Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[CH2:6]1[CH2:10][O:9][CH2:8][CH2:7]1.C(#N)C.[N+](C1C=CC(COC(C2N3[C@H](SC=2)C(C(OC(=O)C)[C:34]2C=[C:40]4[N:36]([CH2:37][C:38]([CH3:43])([CH3:42])[CH2:39]4)[N:35]=2)(Br)C3=O)=O)=CC=1)([O-])=O>[Zn].C(OCC)(=O)C>[CH2:10]([O:9][C:8]([C:7]1[CH:34]=[N:35][N:36]2[CH2:37][C:38]([CH3:43])([CH3:42])[CH2:39][C:40]=12)=[O:2])[CH3:6]
Reactant: C1CCOC1
Reactant: O=P([O-])([O-])[O-]
Reactant: CC(=O)OC(c1cc2n(n1)CC(C)(C)C2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Zn]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2c1CC(C)(C)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.8 %

Procedure:
Freshly activated Zn dust (32.0 g) was added rapidly with 0.5 mol/L phosphate buffer (pH 6.5, 167 mL) to the THF (114 mL) and acetonitrile (53 mL) solution of crude (5R)-6-[acetoxy-(5,5-dimethyl-4H-1,6a-diazapentalen-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester. The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction solution was cooled at 0° C., and then the pH was adjusted to 8.0. Ethyl acetate (85 mL) was added to the mixture and filtered through a pad of Celite. The pad was washed with water (120 mL). The aqueous layer was separated and then the organic layer was extracted with 0.5 mol/L phosphate buffer (pH 6.5, 2×50 mL). The combined aqueous layers were cooled at 0° C., and then the pH was adjusted to 8.5. The mixture was concentrated to 325 g, and then applied to Diaion HP-21 resin (240 mL, Mitsubishi Kasei Co. Ltd.) column chromatography. After adsorbing, the column was eluted with water (480 mL) and then acetonitrile aqueous solution (10%; 480 mL, 20%; 720 mL). The combined active fractions were concentrated under high vacuum at 35° C. and lyophilized to give the titled compound as a yellow amorphous solid (2.00 g, 42.8%, pH 7.16).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1ccc(C2CCNC2)nc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(c4ccccn4)C3)c(F)cc2c1=O
Yield: 85 %

Procedure:
Starting from 1 cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.25 g, 4.7 mmol) and 2-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.57 g, 85%) as an off-white solid, mp 216°-219° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1)=O)C.O.C(OCC)(=O)C>C1COCC1>[OH:9][CH2:10][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccnc2ccc(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(CO)c2c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
17 ml of a 1M solution of LiAlH4 in THF are added dropwise to a solution of 4 g of 4-ethoxycarbonyl-6-methoxyquinoline in 100 ml of anhydrous THF, under an inert atmosphere of argon at a temperature in the region of 5° C. The reaction medium is maintained with stirring for 16 hours at a temperature in the region of 20° C. 50 ml of water and 50 ml of ethyl acetate are added. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The foam obtained is purified by flash chromatography (SiO2, EtOAc as eluent, Ar). The fractions containing the product are concentrated under reduced pressure. 0.86 g of 4-hydroxymethyl-6-methoxyquinoline is thus obtained, the characteristics of which product are as follows:
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[C:38]([O:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH:37]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([OH:64])=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:49][CH:50]=2)=[C:38]([O:70][C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH:37]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4Oc4ccccc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4Oc4ccccc4)cc3)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 44 was prepared analogous to compound of example 8 by hydrolysis of compound of example 43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].CO.[BH4-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH2:23][OH:24]
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1CO)C3=O
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (9.0 g, 26.1 mmol, 1.0 eq.), methanol (50 mL), dichloromethane (30 mL), and NaBH4 (5.95 g, 156.6 mmol, 5.0 eq.) at 0° C. The reaction mixture was stirred for 1 h. After the reaction was completed, the reaction was quenched with water and concentrated under reduced pressure. The residue was extracted with dichloromethane. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:4 ethyl acetate/petroleum ether to afford 199c as a white solid (7.0 g, 77%). MS-ESI: [M+H]+ 345.9.
Reaction SMILES: [N+:1]([C:4]1C=CNN=1)([O-:3])=[O:2].O[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:42]([C:50](OC(C)C)=O)=[N:43][C:44](OC(C)C)=O>C1COCC1>[N+:1]([C:4]1[CH:50]=[N:42][N:43]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:44]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc([N+](=O)[O-])cn2)CC1
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To a solution of nitropyrazole (3.0 g, 25 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (6.0 g, 30 mmol) and triphenylphosphine (7.9 g, 30 mmol) in THF (200 mL) at room temperature was added diisopropyl azodicarboxylate (6.0 g, 30 mmol) and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes/ethyl acetate) to provide the desired product (4.2 g, 57%) as a white solid:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.CO[C:19](=[O:26])[C@H:20]([CH2:22][CH2:23][CH2:24][CH3:25])[NH2:21].[CH3:27][CH:28]1[CH2:33][NH:32][CH2:31][CH:30]([CH3:34])[NH:29]1>>[CH3:27][CH:28]1[NH:29][CH:30]([CH3:34])[CH2:31][N:32]([C:19]([CH:20]([NH:21][C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH2:22][CH2:23][CH2:24][CH3:25])=[O:26])[CH2:33]1
Reactant: CC1CNCC(C)N1
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Product: CCCCC(NC(=O)Cc1ccc(-c2ccccc2)cc1)C(=O)N1CC(C)NC(C)C1

Procedure:
Following the procedure of Example 3, and using 4-biphenylacetic acid, norleucine methyl ester and 2,6-dimethylpiperazine, there is obtained the title compound in 375 mg yield.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 120 °C

Procedure:
2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (11.93 g, 1.0 eq), sodium azide (3 eq), and ammonium chloride (3 eq) were mixed and stirred in DMF (150 mL) in a round bottom connected to a reflux condenser under N2. An oil bath with a temperature controller was then used to heat the reaction at 100° C. for 2 days, after which the temperature was raised to 120° C., for 6 days. The reation was cooled and 3 more equivalents of ammounium chloride and sodium azide were added. The reaction was again heated for 5 more days at 120° C. The reaction was cooled, the inorganic salts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with ehtyl acetate (2×200 mL), the organic layers were collected, dried (MgSO4) and the solvent removed in vacuo, to yield a dark yellow oil. The product was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow solid. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid; m.p. 183.5°-184.5°. Upon cooling, the mother liquor yielded an additional 1.03 g of product as a light yellow solid; m.p. 179.0°-180.0°. NMR (200 MHz, DMSO-d6) δ 7.75-7.48 (m, 4H); 7.07 (d, 2H, J=9 Hz); 7.04 (d, 2H, J=9 Hz); 5.24 (s, 2H); 5.24 (bs, 1H); 4.34 (s, 2H); 2.48 (t, 2H, J=7 Hz); 1.48 (t of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz). Anal. Calcd. for C22H23ClN6O: C, 62.48; H, 5.48; Cl, 8.38. Found for the solids which did not dissolve in 100 mL of acetonitrile: C, 62.73; H, 5.50; Cl, 8.26. Found for the solids obtained from the mother liquor: C, 62.40; H, 5.23; Cl, 8.35.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]2[C:33]([C:36](O)=[O:37])=[N:34][NH:35][C:29]=2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:2][C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]([CH:10]2[CH2:11][CH2:12][N:13]([C:36]([C:33]3[C:30]4[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][C:29]=4[NH:35][N:34]=3)=[O:37])[CH2:14][CH2:15]2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Fc1cc(F)c(C(F)(F)F)c(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)n[nH]c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)cc(F)c4C(F)(F)F)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
To a suspension of 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (28, 500 mg, 1.66 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1Hpyrazolo[3,4-c]pyridine-3-carboxylic acid (443 mg, 1.66 mmol), and diisopropylethylamine (36 μL, 2.04 mmol) in DMF (5 mL) was added HBTU (1.10 g, 2.49 mmol). The resulting mixture was stirred at ambient temperature for 18 h. the reaction was diluted in H2O (50 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (40 g Redisep column, 0-100% EtOAc in hexanes) to afford tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5 dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (59) as a white solid (200 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 7.017-6.876 (m, 1H), 6.876-6.741 (m, 1H), 5.306 (s, 1H), 4.632 (s, 2H), 3.776-3.581 (m, 2H), 2.762-2.631 (m, 2H), 1.986-1.653 (m, 4H), 1.500 (s, 9H), 1.399-1.189 (m, 4H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[S:11][C:10]([N:12]3[CH2:19][C:18]4[CH2:17][NH:16][CH2:15][C:14]=4[CH2:13]3)=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.F[C:21](F)(F)C([O-])=O.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>>[CH:3]1([CH2:1][NH:4][C:5]([C:7]2[S:11][C:10]([N:12]3[CH2:13][C:14]4[CH2:15][N:16]([C:31](=[O:32])[C:30]5[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=5[C:28]([F:39])([F:38])[F:27])[CH2:17][C:18]=4[CH2:19]3)=[N:9][CH:8]=2)=[O:6])[CH2:2][CH2:21]1
Reactant: O=C(NC1CC1)c1cnc(N2CC3=C(CNC3)C2)s1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: O=C(NCC1CC1)c1cnc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)s1

Procedure:
N-(cyclopropyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (106 mg, 0.26 mmol) was reacted with 2-trifluoromethylbenzoyl chloride analogously to example 3f. M+H+: 463.05.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[CH3:19][O:20][C:21](=[O:27])[CH2:22][CH2:23][S:24]([O-:26])=[O:25].[Na+].CS(C)=O.[Si](C=[N+]=[N-])(C)(C)C>ClCCl.[Cu]I.CO>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([S:24]([CH2:23][CH2:22][C:21]([O:20][CH3:19])=[O:27])(=[O:26])=[O:25])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Reactant: COC(=O)CCS(=O)[O-]
Agent: [Cu]I
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)CCS(=O)(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1
Temperature: 105 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen gas purged sealable vial of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine 4-1a (3000 mg, 9.17 mmol), copper(i) iodide (6983 mg, 36.7 mmol) and sodium 3-methoxy-3-oxopropane-1-sulfinate (TYGER) (6385 mg, 36.7 mmol) was added DMSO (15 ml). The reaction mixture was heated in an oil bath at 105° C. for 18 hrs. LCMS analysis showed reaction to be a mixture of desired ester and acid. The reaction was quenched into ethyl acetate (200 ml) and water (200 ml) and the ph adjusted from 7 to 3 with 1N HCl. The reaction was filtered thru celite and sand and the filtrate layers separated. The organic which contained a mix of acid and ester was dried over sodium sulfate, filtered and concentrated to an oil. The oil was azeotroped with toluene to remove any remaining water to give a brown oil, 3.4 gms. The oil was dissolved in dichloromethane (20 ml) and methanol (20.00 ml) cooled to 0° C. and TMS-Diazomethane (4.94 ml, 9.88 mmol) slowly added dropwise. The reaction was stirred at 0° C. for 10 minutes, quenched with aq. KHSO4 and allowed to stir at room temperature for 1 hr. The reaction was concentrated to remove methanol and the product extracted into ethyl acetate (100 ml), dried over sodium sulfate and concentrated to oil. The oil was chromatographed on silica (100 g, 0-50% ethyl acetate/hexanes) to give the product 4-1b as oil, 1.46 g.
Reaction SMILES: [C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:41])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH2:31][C@H:32]4[CH2:37][CH2:36][C@H:35]([NH:38][CH2:39][CH3:40])[CH2:34][CH2:33]4)[CH3:30])=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:42][CH3:43])([CH2:3][CH3:4])[CH3:2].[CH3:44]C(O)=O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC#N>[C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:41])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH2:31][C@H:32]4[CH2:33][CH2:34][C@H:35]([N:38]([CH2:39][CH3:40])[CH3:44])[CH2:36][CH2:37]4)[CH3:30])=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:8][C:7]=1[O:42][CH3:43])([CH2:3][CH3:4])[CH3:2]
Reactant: CCN[C@H]1CC[C@H](CN(C)c2ccc(N3C(=O)Cc4cc(OC)c(O[C@H](C)CC)cc4C3c3ccc(Cl)cc3)cc2)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CC[C@@H](C)Oc1cc2c(cc1OC)CC(=O)N(c1ccc(N(C)C[C@H]3CC[C@H](N(C)CC)CC3)cc1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 52 (13.8 mg, 0.023 mmol) in MeCN (0.5 ml) were successively added AcOH (0.003 ml, 0.046 mmol), formaldehyde (37% in water, 0.003 ml, 0.046 mmol) and NaBH(OAc)3 (9.7 mg, 0.046 mmol) at RT. The reaction mixture was stirred at RT for 2 h then directly subjected to purification by reverse phase prep-HPLC (Waters system) to yield the title compound (TFA salt, 7.4 mg, 0.010 mmol, 44%) as a colorless solid. HPLC: AtRet=2.01 min; LC-MS: m/z 618.4 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=1)([O-:3])=[O:2].[BH4-].[Na+]>CCO>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-enone (1.0 equiv.) was added EtOH (0.2 M) and CeCl3-7H2O (1.3 equiv.). The reaction was cooled to 0° C., then NaBH4 (1.3 equiv.) was added in portions. Stirred for 2 h at 0° C., then quenched by adding water, concentrated to remove the EtOH, added EtOAc, extracted the organics, dried with brine, then Na2SO4, and concentrated to yield 3-(3-nitropyridin-4-yl)cyclohex-2-enol (99%). LC/MS=221.1 (M+H), LC=2.235 min.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][CH:30]=1.CC#N.C(Cl)CCl>CC#N.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][C:36]([NH:35][C:32]5[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=5)=[N:27][C:22]=4[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccnc(C(=O)NCCCCN3CCCC3)c2)ccc1O
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc3oc(Nc4ccc(Cl)cc4)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-Amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Example 253, Step E, 165 mg, 0.4 mmol, 1.0 eq.) was dissolved in CH3CN/DMF (2/1, v/v, 15 ml) and 1-chloro-4-isothiocyanato-benzene (as described in preparation III, 75 mg, 0.4 mmol, 1.0 eq.) in as a CH3CN solution was added dropwise. The reaction was stirred at RT for 16 h. EDC (85 mg, 0.4 mmol, 1.0 eq.) was added and the reaction was heated to 80° C. for 2 h. The mixture was concentrated and the crude product was purified by column chromatography (0-10% MeOH/CH2Cl2/1% NH4OH) to yield 4-[2-(4-chloro-phenylamino)-benzoxazol-5-yloxy]-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide. MS m/z=506.01 (M+H)+Calc'd for C27H28ClN5O3: 505.19.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13][CH:14]([NH2:18])[CH2:15][O:16][CH3:17].[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([N:18]([CH:14]([CH3:13])[CH2:15][O:16][CH3:17])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:24]
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: COCC(C)N
Product: COCC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 53.3 %

Procedure:
3.6 g of D-galactose, 3.5 g of (1-methyl-2-methoxy-ethyl)amine and 3.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 13-(1). 3.8 g of 1-(2-chloroethyl)-3-(1-methyl-2-methoxy-ethyl)-3-(D-galactopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)N.Cl.[N:11]([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>O.[Cu]Cl.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:11])(=[O:17])=[O:16])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: O=N[O-]
Reactant: O=S=O
Reactant: Nc1cc(F)cc(I)c1
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(F)cc(I)c1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
3-Fluoro-5-iodoaniline (3.06 g) (WO 9623783) was added to a stirred mixture of concentrated hydrochloric acid (4 ml) and water (4 ml). Glacial acetic acid (8 ml) was added and the reaction mixture cooled to −5° C. A solution of sodium nitrite (0.99 g) in water (8 ml) was added dropwise maintaining the temperature between −5° C. and −2° C. After the addition was complete the reaction was stirred for 10 min. In the meantime glacial acetic acid (20 ml) was saturated with sulfur dioxide gas for 0.25 h, then copper(I) chloride (0.353 g) was added. Additional sulfur dioxide was bubbled through the solution until a fine suspension was obtained. The mixture was cooled to 5° C. and then treated portionwise with the diazonium salt prepared above. After stirring at room temperature for 1 h ice (50 g) was added. The mixture was extracted with ether (100 ml) and the organic phases washed with NaHCO3 solution (2×φml) then water (100 ml), dried (MgSO4) and concentrated. The residue was dissolved in THF (30 ml) at 0° C. and aqueous ammonia (0.880; 5 ml) was added. After stirring at room temperature the mixture was partitioned between EtOAc (100 ml) and water (100 ml). The organic phase was washed with brine (50 ml), dried (MgSO4) and concentrated. The residue was purified by chromatography using cyclohexane-EtOAc (5:1 then 3:1). Evaporation of the fractions and trituration of the residue with cyclohexane afforded the title compound (0.886 g). ES-ve 299 (M-H)−