Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]([CH2:12][O:13]S(C1C=CC(C)=CC=1)(=O)=O)([CH2:8][N:9]=[N+:10]=[N-:11])[CH2:4][N:5]=[N+:6]=[N-:7]>O1CCOCC1>[N:9]([CH2:8][C:3]1([CH2:4][N:5]=[N+:6]=[N-:7])[CH2:2][O:13][CH2:12]1)=[N+:10]=[N-:11]
Reactant: Cc1ccc(S(=O)(=O)OCC(CO)(CN=[N+]=[N-])CN=[N+]=[N-])cc1
Solvent: C1COCCO1
Product: [N-]=[N+]=NCC1(CN=[N+]=[N-])COC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
0.1 mole of compound 9 was dissolved in 100 ml of dry dioxane. 0.15 Mole of potassium tert.-butylate was added, with exclusion of moisture. After the reaction mixture had been stirred at 60° C. for 3 hours, it was concentrated. The residue was taken up in 400 ml of ether and the mixture was washed twice with 5% strength (weight: volume) aqueous NaCl solution. The organic phase was dried and concentrated in vacuo. The uniform product was further purified by column chromatography (eluting agent: chloroform/ethyl acetate 5:1).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:13][CH2:14]O>>[CH2:13]([O:11][C:10](=[O:12])[C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:14]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CCO
Product: CCOC(=O)[C@H](N)Cc1ccccc1
Yield: 81 %

Procedure:
D-Phenylalanine (250 mg, 1.52 mmol) was dissolved in 5 ml EtOH previously bubbled in HCl (gas). The solution was brought to 100° C. and allowed to reflux overnight. The solvent was evaporated off affording 280 mg crude product. Recrystallization from EtOH/EtOAc/pentane gave 239 mg (81% yield) of D-phenylalanine ethyl ester as white crystals.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:26]1([NH:32]N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 64 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and phenylhydrazine according to the method described for Example 1 in 64% yield. MS: M=399.1 (M+H)+
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([N:33]2[CH2:37][CH2:36][C@@H:35]([NH:38][C:39]([NH:41][C:42]4[CH:43]=NC=CC=4)=[O:40])[CH2:34]2)=[N:12][C:13]=3[NH:17][CH2:18][C:19]([OH:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][C@@H:3]1[NH:48][C:49](=[O:52])[CH2:50][OH:51].[C:53]1([O:59]C(=O)NC2C=NC=CC=2)[CH:58]=C[CH:56]=[CH:55][CH:54]=1>>[OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([N:33]2[CH2:37][CH2:36][C@@H:35]([NH:38][C:39]([NH:41][CH2:42][C:43]4[CH:56]=[CH:55][CH:54]=[C:53]([OH:59])[CH:58]=4)=[O:40])[CH2:34]2)=[N:12][C:13]=3[NH:17][CH2:18][C:19]([OH:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][C@@H:3]1[NH:48][C:49](=[O:52])[CH2:50][OH:51]
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-((1S,2R,3S,4R)-2,3-dihydroxy-4-{6-(2-hydroxy-2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-cyclopentyl)-2-hydroxy-acetamide (Example 192), by substituting (3-hydroxy-benzyl)-carbamic acid phenyl ester (Intermediate ZD) for pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:23][CH:24]1[O:40][C@H:39]([CH2:41][OH:42])[C@@H:29]([O:30][CH2:31][C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)[C@H:27]([OH:28])[C@@H:25]1[OH:26]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:23][CH:24]1[O:40][C@H:39]([CH2:41][OH:42])[C@@H:29]([O:30][CH2:31][C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)[C@H:27]([OH:28])[C@@H:25]1[OH:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OC1CCCCC1)C(=O)O
Agent: Cc1ccc(CO[C@H]2[C@H](O)[C@H](O)C(O)O[C@@H]2CO)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC(=O)OC1CCCCC1)C(=O)O

Procedure:
Boc-Asp(O-cHex)-Man(4-MBzl) (52 g) was treated with 50% TFA/methylene chloride (400 mL) for 45 min at room temperature. The solvent was evaporated and chased several times with methylene chloride to eliminate traces of TFA. The product precipitated as its TFA salt upon addition of ether. The solid was collected and air dried to yield a white solid (46.7 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:23])=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:23])=[CH:19][CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(Br)c3O2)cc1
Reactant: Cc1ccccc1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(-c4ccccc4C)c3O2)cc1
Yield: 65.5 %

Procedure:
Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.05 g, 5.11 mmol) with 2-methylphenyl boronic acid (1.04 g, 7.66 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.201 g, 0.255 mmol), and potassium carbonate (1.77 g, 12.77 mmol) generally according to the procedure described for Intermediate 37 provided 1.38 g (65%) of (±)-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.34 (silica, ethyl acetate:hexanes 1.5:8.5); Anal. calcd. for C23H21FO4S: C, 66.97; H, 5.13. Found: C, 66.95; H, 4.76.
Reaction SMILES: C(O[CH2:5][CH2:6][N+:7]([O-:9])=[O:8])(=O)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[CH:20][N:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:18]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:13][CH:12]=1>C(O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[CH:20][N:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH2:5][CH2:6][N+:7]([O-:9])=[O:8])[CH2:26][CH2:27]3)[C:18]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(-c2ccn(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: CC(=O)OCC[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])CCN1CCC(n2ccc(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
186 mg (1.40 mmol) of 2-nitroethyl acetate were added to a solution of 300 mg (0.93 mmol) of 3-(4-fluorophenyl)-1-(piperidin-4-yl)-2-(pyridin-4-yl)-1H-pyrrole (prepared as described in Example 13 above) in 6 ml of ethanol. The resulting mixture was stirred at room temperature for 30 minutes, after which the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue and then this was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residual solid was washed with diethylether to give 280 mg (yield 76%) of the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:15][C:13]1[CH:14]=[C:10]2[N:9]=[C:8]([CH3:16])[C:7]3[C:2]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:4]=[N:5][C:6]=3[N:11]2[N:12]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1Cl
Reactant: C1CCNCC1
Product: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1N1CCCCC1
Yield: 88 %

Procedure:
When 6-chloro-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester of Example 1c is treated with piperidine according to the procedure of Example 1d, 2,5-dimethyl-6-(1-piperidinyl)-pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester is obtained, yield 88%, m.p. 161°-163° (ethyl acetate).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]1.[H-].[Na+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][C:21]#[N:22])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]2)[C:21]#[N:22])=[CH:18][CH:17]=1
Reactant: CC1CN(CCCCl)CC(C)O1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1CN(CCCC(C#N)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This intermediate (2.0 g.) was prepared using the procedure described in Example 2a except using 2.3 g. (11 moles) of 4-(3-chloropropyl)-2,6-dimethylmorpholine, 0.48 g. of sodium hydride, and 1.69 g. (11 mmoles) of 4-chlorobenzyl cyanide in 15 ml. of a 2 to 1 mixture of toluene and DMF and was isolated as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2C3C=CC=CC=3N3C=NN=[C:10]3[CH2:9][N:8]=2)C=CC=CC=1.C(NCCC)CC.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[N:38]3[C:39]([CH2:42]Cl)=[N:40][N:41]=[C:37]3[CH2:36][N:35]=[C:34]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:33]=2[CH:50]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[N:38]3[C:39]([CH2:42][N:8]([CH2:9][CH3:10])[CH2:7][CH3:1])=[N:40][N:41]=[C:37]3[CH2:36][N:35]=[C:34]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:33]=2[CH:50]=1
Reactant: c1ccc(C2=NCc3nncn3-c3ccccc32)cc1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: CCCNCCC
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 4, 8-chloro-1-[di-propylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine is prepared by reacting dipropylamine with 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]-benzodiazepine.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1noc2ccccc12)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added benzyl chloroformate (0.120 ml, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to yield 152 mg (72.0%) of the desired product. mp 137-138° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:7]=2[OH:16])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:13][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:7]([OH:16])[CH:8]=1
Reactant: Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C2CCCC2)c(O)cc1N
Reaction time: 4 h

Procedure:
A flask charged with 10% Pd/C (16 mg) was evacuated and placed under a N2 atmosphere. To this was added 2-cyclopentyl-4-methyl-5-nitro-phenol (160 mg, 0.72 mmol) as a solution in methanol (3 mL). The reaction mixture was stirred under H2 atmosphere for 4 h, then filtered and concentrated in vacuo to provide 5-amino-2-cyclopentyl-4-methylphenol a light tan solid (130 mg, 94% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.47 (s, 1H), 6.60 (s, 1H), 6.08 (s, 1H), 4.44 (s, 2H), 3.02 (dd, J=2.4, 17.2 Hz, 1H), 1.91 (s, 3H), 1.84-1.77 (m, 2H), 1.71-1.66 (m, 2H), 1.58-1.54 (m, 2H), 1.44-1.39 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=C)=[O:5].[BH4-].[Na+].OCCCCCCCCCC(OCC)=O.P(Br)(Br)[Br:34]>>[Br:34][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: C=CCCCCCCCCC(=O)OCC
Reactant: BrP(Br)Br
Agent: CCOC(=O)CCCCCCCCCO
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)CCCCCCCCCBr

Procedure:
The order of functionalization and esterification is not critical. For example, rather than performing an ozonolysis of the starting material, for example, 10-undecylenic acid, as described above, the starting material first may be esterified with ethanol or other alcohol to form an ester, for example, ethyl 10-undecylenate. Next, the ester can undergo functionalization by first ozonating the ester and then reducing the ozonide using, for example, sodium borohydride to form a hydroxylated ester, for example, ethyl 10-hydroxydecanoate. The hydroxylated ester finally is converted to the desired functionalized ester using, for example, PBr3 to form ethyl 10-bromodecanoate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:9]=1[C:10](OC)=[O:11].O.[OH-].[Na+]>C1COCC1>[NH2:7][C:8]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Br)cc1CO
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a suspension of lithium aluminium hydride (0.33 g, 8.7 mmol) in THF (10 ml) was added a solution of methyl 2-amino-5-bromobenzoate (2.0 g, 8.7 mmol) in 20 ml THF at 0° C. under nitrogen. Then stirring was continued for 2 h. 0.64 ml water, 2 M solution of sodium hydroxide (0.64 ml) and again 1.28 ml water were added before the resulting mixture was filtered through celite. Evaporation of the solvent and purification of the crude product by flash chromatography on silica gel (dichloromethane/ethyl acetate, 2/1) yielded (2-amino-5-bromophenyl)methanol (1.0 g, 5.2 mmol, 59%) as off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1c1nn(C(=O)OC(C)(C)C)c2ccc(O)cc12
Yield: 104.6 %

Procedure:
3-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-2-yl)-5-hydroxyindazole-1-carboxylic acid tert-butyl ester is prepared, according to procedure D, using 800 mg of 5-benzyloxy-3-(1-tert-butoxycarbonyl-1H-indol-2-yl)indazole-1-carboxylic acid tert-butyl ester, 560 mg of ammonium formate, and 800 mg of 10% palladium-on-charcoal in 30 ml of absolute ethanol. 700 mg of 3-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-2-yl)-5-hydroxyindazole-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[CH:14]1([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of compound tert-butyl piperazine-1-carboxylate (37.2 g, 200 mmol) in ClCH2CH2Cl (500 mL) was added cyclobutanone (21 g, 300 mmol) and NaBH(OAc)3 (84.8 g, 400 mmol). The reaction mixture was stirred at rt for 16 h, quenched with saturated aq. Na2CO3 (500 mL) and extracted with DCM (3×500 mL). The combined organic layers were washed with brine (50 mL), dried, filtered and concentrated under reduced pressure to afford the desired compound tert-butyl 4-cyclobutylpiperazine-1-carboxylate (48 g, 100%) [LCMS: Rt=1.67 min, m/z 241.2 (M+H)+].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]2[CH:11]=1.[I:12]N1C(=O)CCC1=O.C(#N)C>C(Cl)Cl>[I:12][C:11]1[N:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cn2c(C)cccc2n1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nc2cccc(C)n2c1I
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,5-dimethylimidazo[1,2-a]pyridine (0.5 g, 3.4 mmol), N-iodosuccinimide (770 mg, 3.4 mmol) and ACN (5 ml) is stirred at RT for 45 minutes. The mixture is diluted with DCM and extracted with an aqueous solution sodium thiosulfate. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 775 mg (83%). HPLC-MS: M+H=273; tR=1.02 min (METHOD—1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:16]=[C:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]1[CH2:27][C:28](O)=[O:29]>>[Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[N:9]=2)=[C:4]([NH:7][C:28](=[O:29])[CH2:27][N:18]2[C:19]3[C:24](=[N:23][CH:22]=[CH:21][CH:20]=3)[CH2:25][CH2:26][C:17]2=[O:16])[S:5][CH:6]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: CC(C)c1n[nH]c(-c2c(Cl)csc2N)n1
Product: CC(C)c1n[nH]c(-c2c(Cl)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1

Procedure:
The title compound was prepared from 4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine (117 mg, 482 umol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (155 mg, 752 umol) using protocol A and was purified by HPLC to yield N-(4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide. Method [7] Retention time 0.35 min by HPLC (M+=431 and 433) and (M+Na=453 and 455). 1H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.30 (d, J=5.1 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.51 (m, 1H), 7.16 (d, J=1.8 Hz, 1H), 4.89 (s, 2H) 3.17 (m, 2H), 2.98 (m, 1H), 2.81 (m, 2H), 1.28 (d, J=7.2 Hz, 6H).
Reaction SMILES: [CH:1]1([C:4]2[NH:13][C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1.[Cl-].[NH4+]>CN(C)C=O>[CH:1]1([C:4]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccnc2[nH]c(C3CC3)nc12
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.64 g of 2-cyclopropyl-7-methyl-3H-imidazo[4,5-b]pyridine dissolved in 30 ml of dimethylformamide was dropwise added to 400 mg of sodium hydride. The mixture was stirred at room temperature for 30 min, and 3.1 g of methyl 2-(4-bromomethylphenyl)benzoate dissolved in 20 ml of dimethylformamide was dropwise added thereto. The mixture was stirred for 10min and then cooled, and an aqueous ammonium chloride solution was added thereto. The mixture was extracted with ethyl acetate. The extract was washed thrice with water, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (chloroform:ethanol=99:1). The first eluted isomer was the title compound (yield: 1.32 g) .
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[O:11])=[CH:8][C:7]=2[CH:26]=O)[CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])=[O:11])=[CH:8][C:7]=2[CH2:26][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=Cc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-formylbenzoate (3.73 g, 10.13 mmol) and morpholine (1.15 g, 13.17 mmol) in dry THF (50 ml), under argon atmosphere, was stirred for 15 minutes at RT. Na(OAc)3BH (2.79 g, 13.17 mmol) and CH3COOH (754 μl, 13.17 mmol) were added. CH3COOH was added to reach a pH between 5 and 6. The mixture stirred at RT for 24 hours. The solvent was removed, and the crude was dissolved in EtOAc and washed with NaHCO3 sat. sol. and brine. The organic phase was dried over Na2SO4, and the solvent was removed to give 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-(morpholinomethyl)benzoate (4.45 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([N:23]=[C:24]([NH2:27])[NH:25][CH3:26])=[O:22])[NH:6]2.O.O.[Sn](Cl)Cl.O.N>C(O)C>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[C:7]2[C:3]([CH:4]=[C:5]([C:21]([N:23]=[C:24]([NH2:27])[NH:25][CH3:26])=[O:22])[NH:6]2)=[C:2]([Cl:1])[CH:10]=1
Reactant: CNC(N)=NC(=O)c1cc2c(Cl)cc(Oc3ccccc3[N+](=O)[O-])cc2[nH]1
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CNC(N)=NC(=O)c1cc2c(Cl)cc(Oc3ccccc3N)cc2[nH]1
Yield: 51.2 %

Procedure:
A mixture of 0.23 g (0.60 mmol) of 4-chloro-1-methyl-6-(2-nitrophenoxy)-2-indoloylguanidine, 0.72 g (3.20 mmol) of tin (II) chloride dihydrate and 15 ml of ethanol was heated to reflux for 3 hours. After cooling, 28% ammonia water was added to the reaction mixture and ethanol was then distilled off under reduced pressure. The residue was extracted three times with ethyl acetate. The combined extracts were then washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography to give 0.11 g (51.6%) of 6-(2-aminophenoxy)-4-chloro-1-methyl-2-indoloylguanidine. The product was converted into the hydrochloride with hydrogen chloride/methanol to give 0.097 g of 6-(2-aminophenoxy)-4-chloro-1-methyl-2-indoloylguanidine hydrochloride.