Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:31])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:31][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (400 mg, 1.94 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (523 mg, 2.33 mmol), HATU (1.11 g, 2.91 mmol) in anhydrous DMF (18 mL) is added DIPEA (480 μL, 2.91 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give a pure product (102) as white solid (681 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([OH:17])=[N:7]1.[H-].[Na+].[OH:24][C:25]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:26]=1[CH2:27]Cl.O>CS(C)=O>[OH2:17].[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15][CH3:16])=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]1[CH2:27][C:26]1[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:25]=1[OH:24]
Reactant: CSc1ccc2c(c1)c(O)nn2Cc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc2c(c1)c(=O)n(Cc1cc([N+](=O)[O-])ccc1O)n2Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
3.6 g (11 mmol) of 1-(3,4-dichlorobenzyl)-5-methylthio-1H-indazol-3-ol are dissolved in 100 ml of DMSO and treated in portions with 0.34 g (13.2 mmol) of sodium hydride (95 percent). After stirring for 2 hours, a solution of 2.1 g (11 mmol) of 2-hydroxy-5-nitrobenzyl chloride in 20 ml of DMSO is added dropwise and the mixture is stirred at 60° C. for 3 hours. After cooling, 200 ml of water are added dropwise, the mixture is stirred for 4 hours and the solid is filtered off with suction. The precipitate is extracted by stirring with methanol whilst hot and recrystallized from 2-propanol.
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][C:7]=1[C:13](OC)=[O:14])Br.OC1C=CC=CC=1C#N.COC(=O)C(C1C=CC=CC=1C(OC)=O)Br.[OH:43][C:44]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:45]=1[C:46]#[N:47]>>[OH:14][C:13]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2[O:43][C:44]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][C:45]=3[C:46]=2[N:47]=1
Reactant: COc1ccc(O)c(C#N)c1
Reactant: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Agent: COC(=O)c1ccccc1C(Br)C(=O)OC
Agent: N#Cc1ccccc1O
Product: COc1ccc2oc3c4ccccc4c(O)nc3c2c1

Procedure:
The procedure was similar to step S19B, while the starting material 19A and 2-hydroxy-benzonitrile were replaced with 21A and 2-hydroxy-5-methoxy-benzonitrile, respectively.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH-].[Na+]>Cl>[NH2:1][C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1-n1cncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccnc1-n1cncn1
Temperature: 0 °C
Yield: 35.6 %

Procedure:
To a suspensionn containing 35.4 g of stannous chloride dihydrate in 100 ml of concentrated hydrochloric acid was added portionwise 10 g of the compound prepared in Example 1 over a 0.25 hour period. After the resulting exotherm (23°-79°) slowed, the suspension was heated at 85°-90° for one hour, then cooled to 0°. The mixture was poured onto excess ice-water (about 700 ml), and the suspension was made strongly basic to litmus by addition of 50% aqueous NaOH to yield a precipitate. After filtering the mixture, the isolated solid was washed with water, suction-dried, then recrystallized from ethyl acetate-hexanes to yield 3 g of the subject compound; m.p. 103°-105°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([O:17][C:18]([N:20]([CH2:25][CH:26](OCC)OCC)[CH2:21][C:22](O)=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[CH2:10]([O:17][C:18]([N:20]1[CH:25]=[CH:26][N:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:22](=[O:23])[CH2:21]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(CN(CC(=O)O)C(=O)OCc1ccccc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NN1C=CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.7 %

Procedure:
A solution of tert-butoxycarbonylhydrazine (3.96 g) and N-benzyloxycarbonyl-N-(2,2-diethoxyethyl) glycine (9.76 g) in acetonitrile (100 ml) was treated with WSC (5.75 g) and stirred at room temperature for 15 hours. The reaction mixture was concentrated to obtain a residue, which was partitioned between ethyl acetate and water, and then the organic phase was washed with water, aqueous sodium bicarbonate, aqueous solution of citric acid and brine, dried and then concentrated. The residue obtained was dissolved in toluene (200 ml), combined with p-toluenesulfonic acid hydrate (285 mg) and then stirred at 100° C. for 90 minutes. The reaction mixture was washed with saturated aqueous sodium bicarbonate and brine, dried and then concentrated. The residue thus obtained was purified by a column chromatography on a silica gel (hexane:ethyl acetate=3:2) to obtain 4-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydropyrazine (1.84 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH:21]=4)=[O:18])[C@@H:13]([CH3:32])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH3:42][N:43](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:42]([C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH:21]=4)=[O:18])[C@@H:13]([CH3:32])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1)#[N:43]
Reactant: CN(C)C=O
Reactant: CC(C)NC(=O)c1cccc(NC(=O)N2CCN(c3ncnc4c3c(Br)cn4S(=O)(=O)c3ccccc3)C[C@@H]2C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)NC(=O)c1cccc(NC(=O)N2CCN(c3ncnc4[nH]cc(C#N)c34)C[C@@H]2C)c1
Temperature: 150 °C

Procedure:
To a solution of (S)-4-(5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(isopropylcarbamoyl)-phenyl)-2-methylpiperazine-1-carboxamide from step D (70 mg, 0.11 mmol) in DMF (2 ml) was added Zn(CN)2 (26 mg, 0.22 mmol) and Pd(PPh3)4 (13 mg, 0.011 mmol). The mixture was heated at 150° C. for 3 min via microwave, cooled to room temperature, and filtered through a pad of celite. The solution was concentrated under vacuum, and the residue was treated with NaOH and MeOH for 2 hrs. The product was purified by Prep-HPLC to obtain (S)-4-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(isopropylcarbamoyl)phenyl)-2-methylpiperazine-1-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[C:16](=O)[CH3:17])[CH3:2].CC([O-])(C)C.[K+].CCCCCC.CCOC(C)=O>C(COC)OC>[CH2:1]([O:3][C:4]([C:5]1[O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=2[C:16]=1[CH3:17])=[O:19])[CH3:2]
Reactant: CCOC(=O)COc1cc(OC)c(Cl)cc1C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cc(OC)c(Cl)cc2c1C
Yield: 40.9 %

Procedure:
The above prepared (2-acetyl-4-chloro-5-methoxy-phenoxy)-acetic acid ethyl ester-(6.05 g, 21.1 mmol) was dissolved in 45 mL of dimethoxyethane and treated at −15° C. with KOtBu (0.947 g, 0.4 eq.). After keeping for 45 Min. at −15° C. and 5 h at 0° C., the reaction mixture was poured onto crashed ice/HCl, twofold extracted with AcOEt, washed with water, dried over magnesium sulfate, and evaporated to dryness to leave 5.26 g of crude product. Flash chromatography (SiO2, hexane/AcOEt=9/1) of the latter afforded 2.32 g of the title compound as white crystals.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[N:19]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)[CH3:4].Br[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:44](#N)[CH3:45]>ClCCl>[CH3:23][C:22]1[N:18]([CH2:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([C:7]3[S:8][CH:9]=[C:5]([C:3](=[N:2][O:1][CH2:44][CH2:45][CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:4])[N:6]=3)[CH2:11][CH2:12]2)=[O:28])[N:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: CC#N
Reactant: CC(=NO)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(=NOCCCCc1ccccc1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 60 °C

Procedure:
A mixture of 1-[4-[4-[1-(hydroxyimino)ethyl)-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (0.5 g, 1.2 mmol) (i.e. the product of Example 1, Step E), (2-bromoethyl)benzene (0.277 g, 1.5 mmol), and cesium carbonate (0.487 g, 1.5 mmol) in acetonitrile (6 mL) was heated at 60° C. overnight, diluted with dichloromethane, and filtered through a fritted SPE tube (Varian® bond elute reservoir). The reaction was concentrated under reduced pressure and the resulting residue purified via silica gel chromatography (hexanes: ethyl acetate gradient) to provide 0.17 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13](Br)([CH3:15])[CH3:14].[I-].[Na+].O>CN(C)C=O>[CH:13]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)Br
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(OC(C)C)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-hydroxybenzoate (15.2 g, 0.10 mol) in N,N-dimethylformamide (100 ml) were added isopropyl bromide (12.1 ml, 0.13 mol) and sodium iodide (19.5 g, 0.13 mol), and the mixture was stirred at 70° C. for 15 hrs. To the reaction solution was added water (500 ml), and the mixture was extracted with ethyl acetate (500,200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give the objective substance (12.4 g, 64%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][O:3]1.[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH3:17][C:18]1[C:19]([N:25]2[CH2:26][CH2:27][N:28]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:7]4[CH2:6][CH2:5][CH2:4][O:3][C:2]4=[O:1])=[CH:16][CH:15]=3)=[O:14])[CH2:29][CH2:30]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: O=C(O)c1ccc(N2CCCOC2=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCOC4=O)cc3)CC2)c(C)c1
Yield: 86.4 %

Procedure:
Using 4-(2-oxo[1,3]oxazinan-3-yl)benzoic acid (111 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (96 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (171 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.C([O:27][C:28](=[O:44])[CH2:29][CH:30]([NH:42][CH3:43])[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)C.[OH-].[Na+].Cl>COC(C)(C)C.CO>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:42]([CH:30]([CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)[CH2:29][C:28]([OH:44])=[O:27])[CH3:43])=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(Cc1ccc2ccccc2c1)NC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: COC(C)(C)C
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)Cc1ccc2ccccc2c1
Reaction time: 12 h

Procedure:
25.3 g (91.4 mmol) of 3,5-bistrifluoromethyl-benzoyl chloride followed by 13.3 ml (95.6 mmol) of triethylamine are added dropwise over a period of 5 minutes to a solution of 22.5 g (83.1 mmol) of 3-methylamino-4-(2-naphthyl)-butanoic acid ethyl ester in 500 ml of tert-butyl methyl ether. After 12 hours at room temperature, 16.6 g (415 mmol) of sodium hydroxide dissolved in 150 ml of methanol are added over a period of 10 minutes and the mixture is stirred for 5 hours. Then, at 0° C., 275 ml of 2N hydrochloric acid are added and the mixture is washed with 300 ml of ethyl acetate. After concentration in a rotary evaporator, the title compound crystallises out from tert-butyl methyl ether/hexane in the form of white needles. M.p.: 128-130° C.; IR: 3400-2500 (b), 1710, 1635 cm1 ; 1H-NMR, 200 MHz, CDCl3, delta, (ppm): 7.9-6.93 (m, 10H), 5.01, 4.30 (2m, rotamer, 1H), 3.9-2.6 (m, 4H), 3.18, 2.68 (2s, rotamer, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:13]([SH:17])[CH2:14][CH2:15][SH:16].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[S:17][CH2:13][CH2:14][CH2:15][S:16]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: SCCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2SCCCS2)cc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
74.7 g of 3,4-dimethoxybenzaldehyde are dissolved in 1250 ml of chloroform, treated with 50 ml of 1,3-propanedithiol and cooled at 0° C with stirring. 20 ml of boron trifluoride etherate are added and the mixture is left to stand in a refrigerator for 18 hours. The mixture is then washed three times successively with 500 ml of a 7% potassium hydroxide solution and 500 ml of a 10% sodium chloride solution. The organic extracts are combined, dried over magnesium sulphate and evaporated. The residue is recrystallized twice from ether. There are obtained 102.6 g of 2-(3,4-dimethoxyphenyl)-m-dithiane of melting point 99° - 101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-])=O)=[C:5]([NH:9]C)[CH:6]=[CH:7][CH:8]=1.[C:14](OCC)(=O)C>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:4]=1[NH:11][CH3:14]
Reactant: CNc1cccc(OC)c1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CNc1c(N)cccc1OC
Reaction time: 4.5 h

Procedure:
7.4 g (3-methoxy-2-nitrophenyl)-methylamine are suspended in 150 ml of ethyl acetate and hydrogenated with 1 g Pd/C 10% at a pressure of 50 psi and at ambient temperature. After 4.5 hours the catalyst is suction filtered and the filtrate is evaporated to dryness. 5.9 g of the product are obtained as an oil.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH:22]=[CH:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[C:31]#[CH:32]>CN(C)C=O.O>[C:31]1([C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH:32]=[N:14][N:15]2[CH:20]=[CH:19][C:18]3[O:21][CH:22]=[CH:23][C:17]=3[C:16]=12
Reactant: N[n+]1ccc2occc2c1
Reactant: C#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn2ccc3occc3c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
To a mixture of 5-aminofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (1.00 g, 3.14 mmol) and potassium carbonate (608 mg, 4.40 mmol) in dimethylformamide (20 mL) was added ethyl propiolate (350 μL, 3.45 mmol) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→440/60) to give the title compound (451 mg, yield 62%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1.[OH-].[Na+]>ClCCl.CO>[CH2:30]([O:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl 4-aminobenzoate in dichloromethane and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:10]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CNC>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:17][CH2:18][C:19]([N:24]([CH3:25])[CH3:22])=[O:21])[C:10]3=[N:15][CH:14]=[CH:13][CH:12]=[C:11]3[N:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5]pyridine-3-propanoic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for one hour with nitrogen bubbling through it and then refluxed for one hour under a nitrogen atmosphere. The solution which had formed was cooled and a solution of dimethylamine in tetrahydrofuran (21.4 ml of 2.3M solution, 0.05 mole) was added. The reaction mixture was stirred at room temperature under nitrogen overnight. The solvent was removed under reduced pressure and the resulting oil was partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the suspended solid was removed by filtration. The aqueous layer was extracted once more with ethyl acetate (100 ml) and the combined organic layer was washed once with a 5% potassium hydroxide solution (100 ml). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 6.3 g of crude product. Attempts to crystallize the pure free base failed (due to imidazole contamination and trapping of solvents by the solid). The impure product, after triturations in water to remove imidazole, was dissolved in hot isopropyl alcohol, filtered while hot and acidified with hydrogen chloride in isopropyl alcohol. Isopropyl ether was added to precipitate the solid. Filtration and drying under high vacuum gave 1.84 g of the title compound, mp. 203°-205° C.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(N(CC)CC)C>C(O)C>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[4-(bromo)butyl]phthalimide (6.21 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour and heated at reflux for 45 minutes. After the solvent was distilled off, chloroform was added to the residue, which was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.50 g of the desired product (64.1%, pale yellow crystals).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[CH:17][N:16]=[C:15]([NH2:21])[C:14]=2[N:13]=[C:12]1[CH2:22][O:23][CH2:24][CH3:25].C(N(CC)CC)C.C(Cl)(Cl)Cl>[OH-].[Na+]>[NH2:21][C:15]1[C:14]2[N:13]=[C:12]([CH2:22][O:23][CH2:24][CH3:25])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:19]=2[C:18]([CH3:20])=[CH:17][N:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (4 eq) was added dropwise to a mixture of 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine (2.25 g, 8.11 mmol), triethylamine (10.2 mL, 73.0 mmol) and chloroform (225 mL). The solvent was removed under reduced pressure to provide an oil. The oil was dissolved in 10% sodium hydroxide (200 mL) then extracted with chloroform (3×300 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure to provide a clear oil. The oil was purified by column chromatography (silica gel eluting with 90/10 dichloromethane/methanol) to provide a white solid. This material was dried overnight under vacuum at 80° C. to provide 0.71 g of N-{4-[4-amino-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamide as a white solid, m.p. 173-175° C.