Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:33]([CH2:34][CH3:35])[C:26]5=[N:27][CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:33]([CH2:34][CH3:35])[C:26]5=[N:27][CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2cc(OC)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2cc(OC)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a stirred solution of (R)-tert-butyl(1-(2-(1-ethyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (24 mg, 0.045 mmol) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol) dropwise with continuous stirring. The reaction was stirred at room temperature under nitrogen for 1 h. The reaction mixture was concentrated in vacuo before being dissolved in MeOH and purified by SPE on sulfonic acid (SCX) 1 g, first washing with MeOH and then eluting using a 10% NH3/MeOH solution to give the free base of the product. The appropriate fractions were combined and evaporated in vacuo before being azeotroped with cyclohexane to give the title compound as a pale yellow solid (13 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3cnn(C)c3)cccc21
Product: CC1c2cccc(-c3cnn(C)c3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CO.C([O:10][C@@H:11]1[C@@H:16]([O:17]CC2C=CC=CC=2)[C@H:15]([O:25]CC2C=CC=CC=2)[C@@H:14]([CH2:33][O:34]CC2C=CC=CC=2)[CH2:13][C:12]1(OC(=O)C)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[CH:43]=1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].C1COCC1>[OH:34][CH2:33][C@H:14]1[CH2:13][C@@H:12]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)[CH:43]=2)[C@H:11]([OH:10])[C@@H:16]([OH:17])[C@@H:15]1[OH:25]
Reactant: COc1ccc(Cc2cccc(C3(OC(C)=O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cc2cccc([C@@H]3C[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)cc1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a methanol (0.2 mL)-THF (0.2 mL) solution of acetic acid [2R,3S,4R,5R]-2,3,4-trisbenzyloxy-5-benzyloxymethyl-1-[3-(4-methoxybenzyl)phenyl]cyclohexyl ester (4.2 mg), a 20% palladium hydroxide-carbon (3 mg) was added and the mixture solution was stirred under a hydrogen atmosphere for three hours. The reaction mixture was filtered and the filtrate was concentrated and the obtained residue was purified by preparative TLC [developing solution=dichloromethane:methanol (9:1)] to obtain the title compound (1.7 mg) as a single diastereomer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[C:20]([F:23])([F:22])[F:21].BrC1C=C2C(=CC=1)NC(=O)C(OC1C=CC([Cl:43])=CC=1)=C2C(F)(F)F>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:43])[C:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[C:20]([F:23])([F:22])[F:21]
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccccc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Product: FC(F)(F)c1c(Oc2ccccc2)c(Cl)nc2ccc(Br)cc12

Procedure:
The title compound was prepared using 6-bromo-3-phenoxy-4-(trifluoromethyl)quinolin-2(1H)-one (Intermediate 8, step a) in place of 6-bromo-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinolin-2(1H)-one (Intermediate 7, step c) according to the procedure described in Intermediate 7, step d.
Reaction SMILES: CO[C:3]1[C:12]2=[CH:13][N:14]([C@@H:16]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]3([CH3:25])[OH:18])[N:15]=[C:10]3[C:11]2=[C:5]([C:6](=[O:26])[NH:7][N:8]=[CH:9]3)[N:4]=1.[NH3:27]>>[NH2:27][C:3]1[C:12]2=[CH:13][N:14]([C@@H:16]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]3([CH3:25])[OH:18])[N:15]=[C:10]3[C:11]2=[C:5]([C:6](=[O:26])[NH:7][N:8]=[CH:9]3)[N:4]=1
Reactant: COc1nc2c(=O)[nH]ncc3nn([C@@H]4O[C@H](CO)[C@@H](O)[C@@]4(C)O)cc1c32
Reactant: N
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(N)nc3c(=O)[nH]ncc(n1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
The product from Step 6 (20 mg, 0.0551 mmol) was dissolved in liquid ammonia (3 mL) at −78° C. then warmed to ambient temperature in a pressure vessel and stirred for 30 minutes. The reaction was then cooled to −78° C. and opened to allow the ammonia to evaporate. The residue was purified on Phenomenex-C18 reverse phase HPLC with a 0-50% B gradient over 30 min at 10 mL/min (Buffer A=H2O, Buffer B=acetonitrile) to afford 11 mg (57%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]3[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=3)=[CH:22][C:17]2=[N:16][CH:15]=1)=[O:13].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:51][C@H:52]1[CH2:57][CH2:56][CH2:55][C@@H:54]([CH3:58])[N:53]1[CH2:59][CH2:60][NH2:61].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH:54]([CH3:58])[N:53]1[CH2:59][CH2:60][NH:61][C:6]([C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]4[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[CH:4]=1)=[O:7]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: Cn1nccc1-c1ccn2c(C(=O)Nc3cc(C(=O)O)ccc3F)cnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCC(C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccnn4C)ccn23)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
4-Fluoro-3-{[7-(2-methyl-2H-pyrazol-3-yl)-imidazo[1,2-a]pyridine-3-carbonyl]-amino}-benzoic acid (step 2) (450 g, 1.19 mol), EDC.HCl (454.8 g, 2.372 mol) and HOBt (181.6 g, 1.186 mol) in DMF (3.2 L) at 25° C. were stirred for 1.5 hr. The reaction was monitored by HPLC. To the reaction mixture was dropwise added cis 2-(2,6-dimethyl-piperidin-1-yl)-ethylamine (222.5 g, 1.423 mol) over 10 min and stirring continued for 30 min. To the reaction mixture was dropwise an aqueous solution of Na2CO3 (5%, 6 L) over 120 min and the resulting solid was collected by filtration and washed with water (5 L). To the solid was added ethanol (5 L) followed by heating to 70° C. to obtain a clear solution. Water (1.5 L) was dropwise added at 70° C. and stirred for 30 min. The clear solution was slowly cooled to 25° C. over 2 hr. The solid was filtered, washed with ethanol (500 mL) and dried under vacuum at 50° C. overnight to afford the title compound as a white solid;
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([OH:3])=[O:2].I([O-])(=O)(=O)=[O:15].[Na+]>CO.O.C(#N)C>[C:1]([CH2:4][S:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:15])([OH:3])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(O)CCCCCSCC(=O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: O=C(O)CCCCCS(=O)CC(=O)O
Temperature: 5 °C

Procedure:
A chilled solution of 4.12 g of the 6-(carboxymethylthio)hexanoic acid of Example 1(a) in 130 ml MeOH was mixed with a chilled solution of 4.28 g sodium meta-periodate in 320 ml water. The mixture was maintained at about 5° C. for two days, after which it was diluted with two volumes of cold acetonitrile. Solid sodium iodate was removed by filtration and the filtrate was concentrated to an oily residue under reduced pressure. The oil was characterized by NMR and was not further purified. NMR (in Unisol-D): 10.2-10.5 (S, 2, COOH), 3.6-3.8 (S, 2, S(O)--CH2 --COOH), 2.7-3.1 (M, 2, --CH2 --S(O), 2.1-2.5 (M, 2, --CH2 --COOH), 1.4-1.9 (M, 6, --CH2 --) (also a small peak at=4.0 indicating some sulfone present).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17](=[O:19])[CH2:16][N:15]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:13]=3[CH:26]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O>C(Cl)Cl>[Cl:30][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17](=[O:19])[CH2:16][N:15]=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH:26]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1CN=C(c2ccccc2)c2cc(C(O)c3ccc(Cl)cc3)ccc2N1
Solvent: ClCCl
Product: O=C1CN=C(c2ccccc2)c2cc(C(Cl)c3ccc(Cl)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of intermediate (28) (0.0125 mol) in thionyl chloride (5 ml) and DCM (100 ml) was stirred at room temperature overnight. The mixture was evaporated till dryness. The product was used without further purification, yielding 4.93 g (100%) of (±)-7-[chloro(4-chlorophenyl)methyl]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (intermediate 29).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[Br:13])(=[O:3])[CH3:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:7][C:6]=1[Br:13])(=[O:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C=O)cc1Br
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1Br

Procedure:
Compound 26, 4-acetamido-3-bromobenzaldehyde, contains a formyl group, and reacts with thiosemicarbazide to produce 4-acetamido-3-bromobenzaldehyde thiosemicarbazone 29 as shown below.
Reaction SMILES: COC([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:6]1=[O:18])=O.CN(C)C(=O)C.Cl.C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH:7]2[CH2:8][CH2:9][CH2:5][C:6]2=[O:18])=[CH:16][CH:15]=1
Reactant: COC(=O)C1CCC(Cc2ccc(Cl)cc2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCCC1Cc1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
In 3-(4-chlorobenzyl)-2-oxocyclopentane carboxylic acid methyl ester (1.0 g, 0.00375 mol), N,N-dimethylacetamide (1 mL) and triethylamine hydrochloride (0.774 g, 0.00375×1.5 mol) were added and stirred at 130° C. for 2 hours, and then at 140° C. for another 3 hours. In the reaction liquid, ethyl acetate and saturated sodium bicarbonate water were added, and the mixture was partitioned. After extracting the aqueous layer using ethyl acetate, the organic layer was dried using anhydrous sodium sulfate and concentrated. Thereafter, the dried and concentrated product was purified using a silica gel column, and a target product was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]2[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:13][S:12]2)=[C:6]([CH3:24])[CH:5]=1)(O)=[O:2].C(C1NC=CN=1)(C1[NH:28]C=CN=1)=O.O>C(Cl)Cl.N>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]2[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:13][S:12]2)=[C:6]([CH3:24])[CH:5]=1)(=[O:2])[NH2:28]
Reactant: Cc1cc(C(=O)O)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(N)=O)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine (0.035 g, 0.10 mmol) in CH2Cl2 (5 mL) was added carbonyl diimidazole (0.047 g, 0.29 mmol). The mixture was allowed to stir at room temp. for 2 h, then anh NH3 (approximately 30 drops) was condensed into the solution at −78° C. The resulting mixture was warmed to room temp. overnight, then treated with H2O (20 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL), sequentially washed with H2O (20 mL) and a saturated NaCl solution (20 mL), dried Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (40% EtOAc/hexane) to give (4S)-2-(4-carbamoyl-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine as a white solid (0.027 g, 73%): mp 130-131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:25]([NH:28][CH2:29][CH2:30][NH2:31])(=[O:27])[CH3:26]>>[C:25]([NH:28][CH2:29][CH2:30][NH:31][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])(=[O:27])[CH3:26]
Reactant: CC(=O)NCCN
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: CC(=O)NCCNC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Yield: 56 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using N-acetylethylendiamine instead of 2-amino-2-methyl-1-propanol, to the title compound (70 mg, 56%) which was obtained as a white solid. MS: m/e=414.1 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[CH3:19][S:20]([CH2:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:22])=[O:21].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][CH:26]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: O=C(O)/C=C/c1cnccc1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(NC(=O)/C=C/c2cnccc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.1 %

Procedure:
A mixture of (2E)-3-[4-(4-fluorophenyl)pyridin-3-yl]prop-2-enoic acid (0.24 g), 4-[(methylsulfonyl)methyl]aniline (0.19 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.25 g), 1-hydroxy-1H-1,2,3-benzotriazole (0.20 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give a solid. The obtained solid was recrystallized from acetone/hexane to give the title compound (0.28 g).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][CH:5]1[O:6][N+]([O-])=O)=[N+:2]=[N-:3].[C:27]([O-])(=[O:29])[CH3:28].[Na+]>C(O)(=O)C>[N:1]([C@@H:4]1[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][CH:5]1[O:6][C:27](=[O:29])[CH3:28])=[N+:2]=[N-:3]
Reactant: CC(=O)OC[C@H]1OC(O[N+](=O)[O-])[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
To a solution of nitrate ester 68 (17.5 g, 46.5 mmol) in 500 mL of glacial acetic acid is added sodium acetate (7.63 g, 93.0 mmol). The solution is stirred at 100° C. for 3 h and then allowed to cool to room temperature. The reaction mixture is diluted with 1000 mL of ice water and extracted with CH2Cl2 (2×200 mL) The organic layers are combined and washed with ice water (2×400 mL), saturated NaHCO3 (400 mL), saturated NaCl (400 mL), dried over Na2SO4, filtered and concentrated. The crude product is crystallized from hexane/EtOAc to give 7.2 g of 2-azido-2-deoxy-1,3,4,6-tetra-O-acetyl-α,β-D-galactopyranose 69 (mixed anomers). The mother liquors from the crystallization are concentrated and purified by flash chromatography (25% EtOAc/hexane) to give an additional 7.0 g of the product (14.2 g, 81.7% in total) as a mixture of anomers: Rf 0.3 (30% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz, mixture of anomers) δ 6.26 (d, J=3.6 Hz, 1 H, H-1α), 5.50 (d, J=8.6 Hz, 1 H, H-1β), 5.42 (d, J=3.0 Hz, 1 H, H-4α), 5.32 (d, J=3.0 Hz, 1 H, H-4β), 5.25 (dd, J=11.2, 3.0 Hz, 1 H, H-3α), 4.85 (dd, J=10.6, 3.3 Hz, 1 H, H-3β), 4.23 (t, J=6.6 Hz, 1 H, H-5α), 3.95-4.10 (m, 5 H, H-6α, H-5β, H-6β), 3.88 (dd, J=11.2, 3.6 Hz, 1 H, H-2α), 3.78 (dd, J=10.9, 8.6 Hz, 1 H, H-2β), 1.90-2.20 (6s, 24 H, OAc).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH:23]=[CH2:24]>>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH:10]([CH2:24][CH:23]=[CH2:22])[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1
Reactant: C=CCBr
Product: C=CCC1C(=O)N(Cc2ccccc2)c2ccccc2N=C1C
Yield: 85 %

Procedure:
Using 1-benzyl-4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one and 3-bromopropene, the titled compound was synthesized in substantially the same manner as in Working Example 21 as an oily product in a yield of 85%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].CO>C1COCC1.O.[Zn]>[C:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2ccccc2)nc1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A mixture of toluene (15 mL) and water (5 mL) was degassed with argon for 5 minutes. Sodium carbonate (0.802 g, 0.00454 mole) was then added and the mixture was degassed with argon for 5 minutes. Phenylboronic acid (0.587 g, 0.00454 mole) and 2-chloro-5-nitro-pyridine (0.6 g, 0.0037 8 mole) were then added and the resulting mixture was degassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.878 g, 0.00076 mole) was added and the mixture was degassed with argon for 5 minutes. The resulting mixture was then heated to reflux for 3 hours. The mixture was diluted with ethyl acetate, and the organic layer was washed with water followed by brine solution. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography using silica gel 60-120 mesh (5% ethyl acetate in hexane) afforded 0.5 g (66%) of 5-nitro-2-phenyl-pyridine. LCMS purity: 201 (M+1)+, 98.2%, 1H NMR (DMSO-d6): δ 9.5 (s, 1H), 8.55 (dd, 1H), 8.1 (m, 2H), 7.9 (d, 1H), 7.55 (m, 3H). To a stirred solution of 5-nitro-2-phenyl-pyridine (0.5 g, 0.0025 mole) in THF (10 mL) was added ammonium chloride (1.1 g, 0.020 mole) dissolved in water (15 mL). Methanol (5 mL) was then added, resulting in a clear solution. Zinc powder (1.3 g, 0.020 mole) was then added portionwise and the resulting mixture was stirred for 1 hour. The mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over Na2SO4, and evaporated under reduced pressure to afford 0.35 g (82%) of 6-phenyl-pyridin-3-ylamine. LCMS purity: 171.08 (M+1)+, 87.9%, 1H NMR (DMSO-d6): δ 8.12 (d, 1H), 8.0 (d, 2H), 7.72 (d, 1H), 7.48 (t, 2H), 7.36 (t, 1H), 7.1 (dd, 1H), 5.6 (s, 2).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11](O)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[Cl:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH2:52])[CH2:47][O:46]1.[NH4+].[Cl-]>C(Cl)Cl>[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH:52][C:11]([C:4]2[C:3]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=3[Cl:22])=[C:2]([F:1])[C:7]3[N:8]=[N:9][S:10][C:6]=3[CH:5]=2)=[O:12])[CH2:47][O:46]1
Reactant: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CC1(C)OCC(CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)OCC(CONC(=O)c2cc3snnc3c(F)c2Nc2ccc(Br)cc2Cl)O1
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (200 mg, 0.49 mmol) in CH2Cl2 (10 mL) was added HOBt (100 mg, 0.74 mmol) followed by EDCI (140 mg, 0.74 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (108 mg, 0.74 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (15 mL×3). The combined organic extracts was washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (213 mg) was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CC(C)=O>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCc1ccc(OCC2CO2)cc1

Procedure:
A mixture of 228 gm (1.27 mole) of methyl 3-(4-hydroxyphenyl)propionate, 263 gm (1.90 mole) of K2CO3 and 298 mL (3.80 mole) of epichlorohydrin in 2 liters of acetone was stirred and heated to reflux for 20 hours. The reaction medium was then filtered and evaporated under reduced pressure. The resulting oil was taken up in 1 liter of toluene andwashed consecutively with 500 mL water, 2×500 mL 1N NaOH and 2×500 mL water. The toluene phase was then dried over MgSO4 andevaporated under reduced pressure to provide a clear oil which was further purified by vacuum distillation. The final yield of purified oil was 131.2gm (44%): bp 156° (p=0.4 mm Hg). The NMR and IR spectra of the product were consistent with the assigned structure and the elemental analysis was consistent with the formula C13H16O4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2-c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2ncccc2N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 4-[2-(4-fluorophenyl)-pyridin-3-yl]-piperazine-1-carboxylic acid t-butyl ester (0.9 g, 2.52 mmol) in DCM (25 mL). Add trifluoroacetic acid (8.6 g, 5.8 mL, 75.6 mmol). Stir the mixture at room temperature for 2 hr. Purify by a SCX ion-exchange column to give the title preparation. MS (ES): m/z=258 [M+H].