Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:16])[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[S:26])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:16])[N:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)nc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=S)Nc1ccc(Cl)nc1Cl
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 2-(2,6-dichloropyridin-3-ylamino)-2-oxoacetate (48.92 g, 186.0 mmol) in toluene (380 mL) was added Lawesson's Reagent (75.21 g, 186.0 mmol), and the resulting suspension was stirred at 90° C. for 4 h. The reaction mixture was then cooled to room temperature and filtered through Celite™, washing with 300 mL toluene. The combined filtrates were concentrated in vacuo at 40° C., and the residue was taken up in CH2Cl2 (200 mL) and filtered through a 200 g pad of silica gel, washing with additional CH2Cl2 (4×150 mL). The filtrate was concentrated in vacuo to afford ethyl 2-(2,6-dichloropyridin-3-ylamino)-2-thioxoacetate as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[N:7]=1.[C:12]([O:15][C:16](=O)[CH3:17])(=O)[CH3:13]>CO.CN(C)C=O>[CH2:12]([O:15][CH2:16][C:17]1[NH:11][C:9](=[O:10])[C:3]2[C:2](=[N:7][C:6]([OH:8])=[CH:5][N:4]=2)[N:1]=1)[CH3:13]
Reactant: NC(=O)c1ncc(O)nc1N
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCOCc1nc2nc(O)cnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 2.1 g (0.0136 mole) of 3-amino-5-hydroxy-2-pyrazinecarboxamide [prepared according to E. C. Taylor et al., J. Org. Chem. 1975, 40, 2341], 14.0 g (0.068 mole) of triethyl orthoethoxyacetate and 14.0 ml of acetic anhydride. Yld: 1.2 g (40%), m.p. 255°-256° C. (methanol/N,N-dimethylformamide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2.[I-].[N:24]1([C:30](N2C=C[N+](C)=C2)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([O:17][C:30]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:31])[CH:10]=2
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Reactant: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(OC(=O)N3CCOCC3)ccc12

Procedure:
The title compound was prepared from 3-(3,4-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(morpholine-4-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=448 (M+1), Rt: 4.73 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]3)=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](O)=[O:30])[O:26][C:27]=1[Br:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:23]1[CH:24]=[C:25]([C:29]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C:10]3[N:11]=[CH:12][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:9]=3)=[O:14])[CH2:16][C@@H:17]2[CH3:21])=[O:30])[O:26][C:27]=1[Br:28]
Reactant: C[C@H]1CN(C(=O)c2ncn(-c3cccc(F)c3)n2)CCN1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)c2ncn(-c3cccc(F)c3)n2)CCN1C(=O)c1cc(Br)c(Br)o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 87 mg (0.30 mmol) [1-(3-fluoro-phenyl)-1H-[1,2,4]triazol-3-yl]-((S)-3-methyl-piperazin-1-yl)-methanone, 84 mg (0.30 mmol) 4,5-dibromo-2-furoic acid, 0.11 g (0.33 mmol) TBTU and 80 μL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.CN.C(Cl)CCl.C[CH2:22][N:23](C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH3:22])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
2-Amino-3-nitro-benzoic acid (1.8 g, 9.9 mmol) and methylamine hydrochloride (1.33 g, 19.8 mmol), were stirred in dry CH2Cl2 (30 ml)/DMF (5 mL) at 0° C. EDC (2.83 g, 14.8 mmol) and DIEA (4.92 mL, 27.7 mmol) were added, and the solution stirred 3 h while warming to r.t. The reaction was concentrated in vacuo and purified by silica gel chromatography (8% MeOH/CHCl3) to give 1.42 g (74%) of 2-amino-N-methyl-3-nitro-benzamide as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (br s, 1H), 8.23 (br s, 2H), 8.15 (dd, 1H, J=8.1, 1.8 Hz), 7.82 (dd, 1H, J=8.1, 1.8 Hz), 6.68 (t, 1H, J=8.1 Hz), 2.76 (d, 3H, J=4.5 Hz). 2,3-Diamino-N-methyl-benzamide. 2-Amino-N-methyl-3-nitro-benzamide (1.4 g, 7.2 mmol) was reduced by hydrogenation using 50 psi of H2 with 10% Pd—C, (250 mg) in EtOAc (25 mL) for 5 h. After filtering through Celite, solvent was removed in vacuo. Purification by silica gel chromatography (10% MeOH/CHCl3) gave 1.08 mg (91%) of 2,3-diamino-N-methyl-benzamide as a faintly yellow solid. 1H NMR (300 MHz, CDCl3) δ6.87 (dd, 1H, J=7.8, 1.5 Hz), 6.76 (dd, 1H, J=7.8, 1.5 Hz), 6.59 (t, 1H, J=7.8 Hz), 6.14 (br s, 1H), 4.28 (br s, 4H), 2.95 (d, 3H, J=5.1 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][S:15]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N[C@@H](CS)C(=O)O
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C2N[C@H](C(=O)O)CS2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
4-Cyanobenzaldehyde (500 mg, 3.8 mmol) was dissolved in 5 ml of ethanol (96%) and L-(+)-cysteine hydrochloride (460 mg, 3.8 mmol) and natriumacetate trihydrate (468 mg, 5.7 mmol) dissolved in 5 ml of water was added. The reaction mixture was stirred for 16 hours at room temperature and the white crystals were collected by filtration and washed twice with 15 ml of water:ethanol (1:1), to afford 400 mg of 2-(RS)-(4-cyanophenyl)thiazolidine-4-(R)-carboxylic acid (48) in 44% yield. 1H-NMR (MEOH, 300 MHz) δ: 7.69 (m, 4H); 5.81 (s, ½H); 5.60 (s, ½H); 4.23 (dd, ½H); 4.02 (dd, ½H); 3.52-3.17 (m, 2H).
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[N:14]=[C:13]([C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:8])[N:14]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1cccc(Br)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cccc(C(c2ccccc2)c2ccccc2)n1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
At 0° C. triethylsilane (0.89 g, 7.7 mmol, 1.3 equiv) was added to compound 2 (2.0 g, 5.9 mmol, 1.0 equiv) in dichloromethane (50 mL). Trifluoroacetic acid (3.36 g, 29.5 mmol, 5.0 equiv) was added dropwise while maintaining the temperature<5° C. The reaction was allowed to warm to room temperature at which point the solution became a yellowish-green color. The reaction was stirred for 18 hr, LC/MS and TLC indicated the reaction was complete. The reaction was carefully quenched with saturated sodium bicarbonate (100 mL). The layers were separated, the organic layer was dried over sodium sulfate and absorbed onto silica gel (5 g) by concentration under reduced pressure. This material was purified on a silica gel column (25 g) by eluting with heptanes (250 mL) and ethyl acetate (2%) in heptanes (250 mL). The desired product was isolated pure in nearly quantitative yield (1.9 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([O:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([CH2:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]([OH:7])=[O:6])[CH:16]=[CH:15][CH:14]=1)=[O:30]
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: CCOC(Cc1cccc(CCOC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:8]=[C:9]([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)[CH:10]=[CH:11][C:12]=1[CH3:13].[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>O1CCCC1.O>[CH3:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)=[CH:8][C:7]=1[B:20]([OH:25])[OH:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nnc(-c2ccc(C)c(I)c2)o1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc(-c2ccc(C)c(B(O)O)c2)o1
Temperature: -10 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 10 mL, 20.0 mmol) was added dropwise over 20 minutes to a stirred solution of 2-(3-Iodo-4-methylphenyl)-5-methyl-1,3,4-oxadiazole (preparation 55c, 4.0 g, 13.3 mmol) in tetrahydrofuran (40 mL) at −10° C. The mixture was stirred for 1 hour at −10° C. then triisopropyl borate (4.71 mL, 20.0 mmol) was added dropwise over 10 minutes and the mixture was stirred for 1 hour at −10° C. Then, the mixture was warmed to room temperature and stirred overnight. Water was then added, the mixture was cooled by means of an ice-water bath and the pH was adjusted to 3-4 with 2M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and the solid was filtered and dried to give the title compound (1.92 g, 66%) as a white solid.
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C(O)(C)C.[C:35]([O:39][C:40]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1Br)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C1C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:35]([O:39][C:40]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:1][Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:21][CH:22]=1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)[Si](OCc1ccc(B(O)O)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 3.2 g (8.2 mmol) of 4-(t-butyldiphenylsilyoxymethyl)phenylboronic acid (Step C) in 64 mL of benzene was added 2.2 mL of water, 6.4 mL of 5 N aqueous sodium hydroxide, and 8.3 mL of isopropanol. To this mixture was added 180 mg (0.16 mmol) of tetrakis(triphenylphosphine) palladium and 2.20 g (7.81 mmol) of N-(t-butoxycarbonyl)-2-bromobenzylamine (Step D). The resulting mixture was heated under nitrogen at reflux for 2 hours then cooled to room temperature. The reaction mixture was diluted with 100 mL of water, transferred to a separatory funnel and extracted with ether (3×150 mL). The combined ether extracts were washed with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL), dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give a crude product which was purified by column chromatography on silica gel eluting with hexanesthyl acetate (9:1) to afford 4.31 g (100%) of the product as a clear oil. 1H NMR (200 MHz, CDCl3): δ 1.11 (s, 9H), 1.41 (s, 9H), 4.27 (d, 6 Hz, 2H), 4.45 (m, 1H), 4.81 (s, 2H), 7.20-7.49 (m, 14H), 8.72 (m, 4H). FAB-MS: calculated for C35 H41NO3Si 551; found 552 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[NH:16][CH:17]=[C:18]([C:20]([CH3:28])([CH3:27])[NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(OCC)(=O)C.N1C=CC=CC=1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[NH:16][CH:17]=[C:18]([C:20]([CH3:27])([CH3:28])[NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=1
Reactant: CCOC(=O)NC(C)(C)c1c[nH]c(C=C2C(=O)Nc3ccc([N+](=O)[O-])cc32)c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)NC(C)(C)c1c[nH]c(C=C2C(=O)Nc3ccc(N)cc32)c1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a suspension of 5-nitro-3-[(4-(dimethylethoxycarbonylaminomethyl)-pyrrol-2-yl)methylene]indolin-2-one (0.8 g, 2 mmol) in ethyl acetate/pyridine (60 mL/9 mL) was added tin (II) chloride dihydrate and the reaction mixture was refluxed for 1.5 hours. The reaction mixture was cooled to ambient temperature, filtered through celite and the filtrate was partitioned in water and ethyl acetate. The organic layer was washed with water and filtered again through celite. The organic layer was then washed with brine, and concentrated to afford 5-amino-3-[(4-(dimethylethoxycarbonylaminomethyl)pyrrol-2-yl)methylene]indolin-2-one as a red colored solid (0.68 g); 1H NMR (400 MHz, DMSO) δ 1.38 (s, 9H), 2.62 (s, 3H), 4.0 (d, 2H), 4.64 (s, 2H), 6.42 (d, 1H), 6.58 (d, 1H), 6.82 (s, 1H), 7.0 (s, 1H), 8.08 (m, 2H), 10.52 (s, 1H) ppm. Hydrolysis under standard conditions yielded 5-amino-3-[(4-(aminomethyl)pyrrol-2-yl)methylene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 2.66 (s, 3H), 4.00 (m, 2H), 6.50. (dd, 1H), 6.64 (d, 1H), 7.08 (s, 1H), 7.26 (s, 1H), 7.38 (s, 1H), 8.06 (brs, 1H), 10.18 (s, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([NH2:17])=O)([O-:3])=[O:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]#[N:17])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(N)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C#N

Procedure:
A finely powdered mixture of 15.5 grams (0.051 mole) of 3,5-dinitro-4-chloro-o-toluamide is heated with 12 grams (0.084 mole) of phosphorus pentoxide for 15 minutes at 300° C. to 350° C. The resulting nitrile is distilled from the reaction flask. Recrystallization of the solidified product from methanol gives the desired product as an analytically pure material.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[N:11][CH:12]=1>CC(O)=O.O1CCOCC1>[Br:6][C:7]1[CH:8]=[C:9]2[NH:14][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:13][C:10]2=[N:11][CH:12]=1
Reactant: O=CC1CC1
Reactant: Nc1cc(Br)cnc1N
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Brc1cnc2nc(C3CC3)[nH]c2c1
Yield: 20.9 %

Procedure:
A solution of cyclopropanecarbaldehyde (0.89 g, 12.76 mmol, 1.2 eq), 5-bromopyridine-2,3-diamine x167 (2 g, 10.63 mmol, 1 eq) in AcOH (20 ml) and 1,4-dioxane (40 ml) is heated at 110° C. during 24 hours. After cooling, the solvents are evaporated under reduced pressure. The resulting brown solid is recrystallized in CH2Cl2/hexane (1/1) to yield 0.53 g of 6-bromo-2-cyclopropyl-1H-imidazo[4,5-b]pyridine x168 as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C([O:45][C:46](=[O:58])[CH2:47]CCCCCCCCCBr)C.COC(C)(C)C>[Cl-].C[N+](C)(C)C.C1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:47][C:46]([OH:58])=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCOC(=O)CCCCCCCCCCBr
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: c1ccccc1
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of benzene is cooled to 0° C. At 0° C., 44 g (150 mmol) of 11-bromoundecanoic acid-ethyl ester, dissolved in 50 ml of benzene, is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 20° C. 250 ml of methyl-tert-butyl ether is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/50 ml of water. 60 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for five hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of dichloromethane, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(Cl)Cl.O>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([N:33]([O:34][CH3:35])[CH3:32])=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cis-4-hydroxycyclohexanecarboxylic acid (6 g, 0.042 mol) and EDCI (9.6 g, 0.05 mol, 1.2 eq.) were dissolved in DCM (100 mL) at 0° C. and stirred for 10 min. DIPEA (16 mL, 0.126 mol, 3.0 eq.) and N,O-dimethylhydroxylamine hydrochloride (4.44 g, 0.046 mol, 1.1 eq.) were added to the mixture at 0° C. The mixture was warmed to room temperature and stirred for 15 h., water was added and the mixture was extracted with DCM. The organic layer was concentrated and purified by silica gel column chromatography using DCM/CH3OH (10/1) to give product as a colorless oil (3.685 g, 40%). 1H NMR (400 MHz, CDCl3) δ: 4.01 (s, 1H), 3.70 (s, 3H), 3.18 (s, 3H), 2.72-2.69 (m, 1H), 1.98-1.85 (m, 4H), 1.62-1.55 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9](O)=[N:10][CH:11]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:15][N:14]=[C:13]([CH3:16])[C:8]=2[C:9]([Cl:19])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(O)c2c(C)n[nH]c12
Product: CCOC(=O)c1cnc(Cl)c2c(C)n[nH]c12

Procedure:
22.1 g. of 4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester (0.1 mol.) and 100 ml. of phosphorus oxychloride are refluxed for 10 hours. After this time, the excess phosphorus oxychloride is removed by distillation. The oily residue is poured into 50 ml. of ice water. On neutralization with aqueous ammonia, 4-chloro-3-methyl-1H-pyrazolo[4,3-c]-pyridine-7-carboxylic acid ethyl ester crystallizes and is filtered. Recrystallization yields 12 g. (50%), m.p. 180°.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[CH3:35][Zn]C>O1CCCC1.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>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[N:8][N:7]4[C:2]([CH3:35])=[C:3]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C[Zn]C
Reactant: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 45.8 %

Procedure:
To a solution of ethyl 7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate (90 mg, 0.19 mmol) in tetrahydrofuran (1 mL) was added dimethylzinc (281 μL 2.0 M in toluene, 0.56 mmol) and tetrakis(triphenylphosphine)palladium (21 mg, 0.018 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was quenched with ice water then extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (49:1 dichloromethane:methanol) provided ethyl 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridine-6-carboxylate (40 mg, 45%). 1H NMR (300 MHz, CDCl3) δ 8.34 (d1H), 8.11 (d, 1H), 7.91 (d, 1H), 7.70 (m, 2H), 7.19 (t, 2H), 6.36 (d, 1H), 5.33 (br, 1H), 4.47 (q, 2H), 4.38 (m, 1H), 3.26 (s, 3H), 2.12 (m, 2H), 1.83–1.43 (m, 9H); MS m/z 460 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH3:20][O:21][C:22]1[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[N:30][C:22]=3[O:21][CH3:20])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: COc1ccc(C(=O)Cl)c(OC)n1
Product: COc1ccc(C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)c(OC)n1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2,6-dimethoxynicotinoyl chloride were combined to provide N3-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2,6-dimethoxynicotinamide as an off white powder, m.p. 175.0-177.0° C. 1H NMR (300 MHz, DMSO-d6) 8.21 (s, 1H), 8.11-8.02 (m, 3H), 7.62 (d, J=8.2 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 6.58 (broad s, 2H), 6.46 (d, J=8.3 Hz, 1H), 4.63 (t, J=7.0 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.30 (m, 2H), 1.90 (m, 2H), 1.57 (m, 2H); MS (EI) m/e 420.1909 (420.1910 calcd for C22H24N6O3).