Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.Cl[Sn]Cl.CC[OH:18]>>[NH2:10][C:5]1[C:6]([C:8]([NH2:9])=[O:18])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CCO
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 90 °C

Procedure:
6-chloro-3-nitro-pyridine-2-carbonitrile (100 mg, 0.54 mmol) is taken up in EtOH (1 mL), combined with SnCl2 (413 mg, 2.18 mmol) and heated to 90° C. for 3 h. Then the solvent is removed, the residue is taken up in ethyl acetate and first of all washed with NaHCO3 to pH 7, then washed with NaOH (2 M) to pH 8-9. Then the residue is filtered through Celite®, the filtrate is extracted again with ethyl acetate and the combined organic phases are dried on Na2SO4. The solvent is eliminated in vacuo and 3-amino-6-chloro-pyridine-2-carboxylic acid amide is obtained (HPLC-MS: tRet.=0.78 min, MS(M+H)+=172, method LCMSBAS1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CS(C)=O.CCOCC>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:18][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20])[CH:7]=1)#[N:9]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCNc1cc(C#N)ccn1

Procedure:
A solution of 2-chloro-4-cyanopyridine (2.00 g, 14.4 mmol), beta-alanine tert-butyl ester hydrochloride (3.14 g, 17.3 mmol) and DIEA (9.88 mL, 57.7 mmol) in anhydrous DMSO (30 mL) was heated at 150° C. for 3 days. The reaction mixture was diluted with Et2O (100 mL) and washed with water (3×60 mL) and brine (60 mL). The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure. Purification by flash chromatography (silica, EtOAc/cHex) gave the title compound as a brown oil. HPLC (Method A), Rt: 2.8 min (purity: 92.2%). UPLC/MS, M+(ESI): 248.1, M−(ESI): 246.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.16 (dd, J=5.2, 0.7 Hz, 1H), 7.16 (t, J=5.7 Hz, 1H), 6.83 (m, 1H), 6.79 (dd, J=5.2, 1.4 Hz, 1H), 3.46 (td, J=6.8, 5.7 Hz, 2H), 2.46 (t, J=6.8 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:39][O:40][CH3:41].[Cl-].[NH4+]>ClCCl>[CH3:39][O:40][CH2:41][O:27][CH:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:21]1
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.2 %

Procedure:
In dichloromethane (45 mL), 7-dehydrocholesterol (2.0 g, 5.2 mmol) was dissolved, then N,N-diisopropylethylamine (2.70 mL, 15.6 mmol) and chloromethylmethylether (1.00 mL, 13.2 mmol) were sequentially added under ice-cooling, followed by stirring at room temperature for 20 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with dilute aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated to yied a residue. To the residue, methanol was added to triturate to obtain the title compound (1.9 g, 83%).
Reaction SMILES: [C:1]([O:5][P:6]([O-:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)C.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1>C1COCC1>[OH:30][CH:29]([P:6](=[O:12])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:26]1[CH:27]=[CH:28][C:23]([CH3:31])=[CH:24][CH:25]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)(C)OP([O-])OC(C)(C)C
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of di-tert-butylphosphite (30 g) in THF (700 mL) cooled at −78° C. was added dropwise a solution of LiN(TMS)2 (165 mL, 1M in THF). After stirring for 30 min at −78° C., a solution of 4-tolualdehyde (18 mL in 100 mL of THF) was added. The reaction mixture was stirred for 30 min at −78° C. and 2 h at 0° C., and then quenched with 400 mL of 50% saturated aqueous NH4Cl solution. The mixture was extracted with 1 L of 2:1 hexane/EtOAc and the extract was dried over Na2SO4. After concentration and swishing from hexane, 32 g of the title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:39]([C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:30]([CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:18]4[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:28][CH:27]=2)[C:31]([CH3:43])=[C:32]3[CH3:42])=[O:40])=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccc(N)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(N)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-aminobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH2:1]([NH:3][C:4]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][NH:19][CH2:18][C:16]=3[N:17]=2)=[CH:10][CH:11]=1)=[O:36])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(4-(3-ethylureido)phenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (intermediate 5) (2.72 g, 5.5 mmol) in DCM (40 mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the resulting residue was dissolved in the minimum MeOH and precipitated from Et2O to give a cream solid (2.35 g, 4.6 mmol, 84% yield).
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH:10]([OH:15])[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[CH:1]1([C:7]([NH:9][C:10]([Cl:18])([OH:15])[C:11]([Cl:13])([Cl:14])[Cl:12])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)C1CCCCC1
Solvent: c1ccccc1
Product: O=C(NC(O)(Cl)C(Cl)(Cl)Cl)C1CCCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 113.3 %

Procedure:
Next, cyclohexyl-N-(1,2,2,2-tetrachloro-1-hydroxyethyl) carboxamide 4 was synthesized as follows. A mixture of compound 3 (8.0 g, 20 mmol) and thionyl chloride (4.7 mL, 63.8 mmol, 2.2 equivalents) in dry benzene (30 mL) was heated at 80° C. in an oil bath. The initial suspension eventually became a clear solution (reaction time depends on the amount of starting materials, in this example it took about 5 hours). The mixture was stirred for an additional 30 minutes. The solvents were removed by evaporation under reduced pressure (rotovapor), and the resulting white solid was washed with hexanes and filtered, to produce the desired product 4 (7.0 g). NMR (1H, CDCl3): δ 6.59 (d, 1H), 6.30 (d, 1H), 2.19 (m, 1H), 1.89-1.19 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([O:11][CH3:18])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)c1cc(Cl)c(C)c(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1I
Yield: 86.6 %

Procedure:
A mixture of 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (10 g, 32 mmol), dimethyl sulfate (3.7 mL, 39 mmol) and potassium carbonate (8.9 g, 64 mmol) in acetone (200 mL) was heated at reflux overnight. After evaporation to dryness, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (8.99 g, 86%). LCMS calculated for C10H11ClIO2 (M+H)+: m/z=324.9. found: 324.9.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH2:22]([NH:24][CH2:25][CH2:26][OH:27])[CH3:23]>>[CH2:22]([N:24]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1)[CH2:25][CH2:26][OH:27])[CH3:23]
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Reactant: CCNCCO
Product: CCN(CCO)CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and 2-(ethylamino)ethanol were converted to yield 2-(Ethyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-amino)-ethanol as colorless oil, MS: 374 (MH+).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[Cl:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:40][CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Clc1ccccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(CCc2ccccc2Cl)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((2-chlorophenyl)ethynyl)pyridazine (Intermediate 35) except that the solvent used for the hydrogenation was ethyl acetate and the final material was recrystallised from a mixture of ethyl acetate and heptane
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]1=[O:17].CCN(C(C)C)C(C)C.Cl[C:37]1[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:37]3[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=3)[CH2:13][CH2:12]2)[C:6]1=[O:17]
Reactant: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](Oc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Yield: 38.3 %

Procedure:
A stirred solution of (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one (Preparation G; 18 mg, 0.047 mmol), DIEA (24 μL mL, 0.14 mmol), and 2-chloro-5-ethylpyrimidine (20 mg, 0.14 mmol) in DMF (1 mL) was heated at 100° C. for 2 hours in a sealed tube. The mixture was cooled, diluted with EtOAc (25 mL), washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc/DCM 4:1) to afford (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1′-(5-ethylpyrimidin-2-yl)-[1,4′-bipiperidin]-2-one (9 mg, 0.018 mmol, 38% yield) as a white solid. Mass spectrum (apci) m/z=495.1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.Br[CH:12]1[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:12]2[CH2:14][CH2:13]2)[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1O
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1OC1CC1
Temperature: 170 °C

Procedure:
A mixture of 4-bromo-2-hydroxybenzonitrile (300 mg, 1.5 mmol), bromo-cyclopropane (480 mg, 4.0 mmol) and Cs2CO3 (300 mg, 1.6 mmol) in 2 mL of anhydrous DMF were heated to 170° C. for 2 hours by microwave. The solid was filtered off, and the filtrate was poured to water, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified with prep-TLC to give 4-bromo-2-(cyclopropyloxy)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.46˜7.48 (m, 1H), 7.36˜7.38 (m, 1H), 7.14˜7.16 (m, 1H), 3.79˜3.84 (m, 1H), 0.86˜0.87 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Br:15]Br>CO>[NH2:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][C:7]=1[Br:15]
Reactant: Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CO
Product: Nc1c(Br)cc(S(N)(=O)=O)cc1[N+](=O)[O-]

Procedure:
7.0 G. of 4-amino-3-nitrobenzenesulfonamide is suspended in 150 ml. of methanol at room temperature and brominated with 5.2 g. of liquid bromine added dropwise over 15 minutes. The reaction mixture is filtered and the solid material recrystallized from isopropanol affording 4-amino-3-bromo-5-nitrobenzenesulfonamide, m.p. 216°-218° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])=[O:7].C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35].Cl>CS(C)=O.O>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33][C:34]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:9]1=[O:17])=[O:35]
Reactant: O=C1Nc2ccccc2C1C(=O)c1ccco1
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1ccco1)C1C(=O)N(C(=O)Nc2ccc(F)cc2F)c2ccccc21
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a stirred solution of 682 mg (3.0 mmole) of 3-(2-furoyl)-2-oxindole in 8 ml of dimethyl sulfoxide was added 668 mg (6.6 mmole) of triethylamine followed by 512 mg (3.3 mmole) of 2,4-difluorophenyl isocyanate. Stirring was continued for 1 hour, and then the reaction mixture was poured into 60 ml of water. The resulting mixture was acidified with 3N hydrochloric acid and then it was cooled in an ice-bath. The solid was removed by filtration and recrystallized from ca. 35 ml of acetic acid, to give 925 mg of the title compound as yellow crystals, mp 191°-192° C.
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[CH2:26](Br)[C:27]#[CH:28]>>[CH2:28]([O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:1][CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH3:9])[CH3:4])=[CH:25][CH:24]=1)[C:27]#[CH:26]
Reactant: C#CCBr
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCOc1ccc(C(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OCC=C(C)CCC=C(C)CCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-farnesyloxybenzoic acid with propargyl bromide, there is obtained p-farnesyloxybenzoic acid propargyl ester; B.P. 245°-250°C/0.1 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=2)[C:30](=[O:31])[N:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)[C:22]1=[O:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: BrCc1ccccc1
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5ccccc5)c4=O)CC3)c2cc1OC
Yield: 80 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 200 mg (0.42 mmol) of Compound 24 was used and benzyl bromide was used in place of methyl iodide. As a result, 190.5 mg (yield: 80%) of Compound 8 was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C@:4]12[C@@H:17]3[N:18]([CH3:21])[CH2:19][CH2:20][C@:9]1([C:10]1[C:11]([OH:24])=[C:12]([O:22][CH3:23])[CH:13]=[CH:14][C:15]=1[CH2:16]3)[C@H:8]([CH3:25])[C:7](=[O:26])[CH2:6][CH2:5]2)[CH3:2].[C:27]([O-:30])([O-])=[O:28].[K+].[K+]>[Cl-].C1([N+](C)(C)C)C=CC=CC=1.O>[C:27]([OH:30])(=[O:28])[C:5]1[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:3].[CH2:1]([O:3][C@:4]12[C@@H:17]3[N:18]([CH3:21])[CH2:19][CH2:20][C@:9]1([C:10]1[C:11]([O:24][CH3:27])=[C:12]([O:22][CH3:23])[CH:13]=[CH:14][C:15]=1[CH2:16]3)[C@H:8]([CH3:25])[C:7](=[O:26])[CH2:6][CH2:5]2)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCO[C@@]12CCC(=O)[C@@H](C)[C@@]13CCN(C)[C@@H]2Cc1ccc(OC)c(O)c13
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCO[C@@]12CCC(=O)[C@@H](C)[C@@]13CCN(C)[C@@H]2Cc1ccc(OC)c(OC)c13
Product: O=C(O)c1ccccc1O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of the compound 33 (1.895 g, 5.3 mmol) (evaporation residue of the mother liquor, see above), K2CO3 (2.12 g, 15.3 mmol), phenyltrimethyl ammonium chloride (1.8 g, 10.5 mmol) and water free N,N-dimethylformamide (20 ml) was stirred at 80° C. (bath temperature) under N2 for 3 h. After filtration from the inorganic material and washing with dichloromethane, the filtrate was evaporated down. The evaporation residue was dissolved in dichloromethane, washed with water (2×50 ml) and saturated NaCl solution (1×50 ml), dried over sodium sulphate and evaporated down. The evaporation residue (2.11 g of dark brown oil) was purified using column chromatography (basic aluminium oxide, activity level III; dichloromethane). The evaporation residue was crystallised as compound 34.C7H6O3 with salicylic acid in diisopropylether. Yield: 1.32 g (49%). Fp. 135-141° C.; IR (KBr): 3400 (+NH, OH), 1710 (C═O), 1630 (CO2) cm−1; 1H-NMR (CDCl3): δ 7.88 (m, +NH), 7.27 (m, 2 arom. H), 6.81 (m, 4,arom. H), 3.86 (s, OCH3), 3.83 (s, OCH3), 2.84 (s, +NCH3), 1.40 (d, C5—CH3, 5.8 Hz), 1.17 (t, CH3CH2, J=5.3 Hz); MS (CI): m/z 374 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[CH3:7].[C:12]([O:15]C(=O)C)(=O)[CH3:13].C([O-])(=O)C.[K+].[N:24](OCC(C)C)=O>C1(C)C=CC=CC=1.O>[C:12]([N:1]1[C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=2[CH:7]=[N:24]1)(=[O:15])[CH3:13]
Reactant: CC(C)CON=O
Reactant: COC(=O)c1cc(N)c(C)s1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc2c(cnn2C(C)=O)s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
To a solution of methyl 4-amino-5-methylthiophene-2-carboxylate (F-4) (5.1 g, 30 mmol) in toluene (120 mL) were added acetic anhydride (16.0 g, 0.12 mol) and potassium acetate (1.5 g, 15.1 mmol). The reaction mixture was stirred at 100° C. for 3 h. After cooled to room temperature, the reaction mixture was treated with isobutyl nitrite (10.5 g, 90.0 mmol), and then stirred at 100° C. overnight. Water was added, and then the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography eluting with Pet/EtOAc=10/1 to afford the title compound (5.3 g) as the product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)[NH2:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[I:1][C:2]1[CH:3]=[C:4]([NH:5][S:16]([CH3:15])(=[O:18])=[O:17])[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(I)cc(N2CCOCC2)c1
Product: CS(=O)(=O)Nc1cc(I)cc(N2CCOCC2)c1
Yield: 105 %

Procedure:
3-Iodo-5-morpholinoaniline (279 mg, 0.76 mmol) was treated with methanesulfonyl chloride (82 μl, 1.06 mmol) according to the method described in Preparation 15b to give 305 mg (95% yield) of the title compound as an oil. Purity 90%.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[CH:12]1([N:18]2[CH2:27][CH2:26][C:21]3([CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([N:18]2[CH2:19][CH2:20][C:21]3([CH2:25][N:24]([CH2:1][C:3]4[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=4)[CH2:23][CH2:22]3)[CH2:26][CH2:27]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C1CCC(N2CCC3(CCNC3)CC2)CC1
Product: O=C(O)c1ccc(CN2CCC3(CCN(C4CCCCC4)CC3)C2)cc1
Yield: 169.2 %

Procedure:
Except for using 4-formylbenzoic acid (112 mg) in place of 4-(diethoxymethyl)benzaldehyde and using 8-cyclohexyl-2,8-diazaspiro[4.5]decane (170 mg) in place of 8-isobutyl-2,8-diazaspiro[4.5]decane, the same operation as in Example 26 was performed to obtain the title compound (450 mg) having the following physical properties.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]([CH:21]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]([CH2:32][OH:33])[CH2:22]1)[C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:11][N:12]([CH:21]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]([CH:32]=[O:33])[CH2:22]1)[C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C(=O)c1ccccc1)C1CC(CO)C(c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccccc1)C1CC(C=O)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (0.884 mL, 10.2 mmol) was dissolved in dichloromethane (30 mL) and chilled to −78°. Dimethylsulfoxide (1.44 mL, 10.3 mmol) was added slowly and the solution was aged 15 minutes. A solution of 1-(RS)-(N-(methyl)-N-(benzoyl)amino)-3-(SR)-(hydroxymethyl)-4-(SR)-phenylcyclopentane (1.26 g, 4.1 mmol), the higher Rf isomer from Step C, in methylene chloride (3 mL) was added slowly and the solution was aged for one hour. N,N-diisopropylethylamine (7.09 mL, 40.7 mmol) was added to the solution. After aging 10 minutes at −78°, the bath was removed and the solution was warmed to ambient temperature over one hour. The organic layers were washed sequentially with 1N HCl, water and brine, then dried over sodium sulfate and concentrated to afford the crude title compound which was essentially the same as Example 11, Step D.