Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:20](O)=[O:21])=[CH:18][NH:19][C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:20]([NH:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[O:21])=[CH:18][NH:19][C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: CC(C)(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.5 %

Procedure:
A mixture of 2-(6-chloro-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (140 mg, 0.446 mmol), 2-amino-2-methylpropan-1-ol (48 mg, 0.536 mmol), EDCI (256 mg, 1.338 mmol), HOBt (181 mg, 1.338 mmol) and DIPEA (173 mg, 1.338 mmol) in dry DMF (5 mL) was stirred for 16 hours at room temperature. Water (5 mL) was added and the formed precipitate was separated by filtration, then was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 35% acetonitrile/65% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(6-chloro-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (6 mg, 3%) as a white solid. LCMS: (M+H)+=385; 1H NMR (300 MHz, DMSO+D2O): δ 9.09 (s, 1H), 8.52 (d, 1H, J=8.4 Hz), 8.31 (s, 1H), 7.72 (s, 1H), 7.25 (d, 1H, J=9.0 Hz), 3.59 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:9]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35]C)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O.CO.[OH-].[Na+]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:9]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3OC)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1[C@H]1SC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 33.8 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 77, but starting from 0.76 g of methyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-methoxyphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetate in 6 cm3 of a water/methanol (30/70 by volume) mixture and 0.09 g of potassium hydroxide. The crude product (0.45 g) is dissolved in 7.5 cm3 of a 0.1N aqueous sodium hydroxide solution. The solution thus obtained is washed with 2 times 10 cm3 of diethyl ether, brought to a pH of 2 by addition of a 1N aqueous sulphuric acid solution, then extracted with 2 times 20 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in diisopropyl ether, 0.25 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-methoxyphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenylacetic acid is thus obtained in the form of an amorphous product ([α]D20 =+6.4°±1.0° (C=0.466%; CHCl3), [proton NMR (200 MHz, DMSO D6 plus several drops of CD3COOD, δ in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 1.55 (s, 9H, --C(CH3)3); 3.22 and 3.45 (2dd, J=12.5 and 7, 2H, S--CH2 --); 3.51 (s, 2H, ArCH2COO--); 3.65 (bd, 1H of N--COCH2 --N); 3.93 (s, 3H, --OCH3); 4.05 (d, J=17.5, 1H, the other H of N--COCH2 --N); 4.91 (t, J=7, 1H, N--CH--COO); 6.5 (s, 1H, S--CH--N); 6.85 (bd, J=8, 1H, in position 4 on CO--NM--Ph); 6.9 to 7.4 (m, 6H, aromatic); 7.9 (bd, J=8, 1H, in position 6 on S--CH--Ph--)], [infrared spectrum (KBr), characteristic bands in cm-1 : 3390, 2975, 2930, 2840, 2700 to 2250 (broad band), 1735, 1645, 1610, 1600, 1595, 1560, 1495, 1370, 1245, 1155, 1025, 760, 705].
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>ClCCl.FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C=C2CCNCC2)cc1
Yield: 75.9 %

Procedure:
tert-Butyl 4-(4-nitrobenzylidene)piperidine-1-carboxylate (31.4 mmol, 10 g) was stirred in a mixture of dichloromethane/trifluoroacetic acid for 3 hours. The reaction was concentrated under reduced pressure and water was added. Solid sodium hydrogen carbonate was added portionwise until no further gas was evolved. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the title compound (5.2 g). MS (ESI) m/z 219.1 [M+H]+
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:12][C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH2:29]([NH2:32])[CH2:30][CH3:31].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([S:12][C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[CH2:1][NH:32][CH2:29][CH2:30][CH3:31])([O-:11])=[O:10]
Reactant: CCCN
Reactant: O=Cc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCCNCc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]

Procedure:
A mixture of N-[3-(3-formyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide (0.0027 mol), propylamine (0.003 mol) and NaBH(OAc)3 (0.0041 mol) in DCE (60 mL) was reacted overnight at room temperature. Then a 10% NaOH solution was added and the mixture was extracted with CH2Cl2. The extract was dried (MgSO4) and then purified by column chromatography over silica gel (eluent: 1:0 to 7:1 CH2Cl2:CH3OH). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][OH:17].O.[C:20]([O-])(=[O:22])C.[Ca+2].C([O-])(=O)C>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[OH:17][CH2:16][CH2:14][O:13][C:1](=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH2:9][CH2:20][OH:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CC(=O)[O-]
Reactant: OCCO
Agent: [Co+2]
Agent: [Ca+2]
Solvent: O
Product: O=C(OCCO)c1ccc(C(=O)OCCO)cc1
Temperature: 160 °C

Procedure:
1.4 moles of dimethyl terephthalate (277 g) and 7.2 moles of ethylene glycol (445 g) were weighed into a one-liter round-bottomed flask connected to a vacuum line. A catalytic amount of cobalt (II) acetate tetrahydrate (180 mg, 0.5 mole) and calcium acetate hydrate (90 mg, 0.4 mole) were added. The reaction mixture was heated at 160° C. in an oil bath under a mild vacuum.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])[C:17]([CH3:31])=[C:16]([CH3:32])[N:15]=1>CN(C)C=O>[CH3:31][C:17]1[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:19][C:14]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:15][C:16]=1[CH3:32]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NCC(C)C)nc(N2CCc3ccccc3C2C)c1C
Yield: 23.6 %

Procedure:
After isobutylamine(0.26 ml, 2.58 mmol) and triethylamine(0.36 ml, 2.59 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 133 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:22])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][CH:30]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH:34][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][CH2:16][C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:22])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:31][CH:30]=1)[CH3:24]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(OCc2ccsc2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCc3ccsc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-((S)-2-methoxy-1-methyl-ethoxy)-5-(thiophen-3-ylmethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [NH2:1][CH:2]([PH:9](=[O:11])[OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:17]1([CH2:16][O:15][C:13]([NH:1][CH:2]([PH:9](=[O:10])[OH:11])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(c1ccccc1)[PH](=O)O
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(NC(c1ccccc1)[PH](=O)O)OCc1ccccc1
Yield: 90 %

Procedure:
The process is performed according to the operating conditions described in 1.4., starting with 1 g (5.85 mmol) of (aminophenylmethyl)phosphinic acid and 1.17 g (6.86 mmol) of benzyl chloroformate. 1.6 g of product are recovered (yield=90%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([Br:15])=[CH:13][CH:14]=1)=[O:9])C(C)=O.[ClH:16]>>[ClH:16].[Br:15][C:12]1[S:11][C:10]([C:8]([NH:7][CH2:6][CH2:5][NH2:1])=[O:9])=[CH:14][CH:13]=1
Reactant: CC(=O)NCCNC(=O)c1ccc(Br)s1
Agent: Cl
Product: NCCNC(=O)c1ccc(Br)s1

Procedure:
N-(2-Acetaminoethyl)-5-bromo-2-thiophenecarboxamide was reacted with hydrochloric acid in an analogous manner to that described in Example 1, paragraph 3. The residue was dissolved in alcohol (pH 1), filtered and concentrated to about 300 ml under reduced pressure. After cooling to 5° the product was filtered off under suction and dried, whereby 5-bromo-N-(2-aminoethyl)-2-thiophenecarboxamide hydrochloride was obtained as white crystals, m.p. 221°-222°, after recrystallization from ethanol.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH2:18][CH3:19])([CH3:17])[C:13]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:13]2[C:14]([CH2:18][CH3:19])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:34]4[C:30](=[O:36])[CH2:31][CH2:32][C:33]4=[O:35])[CH2:10][CH2:9]3)[N:12]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: O=C1CCC(=O)N1
Reactant: CCC1(C)C(=O)N(C2CCN(C(=O)CCl)CC2)N=C1c1ccc(OC)c(OC)c1
Product: CCC1(C)C(=O)N(C2CCN(C(=O)CN3C(=O)CCC3=O)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2,4-dihydro-3H-pyrazol-3-one (compound A9) and succinimide as starting compounds.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7](NN)[N:6]=[C:5]([F:12])[C:4]=1[F:13].O.CCCCCC.C(OCC)C.[ClH:26]>[Cu](Cl)Cl>[Cl:26][C:7]1[C:8]([F:9])=[C:3]([CH2:2][OH:1])[C:4]([F:13])=[C:5]([F:12])[N:6]=1
Reactant: NNc1nc(F)c(F)c(CO)c1F
Reactant: Cl
Agent: Cl[Cu]Cl
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: OCc1c(F)c(F)nc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.35 g (0.0026 mole) of copper (II) chloride in 25 ml of concentrated hydrochloric acid was added slowly at room temperature 0.5 g (0.0026 mole) of (4-hydroxymethyl-2,3,5-trifluoropyridin-6-yl)hydrazine (from Example 6). This mixture was stirred at ambient temperature for two hours and was then refluxed for one hour. After being cooled, the reaction mixture was poured into water and was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure, leaving a brown, oily residue. This residue was passed through a short column of silica gel using a hexane/diethyl ether (50/50) mixture as eluant. The appropriate fractions were combined, and the solvent evaporated under reduced pressure, yielding 0.31 g of 2-chloro-4-hydroxymethyl-3,5,6-trifluoropyridine as a yellowish-brown liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCNCc1ncccn1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCNCc1ncccn1)c1ccccc1

Procedure:
By the procedure of Example 46, N-(2-pyrimidylmethyl)ethylenediamine is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(2-pyrimidylmethylamino)-ethyl]thiourea.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@:20]([O:24]C(C1C(C(O)=O)=CC=CC=1)=O)([C:22]#[CH:23])[CH3:21])(=[O:3])[CH3:2].Cl>CO.[OH-].[Na+]>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@:20]([CH3:21])([OH:24])[C:22]#[CH:23])(=[O:3])[CH3:2]
Reactant: C#C[C@](C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#C[C@@](C)(O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
A solution of 600 mg (1.25 mmol) of (S)-(+)-1,2-benzenedicarboxylic acid[3-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl]ester (Example 9) in 10 mL of methanol and 10 mL of 1.0N NaOH was degassed with argon, and heated under reflux for 1.0 h. It was cooled to 0° C. and treated with 100 mL of cold 1.0N HCl. It was then extracted with ether (3×100 mL). The extracts were combined, washed with saturated sodium bicarbonate solution (3×100 mL) dried over MgSO4, and filtered. Dry pyridine (1 mL) was added to the filtrate which was concentrated to near dryness at reduced pressure. The residue was cooled to 0° C. and treated with 3 mL of dry pyridine and 3 mL of acetic anhydride. The resultant solution was kept under argon at 0° C. for 3.0 h, then taken into 100 mL of cold 1N HCl. It was then extracted with ether (3×100 mL). The ether extracts were combined, washed with cold 1.0N HCl (2×100 mL), saturated sodium bicarbonate solution (3×100), brine (1×100 mL), and dried over MgSO4. The crude product (369 mg) was crystallized twice from ether-hexane (1:2) to give (S)-(+)-5-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-3-methyl-1-pentyn-3-ol as a white solid (114 mg): mp 96°-102° C., [α]D25 +14.30° (c 0.965, ethanol); [α]D25 +17.17° (CHCl3)
Reaction SMILES: [N:1]1[C:2]([CH2:10][O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[I:18]N1C(=O)CCC1=O>C(#N)C>[I:18][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[CH2:10][O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)COCc1cn2ccccc2n1
Solvent: CC#N
Product: CCOC(=O)COCc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
0.45 g (1.921 mmol) of ethyl 2-(imidazo[1,2-a]pyridin-2-ylmethoxy)acetate were solubilised in 6 ml of acetonitrile with magnetic stirring, to this solution were added 0.475 g (2.113 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h. A solid was removed by filtration and the obtained filtrate was concentrated in vacuo. The residue was triturated with 10 ml of diisopropyl ether and a precipitate was isolated by filtration. 0.465 g (yield=67%) ethyl 2-((3-iodoimidazo[1,2-a]pyridin-2-yl)methoxy)acetate were obtained as a yellow solid. LC-MS: m/z=361 (MH+); UV purity at 254 nm=75%. 1H NMR (300 MHz, DMSO) δ 8.34 (d, J=6.9 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.47-7.28 (m, 1H), 7.07 (d, J=5.7 Hz, 1H), 4.67 (s, 2H), 4.14 (t, J=10.7 Hz, 4H), 1.22 (d, J=1.9 Hz, 3H)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCCn1ccnc1
Product: Cc1cc([N+](=O)[O-])ccc1NCCCn1ccnc1
Temperature: 96 °C
Yield: 44.2 %

Procedure:
Starting with 31.2 g (0.2 mol) of 1-fluoro-2-methyl-4-nitrobenzene and 37.5 g (0.3 mol) of 3-imidazol-1-ylpropylamine, and after purification by recrystallization from refluxing 96° C. ethanol, 23.0 g of orange-yellow crystals melting at 163° C. (Kofler) were obtained, the elemental analysis of which, calculated for C13H16N4O2.¼H2O, was:
Reaction SMILES: [C:1]([O:9][C@:10]1([CH3:35])[C@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:13][C@H:11]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC([O:42][CH3:43])N(C)C.CO>CN(C)C=O.ClCCl>[C:43]([O:12][C@@H:11]1[O:13][C@H:14]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@:10]1([CH3:35])[O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 21 °C
Reaction time: 12 h
Yield: 68.6 %

Procedure:
To a suspension of compound 3 (19 g, 0.0738 mol) in anhydrous N,N-dimethylformamide (150 ml) was added N,N-dimethylformamide dimethyl acetal (98 ml, 0.7385 mol) and the mixture was stirred at 20-22° C. After one hour TLC (silica gel, 30% methanol in dichloromethane, Rf for compound 3: 0.21 and for product 4: 0.55) indicated that reaction was complete. Solvent and reagent were removed under reduced pressure (temperature was kept below 40° C.). Ethanol (50 ml) was added to the obtained oily residue and the solvent was removed under reduced pressure. This process was repeated twice and crude product solidified. The crude product was stirred with 190 ml of ethanol at 20° C. for one hour and kept at 5° C. for 12 hours. Solids were collected by filtration and filter cake washed with 30 ml of cold ethanol and 30 ml of cold tert-butyl-methyl ether. Drying the solid under vacuum gave 14.7 g (64%) of compound (4) as a first crop. TLC (silica gel, 30% methanol in dichloromethane, Rf for product (4): 0.55) and (silica gel, 10% methanol in dichloromethane, Rf for product (4): 0.1) showed only a single spot for compound (4) Mother liquor from the ethanol purification was evaporated to dryness and the residue was stirred with ethanol (80 ml) at 20° C. for one hour and kept at 5° C. for 12 hours. Solids were collected by filtration and filter cake washed with 15 ml of cold ethanol and 15 ml of cold tert-butyl-methyl ether. After drying the solid under vacuum, 3.5 g (15%) was obtained as a second crop. TLC (silica gel, 30% methanol in dichloromethane, Rf for product (4): 0.55) and (silica gel, 10% methanol in dichloromethane, Rf for product (4): 0.1) showed only a single spot for compound (4); m.p. 201-209° C.; 1H NMR (DMSO-d6) δ ppm 8.62 (s, 1H, N═CH), 8.17 (d, 1H, H-6, J5-6=7.3 Hz), 5.91 (m, 2H, H-1′, H-5), 5.16 (t, 1H, OH-5′, D2O exchangeable), 5.06 (s, 1H, OH-2′, D2O exchangeable), 3.8-3.5 (m, 4H, H-3′, H-4′, H-5′ and H-5″), 3.15 and 3.02 (2s, 6H, N(CH3)2), 0.92 (s, 3H, CH3); FAB>0 (GT) 625 (2M+H)+, 313 (M+H)+, 167 (B+2H)+; FAB<0, (GT) m/z 419 (M+T−H)−, 403 (M+G−H)−, 311 (M−H)−, 165 (B)−.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:48]1([O:53][C:54](=[O:58])[C@H:55]([CH3:57])[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:56][C@H:55]([C:54]([O:53][CH:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:58])[CH3:57])[CH2:30][CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C[C@H](N)C(=O)OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@@H](C)C(=O)OC3CCCC3)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-alanine cyclopentyl ester tosylate. 1H NMR (300 MHz, d3-MeOD) 6.96 (1H, s), 6.34 (1H, s), 5.34 (1H, m), 4.17 (2H, m), 4.07 (1H, m), 3.19 (3H, m), 2.98 (2H, t, J=12 Hz), 1.96 (2H, m), 1.93 (11H, m), 1.56 (3H, d, J=7.2 Hz), 1.29 (2H, m), 1.18 (6H, d, J=6.9 Hz). LC/MS: purity >98%, m/z 447.25 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2C1CCNCC1.N1C=CC(CCCCl)=N1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Agent: ClCCCc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Temperature: 100 °C

Procedure:
A mixture of 3.26 gm (14 mMol) 5-chloro-3-(4-piperidinyl)-1H-indole, 2.03 gm (14 mMol) 3-(1H-pyrazol-3-yl)-1-chloropropane and 3.71 gm (35 mMol) sodium carbonate in 76 mL dimethylformamide was heated at 100° C. for 18 hours. The reaction mixture was cooled to ambient and the solvent removed under reduced pressure. The residue was partitioned between water and dichloromethane, then the phases were separated. The organic phase was washed with water followed by saturated aqueous sodium chloride and the remaining organics were dried over sodium sulfate. The dichloromethane was removed under reduced pressure and the residual yellow oil subjected to flash silica gel chromatography, eluting with a gradient system of dichloromethane containing 0-10% methanol. Fractions shown to contain product were concentrated under reduced pressure to give 1.72 gm (35.9%) 5-chloro-3-<1-<3-<1H-pyrazol-4-yl>propyl>-4-piperidinyl>-1H-indole as a colorless foam. The oxalate salt was formed to give the title compound as a light yellow foam. m.p.=110° C. MS(m/e): 343(M+) Calculated for C19H32N4Cl·C2H2O4 : Theory: C, 58.27; H, 5.82; N, 12.94. Found: C, 58.07; H, 5.97; N, 12.88.