Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:20][CH2:19][C:18]3[CH:17]=[CH:16][N:15]([CH2:21][CH:22](O)[CH3:23])[C:14]=3[C:12]=2[CH:13]=1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:32]([CH:22]([CH3:23])[CH2:21][N:15]1[CH:16]=[CH:17][C:18]2[CH2:19][O:20][C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][C:12]=3[C:14]1=2)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)-c1c(ccn1CC(C)O)CO2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2c(c1)-c1c(ccn1CC(C)N=[N+]=[N-])CO2
Yield: 75.1 %

Procedure:
1.15 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.92 g of (RS)-1-(1,4-dihydro-8-methoxy[1]benzopyrano[4,3-b]pyrrol-1-yl)-propan-2-ol and 4.13 ml of triethylamine in 50 ml of anhydrous dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 280 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of diethyl ether. The combined organic phases were washed with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.96 g of sodium azide and the reaction mixture was heated to 60° while stirring for 18 hours. After cooling, the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.58 g (75%) of (RS)-1-(2-azido-propyl)-1,4-dihydro-8-methoxy-[1]benzopyrano[4,3-b]pyrrole were obtained as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([C:14](=[O:33])[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]3[C:24](=[O:32])[C:25](=[O:31])[C:26]=3OC(C)C)[CH2:19][CH2:18]1)=[O:16])=[CH:8][NH:9]2>C(O)C>[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([C:14](=[O:33])[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:23]3[C:24](=[O:32])[C:25](=[O:31])[C:26]=3[N:2]([CH3:3])[CH3:1])[CH2:21][CH2:22]1)=[O:16])=[CH:8][NH:9]2
Reactant: CC(C)Oc1c(N2CCN(C(=O)C(=O)c3c[nH]c4cccc(F)c34)CC2)c(=O)c1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)c1c(N2CCN(C(=O)C(=O)c3c[nH]c4cccc(F)c34)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a saturated solution of dimethylamine in ethanol (2 mL), cooled at 5° C. under Ar, was added 3-[4-[2-(4-fluoro-1H-indol-3-yl)-2-oxoacetyl]piperazin1-yl]-4-isopropoxy-cyclobut-3-ene-1,2-dione (0.020 g, 0.048 mmol) and the mixture was then allowed to stir at room temperature for 2 h. The volatiles were then removed in vacuo to give the essentially pure title compound (0.019 g, 99%) as a white solid:
Reaction SMILES: CN(C=O)C.CS(O[CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:16]([Cl:28])=[C:15]([Cl:29])[CH:14]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CCOCC>[N:30]([CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([Cl:29])[C:16]([Cl:28])=[C:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:18]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCOS(C)(=O)=O)cc(Cl)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCN=[N+]=[N-])cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a DMF (0.4 M) solution of 2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]ethyl methanesulfonate (1 eq.) from Step 5, Amine 26 was added at RT sodium azide (5 eq.). The resulting solution was stirred at RT for 12 h and then at 80° C. for 3 h. The reaction mixture was then diluted with ether and washed with water. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a pink oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[N:6][C:7]=1Cl.[CH3:13][C@@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[N:6][C:7]=1[N:18]1[CH2:17][CH2:16][NH:15][C@H:14]([CH3:13])[CH2:19]1
Reactant: CC(C)(O)c1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(c2ncc(C(C)(C)O)cc2Cl)CCN1

Procedure:
A mixture of 2-(5,6-dichloro-pyridin-3-yl)-propan-2-ol from step (b) above (140 mg, 0.68 mmol) and (R)-(−)-2-methyl-piperazine (75 mg, 0.75 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound. MS (ESI, pos. ion) m/z: 270 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].[CH3:14][C@H:15]1[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][C:16]1=[O:29].Cl.CCOCC>C(O)(C)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:15]([CH3:14])[C:16]([OH:29])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C[C@@H]1C(=O)O[C@@H]1CCCCc1ccccc1
Reactant: COc1ccc(S)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1ccc(S[C@@H](CCCCc2ccccc2)[C@H](C)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
A solution of 3,4-dimethoxybenzenethiol (0.35 g, 2.1 mmol) in isopropanol (2 mL) is cooled in an ice bath and 1 M sodium hydroxide (1.5 mL, 1.5 mmol) is added slowly. This mixture is then added to a 0° C. solution of (3S,4R)-3-methyl-4-(4-phenylbutyl)oxetan-2-one (0.30 g, 1.4 mmol) in isopropanol (2 mL) over 3 minutes. The reaction is stirred for 5 minutes in ice and then allowed to warm to room temperature. After stirring for a total of 1.5 hours, the reaction is neutralized with HCl/ether. Methanol is added and the reaction mixture is azeotroped twice. The crude product is purified by gradient elution column chromatography (silica, 1 to 5% MeOH in CH2Cl2) to yield (2R,3S)-3-(3,4-dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.48 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.29-7.25 (m, 2H), 7.19-7.14 (m, 3H), 7.03-6.99 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.35-3.25 (m, 1H), 2.71-2.61 (m, 1H), 2.60 (t, J=7.0 Hz, 2H), 1.75-1.37 (m, 6H), 1.23 (d, J=7.0 Hz, 3H); MS (ion spray) m/e 389 (M+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]3[C:45]4=[CH:46][CH:47]=[CH:48][CH2:49][CH:44]4[NH:43][CH2:42]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]3[C:45]4=[CH:46][CH:47]=[CH:48][CH2:49][CH:44]4[NH:43][CH2:42]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCCCCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-1-yl)-pentyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([Br:15])[C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)C(C)(C)Cc1ccc(Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(C)(C)C(Br)c1ccc(Cl)cc1
Yield: 82 %

Procedure:
50 g (0.237 mol) of 1-(4-chlorophenyl)-2,2-dimethyl-3-butanone are dissolved in 500 ml of tetrachloromethane, and 44.5 g (0.25 mol) of N-bromosuccinimide and 0.5 g of azobisisobutyronitrile are added. The reaction mixture is heated to boiling under reflux until solid material no longer sinks to the bottom on switching off the stirrer. After cooling down, the succinimide is filtered off with suction, the solvent is distilled off from the filtrate under waterpump vacuum and the residue is distilled under high vacuum. 56.3 g (82% of theory) of 1-(4-chlorophenyl)-1-bromo-2,2-dimethyl-3-butanone of boiling point 112°-118° C./0.2 mbar are obtained.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C)C=O.Cl.[CH2:13]([N:16]([CH:20]=[C:21]1[CH:29]=[CH:28]C(C(O)=O)=[CH:23][CH2:22]1)[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>ClCCl>[CH2:17]([N:16]([CH:20]=[C:21]1[CH:22]=[CH:23][C:1]([C:2]([Cl:4])=[O:3])=[CH:28][CH2:29]1)[CH2:13][CH2:14][CH3:15])[CH2:18][CH3:19]
Reactant: CCCN(C=C1C=CC(C(=O)O)=CC1)CCC
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C=C1C=CC(C(=O)Cl)=CC1)CCC

Procedure:
0.283 cm3 of oxalyl chloride and then a drop of dimethylformamide are successively added, at a temperature close to 20° C., to a suspension of 0.748 g of 4-(N,N-di-n-propylaminomethylene)benzoic acid monohydrochloride in 20 cm3 of dichloromethane. The reaction medium is kept stirred at a temperature close to 20° C. until the gaseous emission ceases, and then concentrated to dryness under reduced pressure (about 0.5 kPa) at a temperature close to 35° C. The white solid thus obtained is used as a base for the preparation of 4,4′-O,O-di(4-(N,N-di-n-propylaminomethylene)benzoyl)-2-[(1R,2S,3R)(1,2,3,4-tetrahydroxybutyl)]-5-[(2′S, 3′R)(2′,3′,4′-trihydroxybutyl)]pyrazine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[N:20]=[CH:19][S:18][C:14]=2[N:15]=[CH:16][N:17]=1.F[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1.[H-].[Na+]>CN(C=O)C.O.Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:21][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[N:20]=[CH:19][S:18][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: Fc1cc(C(F)(F)F)ccn1
Reactant: Cc1cc(O)ccc1OCCNc1ncnc2scnc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(C(F)(F)F)ccn2)ccc1OCCNc1ncnc2scnc12
Reaction time: 2 h
Yield: 104 %

Procedure:
3-Methyl-4-[2-(thiazolo[5,4-d]pyrimidin-7-ylamino)-ethoxy]-phenol (0.13 g, 0.43 mmol) and 2-fluoro-4-trifluoromethylpyridine (0.1 g, 0.6 mmol) were dissolved with magnetic stirring in DMF (4 mL) in a 25 mL round bottom flask equipped with a dry nitrogen line at 25° C. To the solution was added NaH (60% dispersion in oil; 60 mg, 1.5 mmol) and the reaction mixture was stirred for 2 h. The reaction was diluted with H2O (100 mL), and 2 N HCl was added to adjust the pH to 6. After 24 h, a pale brown film had formed on the flask wall. The aqueous supernatant was extracted with Et2O (2×50 mL), and the pooled aqueous fractions were combined with the brown film, and then concentrated in vacuo to yield 0.2 g of a tan semi-solid. Recrystallization from hexane afforded {2-[2-methyl-4-(4-trifluoromethylpyridin-2-yloxy)-phenoxy]-ethyl}-thiazolo[5,4-d]pyrimidin-7-ylamine (Compound 9; 70 mg) as white crystals: mp 107-111° C.; 1H NMR (600 MHz, CDCl3) δ 8.78 (s, 1H), 8.53 (s, 1H), 8.29 (d, J=5.2 Hz, 1H), 7.17-7.11 (m, 1H), 7.08 (s, 1H), 6.92-6.90 (m, 2H), 6.85 (d, J=8.7 Hz, 1H), 6.56 (s, 1H), 4.29-4.20 (m, 2H), 4.11 (d, J=4.4 Hz, 2H), 2.25 (s, 3H); ESIMS m/z 448.1 ([M+H]+).
Reaction SMILES: [Li].N.[CH:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C1C=CC=CC=1.[Na+]>O1CCCC1.C(O)(C)(C)C>[CH2:14]1[C:10]2[CH2:11][CH2:12][C:13]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]([CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:9]=2[CH2:17][CH:16]=[CH:15]1
Reactant: c1ccc2c(c1)CCc1ccccc1C2CCN1CCCC1
Agent: N
Agent: O=C([O-])c1ccccc1
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C1=CCC2=C(C1)CCc1ccccc1C2CCN1CCCC1
Reaction time: 0.04 h

Procedure:
10.4 g of lithium are added to a mixture of 2.6 l of dry ammonia and 1.6 l of dry tetrahydrofuran at -50° under an argon atmosphere. After 2.5 minutes, the deep blue solution is treated while stirring well at -50° to -43° over a period of 6 minutes with a solution, pre-cooled to -50°, of 150 g of 1-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine and 351 g of t-butanol in 1.8 l of dry tetrahydrofuran. After completion of the addition, the dark blue mixture is stirred at -43° to -39° until decolorization has occurred (about 10 minutes). After an additional 2 minutes, the mixture is treated with 12.0 g of sodium benzoate and subsequently the ammonia is removed. The residue is subsequently washed six times with 500 ml of saturated sodium chloride solution each time, dried over magnesium sulfate and evaporated in vacuo. The light brown oil obtained is purified by column chromatography on 500 g of aluminum oxide (activity grade II, neutral) using benzene for the elution, there being obtained crude 1-[2-(4,5,10,11-tetrahydro-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine as a light yellow oil which crystallizes slowly upon standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:5][CH:4]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C(C)=O.[Na].O>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:12])[CH2:15][C:14]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(CCC(=O)Cl)cc1
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
3-(4-Methoxyphenyl)propionyl chloride (84.6 g, 0.426 mole) was added to a stirred suspension of ethyl acetoacetate, sodium salt (64.7 g, 0.426 mole) in ether (250 ml) over a period of 1.5 hours and the reaction was allowed to sit for 16 hours. The reaction mixture was treated with water (100 ml) and extracted with ether. The ether extract was cooled in an ice bath and ammonia gas was bubbled into the solution for 2.5 hours while the reactants were allowed to warm to room temperature. The reaction was washed with water, filtered and the ether fraction was stirred with 3N hydrochloric acid (100 ml) for 16 hours. The ether layer was washed with water, 5% sodium bicarbonate, brine and dried with sodium sulfate. The solvent was removed and the residue was distilled under high vacuum to give the product as an yellow oil (30.0 g, 28%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]([CH2:15][CH:16]=C)=[C:13]([NH:18][C:19](=[O:21])[CH3:20])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].I([O-])(=O)(=O)=[O:23].[Na+].C1CCCCC1>O1CCOCC1.C(O)(C)(C)C.C(Cl)Cl.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=[C:13]([NH:18][C:19](=[O:21])[CH3:20])[C:14]=1[CH2:15][CH:16]=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1OCOC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COCOc1c(C(=O)OC)ccc(NC(C)=O)c1CC=O
Reaction time: 0.25 h

Procedure:
A solution of 5 g (17.1 mmol) of methyl 2-methoxymethyloxy-3-allyl-4-acetylaminobenzoate in 20 ml of 1,4-dioxane is heated to 45° C. and 0.86 ml (6.86 mmol) of a 1M solution of osmium tetroxide in t-butanol is added in a single portion. Stirring is continued 15 minutes at 45° C. 7.32 g (34.2 mmol) of sodium periodate is added portionwise and stirring is continued 1 hour. Cyclohexane (1 ml) is added and stirring continued for 1 hour. The reaction mixture is then diluted with CH2Cl2 and washed with water. The organic layer is dried over MgSO4, filtered and concentrated. Flash chromatography (10% EtOAc/hexanes) affords pure 2-methoxymethyloxy-3-carbomethoxy-6-acetylaminophenylacetaldehyde which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[N:22]=[CH:23][S:24][CH:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:33][CH2:20][C:13]1[NH:12][C:11]([C:21]2[N:22]=[CH:23][S:24][CH:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2cscn2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2cscn2)=NC1c1ccc(Cl)cc1Cl
Yield: 57 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-4-yl)-1,4-dihydropyrimidine-5-carboxylate (5.31 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in CN200610098646.3) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.63 g, 57%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:13]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14]1)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([SH:23])[CH3:22].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[CH2:1]([O:8][C@H:9]([C@@H:13]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14]1)[C:10](=[O:12])[S:23][CH2:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCS
Reactant: CC1(C)OC(=O)[C@@H]([C@@H](OCc2ccccc2)C(=O)O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCSC(=O)[C@H](OCc1ccccc1)[C@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Yield: 15.4 %

Procedure:
Crude (R)-2-(benzyloxy)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (13 g, 46 mmol) was dissolved in CH2Cl2 (150 mL) and cooled in an ice bath. Ethanethiol (6.9 mL, 93 mmol) and N,N-dimethylpyridin-4-amine (0.11 g, 0.93 mmol) were added followed by DCC (11 g, 56 mmol). This mixture was stirred in ice bath and allowed to slowly warm to ambient temperature overnight. Acetic acid (15 mL) was added and the reaction was stirred for 10 minutes. The reaction mixture was poured into vigorously stirring ether (400 mL) and then filtered. The filtrate was washed with 10% sodium carbonate, water, 0.5 N HCl, water, brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified over silica gel (1-5% EtOAc in hexanes) to afford (R)—S-ethyl 2-(benzyloxy)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (2.3 g, 7.1 mmol, 15% yield) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([OH:28])=O)[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:42])[C@@H:35]([NH2:41])[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38]>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:41][C@@H:35]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:34]([OH:42])=[O:33])=[O:28])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)[C@@H](N)CC(C)(C)C
Agent: Cl
Product: CC(C)(C)C[C@H](NC(=O)c1cc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2c(CC2CCCC2)n1)C(=O)O
Yield: 88.7 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-4, 4-dimethyl-pentanoic acid methyl ester HCL (26.4 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 56.5 mg of the title compound as a white solid.
Reaction SMILES: [Na].[SH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=2)[CH:15]=1>CN1CCCC1=O>[N+:19]([C:16]1[N:14]2[CH:15]=[C:10]([S:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[CH:11]=[CH:12][C:13]2=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: Sc1ccccn1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cn12
Agent: [Na]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cnc2ccc(Sc3ccccn3)cn12

Procedure:
A solution of 1.61 g. (0.012 mole) of the sodium salt of 2-mercapto pyridine and 2.42 g. (0.01 mole) of 6-bromo-3-nitroimidazo [1,2-a] pyridine in 10 ml. N-methylpyrolidinone is heated at 150° C for 40 minutes under a nitrogen atmosphere. The cooled solution is poured onto 100 ml. of ice-water and the resultant suspension is extracted with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent to a small volume and dilution with N-hexane yields crystalline material. The solids are purified by chromatography on silica gel. Elution with methylene chloride yields pure 3-nitro 6-(2-pyridylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([S:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([N:25](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+].C(P(CCCC)CCCC)CCC>CC(C)=O.O>[O:15]=[C:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[S:11][C:9]([C:8]2[CH:21]=[CH:22][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)=[N:25]1
Reactant: CC(=O)Nc1ccc(C(=O)Sc2ccccc2C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(-c2nc(=O)c3ccccc3s2)cc1
Temperature: -10 °C
Yield: 28.9 %

Procedure:
2-{[4-(Acetylamino)benzoyl]thio}benzoic acid (1.10 g, 3.5 mmol) was suspended in acetone (10 ml). While stirring under ice cooling, triethylamine (0.50 g, 4.9 mmol) and then ethyl chloroformate (0.53 g, 3.8 mmol) were dropwise added to the suspension. After stirring at the same temperature for an hour, an aqueous solution (10 ml) of sodium azide (0.34 g, 5.2 mmol) was dropwise added to the reaction mixture, followed by further stirring for an hour. The reaction mixture was diluted with water and the dilution was extracted with toluene (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then filtered. The toluene solution was cooled to about −10° C. and tributylphosphine (0.85 g, 4.2 mmol) was dropwise added to the solution. After completion of the dropwise addition, the reaction temperature was reverted to room temperature and the mixture was heated under reflux for 15 minutes. The reaction solution was concentrated under reduced pressure and washed with isopropyl ether. Then, the residue was recrystallized from tetrahydrofuran-ethanol to give the title compound (0.30 g, 29%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH2:11]O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10]
Reactant: Cc1c(CO)ccc(C#N)c1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1c(CBr)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 3 h

Procedure:
To a solution of compound 7B (700 mg, 3.9 mmol) in CH2Cl2 (15 mL) was added PBr3 (5.8 mL, 5.8 mmol, 1N in CH2Cl2) at −15° C., and stirred at −15° C. for 3 hr. The reaction was slowly quenched with saturated NaHCO3 solution at −15° C.