Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[C:16]([O:26][CH3:27])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][S:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:23])=[O:24])=[C:16]([O:26][CH3:27])[CH:15]=1
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Product: COc1cc(Cl)ccc1C=CS(=O)(=O)Nc1ccc(C)cc1S(N)(=O)=O
Yield: 81 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 81% yield, starting from 2-amino-5-methylbenzenesulfonamide and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride (1 equiv.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Mg].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20](Br)[CH:19]=[CH:18]2.[Br-].[Mg]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C:10]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:20]1[CH:19]=[CH:18][C:17]3[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH3:13])[CH:16]=3)[CH:21]=1)=[O:8])[CH:19]=[CH:18]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(OC)cc2-c2ccc3cc(OC)ccc3c2)c(-c2ccc3cc(OC)ccc3c2)c1

Procedure:
36 g of p-methoxybenzoyl chloride are reacted with 1 Eq of 6-methoxy-2-bromonaphthalene magnesium in a solution in THF (solution prepared by reacting the bromide with 1.5 Eq of magnesium, followed by filtration) at 0° C. for 2 h. The medium is then poured into a mixture of 300 g of ice and 50 mL of concentrated HCl. The precipitate formed is recovered and washed with water (3×500 mL). After drying, 61 g of 2-(6-methoxynaphth-2-yl)-(4-methoxyphenyl) ketone are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[N:23]=2)[CH:16]=1>CN(C=O)C>[NH2:28][C:24]1[N:23]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:20]=[CH:19][N:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
To a stirring solution of 2 (0.25 g, 1.235 mmol) and K2CO3 (0.512 g, 3.705 mmol) in dry DMF (2.5 mL) was added 1 (0.320 g, 1.235 mmol) at rt, and the reaction was stirred at 110° C. for 16 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water (2×25 mL), brine (25 mL), dried over Na2SO4 and concentrated under reduced pressure to give 3 (0.130 g, 21%) as a white solid, which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[NH2:6].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:18])[CH:10]=1)[NH2:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.7 %

Procedure:
To a suspension of 4-nitroanthranilic acid methyl ester (16.5 g, 84 mmol) in glacial acetic acid (500 mL), a solution of sulfuryl chloride (13.6 g, 0.1 mol) in glacial acetic acid (20 mL) was added dropwise. The homogeneous mixture was stirred at room temperature for 18 h and the solvent was evaporated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) and washed with saturated NaHCO3 (100 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The 1H NMR spectrum of the crude compound revealed the formation of a mixture of products, namely the desired 5-chloro regioisomer, and the byproducts 3-chloro regioisomer and the 3,5-dichlorinated compound. The crude mixture was purified by flash chromatography (silica gel, gradient 30-100% hexanes/CH2Cl2) to afford the desired 5-chloro-4-nitroanthranilic acid methyl ester (7.1 g, 36%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][N:28]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:29][CH2:30]OS(C)(=O)=O)=[CH:21][CH:20]=1)#[N:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[O:16][CH:14]([CH2:13][N:12]([CH2:30][CH2:29][N:28]([CH2:27][CH2:26][CH2:25][C:22]3[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)OCCN(CCCc1ccc(C#N)cc1)S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCN(CCCc3ccc(C#N)cc3)S(C)(=O)=O)CC(C1)O2
Temperature: 57.5 °C
Reaction time: 72 h

Procedure:
A mixture of 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (2.35 g, 0.01 mol; see WO 01/28992), methanesulfonic acid 2-{[3-(4-cyanophenyl)propyl]methanesulfonylamino}ethyl ester (3.7 g, 0.01 mol; see Preparation A above) and anhydrous K2CO3 (2.1 g, 0.015 mol) in dry acetonitrile (70 mL) was stirred under nitrogen atmosphere at 55-60° C. for 3 days. After filtration and concentration, the crude product was purified by column chromatography (silica gel: 60-120 mesh, eluent: petroleum ether-ethyl acetate, 50:50). Yield: 3.25 g (66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.NC(N)=[S:16].N.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][SH:16])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CCCCCBr)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: N
Solvent: CCO
Product: SCCCCCc1ccc(Cl)cc1
Yield: 63649.6 %

Procedure:
24.2 g (92.6 mmol) 5-(4-chlorophenyl)-pentyl bromide 60 in 60 ml ethanol was added to a solution of 10.6 g (0.139 mmol) thiourea in 40 ml ethanol. It was heated for 5 h to reflux, allowed to cool, admixed with 50 ml concentrated ammonia solution and again heated for 3 h to reflux. After cooling it was acidified to pH 1 with ca. 30 ml concentrated HCl and extracted twice with 150 ml ether. It was washed with saturated NaCl solution, dried over sodium sulfate and the solvent was removed on a rotary evaporator, 19.0 g (95%) 79 was obtained. A mixture of 5.00 g (16.3 mmol) 79, 2.25 g (16.3 mmol) potassium carbonate, 3.50 g (16.3 mmol) 6 and 50 ml dimethylformamide was stirred for 12 h at room temperature. It was admixed with water and extracted with ether. The ether phase was washed with water, dried over sodium sulfate and concentrated by evaporation. 7.1 g yellow oil which yielded 5.06 g (71%) of the ethyl ester of 27 after flash chromatography (toluene/heptane 1:2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.CN(C=O)C.Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Potassium carbonate (152 g, 1.1 mol) and 4-bromophenol (95.2 g, 550 mmol) were added to a DMF (500 mL) solution of methyl 2-bromomethylbenzoate (115 g, 500 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and thereafter the solvents were distilled off under a reduced pressure. The residue was purified by column chromatography (hexane-toluene=1:1), to give 139 g (86%) of the captioned compound in the form of a colorless oily product.
Reaction SMILES: Br.[NH2:2][C@H:3]([C:7]([OH:9])=[O:8])[CH2:4][CH2:5]O.[Al+3].[Cl-].[Cl-].[Cl-].[CH:14]([SH:17])(C)C>>[NH2:2][C@H:3]([C:7]([OH:9])=[O:8])[CH2:4][CH2:5][S:17][CH3:14]
Reactant: CC(C)S
Reactant: N[C@@H](CCO)C(=O)O
Agent: Br
Agent: [Al+3]
Agent: [Cl-]
Product: CSCC[C@H](N)C(=O)O
Reaction time: 0.17 h

Procedure:
iPrSH (20 ml) was treated slowly with gaseous HBr. Subsequently L-homoserine (10 mmol) was added and the mixture was stirred for 10 minutes. Thereafter, AlCl3 (40 mmol) was added and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched using H2O/HCl and then made basic with NaOH. After filtering off Al(OH)3 by suction the filtrate solution was concentrated to dryness and analysed by HPLC. Yield of (1)=8.2%. Activation of L-homoserine at the C-4 atom and reaction to give L-methionine
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1.C(O)(=[O:29])C.OO>C(OCC)(=O)C>[CH3:1][S:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH:6]=[N:5][CH:4]=1)=[O:29]
Reactant: CC(=O)O
Reactant: CSc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: OO
Solvent: CCOC(C)=O
Product: CS(=O)c1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Intermediate 74 (746 mg) obtained in Example 105, Step B was added with acetic acid (1.5 ml) and 30% aqueous hydrogen peroxide (2 ml) and stirred at room temperature for 17 hours. The reaction mixture was added with ethyl acetate (50 ml) and washed three times with saturated aqueous sodium hydrogencarbonate (25 ml for each time), and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:acetone=3:1) to obtain the title compound (390 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17].CC1[C:24](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23](OC)C(OC)=C(OC)C=1OC>>[CH3:1][C:2]1[C:7](/[CH:8]=[C:26](\[CH2:25][CH2:24][CH3:23])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: CCOC(=O)/C=C/c1c(C)c(OC)c(OC)c(OC)c1OC
Product: CCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)OCC

Procedure:
Compound 8d was prepared from 7 (0.437 g, 1.82 mmol) as described above for 8a to give 0.275 g (0.780 mmol, 43%) of the product as a colorless oil following flash chromatography (1:3 EtOAc:hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[CH2:5]2.[C:15]([O:19][C:20](=[O:26])[NH:21][CH2:22][C@H:23]1[CH2:25][O:24]1)([CH3:18])([CH3:17])[CH3:16].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20](=[O:26])[NH:21][CH2:22][C@H:23]([OH:24])[CH2:25][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[CH2:5]2)([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Reactant: CCN1C(=O)Cc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21

Procedure:
5-Amino-1-ethyl-7-fluoro-1,3-dihydro-indol-2-one (2.25 g, 11.6 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (2.00 g, 11.6 mmol) and lithium trifluoromethanesulfonate (1.80 g, 11.6 mmol) in acetonitrile (12 ml) are heated at 90° C. for 20 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow-brown foamy solid. HPLC r.t. 3.95 min; MS for C 18H26FN3O4 m/z 368.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.C(O)(=[O:19])C.N([O-])=O.[Na+].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:14]=[CH:13][C:11]([OH:19])=[CH:10][CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccc(N)cc1
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(F)ccc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 32.00 grams of 4-(4'-fluoro-2'-methoxyphenyl)-aniline in 120 ml. of glacial acetic acid is cooled to 10° - 12° C. To this solution is added slowly a solution of 12.25 grams of sodium nitrite in 120 ml. of water with stirring and continued cooling. Five minutes after this addition, the suspension of the diazonium acetate is added slowly to a boiling solution of 100 ml. of concentrated sulfuric acid and 200 ml. of water. After the final addition of the diazonium salt, the suspension is boiled for an additional 5 minutes and then allowed to cool to room temperature. The reaction mixture is then filtered and the cake dried in vacuo to yield 4-(4'-fluoro-2'-methoxyphenyl)-phenol.
Reaction SMILES: Br[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:17](=[O:30])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S-:31][CH2:32][CH3:33].[Na+]>C(O)C>[CH2:32]([S:31][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:17](=[O:30])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:33]
Reactant: CCOC(=O)C(Br)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)SCC
Yield: 353.2 %

Procedure:
Ethyl 2-bromo-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoate (1.00 g, 2.05 mmol; Example 37) and 56 ml of ethanol were mixed and, after sodium thioethoxide (268 mg, 2.55 mmol) was added under stirring, the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated, water was added, and the solution was extracted with ethyl acetate. The extract was washed with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=2:1 v/v) to obtain 3.4 g (43%) of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1>O>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([N:1]2[CH2:9][CH2:10][CH2:11][C:12]2=[O:13])[CH2:3][CH2:4]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C1CCCO1
Solvent: O
Product: O=C1CCCN1[C@H]1CC[C@H](O)CC1
Temperature: 190 °C

Procedure:
Add trans-4-aminocyclohexanol (230 g, 2.0 mol) to γ-butyrolactone (140 mL, 1.82 mol) in a 1 L round-bottom flask equipped with large magnetic stirrer, thermometer and condenser/nitrogen bubbler. Heat the mixture at 190° C. for 68 hours. Cool to ambient temperature and mix with water (1 L). Extract into dichloromethane (10×1.5 L). Dry the extracts over magnesium sulfate, filter and evaporate to a brown solid. Triturate with diethyl ether to afford 144.7 g (43%) of the title compound: MS (m/z): 184 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13]C.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:11])[CH3:12])=[CH:4][C:3]=1[OH:13]
Reactant: COc1cc2c(cc1F)C(C)(C)CC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CCc2cc(O)c(F)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 6-fluoro-5-methoxy-1,1-dimethyl-indan (1.40 g, 7.21 mmol) in 20.0 ml of DCM at −78° C. was added BBr3 (1.40 ml, 14.4 mmol) in DCM (10.0 ml). The reaction mixture was stirred at −78° C. for two hours before being treated with 2.0 ml of methanol. This mixture was stirred for few minutes after which a saturated solution of NaHCO3 was carefully added and the resulting mixture stirred for an additional 1 hour. The mixture was extracted with DCM (3×40 mL) and the combined organic extracts were washed with brine and dried over Na2SO4. Flash column chromatography on silica gel (2-10% ethyl acetate/heptanes) afforded 0.985 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:14](NC(C)C)([CH3:16])[CH3:15].[Li].C(Br)C=C>>[CH2:16]([CH:6]1[CH2:5][CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2]1=[O:1])[CH:14]=[CH2:15]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Li]
Solvent: C=CCBr
Product: C=CCC1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
To a stirred solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.26 g, 6.80 mmol) at −78° C., was added lithiumdiisopropyl amine (4.76 mL, 9.52 mmol) (2 M in heptane/THF/benzene) dropwise over 15 minutes. After 15 min, allyl bromide (1.18 mL, 13.6 mmol) was added and the reaction stirred at −78° C. for 1 h then quenched with acetic acid (0.5 mL). The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on ISCO (0-100% ethyl acetate/hexanes) to afford Compound 1a (550 mg, 36%) as a clear oil. LCMS=1.95 min using analytical Method (B), 473.4 (2M+Na). 1H NMR (400 MHz, CDCl3-d) δ 5.89-5.69 (m, 1H), 5.18-5.00 (m, 2H), 3.76 (ddd, J=11.2, 8.5, 2.9 Hz, 1H), 3.58 (ddd, J=10.8, 9.0, 7.5 Hz, 1H), 2.70-2.50 (m, 2H), 2.29-2.07 (m, 2H), 1.79-1.64 (m, 1H), 1.53 (s, 9H).
Reaction SMILES: FC1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=CC=1.C1(C[N:28]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)CC1>>[CH:5]1([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([NH2:28])=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)[CH2:22][CH2:23]1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(N)=O
Yield: 43 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as an off-white solid in 43% yield: mp 180-181° C. (ethanol/water); 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.63 (br, 2H), 3.66 (d, J=7.0 Hz, 2H), 2.55 (s, 3H), 1.21-1.11 (m, 1H), 0.54-0.48 (m, 2H), 0.38-0.32 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.6, 151.3, 150.9, 149.5, 131.4, 122.9, 49.4, 16.8, 10.0, 3.3; MS (ES+) m/z 280.3 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[CH:8]2)([CH3:3])[CH3:2].[CH2:15]([O:17]C1C=C2C(=CC=1)NC(C)=C2C=O)C>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[C:8]2[CH:15]=[O:17])([CH3:3])[CH3:2]
Reactant: CCOc1ccc2[nH]c(C)c(C=O)c2c1
Reactant: Cc1cc2cc(OC(C)C)ccc2[nH]1
Product: Cc1[nH]c2ccc(OC(C)C)cc2c1C=O
Reaction time: 1.5 h

Procedure:
This compound was prepared from 408c (347 mg, 1.83 mmol) in a manner similar to that for 409a except for after the drop-wise addition of substituted indole, the solution was stirred for 90 min A cream-colored powder was obtained (313 mg, 78%): mp 179-181° C. TLC Rf 0.43 (75% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.84 (s, 1H), 10.00 (s, 1H), 7.56 (d, 1H, J=2.4 Hz), 7.26-7.25 (d, 1H, J=8.64 Hz), 6.77-6.76 (dd, 1H, J1=8.7 Hz, J2=2.46 Hz), 4.56-4.50 (sep, 1H, J=6 Hz), 2.64 (s, 3H), 1.27-1.26 (d, 6H, J=6 Hz). 13C NMR (150 MHz, d6-DMSO) δ 184.0, 153.4, 148.6, 130.1, 126.4, 113.58, 113.56, 112.0, 105.5, 69.9, 22.0, 11.5. Elemental analysis calculated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.70; H, 6.83; N, 6.60.
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]([C:28]([O:30]CC)=[O:29])=[CH:26][N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+].CO>C1COCC1>[CH2:1]([O:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO[C@@H]1CN(c2ncc(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 82.2 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(3-butoxy-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (119f) (0.39 g, 0.8 mmol), 2 N lithium hydroxide (5 mL, 10 mmol), methanol (3 mL) and THF (3 mL), to obtain 0.30 g of the title compound as a colorless solid (82%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]([CH3:10])[CH2:5][NH:6][CH2:7][CH:8]=[CH2:9].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:11])[CH:4]([CH3:10])[CH2:5][N:6]([CH2:7][CH:8]=[CH2:9])[C:17]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=[C:13]([Cl:12])[N:18]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: C=CCNCC(C)C(=O)OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCN(CC(C)C(=O)OC)c1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 81 %

Procedure:
To a mixture of 1.71 g (0.010 mole) of (rac)-2-methyl-3-(2-propenylamino)-propanoic acid methyl ester, 1.94 g (0.010 mole) of 2,4-dichloro-5-nitro-pyrimidine, 50 mL of ethyl acetate and 25 mL of water was added 3.0 g (0.030 mole) of potassium bicarbonate. The mixture was stirred for 3 hours, and then diluted with 50 mL of ethyl acetate and 50 mL of water. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (100:0-97.5:2.5) to give 2.55 g of (rac)-3-[allyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-2-methyl-propanoic acid methyl ester (IV-65) as a pale yellow oil.