Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1.[CH2:15]([NH2:18])[CH:16]=[CH2:17]>CN(C=O)C>[CH2:15]([NH:18][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:16]=[CH2:17]
Reactant: CCCc1csc2c(Cl)nc(Cl)nc12
Reactant: C=CCN
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(CCC)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.7 %

Procedure:
In 5 ml of DMF, 371 mg (1.5 mmol) of 2,4-dichloro-7-propylthieno[3,2-d]pyrimidine was dissolved, and then 188 mg (3.3 mmol) of allylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 244 mg (yield: 60.7%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].CCN(C(C)C)C(C)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1COCC1>[N:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:31](=[O:33])[CH3:32])(=[O:10])=[O:9])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 17.8 %

Procedure:
In the similar fashion using route 15 general procedure 30, 2-amino-N-(quinolin-8-yl)benzenesulfonamide (Example Compound 8) (100 mg, 0.33 mmol), DIPEA (140 μl, 0.83 mmol), acetic anhydride (23 μl, 0.49 mmol), THF (3 ml) gave the title compound (20 mg, 18%) after purification by column chromatography with DCM/MeOH/NH3 (49:1:1) as the eluent.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][SH:10].[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:20])=[O:21])[CH:15]=[CH:16][C:17]=1[S:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH3:3]
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COCCOCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCSc1ccc(S(N)(=O)=O)cc1Cl
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL microwave tube was added sodium hydride (0.6 g) in terahydrofuran (10 mL) to give a suspension. 2-(2-Methoxyethoxy)ethanethiol (1 g) was added slowly. After stirring for 30 minutes, 3-chloro-4-fluorobenzenesulfonamide (1.54 g) dissolved in 10 mL tetrahydrofuran was added slowly. The mixture was heated at 110° C. for 30 minutes in a Biotage Initiator microwave reactor. Water was added, the product was extracted with ether (20 mL×3), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica eluting with 0-25% ethyl acetate in hexane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:26]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH2:27][CH2:28][CH3:29]>CN(C=O)C.C(OCC)(OCC)OCC>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:34][C:33]2[CH:35]=[CH:36][C:30]([CH2:26][CH2:27][CH2:28][CH3:29])=[CH:31][CH:32]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Reactant: CCCCc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Solvent: CN(C)C=O
Product: CCCCc1ccc(NCc2ccc(C(=O)NCCC(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
The above propionic acid methyl ester (2.0 g, 8.5 mmol) was dissolved in DMF (20 mL) and triethyl orthoformate (10 mL), glacial acetic acid (1 mL), sodium cyanoborohydride (0.81 g, 12.8 mmol) and 4-butylaniline 1.27 g, 8.5 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride (3×100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (3:1) to afford 1.54 g (49%) of 3-{4-[(4-butylphenylamino)methyl]-benzoylamino}propionic acid methyl ester as an oil.
Reaction SMILES: [BH4-].[Na+].[CH2:3]1[O:13][C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.Cl>O1CCCC1.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH:7]1([O:6][CH2:5][CH2:4][CH2:3][OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCC2(CC1)OCCCO2
Agent: [Zr+4]
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: OCCCOC1CCCCC1
Yield: 77 %

Procedure:
Subsequently, to a suspension of zirconium chloride (24.9 g, 0.11 mol) in tetrahydrofuran (500 ml) was added slowly sodium borohydride (20.5 g, 0.54 mol) in portions with stirring under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 20 minutes. After stirring, to the reaction mixture was added dropwise a solution of cyclohexanone trimethylene ketal (16.9 g, 0.11 mol) obtained above in tetrahydrofuran (170 ml) with stirring while ice-cooling under a nitrogen atmosphere, and then the resulting mixture was stirred at room temperature for one day. After stirring, to the reaction mixture was added ice-chilled 2N hydrochloric acid (600 ml) with stirring under ice-cooling to quench the reaction, and then the tetrahydrofuran was evaporated in vacuo. The aqueous layer which remained was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (10:1–5:2) as the eluent to afford 3-cyclohexyloxypropan-1-ol (13.4 g, yield: 78%).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[CH:42][CH:41]=4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:41]=[CH:42][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[CH:44][CH:45]=4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: OCCO
Product: COC1=C(C)C(c2ccc(-c3ccccc3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 60 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(biphen-4-yl)-1H-pyrrol-2(5H)-one (1 g, 2.63 mmol, 1 eq) and MeOH (20 ml); yield 0.070 g (17.7%); MS m/z: 396.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.39 (s, 1H), 8.14 (s, 1H), 7.76-7.72 (m, 1H), 7.59-7.28 (m, 11H), 5.88 (s, 1H), 3.96 (s, 3H),1.75 (s, 3H); HPLC (METHOD [A]): rt 14.00 min (98.38%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[O:10])=[C:4]([OH:20])[C:3]=1[S:21]([NH:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:23])=[O:22].I([O-])(=O)(=O)=[O:31].[Na+]>C(#N)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[O:10])=[C:4]([OH:20])[C:3]=1[S:21]([NH:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:31])(=[O:22])=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)CCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 81.6 %

Procedure:
A solution of N-[4chloro-2-hydroxy-3-[N″-(3-methylthiopropyl)aminosulfonyl]-phenyl]-N′-(2,3-dichlorophenyl) urea (50 mg, 0.10 mmol) and sodium periodate (26 mg, 0.12mmol) in acetonitrile (6 mL) and water (2 mL) was stirred for 3 days at room temperature. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Recrystallization from acetone and hexane gave the desired product (42 mg, 81%). 1H NMR (DMSO-d6): δ 9.32 (s, 1H), 9.27 (s, 1H), 8.59 (s, 1H), 8.29 (d, 1H), 8.07 (m, 1H), 7.33 (m, 2H), 7.13 (d, 1H), 3.00 (m, 2H), 2.75 (m, 1H), 2.65 (m, 1H), 2.47 (s, 3H), 1.79 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperidine-1-carboxylate (0.0500 g, 0.125 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0166 g, 0.114 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-ynyl)piperidine-1-carboxylate (0.0507 g, 84%).
Reaction SMILES: [OH:1][C:2]1([C:15]([O:17]C)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@:19]12([OH:28])[N:26]([CH3:27])[C@@H:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]=[CH:20]2.[Na].O>C(#N)C>[C@@:19]12([OH:28])[N:26]([CH3:27])[C@@H:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]=[CH:20]2.[OH:1][C:2]1([C:15]([O-:17])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)C1(O)c2ccccc2-c2ccccc21
Agent: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: O=C([O-])C1(O)c2ccccc2-c2ccccc21

Procedure:
13.4 g (0.056 mol) of methyl ester 3a 11.65 g (0.084 mol) of tropenol, and 0.3 g of sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water with occasional agitation. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue is extracted with dichloromethane/water. The organic phase is washed with water, dried over magnesium sulfate (MgSO4), and the solvent is distilled off. The product is purified by recrystallization from diethyl ether. Yield: 11.40 g of white crystals (29% of theoretical yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[CH3:29][CH:30]([CH3:50])[C:31](=[O:49])[CH2:32][NH:33][C:34]([CH2:36][CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O>ClCCl>[CH2:41]([O:40][C:39](=[O:48])[NH:38][CH2:37][CH2:36][C:34]1[O:49][C:31]([CH:30]([CH3:50])[CH3:29])=[CH:32][N:33]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)C(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cnc(CCNC(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
100.00 g (215 mmol) PS-triphenylphosphine are suspended in 1000 ml dichloromethane, 59.92 g (236.06 mmol) iodine are added. The mixture is stirred for 0.1 hours at ambient temperature, then 65.32 ml (470.24 mmol) triethylamine are added dropwise. 28.80 g (94.91 mmol) benzyl [2-(3-methyl-2-oxo-butylcarbamoyl)-ethyl]-carbamate dissolved in 200 ml dichloromethane are added. The reaction mixture is stirred for 16 hours at ambient temperature. As the reaction is incomplete, a further 0.1 eq triphenylphosphine and 0.1 eq iodine are added. The mixture is stirred for 16 hours at ambient temperature, then the precipitate is filtered off. The filtrate is evaporated down, the residue is extracted with water and chloroform, the organic phase is dried and evaporated to dryness. The residue is purified by chromatography.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([NH:25][C:26]2([C:29](O)=[O:30])[CH2:28][CH2:27]2)=[O:24])=[CH:21][CH:20]=1)[CH3:17].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11][C:29]([C:26]3([NH:25][C:23](=[O:24])[C:22]4[CH:32]=[CH:33][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=4)[CH2:28][CH2:27]3)=[O:30])[C:4]2=[N:3][CH:2]=1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Reactant: CCOc1ccc(C(=O)NC2(C(=O)O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(C(=O)NC2(C(=O)N[C@@H]3CCc4ccccc4-n4ccnc43)CC2)cc1
Yield: 79.6 %

Procedure:
Combine (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (0.50 g, 2.51 mmol), 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylic acid (0.75 mg, 3.01 mmol), 1-hydroxybenzotriazole (407 mg, 3.01 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (577 mg, 3.01 mmol) in tetrahydrofuran (40 mL). Add diisopropylethylamine (0.53 mL, 3.01 mmol) and stir the reaction for approximately 16 hours at ambient temperature under nitrogen. Dilute the reaction with ethyl acetate, wash with saturated sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (25% EtOAc/hexanes to 100% EtOAc) to give the title compound (860 mg, 80%): MS (m/z): 431 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:22][CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:22][CH:23]4[CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](CNC1Cc2ccccc2C1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-aminoindan in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=419.
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]=CC3C=CC(OCCC)=CC=3)=[CH:14][CH:13]=2)[CH:7]([CH3:30])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C[C@H]1CC(=O)[C@H](C(C)C)CC1.NC1C=CC(C=O)=CC=1.[OH-].[K+]>CS(C)=O.O.C(OCC)(=O)C>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]=[C:8]2[CH:7]([CH3:30])[CH2:6][CH2:5][CH:4]([CH:1]([CH3:2])[CH3:3])[C:9]2=[O:10])=[CH:17][CH:16]=1
Reactant: CCCOc1ccc(C=Nc2ccc(C=C3C(=O)C(C(C)C)CCC3C)cc2)cc1
Agent: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Agent: Nc1ccc(C=O)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1CCC(C(C)C)C(=O)C1=Cc1ccc(N)cc1

Procedure:
A compound having general Formula 3, exemplified by 6-Isopropyl-3-methyl-2-{4-[(4-propoxy-benzylidene)-amino]-benzylidene}-cyclohexanone (Compound 3; FIG. 1) can be prepared as follows. A solution of menthone (154 mg, 1.0 mmol) and 4-aminobenzaldehyde (121 mg, 1.0 mmol) in dimethylsulfoxide is treated with potassium hydroxide (56 mg, 1.0 mmol). The reaction is stirred until no futher reaction occurs. The reaction mixture is poured into ethyl acetate and water. The organic phase is collected, dried and concentrated to give 2-(4-Amino-benzylidene)-6-isopropyl-3-methyl-cyclohexanone. The 2-(4-Amino-benzylidene)-6-isopropyl-3-methyl-cyclohexanone is dissolved in dichloromethane and treated with 4-propoxybenzaldehyde (164 mg, 1.0 mmol) and anhydrous Na2SO4. The reaction mixture is stirred until no further reaction occurs. The reaction mixture is filtered and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1.[OH-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: ClCc1ccccc1
Reactant: Nc1nc(S)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(SCc2ccccc2)n[nH]1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
5-Amino-3-mercapto-1,2,4-triazole (40.36 g) in ethanol (450 ml) was treated at room temperature with solid sodium hydroxide (13.9 g), and benzyl chloride (44.3 g) was added dropwise. The solution was stirred overnight, filtered, and the residue was recrystallised from ethyl acetate and dried to give 64.97 g of desired product, mp 104° C.
Reaction SMILES: O[C:2]1([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[O:5]1[CH2:4][CH:3]=[C:2]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH2:7][CH2:6]1
Reactant: N#CC1(C2(O)CCOCC2)CCC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1(C2=CCOCC2)CCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of Example 239A (0.4 g, 2.2 mmol) in pyridine (5 mL) was added POCl3 (2 mL, 22 mmol) at room temperature. and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature and carefully quenched with cold water. The resulting mixture was extracted with EtOAc (2×30 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to obtain a dehydration product 1-(3,6-dihydro-2H-pyran-4-yl)cyclobutanecarbonitrile (0.28 g). This crude material was dissolved in EtOH, followed by the addition of Pd/C. The solution was hydrogenated at room temperature overnight, filtered, and concentrated to obtain the title compound (0.24 g), which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([CH3:13])[C:7]([CH3:15])([CH3:14])[CH:6]1[NH2:16])#[N:2].[H][H].N>CO.[Co]>[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([CH3:13])[C:7]([CH3:15])([CH3:14])[CH:6]1[NH2:16]
Reactant: CN1C(C)(C)CC(CCC#N)C(N)C1(C)C
Reactant: [H][H]
Agent: [Co]
Agent: N
Solvent: CO
Product: CN1C(C)(C)CC(CCCN)C(N)C1(C)C

Procedure:
100 parts of 4-(β-cyanoethyl)-amino-1,2,2,6,6-pentamethylpiperidine were dissolved in 500 parts of methanol and hydrogenated at a hydrogen pressure of 80 to 100 bar and a temperature of 80° to 100° C. with the addition of 150 parts of liquid ammonia and 25 parts of Raney cobalt until uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate was fractionated under vacuum. 95 parts of 4-(γ-aminopropyl)-amino-1,2,2,6,6-pentamethylpiperidine, boiling point 110° to 112° C./0.1 torr, were obtained.
Reaction SMILES: [N-]=[N+]=[N-].[N:4]([C@H:7]1[CH2:12][CH2:11][CH2:10][C@:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])([CH3:13])[C@@H:8]1[OH:22])=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:4][C@H:7]1[CH2:12][CH2:11][CH2:10][C@:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])([CH3:13])[C@@H:8]1[OH:22]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H](N=[N+]=[N-])[C@H]1O
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H](N)[C@H]1O

Procedure:
A solution of azide, 50d, (0.25 g; 0.89 mmol) in 20 mL of ethyl acetate was hydrogenated with Degussa palladium (20 mole %) under 1 atmosphere of hydrogen overnight. The reaction mixture was filtered over celite and the celite was eluted with 2×10 mL of EtOAc. The filtrate was concentrated in vacuo to afford 230 mg of an oil that was used directly for the next step without further purification.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(OCC)C.O>C1(C)C=CC=CC=1>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)(=[S:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccnc(N2CCN(C(=O)c3ccccc3)CC2)n1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccnc(N2CCN(C(=S)c3ccccc3)CC2)n1
Temperature: 85 °C
Yield: 43.9 %

Procedure:
0.56 g (1.9 mmol) of 2-(4-benzoyl-1-piperazinyl)-4-methoxypyrimidine are dissolved in 25 mL of dry toluene, and 0.46 g (1.14 mmol) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,32,4-dithiadiphosphaethano-2,4-disulphide) added. The mixture is heated to 80-90° C. for 16 hours. Ethyl ether is added, basic water is used to wash the residue and the organic extract is dried with NaSO4 and the solvent evaporated off under reduced pressure. The resulting crude residue is crystallised with ethyl ether-petroleum ether to give 160 mg (0.5 mmol) of 2-(4-thiobenzoyl-1-piperazinyl)-4-methoxypyrimidine. m.p.=125-129° C.
Reaction SMILES: [CH2:1]([P:3]([OH:11])([CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])=[O:4])[CH3:2].[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4:32]>C1(C)C=CC=CC=1>[Ti+4:32].[CH2:1]([P:3]([OH:11])([CH2:5][CH:6]([CH3:10])[C:7]([O-:9])=[O:8])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][CH:6]([CH3:10])[C:7]([O-:9])=[O:8])([OH:11])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][CH:6]([CH3:10])[C:7]([O-:9])=[O:8])([OH:11])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][CH:6]([CH3:10])[C:7]([O-:9])=[O:8])([OH:11])=[O:4])[CH3:2]
Reactant: CCP(=O)(O)CC(C)C(=O)O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Product: CCP(=O)(O)CC(C)C(=O)[O-]
Yield: 96.3 %

Procedure:
180 g (1 mol) of 3-(ethylhydroxyphosphinyl)-2-methylpropionic acid (produced as in Example 17) and 170 g of titanium tetrabutoxide are refluxed in 500 ml of toluene for 40 hours. The resulting butanol is distilled off from time to time with proportions of toluene. The solution formed is subsequently freed of solvent to leave 184 g (91% of theory) of 3-(ethylhydroxyphosphinyl)-2-methylpropionic acid titanium salt.
Reaction SMILES: [NH2:1][C@H:2]([CH2:12][F:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.C([O:23][C:24](=O)[CH:25]([Cl:27])[Cl:26])C>CO>[Cl:26][CH:25]([Cl:27])[C:24]([NH:1][C@H:2]([CH2:12][F:13])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=[O:23]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To a solution of commercially available (1R,2S)-2-amino-3-fluoro-1-(4-iodophenyl)propan-1-ol (5.0 g, 20.0 mmol) in methanol (100 mL) is added triethylamine (9.56 mL, 67.8 mmol) and ethyldichloroacetate (6.22 mL, 50.8 mmol) and the mixture heated to reflux for 16 hours. After allowing to cool to room temperature, the solvent is removed under reduced pressure and the resultant oil purified by column chromatography eluting from neat heptanes to 80% ethylacetate/heptanes to give the title compound (5.94 g). m/z (Cl) M+H 405.