Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1.[OH-].[NH4+]>C(Cl)(Cl)Cl.O>[C:1]1([N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[N:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=CN(c1ccccc1)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1ccc(N=CN(c2ccccc2)c2ccccc2)cc1

Procedure:
To a solution of N,N-diphenylformamide (19.7 g, 0.10 mol) in 100 ml of chloroform was added 22.8 g (0.11 mol) of phosphorus pentachloride in small portions. After the addition was completed the solution was refluxed for 1 hr. Ethyl 4-aminobenzoate (16.5 g, 0.10 mol) was added in small portions and the solution was refluxed 1 hr. The solution was poured into 100 ml of water and neutralized with concentrated ammonium hydroxide. The chloroform phase was separated, dried (MgSO4), filtered and concentrated to yield a yellow oil. Purification by chromatography using silica gel/benzene yielded the desired product. ##STR11##
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[C@H:3]1[C:14]([O:16]C(C)(C)C)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(F)F)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(F)F
Yield: 96.8 %

Procedure:
A mixture of 5.2 g of the product of Step B and 500 mg of p-toluene sulfonic acid in 40 ml of toluene was refluxed for 25 minutes and after cooling, 400 ml of ether were added thereto. The mixture was washed with water and the organic phase was dried and evaporated to dryness to obtain 4.1 g of (1R,cis)2,2-dimethyl-3-[3-oxo-3-(2,2-difluoroethoxy)-1-propynyl]-cyclopropane-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[C:8](OC(=O)C)(=[O:10])C>C(O)=O>[CH:8]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)C(=O)O
Solvent: O=CO
Product: CC(C)(NC=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation of ethyl-60 -aminoisobutyrylglycinate hydrochloride: To a solution of 10.3 gms (0.10 mol) of α-aminoisobutyric acid in 210 ml of 98% formic acid at 0° C, there was added dropwise with stirring 70 ml of acetic anhydride. After stirring at room temperature for 2 hr., 85 ml of ice water was added and the solution evaporated under reduced pressure to give an off-white solid. Recrystallization from absolute ethanol gave 11.2 g (0.085 mol), 85%, N-formyl-α -aminoisobutyric acid, mp 129.5°-131° C; pmr (D2O) δ 1.50 (s, 6H), 4.06 (s, 2H) and 8.16 (s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=O)c1cccc(Br)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(O)c1cccc(Br)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a solution of 1-(3-bromo-2-methylphenyl)-1-pentanone (706 mg, 2.77 mmol) in anhydrous THF (12 mL) under nitrogen at 0° C. was added sodium borohydride (209 mg, 5.53 mmol) in water (8 mL) and the resulting mixture stirred at 0° C. for 2 h. Additional sodium borohydride (105 mg, 2.77 mmol) was then added, along with more THF (40 mL), and the resulting mixture stirred at 0° C. for an additional 30 min. The reaction mixture was then partitioned between EtOAc (50 mL) and water (50 mL), the layers separated, and the aqueous re-extracted with EtOAc (50 mL). The combined organic solution was then dried (Na2SO4) filtered, and reduced under vacuum. Purification by SPE (silica, 20 g cartridge), eluted with cyclohexane:EtOAc (gradient 99:1 to 19:1) afforded the title compound as a colourless oil (495 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.Cl.[NH2:27][N:28]1[CH2:35][CH:34]2[CH:30]([CH2:31][CH2:32][CH2:33]2)[CH2:29]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:27][N:28]3[CH2:35][CH:34]4[CH2:33][CH2:32][CH2:31][CH:30]4[CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NN1CC2CCCC2C1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(NN3CC4CCCC4C3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:15][CH3:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CS(C)=O.CCOC(C)=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[CH2:15][CH3:16])=[O:14])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CCc1oc(-c2ccccc2)nc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-phenyl-5-ethyl-oxazole-4-carboxylic acid (180 mg, 0.829 mmol), 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (218 mg, 0.79 mmol), triethylamine (467 mL, 3.316 mmol), and BOP (366 mg, 0.89 mmol) in 5 mL DMSO was stirred at room temperature for 1.0 hr. The reaction was taken up in EtOAc (50 mL) and washed with hydrochloric acid (0.1N, 20 mL), water (20 mL), saturated sodium bicarbonate solution (20 mL), and brine (20 mL). The organic layer was dried with anhydrous magnesium sulfate and filtered to give 4-{4-[(2-phenyl-5-ethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester. ES-MS for C28H33N3O4 calcd. (m/e) 47.5, observed 476 (M−H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17].[OH-].[Na+].Br[CH2:34][C:35]([OH:37])=[O:36].Cl>CCO.O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:34][C:35]([OH:37])=[O:36])[CH2:22][CH2:21]1)=[O:17]
Reactant: COc1ccc(C(=O)NCC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Reactant: O=C(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)NCC2CCN(CC(=O)O)CC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
To 1 g 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide hydrochloride and 400 mg NaOH in 50 ml EtOH/H2O 1:1 0.35 g bromo acetic acid were added at RT. After stirring over night the reaction mixture was acidified with half concentrated HCl. After evaporation of the solvent the residue was coevaporated with toluene. The waxy brown solid was subjected to the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C@H:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[ClH:48].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]([C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)[CH2:57][CH2:58][CH2:59][NH2:60])=[CH:52][CH:51]=1>CN(C=O)C.C(OCC)C>[ClH:48].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH:56]([C:61]2[CH:62]=[CH:63][C:64]([F:67])=[CH:65][CH:66]=2)[CH2:57][CH2:58][CH2:59][NH:60][C:5](=[O:7])[C@@H:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3][CH:2]([CH3:1])[CH3:14])=[CH:52][CH:51]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
(S)-4-Methyl-2-morpholin-4-yl-pentanoic acid (0.300 g, 1.49 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.779 mL, 4.47 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.565 g, 1.49 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)butylamine monohydrochloride (0.444 g, 1.49 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 45 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4.The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.55 g (75%) of the pure titled compound as a white foam; mp 63-78° C. APCI-MS m/z 445.4 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[C:3]1([CH2:2][O:1][N:33]2[C:34](=[O:43])[C:35]3=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]3[C:37]2=[O:38])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1cccc2ccccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1cccc2ccccc12
Reaction time: 8 h
Yield: 63 %

Procedure:
1-(hydroxymethyl)naphthalene (1.00 g, 6.33 mmol), triphenyl phosphine (1.73 g, 6.60 mmol, 1.04 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol, 1.09 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture was diluted with 25 mL of Et2O and placed in a freezer for 2 hours. The reaction mixture was then filtered to give a white solid. Recrystallization from EtOH gave the desired product (1.21 g) as a white solid. MS(CI) m/e 321 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:25]4[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=4[NH:19][C:18]4[NH:29][N:30]=[C:31]([C:32]([O:34]C(C)(C)C)=[O:33])[C:17]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:25]4[C:24](=[O:26])[CH2:23][C:22]([CH3:27])([CH3:28])[CH2:21][C:20]=4[NH:19][C:18]4[NH:29][N:30]=[C:31]([C:32]([OH:34])=[O:33])[C:17]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)C2=C(C1)Nc1[nH]nc(C(=O)OC(C)(C)C)c1C2/C=C/c1ccc(-c2cccc(F)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(=O)C2=C(C1)Nc1[nH]nc(C(=O)O)c1C2/C=C/c1ccc(-c2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
83 mg of tert-butyl 4-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-7,7-dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinoline-3-carboxylate are dissolved in DCM (2.5 ml), admixed with TFA (2.5 ml) and stirred at RT for 3 h. The solvent is removed under reduced pressure, and the residue is suspended in toluene and concentrated by rotary evaporation once again. The resulting solid is used further without purification.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[Cl:11][C:12]1[C:17]([F:18])=[CH:16][C:15](B2OC(CC)(CC)C(CC)(CC)O2)=[CH:14][N:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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.C(OC)(C)(C)C>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][N:3]=2)=[CH:16][C:17]=1[F:18]
Reactant: CCCc1cnc(I)nc1
Reactant: CCC1(CC)OB(c2cnc(Cl)c(F)c2)OC1(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CCCc1cnc(-c2cnc(Cl)c(F)c2)nc1
Temperature: 100 °C

Procedure:
65 mmol of 2-iodo-5-propylpyrimidine and 65 mmol of 2-chloro-3-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)pyridine are dissolved in 155 ml of dioxane, and 130 mmol of tripotassium phosphate and 2 mmol of tetrakis(triphenylphosphine)palladium catalyst are added. The mixture is heated at 100° C. for 17 hours with stirring. Water and methyl tert-butyl ether are added to the reaction solution, and the organic phase is washed with water, dried using sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with dichloromethane/MTB ether 90/10, giving 2-(6-chloro-5-fluoropyridin-3-yl)-5-propylpyrimidine.
Reaction SMILES: C[C@@H](OC([N:12]1[C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14](=[O:29])[NH:13]1)=O)C1C=CC=CC=1>[Pd].C1COCC1>[C:23]1([C@H:15]2[C@H:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:12][NH:13][C:14]2=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[C@@H](OC(=O)N1NC(=O)[C@@H](c2ccccc2)[C@@H]1c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1NN[C@@H](c2ccccc2)[C@@H]1c1ccccc1
Reaction time: 15.5 h
Yield: 96 %

Procedure:
A thick -walled glass hydrogenation tube was charged with diastereomer B of 1-[((R)-α-methylbenzyl)oxycarbonyl]-trans-4,5-diphenyl-3-pyrazolidinone [from Example 139A/139B] (226 mg, 0.586 mmol), 15.0 mL THF and 5% Pd/C catalyst (112 mg) and was shaken on a Parr apparatus under an atmosphere of hydrogen at c. 50 psi pressure for 15.5 hr. The catalyst was filtered off using Celite and washed with THF. The filtrate was evaporated in vacuo to obtain 134 mg (96%) of a white foam:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([OH:19])=O)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[S:40]1[C:44]2([CH2:48][CH:47]([C:49]([OH:51])=[O:50])[NH:46][CH2:45]2)[S:43][CH2:42][CH2:41]1>C(#N)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([N:46]1[C@H:47]([C:49]([OH:51])=[O:50])[CH2:48][C:44]2([S:40][CH2:41][CH2:42][S:43]2)[CH2:45]1)=[O:19])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: O=C(O)C1CC2(CN1)SCCS2
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of 2.0 g of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid and 1.1 g of carbonyldiimidazole in acetonitrile is stirred under argon at 0° C. for 1 hour and then treated with 1.9 g of triethylamine and 1.7 g of 1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, hydrochloride. After 4.5 hours the acetonitrile is stripped and the residue is partitioned between ethyl acetate and 1 N HCl. The organic phase is washed with brine, dried (MgSO4), and the solvent is stripped to give 3.2 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([Si:3]([CH2:11][CH3:12])([CH2:9][CH3:10])[C:4]#[C:5][CH2:6][CH2:7][OH:8])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:8][CH2:7][CH2:6][C:5]#[C:4][Si:3]([CH2:1][CH3:2])([CH2:9][CH3:10])[CH2:11][CH3:12])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[Si](C#CCCO)(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[Si](C#CCCOS(=O)(=O)c1ccc(C)cc1)(CC)CC
Yield: 102.5 %

Procedure:
A solution of 4-(triethylsilyl)but-3-yn-1-ol (2 mL; 9.22 mmol), p-toluensulfonyl chloride (3.52 g; 18.44 mmol) and pyridine (1.49 mL; 18.44 mmol) in dichloromethane (30 mL) was stirred at room temperature for 3 days. The reaction mixture was then washed with a saturated solution of sodium hydrogen sulphate and brine. The organic layer was dried, concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 3.20 g (quantitative yield) of the desired product as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:19][CH:20]=1)(=[O:31])=[O:30]
Reactant: CC(=O)Nc1nc(COc2ccc(CCO)cc2)cs1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(COc2ccc(CCOS(C)(=O)=O)cc2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of N-(4-{[4-(2-hydroxyethyl)phenoxy]methyl}-1,3-thiazol-2-yl)acetamide (310.0 mg, 1.060 mmol) in anhydrous dichloromethane (8 ml) were added triethylamine (0.27 ml, 1.91 mmol) and 4-dimethylaminopyridine (13.0 mg, 0.106 mmol), and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.12 ml, 1.60 mmol) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred for 1 hr. Iced water (20 ml) was added to the reaction mixture and the mixture was stirred for 20 min, extracted 3 times with ethyl acetate. The combined organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-(4-{[2-(acetylamino)-1,3-thiazol-4-yl]methoxy}phenyl)ethyl methanesulfonate (410.8 mg, containing N-(4-{[4-(2-chloroethyl)phenoxy]methyl}-1,3-thiazol-2-yl)acetamide) as an orange solid.
Reaction SMILES: I(Cl)(=O)=O.I([Cl:8])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:20][N:21]([CH3:35])/[CH:22]=[CH:23]/[C:24]([C:26]1[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=1)=[O:25].O.C(=O)([O-])O.[Na+]>CO.C(Cl)Cl.C(Cl)Cl>[Cl:8]/[C:23](=[CH:22]/[N:21]([CH3:20])[CH3:35])/[C:24]([C:26]1[N:30]([CH:31]([CH3:32])[CH3:33])[C:29]([CH3:34])=[N:28][CH:27]=1)=[O:25]
Reactant: O=I(=O)Cl
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1ncc(C(=O)/C(Cl)=C\N(C)C)n1C(C)C

Procedure:
Benzyltrimethylammonium dichloroiodate (2.6 g 7.5 mmol) was added in portions to a stirred solution of (2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 24 of WO 03/076436; 1.1 g 5 mmol) in MeOH/DCM (15/30 ml) at room temperature. After 1 hour water (10 ml) and DCM (20 ml) were added followed after a further 30 minutes by saturated sodium hydrogen carbonate solution (20 ml). The organics were separated, re-extracted the aqueous with DCM (25 ml). The combined organics were washed with 5% (w/v) sodium thiosulphate solution (30 to 35 ml) and brine (25 ml), dried (Na2SO4) and evaporated to give the title compound as an oil (crude yield 1.68 g still wet). M/z 256.
Reaction SMILES: [C:1]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(OCC)=[O:2].C1COCC1.[BH4-].[Na+]>O>[OH:2][CH2:1][C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2c(cn1)[nH]c1ccccc12

Procedure:
3-carboethoxy-β-carboline or a derivative thereof (J in Scheme 4 above) is dissolved in a polar solvent (e.g., THF), and a reducing agent (e.g., NaBH4) is added to the solution. The mixture is stirred for a few hours and cooled. An excess of water is then added, and the mixture is stirred for another few hours. The solvent is thereafter evaporated and the resulting residue is dissolved in water, washed several times with one or more non-polar solvents such as dichloromethane and ethyl acetate, and the combined organic extracts are then evaporated. The remaining residue is purified by column chromatography (e.g., on a silica gel with elution by a 9:1 mixture of ethylacetate and methanol), to give a 3-hydroxymethyl-β-carboline intermediate.
Reaction SMILES: [OH:1][C:2]1[CH:7](C(OCC)=O)[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C(=O)CC)[CH:14]=2)[CH2:5][C:4](=[O:24])[C:3]=1[C:25](=[O:28])[CH2:26][CH3:27].CO.C(Cl)(Cl)Cl>[OH-].[Na+]>[C:25]([C:3]1[C:4](=[O:24])[CH2:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH2:7][C:2]=1[OH:1])(=[O:28])[CH2:26][CH3:27]
Reactant: CCOC(=O)C1C(O)=C(C(=O)CC)C(=O)CC1c1cccc(OC(=O)CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(=O)C1=C(O)CC(c2cccc(O)c2)CC1=O
Temperature: 25 °C

Procedure:
A solution of 36.0 g (0.0927 mol) of 3-hydroxy-5-(3-propionyloxyphenyl)-2-propionyl-4-(carboethoxy)-cyclohex-2-en-1-one in 520 mL of 1N NaOH was heated at 75° C. for 4 hours and cooled to room temperature. The reaction mixture was filtered and the filtrate was diluted with 100 mL of water and acidified with 50 mL of concentrated HCl with the product precipitating as an oil. The oil was dissolved in a mixture of 300 mL of methylene chloride and 200 mL of ethyl ether. The organic layer was separated, washed twice with 200 mL portions of water and dried over Na2SO4. The solvent was removed in vacuo leaving 20.4 g of a partially crystalline product which was purified by column chromatography using a 20:80 acetone:chloroform mixture as eluent. The fractions containing the product were combined and the solvent removed in vacuo leaving 13.1 g (54.4 percent of theoretical) of the above named product which melted at 124°-131° C.; Rf -0.38 (silica gel, 10:90 methanol-chloroform), 1H NMR (CDCl3 +D6 -DMSO): δ1.10 (t, 3H, --CH2CH3), 2.5-3.5 (m, 7H, ring protons and --CH2CH3), 6.55-7.25 (m, 3H, ArH), 8.8 5 (s, H, ArOH), 18.1 (s, 1H, OH).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH3:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[CH3:26][C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[C:17]1[N:28]=[N:29][C:2]2[CH:1]3[CH2:7][CH:4]([C:3]=2[CH:16]=1)[CH2:5][CH2:6]3
Reactant: COP(=O)(CC(=O)c1ccc(C)cc1C)OC
Reactant: O=C1C(=O)C2CCC1C2
Reactant: NN
Solvent: O
Product: Cc1ccc(-c2cc3c(nn2)C2CCC3C2)c(C)c1

Procedure:
off-white solid. MS (ESI): 251.0 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(2,4-Dimethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.