Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:13]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([CH3:3])[CH3:2].[OH-].[K+].O1CCOCC1>O>[CH:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc3ccccc3nc2C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nc2ccccc2cc1O
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-isopropyl-quinolin-3-yl ester (1.31 g, 3.8 mmol), 0.64 g (11.4 mmol) of KOH in 10 mL of water, and 50 mL of p-dioxane was heated to refluxe for 1.5 hours until completion. The p-dioxane was removed under reduced pressure and the residue was diluted with water and acidified with 1N HCl to pH=6. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure to afford quantitatively 0.71 g of 2-isopropyl-quinolin-3-ol
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1
Reactant: Fc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cccnc2)cc1-c1nc(-c2ccccn2)no1
Yield: 8.8 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (101.8 mg, 0.625 mmol) and Pd(PPh3)4 (36.1 mg, 0.0312 mmole) in a solution of 2M sodium carbonate (4 mL) and ethylene glycol dimethyl ether (4 mL) was heated overnight at 105° C. Standard work up afforded 8.7 mg (9%) 3-(2-pyridyl)-5-[2-fluoro-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=[CH:6][N:5]2[C:17]=1[CH3:18].C([Li])(C)(C)C.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>C(OCC)C.CCCCC>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:8]1[CH:7]=[CH:6][N:5]2[C:17]([CH3:18])=[C:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[NH:10][C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccn2c(C)c(C)nc2c1NC(=O)C(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 1 g of 2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 40 ml of diethyl ether is treated dropwise at −78° C. with 8 ml of a 1.5 molar solution of t-butyllithium in n-pentane. The mixture is stirred for 15 min and then treated with 3.3 ml of tri-n-butyltin chloride. The internal temperature is then allowed to rise to room temperature, the mixture is poured onto ice water and extracted three times with ethyl acetate, the combined extracts are washed with a little water and dried over potassium carbonate, the solvent is stripped off in vacuo and the oil obtained is chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) as an eluent. 1.3 g of 7-tributylstannyl-2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine are obtained as a viscous oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[N:28]=[C:29](N2CCC(F)(F)C2)[C:30]2N=NNC=2N=1)(C)(C)C.Br.BrCC1C=CN=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:30]=[CH:29][N:28]=[CH:27][CH:23]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: BrCc1ccncc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccncc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)pyridine hydrobromide and isolated as orange solid (5.4 mg, 35%). MS(m/e): 374.4 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>>[CH2:23]([NH:27][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15])[CH:24]([CH3:26])[CH3:25]
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: CC(C)CN
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NCC(C)C)c(C)n(C)c2c1

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, oxalyl chloride and isobutylamine in a manner as previously described for example 16d. 1H NMR (300 MHz, CDCl3) δ7.56 (1H, d, J=8.6 Hz), 6.85 (1H, dd, J=2.2, 8.6 Hz), 6.78 (1H, d, J=2.2 Hz), 3.87 (3H, s), 3.63 (3H, s), 3.32 (2H, m), 2.69 (3H, s), 1.93 (1H, m), 1.02 (3H, s), 1.00 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 275, found 275.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].C1CCC(NC2CCCCC2)CC1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>CN1CCCC1=O>[CH3:9][CH:8]([O:7][C:5]([O:4][CH2:3][CH2:2][O:29][C:27](/[CH:26]=[CH:25]/[C:24]([OH:31])=[O:30])=[O:28])=[O:6])[CH3:10]
Reactant: CC(C)OC(=O)OCCCl
Reactant: O=C(O)/C=C/C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)OCCOC(=O)/C=C/C(=O)O
Yield: 9.7 %

Procedure:
Following general procedure A, chloroethyl(methylethoxy)formate (0.25 g, 1.50 mmol) was reacted overnight with the pre-formed bis-dicyclohexylamine salt (DCHA) of fumaric acid (FA) (0.50 g, 1.26 mmol) in N-methylpyrrolidinone (NMP) at ca. 100° C. The crude material was purified by mass-guided preparative HPLC to afford (0.030 g, 10% yield) of the title compound (50) as a white, waxy, semi-solid. 1H NMR (CD3CN, 400 MHz): δ 6.86 (q, J=5.6 Hz, 1H), 6.81 (d, J=16.0 Hz, 1H), 6.73 (d, J=16.0 Hz, 1H), 2.57-2.50 (heptet, J=7.2 Hz, 1H), 1.48 (d, J=5.6 Hz, 3H), 1.13 (m, 6H). MS (ESI): m/z=244.99 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])/[C:11](=[CH:20]/[CH3:21])/[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:22][NH2:23].[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]([OH:19])[CH:11]([CH:20]([NH:23][CH3:22])[CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C/C=C1\C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(C)C1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1O
Reaction time: 3 h
Yield: 55.9 %

Procedure:
To a solution of 42 (0.80 g, 2.52 mmol) in THF (10 mL) at ambient temperature was added methylamine solution (2.0 M in THF, 3.78 mL, 7.56 mmol). The reaction mixture was stirred for 4 h before NaBH4 (0.44 g, 11.49) was added. The reaction mixture was stirred for 3 h before being quenched by a saturated solution of NH4Cl (10 mL). The product was extracted with diethyl ether, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/0.1% DEA=1 :7 to 1:5) to give (4S)-4-(3,4-dichlorophenyl)-2-(1-(methylamino)ethyl)-1,2,3,4-tetrahydronaphthalen-1-ol (44) (493 mg, 56%).
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9](Cl)(=[O:11])[CH3:10].CN1CCOCC1>C(OCC)(=O)C>[C:9]([N:3]1[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]1=[O:8])(=[O:11])[CH3:10]
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(=O)N1C(=O)OC(=O)[C@@H]1C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
(S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of acetyl chloride (306 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methyl-morpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in chloroform (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (350 mg, 74%) as a colorless clear syrup.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=C=O.[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>>[C:12]([OH:15])(=[O:14])[CH:13]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: C=C=O
Agent: [Na+]
Product: O=C(O)C=Cc1ccccc1
Yield: 40 %

Procedure:
The reaction of benzaldehyde with ketene at 60° C. with the addition of sodium acetate and subsequent heating of the reaction product to the boiling point is known from Ind. Chem. 41, 768 (1949). Cinnamic acid is thereby obtained in a yield of 40%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29](B(O)O)[C:24]=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=4)[N:3]=3)[C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: OB(O)c1cccc2c1OCCO2
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cccc4c3OCCO4)n2)c1

Procedure:
Example 18 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 2,3-dihydro-1,4-benzodioxin-5-ylboronic acid (Combi-Blocks Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:3][OH:4].[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.CCCCCCC>C1(C)C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[N:1]/[C@H:2]([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:3][OH:4])=[CH:26][CH:27]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@@H](CO)COc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N/[C@@H](CO)COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of Example 1G (3.236 kg) and para-anisaldehyde (1.484 kg) in toluene (6.631 kg) was heated at 80° C. for 2 hours, treated with heptane (33.147 kg) over 50 minutes, cooled to room temperature over 20 hours, and filtered. The filter cake was rinsed with heptane (6.994 kg), air dried, then vacuum dried (100 mmHg) at 50° C. to provide 4.297 kg (97.6%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ8.35 (s, 1H), 7.73 (dt, 2H, J=8.9, 2.9 Hz), 7.61 (dt, 2H, J=8.8, 2.9 Hz), 7.41 (dd, 2H, J=8.9, 1.1 Hz), 7.05 (dt, 2H, J=8.8, 2.9 Hz), 7.01 (dt, 2H, J=8.8, 2.9 Hz), 4.87 (br s, 1H), 4.31 (dd, 1H, J=9.9, 4.1 Hz), 4.13 (dd, 1H, J=9.9, 7.4 Hz), 3.81 (s, 3H), 3.64-3.80 (m, 2H), 3.56 (dd, 1H, J=10.0, 6.3 Hz).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:60][C@@H:58]([C:55]2[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][CH:54]=2)[CH3:59])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.418 g, 1.10 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g, 1 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.156 g, 1.00 mmol) and DIPEA (0.524 mL, 3.00 mmol) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude material was treated with a 10% solution of TFA in DCM (5 mL) and stirred at room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.211 g, 52.9%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:32][C:33](Cl)=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1C=CC=CC=1>[C:33](=[O:34])([O:32][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCCOC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.384 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 3.2 ml. of absolute pyridine and reacted with 0.527 g. of chloroformic acid n-decyl ester as in Example 1. The 0.822 g. of brownish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.714 g. of colorless crystals which are recrytallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-decyl carbonate obtained melts at 59.3°-60.0° and has a clearing point of 74.0°. The compound is smectic in the entire liquid crystalline range. UV (EtOH): ε 270 = 26400.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O>[F:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COCCOc1cnc(Cl)c2ccccc12
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCOc1cnc(F)c2ccccc12
Temperature: 140 °C

Procedure:
To a solution of 1-chloro-4-(2-methoxyethoxy)isoquinoline (368 mg, 1.548 mmol) in DMSO (7 mL) was added CsF (470 mg, 3.10 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 5-25% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give it the desired product 1-fluoro-4-(2-methoxyethoxy)isoquinoline (241 mg, 70.4% yield) as a white solid. MS: MS m/z 222.15 (M++1).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22](O)=[O:23])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:22]([C:19]1[S:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:10]3[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=[CH:8][CH:9]=3)[C:13]=2[C:20]=1[CH3:21])=[O:23]
Reactant: CN(C)CCCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC(C)C)c12
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3OC(C)C)c12

Procedure:
Prepared analogously to example 1.3 using 4-(2-isopropoxypyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (descirbed in 1.2) and 3-dimethylaminopropylamine. The resultant product was purified by chromatography.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])=[CH:9][CH:8]=[C:7]([C:23]2[O:24][C:25]3[CH:31]=[C:30]([O:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[CH:29]=[CH:28][C:26]=3[N:27]=2)[N:6]=1)(=O)C.C1COCC1.[OH-].[Li+].Cl>CO>[CH:34]1([CH2:33][O:32][C:30]2[CH:29]=[CH:28][C:26]3[N:27]=[C:23]([C:7]4[N:6]=[C:5]([O:4][CH3:1])[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH3:14])=[CH:9][CH:8]=4)[O:24][C:25]=3[CH:31]=2)[CH2:35][CH2:36]1
Reactant: CC(=O)Oc1nc(-c2nc3ccc(OCC4CC4)cc3o2)ccc1OC[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(-c2nc3ccc(OCC4CC4)cc3o2)ccc1OC[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A mixture of 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]pyridin-2-yl acetate (111 mg), THF (1 mL), methanol (1 mL) and 1M lithium hydroxide aqueous solution (1 mL) was stirred at 0° C. for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was mixed with toluene (2 mL), methyl iodide (0.021 mL) and silver(I) carbonate (92 mg), and the obtained mixture was stirred at 85° C. for 3 days. To the reaction mixture were further added methyl iodide (0.021 mL) and silver(I) carbonate (92 mg), and the mixture was stirred at 85° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white powder (70.0 mg).
Reaction SMILES: [C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:10][N:9]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][N:9]([CH2:25][C:26]([F:28])([F:29])[F:27])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(c1ccccc1)O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)CN1CC(c2ccccc2)OC2(CCNCC2)C1
Reaction time: 0.67 h
Yield: 100.1 %

Procedure:
To tert-butyl 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (779 mg, 1.86 mmol) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (5 mL, 64.90 mmol) at room temperature. The reaction mixture was stirred for 40 minutes, then diluted with dichloromethane (75 mL) and the organic solution was washed with saturated sodium bicarbonate (twice) and then brine. The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to give 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane as an amber oil (585 mg, 99%). ESI-MS m/z calc. 314.2. Found 315.3 (M+1)+; Retention time: 1.29 minutes (3 min run). 1H NMR (400 MHz, CD3CN) δ 7.44-7.25 (m, 5H), 4.82 (dd, J=10.6, 2.8 Hz, 1H), 3.74 (br s, 1H), 3.06 (q, J=9.8 Hz, 2H), 3.02-2.91 (m, 2H), 2.88 (dd, J=11.2, 1.5 Hz, 1H), 2.85-2.74 (m, 3H), 2.34 (d, J=14.8 Hz, 1H), 2.28 (dt, J=10.9, 5.3 Hz, 2H), 1.76-1.64 (m, J=16.0, 8.7, 5.3 Hz, 1H), 1.64-1.52 (m, 2H).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1>C(O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH:2]2[CH2:3][C:4](=[O:6])[NH:5][C:1]2=[O:7])=[CH:12][CH:11]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc(S)cc1
Solvent: CCO
Product: COc1ccc(SC2CC(=O)NC2=O)cc1

Procedure:
To a solution of maleimide (5.92 g, 61 mmol) in 200 ml of ethanol was added 4-methoxybenzenethiol (7.5 ml, 61 mmol), and after 18 hours at room temperature the solvent was removed to give 3-(4-methoxy-phenylsulfanyl)pyrrolidine-2,5-dione, mp 93-94° C. This compound (5.0 g, 21 mmol) was oxidized with hydrogen peroxide, 30% in acetic acid, 220 ml to give 3-(4-methoxybenzenesulfonyl)pyrrolidine-2,5-dione as a white solid, mp 144-146° C. This compound was reacted with 1-chloro-4-(5iodopent-1-ynyl)benzene in DMF using two equivalents of sodium bishexamethyldisilazide to give the title compound as colorless crystals, mp 160-162° C.; mass spectrum,(M—H) 444.2.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:13]=1[OH:14])[CH3:7].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:15]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:6]([CH3:7])[CH3:5])[C:13]=1[O:14][C:1]([Cl:4])=[O:2])([CH3:17])[CH3:16]
Reactant: O=C(Cl)Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 20% solution of phosgene in toluene (139 mL, 0.269 mol) was added to a stirring solution of propofol (40 g, 0.225 mmol) in toluene (80.0 mL) under a nitrogen atmosphere at 0° C. N,N-Dimethylaniline (34.0 mL, 0.269 mmol) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature slowly and stirred for 14 h. The reaction mixture was filtered through Celite and the solvent was removed in vacuo. The crude product (2) was carried to the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.29-7.25 (m, 1H), 7.19-7.17 (m, 2H), 3.04-3.01 (m, 2H), 1.25 (d, J=7.2 Hz, 12H).