Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([OH:13])(=O)[CH:10]=[CH2:11].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5]3=[C:4]([C:9](=[O:13])[CH:10]=[CH:11][N:6]3[C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]2=3)[CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1ccn2c3ccc(Cl)cc3c3cc(Cl)cc1c32
Yield: 87 %

Procedure:
p-chloroaniline (200 g) was suspended in water (100 ml) and acrylic acid (54.1 ml) was added to the suspension. The mixture was heated under reflux for 2 hours in a nitrogen atmosphere. After allowing to cool, 2 N aqueous solution of sodium hydroxide (500 ml) was added, and the mixture was extracted with ether. The aqueous layer was adjusted to pH 3 with 1 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (137.3g, 87%) was obtained without further purification.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)[CH:3]([CH3:5])[CH3:4].C(N(C(C)C)C(C)C)C.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O>[C:24]([NH:28][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([CH:2]([OH:1])[CH:3]([CH3:4])[CH3:5])[CH:7]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)C(O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C(O)c1cccc(C(=O)NC(C)(C)C)c1
Yield: 82.5 %

Procedure:
A mixture of 3-(1-hydroxy-2-methylpropyl)benzoic acid (677 mg, 3.49 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uronium hexafluorophosphate (1.73 g, 4.54 mmol), N-ethyl-N-isopropylpropan-2-amine (1.21 mL, 6.97 mmol) and tert-butylamine (510 mg, 6.97 mmol) in N,N-dimethylformamide (12.0 mL) was subjected to microwave irradiation at 100° C. for 10 minutes. The reaction mixture was concentrated under vacuum and purified with silica column chromatography (eluting with 9% to 33% ethyl acetate in heptane) to afford the title compound (718 mg). MS (ESI) m/z 250.4 [M+H]+
Reaction SMILES: [C:1]1([C:7]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]([CH3:10])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O.O>[N:17]([CH:9]([CH3:10])[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1OC1(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])C(O)(c1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of 9.35 g (44.5 mmol) 2,2-diphenyl-3-methyloxirane and 9.00 g (138 mmol) NaN3 in 100 ml of 2:1 N,N-dimethylformamide-water was heated at reflux for 72 hours. The solution was concentrated and the residue was partitioned between ether and water. The ether layer was washed with NaHCO3, then water, dried over Na2SO4 and concentrated. HPLC (5% EtOAc-hexane) afforded 7.86 g (70%) of 2-azido-1,1-diphenylpropanol as a clean oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH2:24][CH:23]4[N:25](C(OC(C)(C)C)=O)[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:16])[CH2:11]2)=[N:7][CH:8]=1)#[N:2].[ClH:33].O1CCOCC1>C(Cl)Cl>[ClH:33].[ClH:33].[CH:20]12[NH:25][CH:23]([CH2:22][CH2:21]1)[CH2:24][CH:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][C@@H:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH2:11]1)=[O:16])[CH2:19]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(NC(=O)N1CC[C@@H](Nc3ccc(C#N)cn3)C1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc(N[C@@H]2CCN(C(=O)NC3CC4CCC(C3)N4)C2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl 3-((R)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (49 mg, 0.11 mmol) was dissolved in CH2Cl2 (2.5 mL) and 4 M HCl in dioxane (0.8 mL, 3.2 mmol) was added. The mixture was stirred at rt for 1 h and concentrated to give (3R)—N-(8-azabicyclo[3.2.1]octan-3-yl)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamide dihydrochloride (46 mg, quant).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])[C@@H:5]1[CH2:21][O:22]C(=O)C>CO>[CH3:3][N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])[C@@H:5]1[CH2:21][OH:22]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(OC)c1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A 10% aqueous NaOH solution (596 mL) was added to a solution of the compound of example 3 (241 g, 0.75 mol) in methanol (596 mL). The reaction mixture was stirred at 50° C. for 45 min. It was concentrated to a gum and then poured into ice-cold water (2 L). The resulting solid was filtered to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)=[C:9]([Cl:10])[C:5]=2[CH:4]=1.Cl.[C:30]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38])([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:30]([O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)=[C:9]([Cl:10])[C:5]=2[CH:4]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: FC(F)(F)c1cc(-c2sc3ccc(CBr)cc3c2Cl)ccc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCNCc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 5-bromomethyl-3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene (50 mg, 0.104 mmol) in DMF (1 mL) are added β-alanine tert-butyl ester hydrochloride (19 mg, 1 eq.) and K2CO3 (68 mg, 5 eq.). The mixture is stirred at 50° C. overnight. The mixture is diluted with EtOAc (40 mL), washed with 10% aqueous Na2S2O3, brine, dried over MgSO4, filtered, and concentrated. The mixture is purified by column chromatography (EtOAc/Hexane, gradient) to give 43 mg of 3-{[3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid tert-butyl ester in 76% yield.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.OCC[CH2:30][SH:31]>>[O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:30][S:31][CH2:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: OCCCS
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CSCO4)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.275 mmol) and 3-hydroxypropanethiol (mmol) in at a temperature ° C. for hours in % yield. Mp; 114-116° C., Mass m/z 424.1 (ES+, 100%) for C20H26FN3O4S.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[OH:36][CH:37]1[CH2:40][NH:39][CH2:38]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:39]5[CH2:40][CH:37]([OH:36])[CH2:38]5)=[O:27])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:3]=1
Reactant: OC1CNC1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CC(O)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61B starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61B, Step 2) and 3-hydroxyazetidine hydrochloride (Oakwood, Cat. No. 013898). LCMS (M+H)+: m/z=515.2.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10]
Reactant: N#Cc1cccc(Oc2cc(C(F)(F)F)ccc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cccc(Oc2cc(C(F)(F)F)ccc2CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step (i) (2.0 g) was dissolved in dry ethanol (20 ml) then sodium borohydride (0.15 g) added. The mixture was stirred at RT overnight then evaporated under reduced pressure to give a white solid. The solid was partitioned between 2M hydrochloric acid and ethylacetate, the organics were dried and evaporated under reduced pressure, yield 0.70 g.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10].Cl>C1COCC1.CO>[F:3][C:4]1[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: COCCOc1ncc(C(=O)OC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1ncc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A 5M sodium hydroxide aqueous solution (2 ml) was added to a THF/MeOH (2 ml/2 ml) solution containing methyl 5-fluoro-6-(2-methoxyethoxy)nicotinate (264 mg) obtained in the 2nd step, followed by stirring at room temperature for 1 hour. Next, 6M hydrochloric acid (2 ml) was added to the reaction solution at 5° C. or less so as to acidify the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and a white solid of 5-fluoro-6-(2-methoxyethoxy)nicotinic acid (197 mg) was thus obtained.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH:40]([OH:45])[C:41]([O:43][CH3:44])=[O:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH:40]([OH:45])[C:41]([O:43][CH3:44])=[O:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC
Yield: 25.1 %

Procedure:
To a solution of 30 mg of 2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionic acid and 42 mg of methyl(2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate dihydrochloride in 3 ml of N,N-dimethylformamide were added successively 0.023 ml of diphenylphosphoryl azide and 0.040 ml of triethylamine with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol=5/1 by volume; Rf2 =0.31) to obtain 14 mg of methyl (2RS,3S)-3-{N-[2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>CS(C)=O>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:34][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:29]1
Reactant: Fc1cccc(CNc2cc(C(F)(F)F)cc(-c3ccnc(F)c3)n2)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cc(C(F)(F)F)cc(NCc4cccc(F)c4)n3)ccn2)CC1
Temperature: 105 °C

Procedure:
To 2′-fluoro-N-(3-fluorobenzyl)-4-(trifluoromethyl)-2,4′-bipyridin-6-amine (34 mg, 0.093 mmol) was added DMSO (1.7 ml) and trans-cyclohexane-1,4-diamine (159 mg, 1.396 mmol). The resulting reaction mixture was stirred at 105° C. until completion as indicated by LCMS, about 40 hours. To the crude reaction mixture was added 0.75 ml of DMSO, filtered and purified by prep LC. After lyophilization, 28.1 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 460.3 (MH+), retention time=0.72 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.40-1.72 (m, 4 H) 2.18 (t, J=13.77 Hz, 4 H) 3.11-3.24 (m, 1H) 3.62-3.76 (m, 1 H) 4.72 (s, 2 H) 6.95 (s, 1 H) 7.12 (d, J=9.96 Hz, 1 H) 7.17-7.24 (m, 1 H) 7.27-7.37 (m, 1 H) 7.40 (s, 1 H) 7.42-7.48 (m, 1 H) 7.69 (s, 1 H) 7.87 (d, J=6.74 Hz, 1 H)
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22]Cl)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[CH3:24][S-:25].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][S:25][CH3:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[S-]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCSC
Temperature: 60 °C
Yield: 53.4 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 4.53 mmol), sodium thiomethoxide (0.48 g, 6.80 mmol), and anhydrous dimethyl formamide (18 mL) under a nitrogen atmosphere. The reaction mixture was heated to 60° C. to give a homogeneous solution that was maintained at 60° C. for 16 hours at which time the starting material was completely consumed. The solution was cooled and then partitioned between chloroform and water. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The combined aqueous layers were extracted with chloroform (1×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a dark brown oil. The material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide a light yellow solid. The solid was recrystallized from dimethyl formamide and water to give 2-butyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.83 g, 2.42 mmol) as light yellow needles, m.p. 127-130° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[N:8][C:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[CH2:20](I)[CH3:21]>O1CCCC1>[CH2:20]([N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[N:8]=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18])[CH3:21]
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 4.0 g of sodium hydride (50% dispersion in oil) in 400 ml of anhydrous tetrahydrofuran was added 18.0 g of N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide. The solution was stirred for 0.5 hrs, then 6.4 ml ethyl iodide was added. After stirring for 18 hours, the reaction mixture was treated as described in Example 63 to give 19.8 g of colorless crystals, mp 116°-119° C. Recrystalization from acetone-hexane gave colorless crystals, mp 120°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(OC)c2)c1C(=O)OC
Yield: 122.3 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.1 g, 5.2 mmol) in acetone (45 mL) and potassium carbonate (2.2 g, 15.7 mmol) was added 1-bromomethyl-3-methoxy-benzene (0.77 mL, 5.5 mmol) and refluxed for three hours. The solvent was evaporated and the residue was partitioned between water (50 mL) and ethyl acetate (80 mL) and washed with water (2×50 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-methoxy-benzyloxy)-phthalic acid dimethyl ester (2.1 g, 118% crude yield). The product was used in the next step without further purification.
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[CH:5]=1.[NH3:13]>>[NH2:13][CH2:3][C:4]1[CH:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[CH:5]=1
Reactant: N
Reactant: COC(=O)c1cc(N)nc(N)c1
Product: NCc1cc(N)nc(N)c1
Temperature: 60 °C

Procedure:
A compound of formula I-3 may be prepared as follows: A solution of 2,6-diamino-isonicotinic acid methyl ester (X) is treated for 1 hour with gaseous ammonia. The mixture is heated for 36 hours at about 60° C. in an autoclave and is then filtered through decalite. The obtained 2,6-diamino-isonicotinamide is suspended in THF and boran-dimethylsulfide-complex (or NaBH4) is added. The mixture is refluxed for 4 days. After cooling to room temperature HCl is added and the mixture is neutralized with NaOH, to give 4-aminomethyl-pyridine-2,6-diamine. A solution of this compound in pyridine is treated with a compound of formula XII together with a catalytic amount of 4-dimethylaminopyridine, and stirred for 2.5 hours at room temperature to obtain a compound of formula III. Furthermore, to the obtained solution of a compound of formula III in dioxane is added O-mesitylenesulfonylhydroxylamine and then an aldehyde of formula V. The mixture is heated to about 100° C. and after 2.5 hours KOH in methanol is added. After stirring the mixture at room temperature a compound of formula I-3 is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[N:8][C:7]2=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[CH:5]=1)([O-])=O>CCOC(C)=O.CO.[Pd]>[C:13]1([N:11]2[CH:12]=[C:6]3[C:7]([N:8]=[CH:9][C:4]([NH2:1])=[CH:5]3)=[N:10]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cnc2nn(-c3ccccc3)cc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cnc2nn(-c3ccccc3)cc2c1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A suspension of 3B (350 mg, 1.458 mmol) and palladium (5% wt) on activated carbon (300 mg) in EtOAc(100 mL) and MeOH (200 mL) was stirred under a hydrogen balloon for 1 hour. The reaction mixture was filtered via a pad of Celite. The filtrate was concentrated under reduced pressure to give the title compound as a light brown solid (305 mg, 99% yield). LC/MS (method A): retention time=1.60 min, (M+H)+=211.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:10][CH3:11])[CH:5]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=1)[C:3]([NH:14][NH2:15])=[O:2]
Reactant: COC(=O)c1ccnc(OC)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)NN)ccn1
Temperature: 75 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
2-Methoxy-isonicotinic acid methyl ester (23.0 g, 137 mmol) and hydrazine hydrate (8.95 g, 178 mmol) were dissolved in ethanol and stirred at 75° C. for 12 hours. The reaction mixture was concentrated and the remaining solid was tritiated in hexanes/ether (80:20), filtered and dried to afford the title compound as a solid (18.4 g, 80%).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:22][C:23]([CH3:25])=[O:24]>>[C:1]1([CH:11]=[CH:22][C:23](=[O:24])[CH3:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C=Cc1cccc2ccccc12
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In a 250 ml single neck flask was charged 15.6 g (100 mmoles,1.0 eq) of 1-naphthaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 16.5 g of 4-(1-naphthyl)-3-buten-2-one as a faintly yellow oil in 84.3% yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(O)C>N1C=CC=CC=1>[C:20]([NH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1N
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)Cn1nc(-c2ccc(F)cc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of ethyl 2-(5-amino-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate (6.91 g, 26.3 mmol) in pyridine (62 mL) was added acetic anhydride (3 ml, 31.5 mmol). The reaction was stirred at room temperature for 16 h. Ethanol was added and the mixture was concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 10 to 100% ethyl acetate/isohexane) yielding ethyl 2-(5-acetamido-3-(4-fluorophenyl)-1H-pyrazol-1-yl)acetate as a solid (7.6 g).