Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:27].CO>C1COCC1>[CH2:3]([O:10][C:11]([N:13]([C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[CH3:27])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
Sodium hydride (60% oil dispersion, 0.32 g) was added to a stirred solution of tert-butyl (S)-3-benzyloxycarbonylaminopyrrolidine-1-carboxylate (prepared according to Cheng et al, WO2007 142585, 1.73 g) in THF (20 mL) and the mixture was stirred for 15 minutes. Iodomethane (1.85 g) was added and the mixture was stirred at room temperature for 1 hour. Methanol was carefully added to destroy the excess sodium hydride then ethyl acetate and water were added and the organic layer was washed with brine, dried (Na2SO4), filtered. The filtrate was concentrated in vacuo to give tert-butyl (S)-3-(N-benzyloxycarbonyl-N-methylamino)pyrrolidine-1-carboxylate (1.66 g) as a pale coloured oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][O:14][CH2:15][C:16](Cl)=[O:17]>ClC1C=CC=CC=1>[Cl:12][C:3]1[C:2]([NH:1][C:16](=[O:17])[CH2:15][O:14][CH3:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: COCC(=O)Cl
Reactant: COC(=O)c1cnc(Cl)c(N)c1
Solvent: Clc1ccccc1
Product: COCC(=O)Nc1cc(C(=O)OC)cnc1Cl

Procedure:
A solution of 0.75 g (4.02 mMol) of methyl 5-amino-6-chloro-nicotinate and 0.43 g=0.35 ml (4.5 mMol) of methoxyacetylchloride in 20 ml of chlorobenzene was stirred for one hour at 110° C. After the solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol=100:1), evaporated down again in vacuo and then digested with petroleum ether.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(#N)C.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:8][CH2:7]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CN1CCc2cc(OC)c(OC)cc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3 g, 13.06 mmol) was suspended in acetonitrile (40 ml); potassium carbonate (3.61 g, 26.1 mmol) and methyl 2-bromoacetate (3.00 g, 19.59 mmol) were added; and the reaction mixture was stirred under microwave irradiation at 100° C. for 1 hour. Then the mixture was diluted with ethyl acetate and washed with water, brine and dried over Na2SO4. The organic layer was evaporated and the resulting crude was purified by flash chromatography on silica gel (DCM:MeOH:TEA 100:1:1) affording the title compound (2.6 g, 9.81 mmol, 75% yield). MS/ESI+ 266.1 [MH]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.C[Si](Cl)(C)C.[CH2:16]1[O:18][CH2:17]1.C1C[O:22]CC1>>[OH:18][CH2:16][CH2:17][C:5]1[O:1][C:2](=[O:22])[CH2:3][CH:4]=1
Reactant: c1ccoc1
Reactant: C1CCOC1
Reactant: C1CO1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Product: O=C1CC=C(CCO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a cooled solution of furan (3.40 g, 50.0 mmol) in THF (150 mL) was added n-BuLi (22 mL, 2.5M solution in hexane, 55.0 mmol) at 0° C. under inert gas atmosphere. The solution was allowed to warm to room temperature and stirred for 3 h. Then TMSCl (5.34 g, 50 mmol) was added dropwise at 0° C. and the solution was stirred for further 3 h at room temperature. Subsequently, the solution was again cooled to 0° C. and n-BuLi (22 mL, 2.5M solution in hexane, 55.0 mmol) was added a second time. After stirring for 3 h at room temperature ethyleneoxide (2.42 g, 55.0 mmol) was condensed by an acetone/dry ice condenser into the solution and the solution was stirred for further 12 h at room temperature. The mixture was quenched with aq NH4Cl, and then extracted with EtOAc and the combined organic layers were dried over Na2SO4 to afforded the desired product (5 g, 27.1 mmol, 54% over two steps) as a yellow liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[CH2:8]([Li])CCC.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1>>[CH:13]1([CH:17]([C:5]2[S:1][C:2]([CH3:8])=[C:3]([CH2:6][OH:7])[CH:4]=2)[OH:16])[CH2:14][CH2:15]1
Reactant: C1CCOC1
Reactant: OCc1ccsc1
Reactant: [Li]CCCC
Product: Cc1sc(C(O)C2CC2)cc1CO
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Thiophene-3-methanol of formula UU-1 (4.56 g) is added to THF (100 mL) and cooled to -78° C. n-Butyl lithium (55 cc) is then added and the reaction stirred for 2 hours at -78° C. and then the cooling bath is removed for 30 minutes. The reaction temperature is again reduced to -78° C. and methyl iodide (5.68 g), in THF (5 mL), is added. The reaction is stirred for 1.3-1.0 hours at room temperature and then cooled back to -78° C. n-Butyl lithium is then added and the reaction is left stirring for 1 hour at -78° C. and then the cooling bath removed for 30 minutes and cooled back to -78° C. Cyclopropyl carboxaldehyde (2.8 g) is then added in a single portion and stirring continued for 30 minutes. The reaction is quenched with saturated NH4Cl and extracted with ether. The ether extracts are dried and solvent evaporated in vacuo to yield a pale brown oil. Silica gel chromatography (400 g silica gel; eluting with 1/1 EtOAc/hexane) affords 1.21 g of the title product.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([F:18])[C:11]=1[F:19])[CH3:8]>O>[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:1])=[C:12]([F:18])[C:11]=1[F:19])[CH3:8]
Reactant: CCOc1ccc(C=O)c(F)c1F
Reactant: NOS(=O)(=O)O
Solvent: O
Product: CCOc1ccc(C#N)c(F)c1F
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A mixture of 0.12 mole of hydroxylamine-0-sulfonic acid and 50 ml of water is added, at 30° C., to a mixture of 0.1 mole of 4-ethoxy-2,3-difluorobenzaldehyde and 100 ml of water, and the mixture is stirred for one hour. Warming to 65° C. for 2 hours and working up in the customary manner gives the nitrile in the form of a colourless solid, melting point 45° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:12]([N:14]([CH2:32][CH3:33])[CH2:15][CH2:16][NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:19]1)[CH3:13].O>ClCCl>[CH2:32]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][N:17]([C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:19]1)[C:1](=[O:3])[CH3:2])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCN(CC)CCN[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)CCN(C(C)=O)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (2.9 g) was dissolved in 50 ml of dry dichloromethane, mixed with 5.3 ml of triethylamine, and after addition of N,N-diethyl-N′-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]-ethane-1,2-diamine (5.8 g), stirred at room temperature for 30 minutes. Subsequently, (LCMS check), water (10 ml) was added to the reaction, and the mixture was extracted with dichloromethane (2×10 ml). The combined organic phases were dried over magnesium sulfate, the solvent was removed, and the crude product was separated by chromatography on silica gel (dichloromethane/methanol 10:1). This resulted in the product with the molecular weight of 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH2:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1>[OH:18][CH2:17][CH2:16][CH2:15][O:12][C:9]1[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:13])=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(O)cc1
Reactant: OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/c1ccc(OCCCO)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 29.2 %

Procedure:
15 g (84.2 mmol) of 4-hydroxycinnamic acid methyl ester, 14 g (101 mmol) of 3-bromo-1-propanol, 23.4 g of K2CO3 are dissolved in 90 mL of NMP. The solution is heated up to 80° C. and stirred for 20 hours. Then, the reaction mixture is cooled down to room temperature and carefully acidified with 1N HCl solution. The solution is extracted with ethylacetate. The organic phase is dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on silica gel using hexane:ethyl acetate 7:3 as eluent yielded 5.8 g of methyl (2E)-3-[4-(3-hydroxypropoxy)phenyl]prop-2-enoate as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH2:22]([S:26]([C:29]1[S:33][C:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:31][CH:30]=1)(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([S:26]([C:29]1[S:33][C:32]([N:34]2[CH2:39][CH2:38][N:37]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:36][CH2:35]2)=[N:31][CH:30]=1)(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C(F)(F)F)CC2)s1
Yield: 65 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 65%). MS (m/e): 584.3 (M+H+, 100%), 601.4 (M+NH4+, 60%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[C:4]([F:15])[CH:3]=1.Cl[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].FC(F)(F)C(O)=O>CN(C)C=O.[Mn]>[CH2:11]([S:8]([NH:7][CH2:6][C:5]1[CH:13]=[CH:14][C:2]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][C:4]=1[F:15])(=[O:10])=[O:9])[CH3:12]
Reactant: CCOC(=O)C(C)Cl
Reactant: CCS(=O)(=O)NCc1ccc(Br)cc1F
Agent: [Mn]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)CC)c(F)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-bromo-2-fluorobenzyl)ethanesulfonamide (305 mg, 1.03 mmol) in dimethylformamide, Manganese (113 mg, 2.06 mmol), (2,2′-Bipyridine)nickel(II)-dibromide (27 mg, 0.07 mmol), ethyl 2-chloropropanoate (0.17 mL, 1.34 mmol) was added. It was followed by addition of trifluoroacetic acid (0.002 mL, 0.028 mmol). The mixture was stirred for 24 h at 65° C. The reaction mixture was quenched by concentrated HCl (7 drops). Then it was extracted with diethyl ether, dried over magnesium sulfate, the solvent was evaporated in vacuo. It was purified by column chromatography to obtain ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate in pure form (65 mg, 20%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]2[C:8]=1[CH:9]=[N:10][N:11]2[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.CN([CH:26]=[O:27])C>C1COCC1>[F:16][C:14]1[CH:15]=[C:7]([CH:26]=[O:27])[C:8]2[CH:9]=[N:10][N:11]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:12]=2[CH:13]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c2cnn(C3CCCCO3)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc2c1cnn2C1CCCCO1
Temperature: -40 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of n-butyllithium (13 mL, 21.4 mmol, 1.6 M in hexanes) in THF (60 mL) at −78° C. was added dropwise over 30 min a solution of 4-bromo-6-fluoro-1-tetrahydropyran-2-yl-indazole (4.00 g, 13.4 mmol) in THF (20 mL). The reaction was warmed to −40° C. for 5 min, re-cooled to −78° C., and DMF (4.2 mL, 53.5 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction was then quenched with a satd. aq. NH4Cl at 0° C. EtOAc was added and the layers were separated, and the aqueous layer was extracted once with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by SiO2 chromatography to afford 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbaldehyde (2.18 g, 66%), as a white solid. MS (ESI) m/z: 249.3 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([F:35])=[CH:30][C:29]=1B(O)O>>[F:34][C:33]1[C:28]([O:27][CH3:26])=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:30]=[C:31]([F:35])[CH:32]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1c(F)cc(F)cc1B(O)O
Product: COc1c(F)cc(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methoxy-3,5-difluorophenylboronic acid (CAS RN 737000-76-9) and using preparative HPLC for the chromatographic purification. Off-white solid (49%). MS (ESI): m/z=491.1 [M+H]+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[C:22](C(C)(C)C)[C:21](O)=[C:20](C(C)(C)C)[CH:19]=2)=[O:16])[CH:6]=[C:5]([CH3:33])[CH:4]=1.[CH3:34][N:35](C)[C:36]1C=CC(N)=CC=1.C(C1C=C(N)C=C(C(C)(C)C)C=1O)(C)(C)C>>[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:35]([CH3:36])[CH3:34])=[CH:22][CH:23]=2)=[O:16])[CH:6]=[C:5]([CH3:33])[CH:4]=1
Reactant: Cc1cc(N)nc(CCCCCCC(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Reactant: CN(C)c1ccc(N)cc1
Agent: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: Cl
Product: Cc1cc(N)nc(CCCCCCC(=O)Nc2ccc(N(C)C)cc2)c1

Procedure:
The experimental protocol used is the same as that described for compound 16, N,N-dimethyl-p-phenylenediamine replacing the 2,6-di-t-butyl-4-aminophenol. Hygroscopic yellowish solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[CH:32]=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:30]([CH:38]4[CH2:40][CH2:39]4)=[CH:29][C:23]=3[C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[CH:32]=[C:31]([N:33]([C:2]4[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([C:7]#[N:8])[CH:9]=4)[S:34]([CH3:37])(=[O:35])=[O:36])[C:30]([CH:38]4[CH2:40][CH2:39]4)=[CH:29][C:23]=3[C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[CH:16][CH:15]=1
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzonitrile (0.656 mL, 5.73 mmol), 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (2.0 g, 4.77 mmol) and K2CO3 (1.980 g, 14.32 mmol) in 1,2-dimethoxyethane (20 mL) and water (5.0 mL) in a seal tube was heated to 80° C. overnight. Cooled down to room temperature, it was diluted with EtOAc. The mixture was washed with water and brine, dried over Na2SO4. It was concentrated to dryness to give the crude product (>99%) as yellow solid which was used for the next step without further purification. LCMS (m/z, ES+)=565 (M+H+).
Reaction SMILES: [N+](=C)=[N-].[CH3:4][S:5]([CH:8]([CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:7])=[O:6].[C:28](O)(=O)C>CCOCC>[CH3:4][S:5]([CH:8]([CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:28])=[O:16])(=[O:6])=[O:7]
Reactant: CC(=O)O
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC(O)CCCC(CCCCCCC(=O)OC)S(C)(=O)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 8-methylsulfonyl-12-hydroxyheptadecanoic acid (10.8 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 8-methylsulfonyl-12-hydroxyheptadecanoate, a colorless viscous oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:17][CH2:18][N:19]([CH2:25][CH2:24][C:23]([O:27][CH3:28])=[O:26])[CH2:20][CH2:21]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC1(c2cccc(OCc3ccccc3)c2)CCNCC1
Reactant: C=CC(=O)OC
Agent: Cl
Product: COC(=O)CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)CC1
Yield: 86 %

Procedure:
This compound was prepared from 4-(3-benzyloxyphenyl)-4-fluoropiperidine hydrochloride and methyl acrylate as described in Step 1 of Example 4 in 86% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH3:5].[CH2:9]([O:11]C(C(C)C)=CC)[CH3:10].[CH:18](C=C)=O.C1(C=CC(O)=CC=1)O>>[CH3:1][O:2][C:3]1([CH2:4][CH3:5])[C:6]([CH3:18])([CH3:8])[CH2:7][CH:10]=[CH:9][O:11]1
Reactant: CCC(OC)=C(C)C
Reactant: CC=C(OCC)C(C)C
Reactant: C=CC=O
Agent: Oc1ccc(O)cc1
Product: CCC1(OC)OC=CCC1(C)C
Temperature: 165 °C
Yield: 72 %

Procedure:
54 g of a mixture of 3-methoxy-4-methyl-3-pentene (I, with R = CH3) and 3-methoxy-4-methyl-2-pentene (II, with R = CH3), which according to the nuclear resonance spectrum comprises about 95% of I and about 5% of II, 32 g of acrolein and 1 g of hydroquinone are heated at 165° C. for 20 hours. Distillation of the reaction mixture gives 58 g of the desired 2-methoxy-2-ethyl-3,3-dimethyl-2,3-dihydro-4H-pyran of boiling point 64° - 67° C./13 mm Hg. This corresponds to a yield of 72% of theory.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.O1CCOCC1.[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>O>[OH:22][CH2:21][CH2:20][N:19]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)[CH2:23][CH2:24][OH:25]
Reactant: OCCNCCO
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([N+](=O)[O-])c(N(CCO)CCO)n1
Temperature: 0 °C
Yield: 74 %

Procedure:
1.9 g (0.01 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 30 ml of dioxane, 5 ml of water and 2.1 ml (0.02 mol) of diethanolamine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried. 1.9 g of yellow powder are obtained, ie a yield of 74%.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1)[C:10]([O:18][CH2:19][CH3:20])=[O:17])[CH3:16]
Reactant: Fc1cnc(F)c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(F)cc1F
Temperature: 110 °C
Yield: 85 %

Procedure:
To a stirred solution of 2,3,5-trifluoro-pyridine (2 g, 15.02 mmol) in dimethyl sulfoxide (20 mL) was added diethyl malonate (4.60 g, 28.72 mmol). Then cesium carbonate (9.35 g, 28.72 mmol) was added and the reaction mixture was heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with water (2×25 mL), brine (25 mL), dried over sodium sulphate and evaporated in vacuo to afford the title compound as oil in 85% yield, 3.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[C:23]([CH3:33])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[C:23]([CH3:33])[CH:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cc(O)ccc1CC(=O)N(C)C
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)ccc1CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (90 mg, 0.319 mmol) was dissolved in toluene (1 ml) and 2-(4-hydroxy-2-methylphenyl)-N,N-dimethylacetamide (62 mg, 0.319 mmol), triphenylphosphine (126 mg, 0.479 mmol), and DIAD (93 μl, 0.479 mmol) added and the mixture stirred at RT overnight. The mixture was concentrated in vacuo and the residue purified by chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 10-100% water:acetonitrile+0.1% TFA to afford the title compound. LC/MS (m/z): 457 (M+H)+. GPR119 Human EC50: 1.7 nM.