Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/2)=[CH:12][CH:11]=1)[CH3:8].Br[CH2:25][CH2:26][CH3:27]>CN(C=O)C>[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[N:17]([CH2:25][CH2:26][CH3:27])[C:18](=[O:20])[S:19]/2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Potassium carbonate (93 mg, 0.60 mmol) was added to a solution of compound 2 (75 mg, 0.30 mmol) in 3 mL of anhydrous DMF at 0° C. After stifling of the reaction mixture for 20 min, a solution of 1-bromopropane (30 μL, 0.33 mmol) in 1 mL of anhydrous DMF was added and then the reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water and extracted with ethyl acetate. The ethyl acetate layer was washed with water (4×20 mL) and dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (15% ethyl acetate in hexanes) to afford 82 mg (93.9%) as a light-yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([OH:8])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.N12CCN(CC1)CC2.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(OCC)(=O)C>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([O:8][S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC2CC(C)CCC2C(C)C)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 74.1 %

Procedure:
7.8 g (0.05 mol) DL-menthol and 11.2 g (0.1 mol) 1,4-diazabicyclo[2.2.2]octane are added to 50 mL ethyl acetate. This solution is cooled in an ice bath and 14.3 g (0.075 mol) tosyl chloride in 30 mL ethyl acetate is added dropwise over 15 mins. The ice bath is removed and the mixture is allowed to stir at room temperature for 4 days. After this time the solid precipitate is filtered and washed. The ethyl acetate filtrate and washings are then combined and washed successively with 10% HCl, saturated aq NaHCO3 and brine. The ethyl acetate is then evaporated to yield 11.5 g (74%) of menthyl-p-toluenesulfonate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14](OC)=[O:15])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH2:14][OH:15])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a mixture of methyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (14.53 g) and tetrahydrofuran (300 ml) was slowly added aluminum lithium hydride (1.79 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate 10 hydrate (15.20 g) was slowly added to the reaction mixture at 0° C. and the mixture was stirred at room temperature for 30 min. Insoluble materials were filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and (3-benzyloxy-1-phenyl-1H-pyrazol-5-yl)methanol (11.65 g, yield 88%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 87–88° C.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[SH:10][CH2:11][C:12]1[NH:13][C:14]([CH3:37])=[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[O-]CC.[Na+].CC(O)=O>C(O)C>[N:2]1([CH2:7][CH2:8][S:10][CH2:11][C:12]2[NH:13][C:14]([CH3:37])=[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ClCCN1CCCC1
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(CSCCN2CCCC2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 41.8 %

Procedure:
A solution of 2-(pyrrolidin-1-yl)-1-chloroethane hydrochloride (2.8 g), 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine (5.4 g) and sodium ethoxide (2 g) in ethanol (70 ml) is heated to the reflux temperature for 6 hours, then it is neutralized with AcOH and evaporated under reduced pressure. The residue, after the usual work-up, is purified by column-chromatography (SiO2 ; 210 g; eluent AcOH/MeOH 99/1) to give 2.8 g of 2-[2-(pyrrolidin-1-yl)ethylthio]methyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine, as an oil, that upon treatment with fumaric acid gives the corresponding salt, m.p. 192°-194° C.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][CH2:22][CH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].C(=O)(O)[O-].[Na+].[I-].[K+].Cl>C1(C)C=CC=CC=1.C(OCC)C>[ClH:21].[OH:8][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH2:11][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccccc1

Procedure:
To 53.4 g (0.2 mole) of α,α -diphenyl-4-piperidinemethanol in 1 liter of toluene was added 38.4 g (0.21 mole) of 4-chlorobutyrophenone, 21 g (0.25 mole) of sodium bicarbonate and 0.1 g of potassium iodide. The mixture was stirred and refluxed for 72 hours then filtered. The filtrate was concentrated to 300 ml and allowed to stand at room temperature until a precipitate formed. The precipitate was filtered off and dissolved in hot toluene, filtered and cooled. A solid formed which was dissolved in diethyl ether and treated with ethereal HCl. The resulting product was recrystallized from methanolbutanone to give the title compound, M.P. 193.5°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.[CH3:19][C:20]1([CH3:37])[O:24][C@@H:23]([CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:22][O:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:25][C@H:23]4[CH2:22][O:21][C:20]([CH3:37])([CH3:19])[O:24]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2c(O)cccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2cccc3c2CCc2cc(Cl)ccc2C3=O)O1
Yield: 53 %

Procedure:
For the preparation of the title compound, 0.50 g (1.9 mmol) of 8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.75 g (2.6 mmol) of (R)-toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester and 0.80 g (5.8 mmol) of K2CO3 in 10 ml of dry DMF are reacted by method M. Yield: 53%; C21H21ClO4 (Mr=372.85); GC 22.8 min
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH2:15][CH3:16])=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:17]1([C:23]2[CH:27]=[C:26]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]3)[O:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:1][C:2]1[C:3]([O:14][CH2:15][CH3:16])=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([NH:36][CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][C:26]2[O:25][N:24]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:27]=2)[CH2:34][CH2:33]1)=[O:9]
Reactant: CCOc1nc(OCC)c(C(=O)O)cc1N
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Product: CCOc1nc(OCC)c(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc1N

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 298 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([NH:20][CH2:21]CO)=[N:10][C:9]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.NC[CH2:28][CH2:29][OH:30]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([NH:20][CH2:21][CH2:28][CH2:29][OH:30])=[N:10][C:9]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(NCCO)nc(C#N)c(-c3cccc(F)c3)c2c1
Reactant: NCCCO
Product: COc1ccc2c(NCCCO)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
Following the procedure for 4-(3-fluorophenyl)-1-[(2-hydroxyethyl)amino]-6-methoxyisoquinoline-3-carbonitrile, using 3-amino-1-propanol in place of 2-aminoethanol, the title compound was synthesized.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:49])=[CH:4][C:5]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30](CC3C=CC(OC)=CC=3OC)[C:31]3[S:35][N:34]=[CH:33][N:32]=3)(=[O:29])=[O:28])=[CH:23][C:22]=2[C:47]#[N:48])=[C:6]([C:8]2[CH:9]=[N:10][N:11](C(OC(C)(C)C)=O)[CH:12]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([F:49])=[CH:4][C:5]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]3[S:35][N:34]=[CH:33][N:32]=3)(=[O:28])=[O:29])=[CH:23][C:22]=2[C:47]#[N:48])=[C:6]([C:8]2[CH:12]=[N:11][NH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3cc(F)c(Cl)cc3-c3cnn(C(=O)OC(C)(C)C)c3)c(C#N)c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1cc(F)c(Cl)cc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-[5-chloro-2-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-4-fluorophenyl]-1H-pyrazole-1-carboxylate (Preparation 728, 190 mg, 0.26 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.3 mL, 3.65 mmol) and the reaction mixture was left to stir at room temperature for 16 hours. The reaction was quenched by addition of water (10 mL) and the resulting mixture left to stir for 20 minutes. Then the layers were separated, the organic phase was washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The crude oil was purified using ISCO™ (5 g cartridge) 1-20% v/v gradient of methanol in dichloromethane as the eluent. The title compound was obtained as a white solid (61 mg. 50%).
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:15][S-:16].[Na+]>C1COCC1.O.C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]([S:16][CH3:15])[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: C[S-]
Reactant: CCC(CC)n1cc(Br)nc(Br)c1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)n1cc(Br)nc(SC)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
A solution of 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone (XXX) (3.23 g, 10 mmol), prepared using the conditions described in US6159980 (Example 84, Part A), hereby incorporated by reference, and sodium thiomethoxide (701 mg, 10 mol) in THF (50 mL) was stirred at 25° C. for 72 h. The reaction mixture was diluted with water (75 mL) and ethyl acetate (75 mL). The organic phase was dried over (MgSO4), filtered, and concentrated in vacuo to give crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexane 1:4) gave the product XXXI (2.30 g, 82%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5](C(OC(C)(C)C)=O)[CH:4]=1)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.[B-]C#N.[Na+]>CO.C(O)(=O)C>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[NH:5][CH:4]=2)[CH2:25]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccnc2[nH]cc(CNC3CCCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (304 mg, 1.00 mmol) in 9:1 MeOH-Acetic Acid (2 mL) at 0° C. was added tert-butyl 3-aminopiperidine-1-carboxylate (300 mg, 1.50 mmol) and the reaction mixture was stirred at rt for 1 h. Sodium cyanotrihydroborate (314 mg, 5.00 mmol) was added slowly portion wise and the reaction mixture was stirred at rt over night, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 and with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (30% to 70% Hexane-EtOAc) to give 307 mg of methyl 3-((1-(tert-butoxycarbonyl)piperidin-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate as a colorless oil. [M+H] found 389.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([O:31]C)=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][C@H:21]([OH:23])[C@H:20]([OH:24])[C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([OH:31])=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][C@H:21]([OH:23])[C@H:20]([OH:24])[C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Temperature: 90 °C
Yield: 93.8 %

Procedure:
Sodium hydroxide (0.2′1 mL of 1 N, 0.2 mmol) was added to a solution of methyl (5R,6S)-rel-13-cyclohexyl-6,7-dihydro-5,6-dihydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (20 mg, 0.049 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 90° C. for 7 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid and a precipitate was observed to form. The solid was collected by filtration and purified on the Prep. reverse phase HPLC. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (18 mg, 94%). ESI-MS m/z 392 (MH+) 1H NMR (500 MHz, MeOD) δ 1.25-1.34 (m, 1 H) 1.39-1.54 (m, 2 H) 1.60-1.67 (m, 1 H) 1.77-1.86 (m, 2H) 1.93-2.00 (m, 1 H) 2.01-2.17 (m, 3 H) 2.93-3.02 (m, 1 H) 3.36 (m, 1 H) 4.43 (d, J=4.27 Hz, 1 H) 4.54 (m, 1 H) 4.72 (dd, J=14.19, 7.17 Hz, 1 H) 7.46 (m, 2 H) 7.53 (m, 1 H) 7.74 (dd, J=8.39, 1.37 Hz, 1 H) 7.79 (d, J=7.63 Hz, 1 H) 7.90 (d, J=8.24 Hz, 1 H) 8.19 (s, 1 H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[O:5]1[CH:7]([CH2:8][O:9][C:10]2[S:11][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH3:23])=[O:16])=[CH:13][N:14]=2)[CH2:6]1>C(O)C>[CH:1]([NH:4][CH2:6][CH:7]([OH:5])[CH2:8][O:9][C:10]1[S:11][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH3:23])=[O:16])=[CH:13][N:14]=1)([CH3:3])[CH3:2]
Reactant: CCC(C)CCCNC(=O)c1cnc(OCC2CO2)s1
Reactant: CC(C)N
Solvent: CCO
Product: CCC(C)CCCNC(=O)c1cnc(OCC(O)CNC(C)C)s1
Reaction time: 12 h

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I to the invention. In this example 0.6 g. of isopropylamine is added to a solution containing 0.3 g. of 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol, and then allowed to stand for 12 hours at room temperature. The mixture is then evaporated to dryness and the resulting residue chromatographed on silica gel yielding 1-isopropylamino-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[C:11]3C=CC=C[C:12]=13)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1cc2cn[nH]c2c2ccccc12
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 25 °C

Procedure:
A suspension of 5-nitrobenzoindazole (8.16 g, 50 mmol), 3-fluorobenzyl bromide (10.4 g, 55 mmol) and potassium carbonate (13.8 g, 100 mmol) in acetone (200 mL) was refluxed overnight. After reaction cooled to room temperature, the reaction mixture was diluted with dichloromethane (100 mL), filtered through silica gel (about 100 g), and rinsed with 1:1 ethyl acetate:dichloromethane (about 100 mL). The residue after concentration was purified with column chromatography eluting with 0-30% ethyl acetate in dichloromethane to give the title compound as a white crystalline solid (the first fraction, 5.69 g, 42%). LCMS ESI(+) m/z: 272 (M+1).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=O)=CC=1)([O-])=O.C[O-].[Na+].C([O-])(=O)C.[NH4+]>CO>[OH:10][C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)[C@@H](CC(C)C)OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)[C@H](O)CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-(methoxycarbonyl)-3-methylbutyl 4-nitrobenzoate (1.59 g, 5.4 mmol) in methanol (15 mL) was added a freshly prepared solution of 1.5 M sodium methoxide in methanol (0.5 mL, 0.75 mmol). The resulting mixture was stirred at room temperature for 1 h, aqueous ammonium acetate (30 mL of 25% w/v) was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to afford methyl (2R)-2-hydroxy-4-methylpentanoate as a colorless oil.
Reaction SMILES: CO[C:3](OC)(OC)[CH:4]([CH3:6])[CH3:5].[OH:11][C@@H:12]([CH2:14][C@H:15]([OH:17])[CH3:16])[CH3:13]>C1(C)C=CC=CC=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[C:4](=[C:3]1[O:17][C@H:15]([CH3:16])[CH2:14][C@@H:12]([CH3:13])[O:11]1)([CH3:6])[CH3:5]
Reactant: COC(OC)(OC)C(C)C
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC(C)=C1O[C@H](C)C[C@@H](C)O1
Yield: 52.5 %

Procedure:
To a mixture of 3.8 g (25.6 mmol) of 1,1,1-trimethoxyisobutane and 3 g (28.8 mmol) of 2(R),4(R)-dihydroxypentane in 100 ml of toluene was added 200 mg of PPTS and the resulting reaction mixture was allowed to reflux under nitrogen for 20 hours while azeotroping methanol formed using the Dean-Stark trap. The reaction mixture was cooled, washed successively with saturated sodium bicarbonate solution, water, and brine. The toluene layer was dried, the solvent was concentrated under nitrogen, and the residue was distilled to afford 2.1 g (52.5%) of 2-isopropylidene-4(R),6(R)-dimethyl-1,3-dioxane (Formula V: R3 =R4 =CH3 ; R5 and R6 together are (R,R)--O--CH(CH3)CH2CH(CH3)O--), b.p. 95°-100° C./10 mm.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:13][C:9]1[CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1ccc(OC(F)(F)F)cc1Cl

Procedure:
Part A. A solution of 4-trifluoromethoxyaniline (12.0 mL, 88.8 mmol) and N-chlorosuccinimide (13.04 g, 97.7 mmol) in acetonitrile (90 mL) was heated to reflux for 12 h. After cooling, the solution was filtered and evaporated, and the residual material was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to afford the product, 2-chloro-4-trifluoromethoxyaniline, as a liquid. The product was further purified by distillation to afford 18.14 g (85.7 mmol, 97%) pure product, b.p. 50-60° C./5 mm Hg (bulb-to-bulb). 1H NMR (300 MHz, CDCl3): Δ 7.16 (1H, d, J=2.5 Hz), 6.96 (1H, dd, J=8.8, 2.5 Hz), 6.73 (1H, d, J=8.8 Hz), 4.08 (2H, br s). MS (H2O-GC/MS): m/e 214 (27), 213 (17), 212 (100).
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(OCC)=O.[F:29][C:30]1[CH:55]=[CH:54][C:33]([O:34][CH2:35][CH2:36][N:37]2[C:41](=[O:42])[N:40]([C:43]3[S:44][C:45]([C:49]([O:51]CC)=[O:50])=[C:46]([CH3:48])[N:47]=3)[CH:39]=[N:38]2)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:55]=[CH:54][C:33]([O:34][CH2:35][CH2:36][N:37]2[C:41](=[O:42])[N:40]([C:43]3[S:44][C:45]([C:49]([OH:51])=[O:50])=[C:46]([CH3:48])[N:47]=3)[CH:39]=[N:38]2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1sc(-n2cnn(CCOc3ccc(F)cc3)c2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Product: Cc1nc(-n2cnn(CCOc3ccc(F)cc3)c2=O)sc1C(=O)O
Yield: 90 %

Procedure:
Following the procedure as described in Example 20, making variation as required to replace ethyl 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with ethyl 2-(1-(2-(4-fluorophenoxy)ethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 90% yield: MS (ES−) m/z 363.1 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[S:5][C:6]=1[CH3:7].[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14]>O>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[N:14]/[CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])[S:5][C:6]=1[CH3:7]
Reactant: COC(CN)OC
Reactant: Cc1sc(C=O)cc1Br
Solvent: O
Product: COC(C/N=C/c1cc(Br)c(C)s1)OC
Temperature: 120 °C
Reaction time: 12 h

Procedure:
4-bromo-5-methylthiophene-2-carbaldehyde (11.00 g, 53 6 mmol) was treated with 2,2-dimethoxyethanamine (17.5 ml, 161 mmol) and the mixture stirred at 120° C. for 12 hours. The reaction was poured into water (50 ml) and stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, concentrated under reduced pressure and placed under a vacuum line to give (E)-N-((4-bromo-5-methylthiophen-2-yl)methylene)-2,2-dimethoxyethanamine.