Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15](O)=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:13]=[N:12][C:11]=3[N:10]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:15]1[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:13][N:12]=[C:11]2[N:10]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1c(-c2ccccc2)nnc2c1c(-c1ccc(F)cc1)nn2CCN1CCOCC1
Product: Fc1ccc(-c2nn(CCN3CCOCC3)c3nnc(-c4ccccc4)c(Cl)c23)cc1

Procedure:
3-(4-fluorophenyl)-1-(2-morpholinoethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-4-ol (27.8 mg, 0.07 mmol) was heated to 80° C. in POCl3 (0.5 ml) for 2.75 h the solvent was removed in vacuo and the crude purified by preparative HPLC to give Compound 78 as an orange solid (10.7 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[CH:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>C1COCC1>[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[C:23]2[CH3:1])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To flame-dried flask under N2 was charged 0.57 ml (4.07 mmol) of diisopropylamine and 5.0 mL of dry THF. The solution was cooled to −78° C. and 1.63 mL (4.08 mmol) of a 2.5 M solution of n-butyllithium in hexanes added. The resulting mixture was brought to 0° C. and stirred for 10 min. After cooling the mixture again to −78° C., a solution of 1.0 g (3.40 mmol) of crude product from Method C in 10 mL of dry THF was added over a 10 min period. The resulting mixture was stirred for 1 h, at which time, 0.28 mL (4.50 mmol) of iodomethane were added. The reaction mixture was stirred for 2 h, quenched with a saturated solution of NH4Cl and warmed to room temperature. The mixture was stirred for 5 min., diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo to obtain the title compound. LRMS: 308, 310 (M+2).
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=2)[C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([O:4][N:5]=[C:6]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=2)[C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=NOC1CC1)c1csc(NC=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CNc1nc(C(=NOC2CC2)C(=O)O)cs1
Temperature: 0 °C
Yield: 78 %

Procedure:
To a suspension of ethyl 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer)(9.92 g) in methanol (99.2 ml) was dropwise added 2N aqueous solution of sodium hydroxide (122 ml) below 10° C. The mixture was stirred under ice-cooling for 4 hours. The mixture was poured into ice-water, washed with ethyl acetat, adjusted to pH 2 with 6N hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with petroleum ether to give 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer)(6.97 g).
Reaction SMILES: [NH4+:1].[Cl-].[Br:3][C:4]1[C:5]([F:22])=[CH:6][C:7]([F:21])=[C:8]([C:10]2([CH3:20])[NH:15][C:14](=S)[CH2:13][N:12]3[N:17]=[CH:18][CH:19]=[C:11]23)[CH:9]=1>N.CCO>[Br:3][C:4]1[C:5]([F:22])=[CH:6][C:7]([F:21])=[C:8]([C:10]2([CH3:20])[NH:15][C:14]([NH2:1])=[CH:13][N:12]3[N:17]=[CH:18][CH:19]=[C:11]23)[CH:9]=1
Reactant: [NH4+]
Reactant: CC1(c2cc(Br)c(F)cc2F)NC(=S)Cn2nccc21
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: CC1(c2cc(Br)c(F)cc2F)NC(N)=Cn2nccc21
Temperature: 85 °C
Yield: 78.7 %

Procedure:
NH4Cl (0.72 g, 13.4 mmol) was added to a stirred suspension of rac-4-(5-bromo-2,4-difluoro-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-thione (2.4 g, 6.7 mmol) in ammonia 2 M in EtOH (67 mL) and the mixture was heated at 85° C. for 18 hours. The solvent was removed in vacuo and the residue was suspended in DCM and washed with water. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution of ammonia in methanol in AcOEt 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield rac-4-(5-bromo-2,4-difluoro-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-yl-amine (1.8 g, 78% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CC(=O)c1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 3-(6-fluoropyridin-3-yl)-3-oxopropionate (3.83 g, 18.1 mmol) in 1,2-dimethoxyethane (30 ml) was added sodium hydride (60% in oil, 725 mg, 18.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene (9.30 g, purity 56%, 18.1 mmol) in 1,2-dimethoxyethane (10 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene-toluene:ethyl acetate=5:1) to give ethyl 3-(6-fluoropyridin-3-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (6.67 g, 88%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=1F)=[O:4].[CH3:26][NH2:27]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=1[NH:27][CH3:26])=[O:4]
Reactant: COC(=O)c1c(F)ccc2nc3ccc4c(OC)cccc4c3nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ccc2nc3ccc4c(OC)cccc4c3nc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 10-fluoro-4-methoxy-benzo[a]phenazine-11-carboxylic acid methyl ester (IV.5) (100 mg) and 2.0M solution of methylamine in tetrahydrofuran was stirred at room temperature for 18 hours. The solvent was then removed in vacuo to yield the crude desired title compound as an orange solid.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH3:14])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C.C(Cl)(Cl)Cl>[CH3:17][N:18]([CH3:20])[CH:19]=[N:2][S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH3:14])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc2oc(S(N)(=O)=O)cc2cn1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a suspension of 2-sulfamoyl-6-methylfuro[3,2-c]pyridine (3.65 g, 17.2 mmol) in acetonitrile (80 ml), under a nitrogen atmosphere, was added N,N-dimethylformamide dimethyl acetal (2.6 ml, 19.6 mmol). This reaction was stirred for 1.5 hours at room temperature and then diluted with chloroform and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered through a charcoal pad and the solvent evaporated. The residue was triturated with diethyl ether and the product collected (4.31 g, 93% yield) and used as is. A small portion was crystallized from ethyl acetate for microanalysis, mp. 175°-177° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[OH:28][C:29]([CH3:42])([C:33]([NH:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[O:34])[C:30](O)=[O:31]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:30](=[O:31])[C:29]([OH:28])([CH3:42])[C:33]([NH:35][CH2:36][CH2:37][C:38]([F:41])([F:39])[F:40])=[O:34])[C:3]2[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=2[C:5]2[CH:23]=[CH:22][CH:21]=[CH:20][C:6]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Product: CC(O)(C(=O)NCCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as described for example 1c. Colorless, viscous oil (73%). MS: m/e=570(M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH2:24]>C(OCC)C>[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH:24][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Solvent: CCOCC
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O

Procedure:
4.5 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)-acetate are heated to 100° for 3.5 hours under nitrogen with 7.1 g of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine. Thereafter, diethyl ether is added thereto, the mixture is stirred, filtered and the filter residue (6.5 g) is chromatographed on 30 g of silica gel (granular size 0.2-0.5 mm). The (R/S)-cis-N-pi [2-(2,6-dimethyl-1-piperidinyl)-ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with methylene chloride and methanol has a melting point of 131°-132° after recrystallization from ethyl acetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[NH:13][CH2:12][CH2:11][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)Cl
Reactant: NCCC(c1ccccc1)c1cccc2[nH]ccc12
Solvent: ClCCl
Product: COC(=O)NCCC(c1ccccc1)c1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a stirring solution of 3-(1H-indol-4-yl)-3-phenyl-propylamine (III) (0.40 g, 1.6 mmol) in DCM (15 ml), under N2, was added TEA (0.23 ml, 1.7 mmol). The mixture was cooled to about 0° C. and methyl chloroformate (0.13 ml, 1.7 mmol) in DCM (10 ml) was added dropwise over 15 minutes. The mixture was stirred at room temperature for 30 minutes, quenched by addition of H2O, and stirred for 10 min. The mixture was washed successively with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide [3-(1H-indol-4-yl)-3-phenyl-propyl]-carbamic acid methylester (V) as a white solid (0.48 g, 98% yield).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C@@H:5]1[C:10](O)=[O:11].C[Si](Cl)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([O:3][C:10]([C@H:5]1[CH2:6][CH2:7][C:8](=[O:9])[NH:4]1)=[O:11])[CH3:2]
Reactant: CCO
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCC(=O)N1
Temperature: 30 °C

Procedure:
To a flask containing anhydrous ethanol and D-pyroglutamic acid at ambient temperature (˜23° C.) was slowly added trimethylsilyl chloride while maintaining a reaction temperature NMT 30° C. After stirring at ambient temperature for a period of time, the reaction solution was concentrated under reduced pressure to give a yellow oil. The product was dissolved in toluene and concentrated under reduced pressure to give a yellow oil. The crude product was dissolved in dichloromethane and stirred with the slow addition of aqueous saturated sodium bicarbonate solution until a pH of 7-8 was reached. The organic layer was isolated, and the aqueous layer was extracted further with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give product, (R)-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester, as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[C:6]([CH3:27])([CH3:26])[CH2:7][O:8][C:9]=1[C:10]1[CH:24]=[C:23]([OH:25])[C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[O:29]=[O:30]>C(Cl)Cl>[C:1]([C:5]12[O:30][O:29][C:9]1([C:10]1[CH:24]=[C:23]([OH:25])[C:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:16][C:12]=3[CH:11]=1)[O:8][CH2:7][C:6]2([CH3:27])[CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=O
Reactant: CC(C)(C)C1=C(c2cc(O)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)C12OOC1(c1cc(O)c3nc(-c4ccccc4)oc3c1)OCC2(C)C
Yield: 85.1 %

Procedure:
To 15 mL of methylene chloride were added 1.0 mg of TPP and 156 mg (0.43 mmol) of 4-t-butyl-5-(4-hydroxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [63]), and the mixture was externally irradiated with a 940 W sodium lamp in an oxygen atmosphere for 30 minutes, then concentrated. The concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ether =1:1) to obtain 25.3 mg of 5-t-butyl-1-(4-hydroxy-2-phenylbenzo[d]oxazol-6-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [64]) as colorless granular crystal. Yield 85.1%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([O:10][CH2:11][C:12]([OH:14])=O)([CH3:9])[CH3:8].[C:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[C:36]([NH:38][NH2:39])=[O:37])(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>ClCCl.C1COCC1>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[C:36]([NH:38][NH:39][C:12](=[O:14])[CH2:11][O:10][CH:7]([CH3:8])[CH3:9])=[O:37])(=[O:26])=[O:27])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Reactant: CC(C)OCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)OCC(=O)NNC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.19 mL, 2.20 mmol) was added to a solution of isopropoxyacetic acid (200 mg, 1.69 mmol) in dichloromethane (17 mL) and stirred at room temperature for 2 hours. The reaction was concentrated and 3 mL of THF was added. The acid chloride solution was subsequently slowly added to a solution of 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (645 mg, 1.69 mmol) in 10 mL of THF at 0° C. After the reaction was stirred for 1 h, it was quenched with water and diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×) and dichloromethane (2×), and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude reside was purified by flash column chromatography (0-100% ethyl acetate in hexane) to yield 4-tert-butyl-N-{4-chloro-2-[N′-(2-isopropoxy-acetyl)-hydrazinocarbonyl]-phenyl}-benzenesulfonamide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.O1CCCC1.B>CO>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1CCc1ccc(F)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A mixture of 4-(4-fluorophenethyl)-3-methoxycarbonylbenzoic acid (16.5 g, 54.88 mmol), tetrahydrofuran(500 ml) and borane in tetrahydrofuran (1M, complex, 218 ml, 218 mmol) was stirred under an inert atmosphere at reflux for 6 hours. The reaction was cooled to ambient temperature and methanol (1 L) was added. It was then evaporated to dryness to give a dark oil which was purified by flash chromatography using iso-hexane/ethyl acetate (1:1) as eluant to give as a clear gum methyl 2-(4-fluorophenethyl)-5-hydroxymethylbenzoate (13.10 g).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:13])=O)C1C=CC=CC=1.CSC>C(O)(C(F)(F)F)=O>[NH2:11][C@H:12]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]2[C:26]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:13]
Reactant: COC(=O)c1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)c(-c3ccccc3)n12
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: COC(=O)c1cccc2nc([C@H](C)N)c(-c3ccccc3)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.2 %

Procedure:
The mixture of (S)-methyl 2-(1-(((benzyloxy)carbonyl)amino)ethyl)-3-phenylimidazo[1,2-a]pyridine-5-carboxylate (600 mg, 1.3 mmol) and dimethylsulfide (0.4 mL) in TFA (1.2 mL) was stirred at 25° C. overnight. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with satd. sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to provide (S)-methyl 2-(1-aminoethyl)-3-phenylimidazo-[1,2-a]pyridine-5-carboxylate (400 mg): LC-MS (ESI) m/z 296.2 [M+H]+. The crude product was used without further purification.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[C:5]([O:14][CH3:15])=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][C:9]=1[F:10]>CO>[F:3][C:4]1[C:5]([O:14][CH3:15])=[C:6]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:11]
Reactant: COc1c([N+](=O)[O-])ccc(F)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1c(N)ccc(F)c1F
Yield: 56.2 %

Procedure:
22.6 g (0.422 mole) of ammonium chloride and 38.2 g of reduced iron were added to a solution of 23.0 g (0.114 mole) of 3,4-difluoro-2-methoxy-1-nitrobenzene (VII) [prepared as described in step (a) above] in 1 liter of 80% aqueous methanol. The mixture was then heated under reflux for 4 hours, whilst stirring. At the end of this time, the reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure. The residue was extracted with toluene. The toluene extract was washed with water, dried, and concentrated by evaporation under reduced pressure to give 10.2 g of 3,4-difluoro-2-methoxyaniline (VIII) as a reddish-brown oil [Step (B2)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].Br[C:14]#[N:15]>C(O)C.O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[NH:12][C:14]([NH2:15])=[N:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: N#CBr
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2[nH]c(N)nc2c1
Temperature: 25 °C

Procedure:
3.4 g (20.5 mmol) of methyl 3,4-diaminobenzoate was dissolved in a mixture of 50 mL of ethanol and 10 mL of H2O. To this stirring solution 2.6 g (24.5 mmol) of BrCN was added in one portion, and the resulting mixture was heated under reflux for 1.0 h. The reaction mixture was cooled to room temperature, concentrated to 10 mL, then washed with ethyl acetate (20 mL). The EtOAc layer was extracted with water (20 mL). The combined water extracts were neutralized with saturated NaHCO3 solution to ˜pH 8, and the resulting suspension was extracted with EtOAc (50 mL). The organic layer was washed with water and brine solution, dried with Na2SO4, and evaporated to give 2-amino-1H-benzoimidazole-5-carboxylic acid methyl ester, which was used directly in the next step without further purification.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:5][CH:6]=1.[CH3:20][Si:21]([CH3:34])([CH3:33])[C:22]#[C:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[CH3:12][C@@H:10]1[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:7]([C:4]2[NH:5][CH:6]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:23]#[C:22][Si:21]([CH3:20])([CH3:34])[CH3:33])=[CH:25][CH:26]=3)[N:3]=2)[CH2:11]1
Reactant: C[Si](C)(C)C#Cc1ccc(B(O)O)cc1
Reactant: C[C@H]1C[C@@H](c2nc(I)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(C#C[Si](C)(C)C)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 99.7 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (150 mg, 0.3976 mmol) and ([4-(2-trimethylsilylethynyl)phenyl]boronic acid (130 mg, 0.6 mmol) in isopropanol (3 mL) are added sequentially Pd(DPPF)(Cl)2.CH2Cl2 (16 mg, 0.02 mmol), and 2 M NaHCO3 (600 uL, 1.2 mmol). The mixture is heated to 85° C. in a sealed tube overnight. After reaction, the solvent is removed under reduced pressure and the residue is purified by flash column chromatography on silica gel using methanol/CH2Cl2 0-5% to provide tert-butyl (2S,4S)-4-methyl-2-[4-[4-(2-trimethylsilylethynyl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (168 mg, 95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:2]=12.OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH2:24](O)[CH3:25]>>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([O:12][CH2:24][CH3:25])=[O:11])=[CH:9][C:2]=12
Reactant: O=C(O)c1cc2nccnc2s1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc2nccnc2s1
Temperature: 80 °C
Yield: 80 %

Procedure:
Thieno[3,2-b]pyrazine-6-carboxylic acid (2 g, 11.10 mmol) was dissolved in ethanol (30 mL). Concentrate H2SO4 (5.92 mL, 111 mmol) was slowly added. The resulting mixture was heated at 80° C. overnight. The reaction mixture was cooled en neutralized with saturated Na2CO3 solution. The resulting precipitate was collected to give ethyl thieno[3,2-b]pyrazine-6-carboxylate 86 (1.85 g, 80%) as a brown solid. (m/z)=209 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[N:25]1([CH2:30][CH:31]([OH:33])[CH3:32])[CH:29]=[CH:28][N:27]=[CH:26]1.CN(C)C=O>C1(C)C=CC=CC=1>[C:1]([O:33][CH:31]([CH3:32])[CH2:30][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(O)Cn1ccnc1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OC(C)Cn1ccnc1
Yield: 92.2 %

Procedure:
With ice cooling and stirring, 35.9 g of behenic chloride (16) was added to a mixture of 12.6 g of 1-(1H-imidazol-1-yl)-2-propanol (15) and 50 g of dimethylformamide. Then the mixture was stirred at room temperature for 2 hours. Toluene was added to the solution, followed by neutralization. Subsequent standard aqueous work-up and purification by column chromatography gave 41.3 g of [2-(1H-imidazol-1-yl)-1-methylethyl] behenate (Quencher 1). Yield 92%.