propanesultone in 30 ml of ethanol and heat at reflux for 1-2 hours. Follow the reaction by thin-layer chromatography on silica gel (acetonitrile:NH4OH, 90:10). At the completion of the reaction cool the mixture to -10° C. Collect the resulting solid by filtration and wash with cold ethanol to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([C:30]([NH2:32])=[O:31])[O:27][C:26]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][O:16]CC2C=CC=CC=2)[CH2:10][CH2:9]1.[H][H]>CO.CCO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([C:30]([NH2:32])=[O:31])[O:27][C:26]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][OH:16])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: NC(=O)[C@H]1CN(c2ccc(N3CCN(C(=O)COCc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: NC(=O)[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1

Procedure:
A mixture of (5R)-3-[3-fluoro-4-[4-[(phenylmethoxy)acetyl]-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinecarboxamide (Step 2, 260 mg, 0.570 mmol) and 10% palladium-on-carbon (61 mg, 0.0570 mmol) in a mixture of methanol (5 mL) and EtOH (23 mL) was shaken under a 40 psi hydrogen atmosphere on a Parr apparatus for 22 hours. The catalyst was then removed by filtration through a pad of Celite, rinsing with tetrahydrofuran (200 mL), and the filtrate was concentrated under reduced pressure and triturated with methanol/diethyl ether. Filtration then provided the title compound, mp 232-235° C. (dec.); MS (ESI+) for C16H19FN4O5 m/z 367 (M+H)+; [α]25D=−20 (c 0.98, DMSO).
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9]([CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[CH:3]=[CH:4][C:5](O)=[O:6].O.[OH:22][N:23]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.NO.CCN(CC)CC>CN(C=O)C>[OH:22][NH:23][C:5](=[O:6])[CH:4]=[CH:3][C:2]([CH3:1])=[CH:8][CH:9]([CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1
Reactant: CC(C=CC(=O)O)=CC(C)Cc1ccc(N(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C=CC(=O)NO)=CC(C)Cc1ccc(N(C)C)cc1
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a stirred solution of carboxylic acid 37 (70 mg, 0.256 mmol) at rt in anhydrous DMF (2 mL) was added 1-hydroxybenzotriazole hydrate (41.5 mg, 0.307 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride(65 mg, 0.340 mmol). After 1 h, hydroxylamine hydrochloride (89 mg, 1.28 mmol) and Et3N (0.27 mL, 1.92 mmol) was added, and stirring was continued at rt overnight. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate (30 mL), and washed with water and saturated NaHCO3 solution (5 mL). After drying and concentration, the crude product was purified by flash silica gel chromatography (2-10% methanol in chloroform) to give the title compound 38 (30 mg, 41% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3:CD3OD=5:1) δ 7.10 (d, J=14.4 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 6.58 (d, J=8.7 Hz, 2H), 5.59 (d, J=9.3 Hz, 1H), 5.55 (br. d, J=14.4 Hz, 1H), 2.78 (s, 6H), 2.63 (m, 1H), 2.40 (d, J=6.9 Hz, 2H), 1.48 (s, 3H), 0.89 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3: CD3OD=5:1) δ 11.8, 19.7, 35.3, 40.8, 42.0, 14.3, 20.0, 35.5, 40.8, 42.2, 113.1, 113.7, 128.7, 129.5, 131.1, 145.9, 146.3, 148.9, 165.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[F:21][C:22]1[CH:27]=[C:26](O)[CH:25]=[CH:24][C:23]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:21][C:22]1[CH:27]=[C:26]([O:20][CH2:19][CH2:18][C@@H:16]2[CH2:17][C@@H:15]2[CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=3)[CH2:10][CH2:11]2)[CH:25]=[CH:24][C:23]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)Cc1ccc(O)cc1F
Reactant: COc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(OC)cn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-{(1S,2R)-2-[1-(5-Methoxypyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (1.2 g, 4.33 mmol), methyl 2-(2-fluoro-4-hydroxyphenyl)acetate (0.956 g, 5.19 mmol) and triphenylphosphine (1.702 g, 6.49 mmol) were dissolved in dichloromethane (20 ml). The mixture was stirred at RT under N2 for 5 min and diisopropyl azodicarboxylate (1.274 ml, 6.49 mmol) was added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with water, dried and evaporated. The crude material was purified by column chromatography on silica gel (50 g SNAP, 5˜30% EtOAc in hexane) to afford the desired product which contains some impurities. This material was re-purified by column chromatography on silica gel (50 g SNAP, 2˜5% EtOAc in DCM) to afford the title compound. LC/MS (m/z): 444 (M+H)+. Rf was 0.4 @ 30% EtOAc in hexanes (blue spot on CAM stain).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH2:13][CH2:14][C:15](NN)=[O:16])=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2[O:30][C:29](CCC(O)=O)=NN=2)C=CC=1.IC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:30][C:15](=[O:16])[CH2:14][CH2:13][C:11]1[O:12][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9][N:10]=1
Reactant: O=C(O)CCc1nnc(-c2cccc(Cl)c2)o1
Reactant: NNC(=O)CCc1nnc(-c2cccc(Cl)c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCc1nnc(-c2cccc(Cl)c2)o1

Procedure:
3-Chloro-benzoic acid hydrazide (3.4 g, 20 mmol) and succinic anhydride (2. g, 20 mmol) was mixed in ethyl acetate (50 ml) at room temperature for 15 min. The reaction mixture was diluted with ether and the precipitate was filtered to give 5.1 g of 4-[N′-(3-chloro-benzoyl)-hydrazino]-4-oxo-butyric acid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 10.01 (s, 1H), 9.53 (s, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.21 (d, 1H), 7.12 (t, 1H) and 2.35 (m, 4H). This solid was mixed with conc. H2SO4 and stirred at room temperature for 45 min and the reaction mixture was carefully added to crashed ice (400 g). The precipitate was filtered to give 4.07 g (80.6%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid as white solid. 1H-NMR(DMSO-d6) d(ppm): 12.4 (w, 1H), 7.96 (s, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.63 (t, 1H), 3.15 (t, 2H) and 2.82 (t, 2H). Step 2: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide: 3-[5-(3-Chloro-phenyl)-[1,3,4)oxadiazol-2-yl]-propionic acid (2.52 g, 10 mmol) was mixed with iodomethane (5.68 g, 40 mmol) and K2CO3 (5.52 g, 40 mmol) in DMF (25 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water 3 times, dried with MgSO4 and concentrated to give 2.57 g of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid methyl ester. The methyl ester (2.54 g, 9.52 mmol) was mixed with 98% hydrazine hydrate (4.76 g, 95.2 mmol) in methanol (10 ml) for an h. The reaction mixture was concentrated, diluted with water, filtered to give 2.17 g (81.4%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide as white solid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 8.75 (w, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.42 (m, 2H), 3.45 (w, 2H), 3.19 (t, 2H) and 2.68 (t, 2H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>C1C=CC=CC=1.ClCCl>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([C:7]([F:6])([F:17])[F:18])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)(C)NC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butylamine (2.0 eq) in 75 mL of benzene is added 3-trifluoromethylbenzoyl chloride (1.0 eq). The temperature is maintained below 15° C. during the addition and then the reaction mixture is allowed to warm to ambient temperature and stirred for 3 hours. The solvent is then stripped and the residue is dissolved in 75 mL of dichloromethane. This solution is washed with 5% hydrochloride acid (2×75 mL), water (2×75 mL), dried over MgSO4 and then the solvent is removed in vacuo to provide the title compound.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([OH:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+:2]=[N-:3].[CH3:17]I.[H-].[Na+].O>CN(C=O)C.CCOCC>[N:1]([C@H:4]1[C@H:8]([O:9][CH3:17])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (2.00 g, 8.76 mmol) and MeI (1.64 mL, 26.3 mmol) in DMF (20 mL) was added 60% NaH (0.701 g, 17.5 mmol) at 0° C. The mixture was warmed to ambient temperature and stirred at ambient temperature for 1 hour. Water (20 mL) and ether (40 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/ethyl acetate) to give (3R,4R)-tert-butyl 3-azido-4-methoxypyrrolidine-1-carboxylate (2.04 g, 96.1%) as thick oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[OH:16])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>>[NH2:26]/[C:5](/[C:4]1[CH:17]=[CH:18][CH:19]=[C:2]([CH3:1])[CH:3]=1)=[C:7]1\[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11]\1
Reactant: Cc1cccc(C(=O)c2sc3ccccc3c2O)c1
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1cccc(/C(N)=C2\Sc3ccccc3C2=O)c1
Yield: 36 %

Procedure:
Prepared as in Example 1 from 2-(3-methylbenzoyl)-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 36% of theory. M.p. 114°-115° C. (ethyl acetate/petroleum ether 1:1)