Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=C(Cl)C=1N)CN.[Cl:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)[CH2:16][NH:17]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:16][NH2:17])[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]1
Reactant: CN1CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2Cl)CC1
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(CN)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step F (3): To a solution of tert-butyl 3-chloro-4-(4-methylpiperazin-1-yl)benzylcarbamate (36 mg, 0.1 mmol) from step F (2) in CH2Cl2 (0.5 mL) was added TFA (0.5 mmol). The mixture was stirred at rt for 2 h, and then the mixture was concentrated to give the title compound which was used without further purification. 1H-NMR (500 MHz, CD3OD) δ 7.59 (s, 1 H), 7.43 (d, J=8.24 Hz, 1 H), 7.27 (d, J=8.24 Hz, 1 H), 4.10 (s, 2 H), 3.60-3.70 (m, 2 H), 3.50-3.59 (m, 2 H), 3.29-3.42 (m, 2 H), 3.10-3.22 (m, 2 H), 2.98 (s, 3 H).
Reaction SMILES: COC(=O)C.[F:6][C:7]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:8](O)=[O:9].[NH2:22][NH2:23]>CO>[F:6][C:7]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:8]([NH:22][NH2:23])=[O:9]
Reactant: O=C(O)C(F)(F)c1ccc2ncccc2c1
Reactant: NN
Solvent: COC(C)=O
Solvent: CO
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of difluoro-quinolin-6-acetic acid methyl acetate (670 mg, 2.83 mmol) in methanol (20 mL) was added anhydrous hydrazine (2 mL). The mixture heated to reflux for 2 h, cooled to room temperature, concentrated and dried in high vacuum to give a light orange solid (680 mg, 100%). 1H-NMR (DMSO): δ 9.02-9.01 (1H, dd, J=1.7 Hz), 8.56-8.54 (1H, d, J=9.3 Hz), 8.28 (1H, s), 8.17-8.15 (1H, d, J=8.8 Hz), 7.91-7.88 (1H, dd, J=2.0, 2.0 Hz), 7.66-7.63 (1H, q, J=4.0 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]=1[CH2:13][O:12][C:9]1[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (3.1 g, 9.0 mmol) in ethanol (15 mL) was added aqueous sodium hydroxide (1 N, 27.5 mL). After heating at 60° C. for 30 min it was cooled to ambient temperature and and aqueous sodium carbonate (2 M, 50 mL) added. Addition of aqueous sodium hydroxide (1 M, 50 mL) was followed by extraction with tert-butylmethylether. The aqueous phase was acidified with aqueous hydrogen chloride (25%) to pH=2 and extracted with tert-butylmethylether and ethyl acetate. The combined organic layers were dried over sodium sulfate and concentration afforded the title compound (2.8 g, 100%) as a white solid after trituration from tert-butylmethylether. MS: m/e=309.3 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4](Cl)=[O:5].FC(F)(F)C1C=C(C(F)(F)F)C=CC=1C(OC)=O.[NH2:37][CH:38]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:39]1([N:44]([CH3:46])[CH3:45])[CH2:43][CH2:42][CH2:41][CH2:40]1.COC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1C(NC(C1C=CC=CC=1)C(C)(N1CCCC1)CC)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:45][N:44]([CH3:46])[C:39]1([CH:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:37][C:4](=[O:5])[C:3]2[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=2[CH3:1])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: CCC(C)(C(NC(=O)c1c(OC)cc(C(F)(F)F)cc1C(F)(F)F)c1ccccc1)N1CCCC1
Agent: COC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 2-methyl-4,6-bis(trifluoromethyl)benzoyl chloride and methyl 2,4-bis(trifluoromethyl)benzoate (approximately 0.5 mmol) prepared as described in D53 was dissolved in dry DCM (3 ml) and treated with (+)-{1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (109 mg, 0.50 mmol) and triethylamine (140 ul, 1.00 mmol) and left overnight at room temperature. The volatile components were removed under reduced pressure and the residue chromatographed on silica gel. Elution with 0-80% ethyl acetate in pentane gave the title product (86 mg, ca.36%). 1H NMR (CDCl3) δ: 0.95 (1H, br m), 1.44-1.86 (7H, overlapping m), 2.20 (6H, s), 2.41 (3H, br s), 5.10 (1H, d, J=5.6 Hz), 7.07 (1H, br s), 7.26-7.42 (5H, overlapping m), 7.67 (1H, s), 7.77 (1H, s). Mass Spectrum (Electrospray LC/MS): Found 473 (MH+) C24H26F6N2O requires 472. Ret time 2.25 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][NH:25][O:26][CH3:27].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[N:25]([CH3:24])[O:26][CH3:27])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a suspension of 2-chloroisonicotinic acid (18.0 g, 0.105 mol) in 250 mL of methylenechloride was added 1,1′-carbonyldiimidazole (17.0 g, 0.105 mol) portionwise. The mixture was stirred for 0.5 h and N,O-dimethylhydroxylamine hydrochloride (10.2 g, 0.105 mol) was added rapidly. The reaction mixture was stirred at room temperature overnight. Ether was added and the organic layer was washed with water, dried, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 14.5 g (70%) of product as a yellow oil. This was used in next step without purification.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[CH3:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=O>O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[CH3:22])[CH2:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CNc1ccccc1
Reactant: C=O
Solvent: O
Product: Cc1cc(S(N)(=O)=O)ccc1N1CN(c2ccccc2)CC1=O

Procedure:
2-Phenylamino-N-(2-methyl-4-sulphamoylphenyl)-acetamide (16 g) was dissolved in ethano, (320 ml) and paraformaldehyde (1.9 g) in water (640 ml) added. The mixture was refluxed 11/2 hr, cooled and filtered. The residue was crystallised from DMF/water to yield 16 g, m.p. 206°-210°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].CCN(CC)CC.C(#N)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[CH2:19]([O:18][C:14](/[CH:15]=[CH:16]/[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2)=[O:17])[CH3:20]
Reactant: C=CC(=O)OCC
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc2[nH]c(C(=O)O)cc2c1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
5-Bromoindole-2-carboxylic acid (400 mg, 1.66 mmol) and tri-O-tolyl phosphine (96 mg, 0.32 mmol) were added to a microwave tube. Ethyl acrylate (0.56 ml, 5.6 mmol), Et3N (0.92 ml, 6.6 mmol), acetonitrile (2.5 ml) and Pd(OAc)2 (40 mg, 0.18 mmol) were added. The reaction was placed in a CEM microwave at 150 W, 90° C. for 30 minutes with 5 min ramp time. EtOAc was added and the reaction mixture filtered through celite. The celite pad was washed with DCM and the combined organic fractions removed to give a yellow solid. The solid was redissolved in DCM and extracted into saturated sodium hydrogen carbonate. The aqueous layer was washed with DCM and diethyl ether. The aqueous basic layer was acidified with 2M HCl (pH=5) and the product extracted into EtOAc. The solvent was removed to give the required product (370 mg, 86% yield). LCMS purity 86%, m/z 260 [M++H]+
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15]Br)[O:11][C@H:10]1[N:17]1[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([CH2:15][C@H:12]1[O:11][C@@H:10]([N:17]2[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]2=[O:19])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:13]1[OH:14])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1ccn([C@@H]2O[C@H](CBr)[C@@H](O)[C@H]2OCc2ccccc2)c(=O)[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OCc2ccccc2)[C@@H]1O
Temperature: 60 °C
Yield: 38.6 %

Procedure:
2'-O-Benzyl-5'-bromo-5'-deoxyuridine (4.3 g) was dissolved in DMF (86 ml) and sodium azide (7 g) added. The mixture was stirred and heated at 60° C. for 45 mins. After cooling and decanting from unreacted sodium azide the DMF was evaporated to dryness. The residue was dissolved in ethyl acetate and washed twice with water, dried and evaporated to dryness. The residue was chromatographed on Merck silica gel (Art. 9385). Elution with 10% methanol in toluene gave 1.5 g of pure 5'-azido-2'-O-benzyl-5'-deoxyuridine.
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]([NH2:8])=[N:6][CH:5]=[N:4]1.[C:9]([C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10].Cl>O>[C:9]([C:11]1[CH:12]=[C:13]([S:18]([NH:8][C:7]2[S:3][N:4]=[CH:5][N:6]=2)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10]
Reactant: Nc1ncns1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reaction time: 0.08 h

Procedure:
Sodium hydroxide (5.08 g, 0.127 mol) was dissolved in water (60 mL) and 1,4-1,4-dioxane (300 mL). 1,2,4-Thiadiazol-5-amine (10 g, 0.1 mol) was added and the reaction stirred for 5 minutes. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (8.25 g, 0.0376 mol) was added and the reaction was allowed to stir for 3 hours at 20° C. After this time, the reaction was poured into 150 mL of 1N HCl. This solution was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound as a brown solid. LCMS Rt=1.22 minutes MS m/z 283 [MH]+ 1H NMR (d6-DMSO) δ 8.54 (s, 1H), 8.39 (dd, 1H), 8.19 (m, 1H), 7.71 (m, 1H).
Reaction SMILES: C(O)(=O)C(O)=[O:3].C([O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[OH:29])[CH2:24][CH2:23]2)=[CH:14][CH:13]=1)C.[OH-].[K+].O.C(O)(=O)C>C(O)C>[OH2:3].[F:43][C:40]1[CH:39]=[CH:38][C:37]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)([OH:29])[CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][C:10]([OH:44])=[O:9])=[CH:13][CH:14]=3)[CH2:23][CH2:24]2)=[CH:42][CH:41]=1
Reactant: O=C(O)C(=O)O
Reactant: CCOC(=O)Cc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 3.7 g (0.0073 mole) of the free base of 4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzeneacetic acid ethyl ester oxalate [1:1], 0.8 g (0.0145 mole) of potassium hydroxide, 10 ml of water and 50 ml of 95% ethanol was heated at reflux under a nitrogen atmosphere for 1.5 hr. The solution was poured into a mixture of 1.3 g (0.022 mole) of glacial acetic acid in 500 ml of ice water and let stand at ambient temperature overnight. The solid which had precipitated was collected by filtration, washed with water, air dried, and recrystallized from 2-propanol to yield 2.9 g (78%) of the title compound as a white solid, mp 113°-121° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>ClC(Cl)Cl>[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:34]([N:33]([CH3:37])[CH3:32])=[O:35])[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNC(=O)N(C)C)C[C@H]1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred and cooled solution (5° C.) of 3.99 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide in 90 parts of trichloromethane were added 1.32 parts of N,N-diethylethanamine. Then there was added dropwise a solution of 1.18 parts of dimethylcarbamic chloride in 60 parts of trichloromethane at a temperature below 5° C. Upon completion, stirring was continued first for one hour while cooling in an ice bath and further for 40 hours at room temperature. The reaction mixture was washed successively with water, sodium carbonate solution in water, and water, dried, filtered and evaporated. The product was filtered off and crystallized from acetonitrile, yielding 3.12 parts (73%) of cis-4-amino-5-chloro-N-[1-[2-[(dimethylamino)carbonylamino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 206.5° C. (compound 80).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:12]1[N:13]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[O:10][CH:11]=1)(=[O:25])=[O:24]
Reactant: CC1(c2nc(CO)co2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2nc(COS(C)(=O)=O)co2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methanol (235 mg, 1.27 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.24 mL, 1.68 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 4-(azidomethyl)-2-(2-methyl-1,3-dioxolan-2-yl)oxazole as a brown oil. To a solution of the crude azide in THF (6 mL) were added polymer-supported Ph3P (1.2 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.31 min; [M+H]+=185.01.
Reaction SMILES: Cl.[CH2:2]([C:6]1[NH:10][C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH2:3][CH2:4][CH3:5].[OH-].[K+].[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH2:2]([C:6]1[N:10]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([I:18])=[CH:20][CH:21]=2)[C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: BrCc1ccc(I)cc1
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 23.07 g (100 mmol) of the hydrochloride of 2-butyl-1,3-diazaspiro[4,4]non-1-en-4-one and 19.8 g of potassium hydroxide in 100 mL de water is added to a solution of 29.7 g (100 mmol) of 4-iodobenzyl bromide and 3.4 g (10 mmol) of tetrabutylammonium bisulphate in 30 mL of toluene, and the mixture is heated at reflux for 1 hr. After cooling to 25° C., 100 mL of water is added and the phases are separated. To the organic phase is added 10 mL of concentrated hydrochloric acid, 100 mL is evaporated at reduced pressure, 300 mL of ethyl acetate is added and the resulting solid is filtered to give 39.6 g (88%) of the title compound in the form of hydrochloride.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:17]4[CH:21]=[N:20][N:19]=[CH:18]4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.CN(CCC1C2C(=CC=C(N3C=NN=C3)C=2)NC=1)C>>[CH3:7][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:17]4[CH:21]=[N:20][N:19]=[CH:18]4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:6]1
Reactant: CN1CCC(c2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Agent: CN(C)CCc1c[nH]c2ccc(-n3cnnc3)cc12
Product: CN1CCC(c2c[nH]c3ccc(-n4cnnc4)cc23)C1

Procedure:
3(R)-N-methyl-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]pyrrolidine of formula IA: ##STR3## 3(S)-N-methyl-3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl-]pyrrolidine of formula IB: ##STR4## N-methyl-4-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]piperidine of formula IC: ##STR5## N,N-dimethyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethylamine of formula ID: ##STR6## and salts and prodrugs thereof.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[CH2:28](O)C.O>>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[O:18][CH3:28])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CSc1ccc(C(O)CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)cc1
Reactant: CCO
Solvent: O
Product: COC(CCc1cc(C)c(OC(C)(C)C(=O)O)c(C)c1)c1ccc(SC)cc1

Procedure:
This compound was prepared following the general procedure E, using 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-hydroxy-propyl]phenoxy]-2-methylpropanoic acid at reflux in a 2/3:1/3 ethanol/water mixture for 16 hours;
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2](C)=O.C([O-])(=O)C(C)=O.[Mg+2].C([O-])(=O)C(C)=O.C([O-])(=O)C(C)=O.[K+].C([O-])(=O)C(C)=O.[Ca+2].C([O-])(=O)C(C)=O.C([O-])(=O)C(C)=O.[Na+].[Na].C([O-])(=O)C(C)=O.C(NCC(O)=O)(=O)C(C)=O.C([CH:69]([N:73]([C:75](=[NH:77])[NH2:76])C)C(O)=O)(=O)C(C)=O.O=C(C[N:82]([C:84](=[NH:86])[NH2:85])C)O>O.C(O)(=O)C>[O:5]=[C:1]([CH2:2][N:73]([C:75](=[NH:76])[NH2:77])[CH3:69])[OH:6].[O:5]=[C:1]([CH2:2][NH:85][C:84](=[NH:82])[NH2:86])[OH:6]
Reactant: CC(=O)C(=O)O
Reactant: CC(=O)C(=O)C(C(=O)O)N(C)C(=N)N
Agent: CC(=O)C(=O)NCC(=O)O
Agent: CC(=O)C(=O)[O-]
Agent: CN(CC(=O)O)C(=N)N
Solvent: O
Solvent: CC(=O)O
Product: N=C(N)NCC(=O)O

Procedure:
Pyruvic acid is a colorless liquid with an odor resembling that of acetic acid and has a melting point of 13° C. Pyruvic acid is an intermediate in the breakdown of sugars to alcohol by yeast. The mineral salts of pyruvic acid, such as magnesium pyruvate, potassium pyruvate or calcium pyruvate or mixtures thereof are useful in the present invention. Sodium pyruvate is not especially preferred as it is known that sodium is associated with various negative medical conditions such as high blood pressure, water retention and heart disease. Further, certain athletes, such as bodybuilders, desire to present a defined visual image of their body which shows muscle definition and thus, the water retention properties of the sodium salt are not beneficial. Pyruvate precursors in the form of pyruvamides or pyruvyl-amino acids are also useful in the present invention. Pyruvyl-glycine is representative of the useful pyruvyl-amino acids. Another form of pyruvate precursor is pyruvyl-creatine, wherein pyruvate is bonded to creatine either covalently or ionically. Creatine or methylguanidineacetic acid has the chemical formula: ##STR2## and is present in the muscle tissue of vertebrates. It plays an important part in the cycle of chemical changes involving muscular contraction. Normally, creatine is the form in which creatine is excreted. Creatine is formed in the body by the methylation (by methionine) of glycocyamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:30]([OH:31])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.C1(O)C=CC=CC=1.C(OCC)C>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[O:31][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Reactant: Oc1ccccc1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1
Yield: 24.8 %

Procedure:
A solution of (±) N-tert-butoxycarbonyl-1,2-iminoindane (2.33 g, 10 mmol), 2-hydroxy diphenylmethane (1.84 g, 10 mmol) and pyridinium p-toluenesulfonate (50 mg) in chloroform (100 ml) was heated at reflux for 3 h. On cooling, the solution was washed sequentially with aq. NaHCO3, water and then brine. After drying over Na2SO4, solvents were removed in vacuo and the resultant brown oil subjected to column chromatography on silica gel eluting with 10% diethyl ether in hexanes to afford a pale yellow oil which was a mixture of the desired adduct and the starting phenol. This mixture was taken up in 1:1 diethyl ether:pentane (200 ml) and washed three times with a 1:1 mixture of methanol and 10% aq. NaOH. After washing with water then brine, the organics were dried over Na2SO4 and then concentrated in vacuo. The residue was recrystallised to afford the title compound as a white solid (1.03 g) m.p. 113°-114.5° C. (from diethyl ether-pentane).