Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[N:5]([N:9]=[CH:10][CH:11]=2)[C:6](=O)[CH:7]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl.CC(OC)(C)C>[Cl:14][C:6]1[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cc(=O)n2nccc2[nH]1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Nc1cc(Cl)n2nccc2n1
Temperature: 25 °C

Procedure:
A solution of 5-aminopyrazolo[1,5-a]pyrimidin-7(4H)-one (Z-2) (1.5 g, 10 mmol) in phosphoryl chloride (45 mL) is stirred at reflux overnight. The reaction mixture is allowed to cool to RT and concentrated in vacuo. The residue is then dissolved in ice-water (25 mL) and the resulting mixture is neutralized with aqueous NaOH solution (20%) to adjust the pH to 9-10. The mixture is extracted with ethyl acetate (3×50 mL) after which the combined organic layers are washed with brine (500 mL), dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the crude product which is slurried in a mixture of DCM/MTBE (3 mL/15 mL). The resulting solid is then collected by filtration to afford 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (Z-3).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2S[CH2:7][CH2:8][C:4]=2[CH:3]=1.O[O:12][S:13]([O-:15])=O.[K+]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[S:13](=[O:15])(=[O:12])[CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)CCS2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: O=S1(=O)CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Dissolve 5-bromo-2,3-dihydro-benzo[b]thiophene (J. Am. Chem. Soc, 1973, 1916-1925, 4.3 g, 20 mmol) in MeOH (100 mL) and add oxone (36.9 g, 60 mmol). Stir the reaction mixture at room temperature overnight, and then remove the solid by filtration. Concentrate the filtrate and purify the residue by flash column chromatography (silica gel, 20-40% EtOAc/Hexane) to give 4.24 g of 5-bromo-2,3-dihydro-benzo[b]thiophene 1,1-dioxide (86%).
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]1[CH2:7][CH2:6]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2](=[S:26])[C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]1[CH2:7][CH2:6]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(N)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(N)=S
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
A mixture of (S)-tert-butyl 1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (Example 38 a, 6.7 g, 29 mmol) and Lawesson's reagent (CAN 19172-47-5, 6.06 g, 15 mmol) in toluene (60 mL) was stirred at 90° C. for 2.5 h. After removal of the solvent in vacuo, the residue was purified by column chromatography (silica gel, 100 g, eluting with 5% methanol in ethyl acetate) to yield the title compound (5.1 g, 71%) as yellow solid; MS: m/e=267.1 [M+Na]+
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C1COCC1>[Cl:15][C:9]1[CH:8]=[C:7]([B:20]([OH:21])[OH:19])[CH:12]=[CH:11][C:10]=1[S:13][CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Butyl lithium (15 ml, 1.9M in hexanes) was added over 40 min to a solution of the product from step b) (6.82 g) and triisopropylborate (8.0 ml) in THF (30 ml) at −78° C. and stirred for a further 1 h. 2M HCl (20 ml) was added, the mixture was warmed to 20° C. and extracted with ether (three times). The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol—ether as eluent) to give the sub-title compound (1.82 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:10]([O:9][C:7]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(O)CN
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A mixture of 1-amino-2-propanol (1) (4.6 g, 61.8 mmol), benzyl chloroformate (11.5 g, 67.6 mmol), and sodium carbonate (7.16 g, 67.7 mmol) in water (50 mL) was stirred at 0° C. for 3 h. Water (50 mL) was added to the reaction mixture, the product was extracted with CH2Cl2 (3×20 mL), dried over Na2SO4 and concentrated. The residue was purified by a flash chromatography on SiO2 eluting with 10:1 hex:EtOAc, followed by EtOAc to afford 1-benzyloxycarbonylamino-2-propanol (12.9 g, 100%) as an oil. 1H NMR (CDCl3): □ 7.30 (m, 5H), 5.90 (s, 1H), 5.06 (s, 2H), 3.95 (s, 1H), 3.31 (m, 1H), 3.04 (m, 1H), 1.2 (d, 3H)
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:16]=[CH:15][CH2:14][NH2:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: NCC=NC1CCC(c2ccccc2)CC1

Procedure:
A mixture of 4-phenylcyclohexanone (4.00 g, 22.96 mmol) and ethylenediamine (1.66 g, 27.5 mmol) and p-toluenesulfonic acid (437 mg) in benzene (200 mL) was refluxed for 4 h in Dean-Stark trap to remove the water that formed. Tlc analysis indicated the completion of the reaction. Solvent was evaporated and the product was used in the next step without any further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([C:24]#[N:25])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([C:24]#[N:25])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(C#N)c1
Temperature: 77.5 °C
Yield: 52 %

Procedure:
To a solution of 38 (220.0 mg; 0.58 mmol) in tetrahydrofuran (4 mL) and methanol (1 mL) was added aqueous lithium hydroxide (1.45 mL; 2M. The reaction mixture was heated at 75-80° C. for 6 hours, allow ed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude white solid residue was purified by preparative HPLC to yield the title compound as a white solid (110 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][N:7]=1.Cl[CH:20]([CH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)[CH:21]=O>C(O)C>[CH3:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:20]([CH2:23][C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)=[CH:21][N:1]=3)[N:4]=2)=[CH:9][C:10]=1[CH3:18]
Reactant: CNC(=O)c1ccc(-c2cnc(N)nn2)cc1C
Reactant: O=CC(Cl)Cc1ccc2ncccc2c1
Solvent: CCO
Product: CNC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A mixture of 4-(3-amino-1,2,4-triazin-6-yl)-N,2-dimethylbenzamide (Step 3, 0.30 g, 1.2 mmol) and 2-chloro-3-quinolin-6-ylpropanal (Step 4, 0.32 g, 1.5 mmol) in ethanol (2.5 mL) in a sealed tube was stirred at 120° C. overnight. After cooling, the reaction mixture was purified by RP-HPLC (pH=2) to afford the desired product (150 mg) as the TFA salt. LCMS (M+H)+: m/z=409.3. 1H-NMR (400 MHz, CD3OD): 9.64 (s, 1H), 9.21 (d, J=5.0, 1H), 9.18 (d, J=8.0 Hz, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.32 (d, J=9.0 Hz, 11H), 8.27 (d, J=8.0 Hz, 1H), 8.12 (dd, J=9.0, 5.0, Hz, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 4.86 (s, 2H), 2.92 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH:25]=[C:26]([CH3:29])[CH:27]=O>C1COCC1>[CH2:3]([O:5][C:6](=[O:16])[CH:7]=[CH:27][C:26]([CH3:29])=[CH:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17])[CH3:4]
Reactant: CC(C=O)=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC(C)=Cc1ccc(Cl)cc1Cl
Reaction time: 4 h
Yield: 89.4 %

Procedure:
Sodium hydride (4.88 g of a 60% dispersion in mineral oil, 1.5 eq, 0.122 mol) was suspended in THF (442 mL). To this suspension was added a solution of diethoxyphosphorylactic acid ethyl ester (27.5 g, 0.122 mol, 1.5 eq) in THF (10 mL), dropwise. After 10 minutes a solution of 3-(2,4-dichlorophenyl)-2-methylpropenal (17.56 g, 0.082 mol) in THF (50 mL) was added, dropwise. After stirring for 4 hours the mixture was added to NH4Cl(sat) and extracted with EtOAc. The combined organic extracts were dried (MgSO4), concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-2.5-5% EtOAc in hexanes) to give 20.9 g of 5-(2,4-dichlorophenyl)-4-methylpenta-2,4-dienoic acid ethyl ester.
Reaction SMILES: Br[C@@H:2]1[C@@H:7]([OH:8])[CH2:6][C@H:5]2[C@H:9]3[C@H:19]([C@H:20]([N:22]([CH3:24])[CH3:23])[CH2:21][C@:3]12[CH3:4])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:28])[C@@H:15]([O:25][CH2:26][CH3:27])[CH2:16]1)[CH2:11][CH2:10]3.O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:24][N:22]([C@@H:20]1[CH2:21][C@@:3]2([CH3:4])[C@@H:5]([CH2:6][C@@H:7]3[O:8][C@@H:2]32)[C@H:9]2[C@H:19]1[C@:17]1([CH3:18])[C@@H:12]([CH2:11][CH2:10]2)[CH2:13][C@H:14]([OH:28])[C@@H:15]([O:25][CH2:26][CH3:27])[CH2:16]1)[CH3:23]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@]2(C)[C@H](Br)[C@@H](O)C[C@@H]32)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@@]2(C)[C@H]3C[C@@H]3O[C@@H]32)C[C@@H]1O
Yield: 45.8 %

Procedure:
A solution of 17α-bromo-11α-N,N-dimethylamino-2β-ethoxy-5α-androstane-3α,16β-diol (212 mg) in methanol (33 ml) containing water (1.2 ml) was treated with a 40% solution of potassium carbonate (0.66 ml) and the mixture was refluxed. After 1 hour most of the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The washed and dried (Na2SO4) organic layer was evaporated and the residue was purified by preparative thin layer chromatography over silica (ethyl acetate--petroleum ether 1:1) and crystallization from aqueous methanol to give the title compound (80 mg) m.p. 149°-151°, [α]D +6.7°.
Reaction SMILES: [O:1]=[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])[CH3:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])=[O:1]
Reactant: CC(=O)Nc1ccccc1C(C)=O
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccccc1C(=O)C=CN(C)C
Yield: 63.6 %

Procedure:
A suspension of 48 g of N-[2-(1-oxo-1-ethanyl)phenyl]acetamide and 38 g of N,N-dimethylformamide dimethyl acetal in 150 ml of toluene was heated at reflux for about 16 hours, then concentrated in vacuo to a solid. The solid was recrystallized from 1-chlorobutane to yield 40 g of the title compound; m.p. 90°-95° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]1[C:8]([Cl:14])=[N:9][C:10](Cl)=[N:11][CH:12]=1>C1COCC1.N1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:10]1[N:11]=[C:12]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:7]=[C:8]([Cl:14])[N:9]=1)[CH3:2]
Reactant: CCNCC
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN(CC)c1cc(Cl)nc(N(CC)CC)n1

Procedure:
Diethylamine (80 g) is reacted with trichloropyrimidine (50 g) in THF. The reaction after chromatography yields a mixture of the mono- and di-adduct. This material is dissolved in pyridine (58 g) and reacted with diethylamine (35 g) at 50° for 3 h. The reaction is concentrated to a residue. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is separated and concentrated. The residue is chromatographed on silica gel, eluting with ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give 2,4-bis[diethylamino]-6-chloropyrimidine. This material is dissolved in pyridine (100 g) and reacted with piperazine (40 g) at 100° for 50 h. Following the above workup procedure the title compound is obtained, NMR (CDCl3) 1.15, 2.90, 3.45 and 4.9 δ.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH3:23])[C:15](=[O:24])[C:14]=1[N+:25]([O-:27])=[O:26].CCN(CC)CC>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:12][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[C:14]([N+:25]([O-:27])=[O:26])[C:15]1=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1c(=O)c([N+](=O)[O-])c(O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2c([N+](=O)[O-])c(=O)n(C)c3ccccc23)cc1
Temperature: 35 °C
Yield: 75.5 %

Procedure:
A solution of tosyl chloride (30.0 g, 160 mmol) in 100 mL of acetonitrile was added to a stirred solution of the 4-hydroxy-1-methyl-3-nitro-1H-quinolin-2-one (32.0 g, 145.0 mmol), Et3N (17.65 g, 174.4 mmol), and DMAP (0.178 g, 1.45 mmol) in 300 mL of MeCN at 0° C. After the addition was complete, the reaction mixture was heated at 35° C. for 3 h. After the solvent was evaporated under reduced pressure, water (35 mL) and CH2Cl2 (50 mL) were added to the residue. The resulting precipitate was removed by filtration, and the filtrate was extracted with CH2Cl2 (3×200 mL). The combined extracts were dried, filtered through a plug of SiO2, and concentrated. The resulting residue was combined with the solid isolated earlier, and was triturated with ether to give 41.0 g (75%) of toluene-4-sulfonic acid 1-methyl-3-nitro-2-oxo-1,2-dihydro-quinolin-4-yl ester. 1H-NMR (CDCl3): δ 8.16 (dd, 1H, J=7.6, 1.2 Hz), 7.90 (m, 2H), 7.79 (m, 1H), 7.44 (m, 4H), 3.79 (s, 3H), 2.51 (s, 3H). MS: calculated for C17H14N2O6S+H 375.1; found: 375.3.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12]([CH2:28]S([O-])(=O)=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24]CCC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:28][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC/C=C\CCCCCCCCCS(=O)(=O)[O-]
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC/C=C\CCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
5.32 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 12.26 grams of powdered potassium hydroxide and 10 grams of cis-9-hexadecenyl-methanesulfonate were stirred in 250 ml benzene and refluxed for 10.5 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 50 ml. The reaction mixture was cooled to room temperature, 50 ml water was added, and the mixture was extracted thrice with 100 ml diethyl ether. The combined organic phase was washed with 100 ml water and the solvent was removed under reduced pressure. The residue (12.01 grams) was dissolved in 200 ml of a 90:10:3 (v/v) mixture of methanol:water:concentrated hydrochloric acid, and the resulting solution was stirred at room temperature overnight and then refluxed for 1 hour. After cooling to room temperature, 100 ml water was added. The product was extracted thrice with 75 ml diethyl ether, washed consecutively with 100 ml water, 100 ml saturated aqueous solution of sodium bicarbonate, and again with 100 ml water. After drying on Na2SO4, the solvent was removed under reduced pressure, yielding 9.104 grams of crude 1-(cis-9-hexadecenyl)-sn-glycerol. The crude product was purified by chromatography on a silica gel (30 grams) column. 9.07 grams of pure 1-(cis-9-hexadecenyl)-glycerol was eluted by chloroform followed by a mixture of chloroform and 5% methanol. The yield was 91.8%.
Reaction SMILES: [N:1]([C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH2:5][OH:6])=[N+]=[N-]>[Pd].CCOC(C)=O>[NH2:1][C@@H:4]([C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH2:5][OH:6]
Reactant: COc1ccc([C@@H](CO)N=[N+]=[N-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](N)CO)cn1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A mixture of (S)-2-azido-2-(6-methoxypyridin-3-yl)ethanol (0.90 g, 4.6 mmol), EtOAc (50 mL), and 10% Pd—C (100 mg) was stirred under H2 (1 atm) for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to give a thick oil (0.78 g, 100%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[C:3]([CH3:14])=[C:4]([CH3:13])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[CH:12]=3)[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Br)cc2c(c1C)OC(C)(C)C2
Product: COc1ccc(N2CCN(c3cc4c(c(C)c3C)OC(C)(C)C4)CC2)cc1
Yield: 57.8 %

Procedure:
By using 5-bromo-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran (300 mg, 1.18 mmol) synthesized in Reference example 15 and 1-(4-methoxyphenyl)piperazine (678 mg, 3.53 mmol), the reaction was carried out in the same manner as Example 1 to obtain the title compound 250 mg (yield 58%). Melting point was 180 to 182° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:16]([CH3:15])=[CH:25][C:24]([N+:26]([O-:28])=[O:27])=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (4.2 g), methyl 3-methyl-5-nitrosalicylate (1.8 g) and triphenylphosphine (6.8 g) in dichloromethane (100 ml) was added diethyl azodicarboxylate (4.1 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (3.1 g, yield 91%) as a rose oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3([C:18]([O:20]C)=[O:19])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[OH-].[Na+]>O1CCCC1.CO>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: COC(=O)C1(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of methyl 1-[4-(5-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-cyclopropanecarboxylate (0.32 g, 0.96 mmol) from Example 16D in tetrahydrofuran (5 mL) and methanol (2 mL) was treated with 4 N sodium hydroxide (2.40 mL, 9.60 mmol) and stirred overnight at 60° C. Reaction mixture concentrated under reduced pressure and dissolved in water. Solution neutralized with 1N phosphoric acid (pH 7) and extracted three times with chloroform. Extracts dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound without further purification. MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=[CH:23][C:24]([OH:26])=[O:25]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7](=[O:8])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: Nc1ccccc1C=CC(=O)O
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: O=C(O)C=Cc1ccccc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Yield: 75.6 %

Procedure:
0.76 g (3.5 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate from step a in 6 ml of acetonitrile were added to 0.41 g (2.5 mmol) of 3-(2-aminophenyl)acrylic acid and the mixture was reacted for 2 hours at 40° C. After the mixture has cooled down to room temperature, the precipitate is filtered off with suction, washed twice with acetonitrile, sucked dry and dried. 0.72 g (76%) of the desired product is obtained.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([Cl:16])[CH:9]=2)[S:4][C:3]=1[CH:17]1[O:21]CCO1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[O:29]C>>[Cl:16][C:10]1[CH:9]=[C:8]([C:5]2[S:4][C:3]([CH:17]=[O:21])=[C:2]([C:25]3[CH:26]=[CH:27][C:28]([OH:29])=[C:23]([F:22])[CH:24]=3)[C:6]=2[CH3:7])[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1Cl
Product: Cc1c(-c2ccc(O)c(Cl)c2)sc(C=O)c1-c1ccc(O)c(F)c1
Yield: 27.6 %

Procedure:
Starting from 2-[3-bromo-5-(3-chloro-4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (1.0 g, 2.6 mmol, made in Example 13, Step 1) and substituting 3-fluoro-4-methoxyphenylboronic acid (0.52 g, 3.1 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.26 g, 51%, m.p. 227-29° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:19])=[C:11]1[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:4].[OH-].[Na+].[ClH:27]>C(O)C.C(OCC)C>[ClH:27].[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:19])=[C:11]1[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCCn1c(-n2ccnc2)c(C)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Cc1c(-n2ccnc2)n(CCCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 1.3 h

Procedure:
A mixture of 1-(5-methoxycarbonylpentyl)-2-(1-imidazolyl)-3-methylindole (1.80 g) and 30 ml of 3 N NaOH is stirred at room temperature for 1.3 hours. The resulting clear, yellow solution is neutralized to pH 6 with 2 N HCl. The resulting suspension is extracted with ethyl acetate (2×50 ml). The organic extract is washed with a saturated NaCl solution (1×25 ml), dried (MgSO4), filtered, and concentrated in vacuo to give a cream-colored solid. The solid is dissolved in ethanol and the solution treated with 0.6 ml of 6.5 N HCl in ethanol. The solution is diluted with diethyl ether and after standing for several hours the precipitate whch forms is collected by filtration to give 1-(5-carboxypentyl)-2-(1-imidazolyl)-3-methylindole hydrochloride, m.p. 177.5°-180.5° dec.