Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].[F:16][C:17]([F:46])([C:42]([F:45])([F:44])[F:43])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:41]=[CH:40][C:25]([C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCCCCC>CN(C)C1C=CN=CC=1.ClCCl>[F:16][C:17]([F:46])([C:42]([F:43])([F:44])[F:45])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:41]=[CH:40][C:25]([C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]([O:15][CH2:14][CH2:13][C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])=[O:38])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Reactant: O=C(O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
2.50 g (11.8 mmol) of 2-(2,4-dinitrophenyl)ethanol, 5.24 g (11.8 mmol) of (2E)-3-(4-{[4-(4,4,5,5,5-pentafluoropentoxy)benzoyl]oxy}phenyl)acrylic acid, 144 mg (1.2 mmol) of 4-Dimethylaminopyridine are dissolved in 30 ml of dichloromethane. 2.48 g (13.0 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using toluene:ethyl acetate 95:5 as eluant and crystallization form ethylacetate:hexane mixture to yield 5.35 g (71%) 2-(2,4-Dinitrophenyl)ethyl (2E)3-{4-[(4-(4,4,5,5,5-pentafluoropentoxy)benzoyl)oxy]phenyl}acrylate as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:6]=[CH:5]1.C(OCCN1C2C3C=CC=CC=3N=C(Cl)C=2N=C1)(=[O:25])C1C=CC=CC=1.C(OC(=O)C)(=O)C>>[OH:25][C:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:3][CH2:2][OH:1])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [O-][n+]1cc2ncn(CCO)c2c2ccccc21
Reactant: O=C(OCCn1cnc2c(Cl)nc3ccccc3c21)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: OCCn1cnc2c(O)nc3ccccc3c21

Procedure:
Using the method of Example 133, 1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-5-oxide prepared by hydrolysis of the compound of Example 120 was reacted with acetic anhydride to provide 4-hydroxy-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([OH:20])[C:14]=1[C:21](=O)[CH3:22]>CCO.O.O>[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([OH:20])[C:14]=1[C:21](=[N:2][OH:3])[CH3:22]
Reactant: CC(=O)c1c(O)cc(C)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1c(O)cc(C)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of hydroxylamine hydrochloride (470 mg, 6.76 mmol) and sodium acetate trihydrate (590 mg, 4.34 mmol) dissolved in 20 ml of a mixture of EtOH/H2O (7/3) was added to a solution of 1-(2,6-dihydroxy-4-methylphenyl)ethanone (Intermediate 16, 940 mg) in 15 ml of a mixture of EtOH/H2O (7/3). After refluxing and stirring under N2 for 2 hours, additional hydroxylamine hydrochloride (159 mg, 2.29 mmol) and sodium acetate trihydrate (199 mg) dissolved in 5 ml of water were added. The reaction mixture was heated at reflux overnight. After cooling down to room temperature, the volatiles were removed. Water was added and the solid afforded was filtered, washed with water and dried giving 829 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:20][CH:19]=1
Reactant: C1=Cc2ccccc2C1
Reactant: Clc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.77 g (20 mmole) of para-chloro iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with cold ethanol and dried under vacuum to obtain 2.53 g (56%) of 2-(4-chloro-phenyl)-indene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][CH2:21][NH2:22]>CCO>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:22][CH2:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH3:14])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCCC1CCN
Solvent: CCO
Product: CN1CCCC1CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
Chloro-2,4-dinitrobenzene 1 (1.00 g, 4.937 mmol) was dissolved in anhydrous EtOH (20 mL) in a small argon purged flask and warmed in an oil bath to 40° C. Addition of 2-(1-methylpyrrolidin-2-yl)ethanamine 30 (0.696 g, 5.431 mmol) occurred dropwise. The reaction was stirred at 65-70° C. for 24 hours. After cooling to room temperature the solvent was removed under reduced pressure and the resulting residue partitioned between H2O and ethyl acetate and 1M ammonium hydroxide solution added to adjust pH to 10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with H2O, brine (twice), dried over magnesium sulphate, filtered and then concentrated. Recrystallization of the crude solid from EtOH yielded a yellow powder 31 (2,4-Dinitro-phenyl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine Yield: 0.979 grams (67.4%). 1H NMR (DMSO) 8-1.51-1.71 (m, 3H), 1.78-1.96 (2×m, 3H), 2.06-2.14 (m, 1H), 2.26 (s, 3H), 2.26-2.36 (m, 1H), 2.93-3.03 (m, 1H), 3.48-3.53 (m, 2H), 7.18 (d, 1H, J=9.6), 8.27 (dd, 1H, J=9.7, 2.7), 8.86 (d, 1H, J=2.8), 9.50 (br s, 1H); MS (ESI): 295 (MH+, 100%)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CS(C)=O>[Br:1][C:2]1[C:3]([O:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Clc1ccc(Oc2ncccc2Br)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-2-chloropyridine (10 g, 52 mmol), 4-chlorophenol (6.7 g, 52 mmol), cesium carbonate (34 g, 104 mmol) in 100 mL DMSO was heated to 90° C. with stirring overnight. The reaction mixture was dilution with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/hexane) to provide the title compound.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][O:22][S:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:13])(=[O:11])=[O:10])[CH2:16][CH2:15]1)(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OCCC1CCNCC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)OCCC2CCN(S(=O)(=O)c3c(C)cc(C)cc3C)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 44 h

Procedure:
2-Mesitylenesulfonyl chloride (24.78 g, 0.113 mol) in pyridine (60 ml) was added all at once to 4-piperidineethanol (5.58 g, 43.2 mmol) in pyridine (25 ml) at -16° C.; the temperature rose to -11° C. The flask was stored in the refrigerator at 5.5° C. for 44 hours under argon. The reaction mixture was poured into ice (1 kg) and after 3 hours, 16.00 g (75%) of (2) as a yellow solid was filtered off: mp 93.5°-94° C.; NMR (CDCl3 /TMS) δ 1.4-2.1 (m, 7H), 2.27 (s, 6H), 2.44-2.96 (m+s, 14H), 3.37-3.69 (m, 2H), 3.97 (t, 2H, J=5), 6.90 and 6.93 (2s, 4H). Anal. calcd. for C25H35NO5S5 : C-60.82, H-7.15, N-2.84. Found: C-60.90, H-7.13, N2.85.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:40])[CH2:19][C@H:20]([NH:32]C(=O)OC(C)(C)C)[CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)[CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[NH2:32][CH:20]([CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH2:19][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]2[N:9]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:7]3[NH:8][C:3](=[O:2])[CH:4]=[CH:5][C:6]=3[N:11]=2)[CH2:13]1)=[O:40]
Reactant: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(OC)nc21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COCCCn1c([C@@H]2CCCN(C(=O)CC(N)Cc3ccc4ccccc4c3)C2)nc2ccc(=O)[nH]c21
Temperature: 150 °C
Yield: 3.5 %

Procedure:
(R)-tert-Butyl 4-(3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (33E) (0.114 mmol, 0.070 g) prepared according to Example 33, Steps A-E and pyridine hydrochloride (8.65 mmol, 1.00 g) were added to a 15 mL round bottomed flask equipped for stirring under nitrogen. The reaction was subsequently heated to 150° C. and stirred for 15 min. The reaction was cooled to room temperature and water (2 mL) was added. The solution was stirred for 30 minutes at room temperature to allow the solid to completely dissolve. This solution was then filtered and directly purified by preparative LC/MS (10-50% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording the title compound as a clear colored oil (0.004 mmol, 0.002 g, 3% yield). ESI-MS: m/z 502.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][CH2:24][O:25][CH3:26])[C:20](=[O:27])[C@H:19]([NH:28]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:28][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][CH2:24][O:25][CH3:26])[C:20]1=[O:27]
Reactant: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-ylcarbamate (99 mg, 0.248 mmol) in dichloromethane (5 mL). After 1 h, the solution was concentrated and azeotroped with toluene (2×). Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 299.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:24]#N)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=[O:27]>O.[Al].[Ni]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[O:27])[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(C#N)c2s1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Solvent: O
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(C=O)c2s1
Temperature: 95 °C
Reaction time: 5 h

Procedure:
1-(5-(Benzyloxy)-7-cyanobenzo[d]thiazol-2-yl)-3-ethylurea (1.00 g, 2.84 mmol) was stirred in formic acid (75 ml) and water (20 ml). Aluminum Nickel alloy (5.5 g, 64.7 mmol) was added and the reaction was stirred at 95° C. for 5 h under N2. LCMS indicated 60% conversion to the desired aldehyde. The reaction was allowed to cool then the volatiles were removed under reduced pressure. The resulting concentrated solution was neutralized to pH9 with a 2M aqueous solution of sodium hydroxide then extracted with EtOAc, the combined extracts concentrated and the resulting residue purified by column chromatography eluting with EtOAc 50 to 100% in petroleum-ether to afford the aldehyde as a yellow solid (200 mg, 99% purity by LC-MS) (20%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1.C1C(=O)N([Cl:19])C(=O)C1>>[Cl:19][C:3]1[N:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1ncc(C)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Product: CCOC(=O)c1nc(Cl)c(C)[nH]1
Yield: 82.1 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-methyl-1H-imidazole-2-carboxylate obtained in Example (5a) (0.50 g, 3.23 mmol) and NCS (0.44 g, 3.25 mmol), to obtain 0.50 g of the title compound as a white solid (82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].Br[CH:12]([CH2:17][CH2:18][Br:19])[C:13](OC)=[O:14]>CN(C)C=O>[Br:19][CH2:18][CH2:17][CH:12]1[C:13](=[O:14])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[S:10]1
Reactant: COC(=O)C(Br)CCBr
Reactant: COc1ccc(N)c(S)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)SC(CCBr)C(=O)N2
Temperature: 0 °C
Yield: 65.3 %

Procedure:
A solution of 3.10 g of 2-amino-5-methoxythiophenol and 5.20 g of methyl 2,4-dibromobutyrate in 30 ml of dimethylformamide was stirred at room temperature for 2 hours. The mixture was poured into ice-water and the resulting crystals were collected by filtration and washed with water. Recrystallization from methanol gave 3.94 g (65.2%) of 2-(2-bromoethyl)-7-methoxy-2H-1,4-benzothiazin-3(4H)-one as prisms, m.p. 142°-143° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](F)=[C:27]([Cl:32])[CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:32][C:27]1[CH:26]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:30]=[CH:29][C:28]=1[O:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)CCc1ccc(C(F)(F)F)cc1O
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2cc(C(F)(F)F)ccc2CCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step (v) (0.6 g), the product from step (vii) (0.43 g) and potassium carbonate (0.285 g) in NMP (10 ml) was heated at 70° C. for 4 h. The mixture was partitioned between diethylether and water, the organic layer dried, and the solvent evaporated under reduced pressure. The residue was dissolved in 50% DCM/trifluoroacetic acid (20 ml) and stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue purified by RPHPLC, yield 0.175 g
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([F:15])[CH:7]=1.C(OCC)C.Cl>O>[F:15][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=1)[CH2:5][OH:4]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(F)cc(CO)c1
Yield: 82.3 %

Procedure:
A solution of lithium borohydride (2M in THF, 7.3 ml) was added slowly to a mixture of methyl-3-fluoro-5-nitrobenzoate (JCS Chem. Comm., 1993, 921-922; 2.9 g) and diethyl ether (60 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. Water and a 2N aqueous hydrochloric acid solution were added in turn and the mixture was extracted with diethyl ether. The organic solution was evaporated and the residue was purified by column chromatography on silica using methylene chloride as eluent. There was thus obtained an oil which crystallised on standing to give 3-fluoro-5-nitrobenzyl alcohol (2.05 g); 1H NMR: (DMSOd6) 4.64 (s, 2H), 5.65 (s, 1H), 7.64 (m, 1H), 7.96 (m, 1H), 8.06 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:43])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH2:25][N:26]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=2[N+:38]([O-])=O)[CH3:27])=[O:19])=[CH:13][C:12]=1[O:41][CH3:42]>CO.[Pd]>[NH2:38][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:28]=1[N:26]([CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:18](=[O:19])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[O:43])=[C:12]([O:41][CH3:42])[CH:13]=1)[CH3:27])[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1ccc(N(C)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N(C)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(N)c1
Yield: 33.2 %

Procedure:
A stirred solution of methyl 4-[N-[1-[4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]-3-nitrobenzoate (901.0 mg, 1.518 mmol) in MeOH (18.0 mL) was hydrogenated over 5%Pd-C (1.35 g) at 45 psi overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was made basic with 1N NaOH solution and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and the solvent was removed under a reduced pressure. The residue was chromatographed on silica-gel with CHCl3—MeOH (24:1, v/v) as eluent to afford 283.7 mg (48%) methyl 3-amino-4-[N-[1-[4-[N′-(2-fluorophenyl)ureido]-3-methoxy-phenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]benzoate as a brownish amorphous solid, which was used to the subsequent reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21](OS(C)(=O)=O)[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@H:21]([N:28]=[N+:29]=[N-:30])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](OS(C)(=O)=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@@H](N=[N+]=[N-])[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 72.3 %

Procedure:
A mixture of 80B (650 mg, 1.53 mmol) and sodium azide (597 mg, 9.18 mmol) was heated at 80° C. for 2 days. The reaction was diluted with EtOAc (200 mL), washed with brine:water (1:1, 4×15 mL), dried (MgSO4), filtered and concentrated to give the crude product. Purification by chromatography (40 g ISCO silica gel cartridge, 0-20% EtOAc/hexane) provided 80C as a colorless oil (410 mg). MS (ES) m/z 271 [M-Boc+H]+.
Reaction SMILES: C[O-].[Na+].CO.[CH2:6]([N:8]1[C:12]([CH3:13])=[C:11]([NH:14][S:15]([C:18]2[N:28]=[C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25](Cl)[N:20]3[N:19]=2)(=[O:17])=[O:16])[C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]1)[CH3:7].[C:33](O)(=[O:35])C>CS(C)=O>[CH2:6]([N:8]1[C:12]([CH3:13])=[C:11]([NH:14][S:15]([C:18]2[N:28]=[C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[C:25]([O:35][CH3:33])[N:20]3[N:19]=2)(=[O:17])=[O:16])[C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]1)[CH3:7]
Reactant: CCn1nc(C(F)(F)F)c(NS(=O)(=O)c2nc3cc(C)cc(Cl)n3n2)c1C
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CCn1nc(C(F)(F)F)c(NS(=O)(=O)c2nc3cc(C)cc(OC)n3n2)c1C
Reaction time: 18 h

Procedure:
A 25 percent solution of sodium methoxide in methanol (1.65 g, 5.4 mmol) was added to a solution of 1.14 g (2.70 mmol) of N-(1-ethyl-5-methyl-3-(trifluoromethyl)-4-pyrazolyl)-5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide in 25 mL of dimethyl sulfoxide (DMSO) at ambient temperature with stirring. After 18 hours, 1.0 mL of acetic acid was added and the resulting mixture was concentrated by evaporation under reduced pressure. The residue was diluted with 25 mL of water and the resulting slurry was stirred for 10 min and then the insoluble solids collected by filtration, washed twice with 10 mL portions of water and then with 25 mL of ether, and dried under reduced pressure at 40° C. overnight. The resulting white solid, which amounted to 1.03 g (92 percent of theory) and melted at 230°-231° C. (d), was the title compound (Compound 2).
Reaction SMILES: [CH3:1][N:2]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)[CH3:3].[CH3:11][O:12][C:13](=[O:22])[C@:14]([N:19]=[C:20]=[O:21])([CH:16]([CH3:18])[CH3:17])N>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][O:12][C:13](=[O:22])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:19][C:20]([O:10][CH2:9][C:7]1[N:8]=[C:4]([N:2]([CH3:3])[CH3:1])[S:5][CH:6]=1)=[O:21]
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Reactant: CN(C)c1nc(CO)cs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OCc1csc(N(C)C)n1)C(C)C
Yield: 94.4 %

Procedure:
A solution of 505 mg (3.19 mmol) of 2-(N,N-dimethylamino)-4-(hydroxymethyl)thiazole, 3.19 mmol of α-isocyanato-L-valine methyl ester, and 100 mg of 4-dimethylaminopyridine in 30 ml of dichloromethane was heated at reflux for 3 h. The resulting solution was allowed to cool, diluted with dichloromethane, washed sequentially with 10% citric acid, aqueous Na2CO3, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography using 2% methanol in chloroform to provide 0.95 g (95%) of the desired compound, Rf 0.42 (4% methanol in chloroform). 1H NMR (CDCl3) δ 0.84 (d, J=7 Hz, 3 H), 0.93 (d, J=7 Hz, 3 H), 2.12 (m, 1 H), 3.11 (s, 6 H), 3.73 (s, 3 H), 4.24 (dd, J=8,4 Hz, 1 H), 4.99 (s, 2 H), 5.26 (br d, 1 H), 6.49 (s, 1 H). Mass spectrum: (M+H)+ =316.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][C:18]=3[CH3:20])[N:13]([CH3:28])[N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Li+].[OH-]>O1CCOCC1.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][C:18]=3[CH3:20])[N:13]([CH3:28])[N:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCOC(=O)COc1cc(C)c2c(-c3cc(OC)cc(OC)c3)nn(C)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)cc(-c2nn(C)c3nc(OCC(=O)O)cc(C)c23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.5 %

Procedure:
To a solution of ethyl 2-((3-(3,5-dimethoxyphenyl)-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)acetate (910 mg, 2.36 mmol) in dioxane (10 ml) and water (10 ml) was added LiOH (113 mg, 4.72 mmol) and the reaction mixture stirred at rt for 72 h. Then, water was added and the mixture extracted with CH2Cl2. The aqueous phase was then adjusted to pH ˜2 with aqueous 2M HCl. The resulting precipitate was then filtered off, washed with H2O and dried under vacuum to furnish 620 mg (74%) of the title compound. [1H-NMR (DMSO-d6, 600 MHz): δ 6.70 (br d, 2H), 6.55 (br s, 1H), 6.44 (s, 1H), 4.49 (s, 2H), 3.91 (s, 3H), 3.78 (s, 6H), 2.50 (s, 3H); UPLC-MS RtJ=0.93 min; [M+H]+=358.1]