Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[CH:9]=2.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:29](I)[CH3:30].CCOCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6](=[O:17])[N:7]([CH2:29][CH3:30])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[CH:9]=2
Reactant: COC(=O)Cc1cc2ccc(OC)cc2[nH]c1=O
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(OC)cc21
Yield: 79.9 %

Procedure:
A slurry of (7-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester (5.0 g, 20 mmol) in tetrahydrofuran (40 mL) was treated with potassium bis(trimethylsilyl)amide (0.5 M in toluene, 41 mL, 21 mmol) at 25° C. and the mixture heated to reflux. After 1 h at reflux, ethyl iodide (16 mL, 200 mmol) was added. After an additional 3 h at reflux, the cooled mixture was quenched with 0.1N aqueous HCl (50 mL) and concentrated in vacuo. Water (200 mL) was added and the aqueous phase extracted with chloroform (3×200 mL). The extracts were dried (K2CO3) and concentrated in vacuo to give the crude product (5.3 g). Flash chromatography (225 g silica; 2:1, then 1:1 hexane-ether, then 100% ether) gave the title compound (4.4 g, 79% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4]([Cl:15])[N:3]=1.[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:16])[C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4]([Cl:15])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(CCO)c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCO)c2nc(N)nc(Cl)c21
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one obtained in step 2 (13 g, 56.7 mmol), K2CO3 (11.5 g, 84 mmol), methyl iodide (12 g, 85.15 mmol) and DMF (130 ml) were stirred at 25-30° C. for 16 hours. The reaction mixture was concentrated and purified by column chromatography using 60-120 silica gel and 4% methanol in DCM as an eluent to obtain 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one (8 g, 58%) as an off white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)[CH2:19][CH3:20]>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(CCC)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.6 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.5 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 2.5 mmol) and allowed to stir for 10 min at RT. 2-Propyl-5-vinyl-pyridine (0.18 g, 0.5 mol) was added and stirred for further 15 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.015 g, 9% yield). 2,8-Dimethyl-5-[2-(6-propyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.015 g, 0.043 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.006 g, 0.043 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.008 g, 42% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(O)C.[BH4-].[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH2:4][CH:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)Cc1ccc(Br)cc1F
Yield: 95.7 %

Procedure:
Using 1.02 g of 2-fluoro-4-bromobenzaldehyde, 0.33 g of malononitrile, 8 ml of ethanol, 1.5 ml of water and 57 mg of sodium borohydride, and according to the process described in the REFERENCE PRODUCTION EXAMPLE 19, there was obtained 1.21 g of (2-fluoro-4-bromobenzyl)malononitrile (the intermediate (29)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:28][C:27]([CH3:30])([CH3:29])[CH:26]=[CH:25][C:6]2=[C:7]2[C:16]=1[C:15](=[O:17])[C:14]1[CH:13]=[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]3=[C:10]([N+:22]([O-:24])=[O:23])[C:9]=1[NH:8]2.[H-].[Na+].I[CH3:34]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:28][C:27]([CH3:30])([CH3:29])[CH:26]=[CH:25][C:6]2=[C:7]2[C:16]=1[C:15](=[O:17])[C:14]1[CH:13]=[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]3=[C:10]([N+:22]([O-:24])=[O:23])[C:9]=1[N:8]2[CH3:34]
Reactant: COc1cc2c(c3[nH]c4c([N+](=O)[O-])c5ccccc5cc4c(=O)c13)C=CC(C)(C)O2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4c([N+](=O)[O-])c1n3C)C=CC(C)(C)O2

Procedure:
To a solution of 300 mg of the compound obtained in Step 5 in 30 ml of dimethylformamide there are added 1.48 g of sodium hydride and then 1.8 ml of iodomethane. The reaction mixture is refluxed, under argon, for 3 days, and is then slowly hydrolysed by the addition of ice. The precipitate formed is filtered off and then dried and is chromatographed over silica gel (dichloromethane/methanol: gradient from 0.1 to 0.5%), allowing the expected product to be isolated.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17]CC)=O)[CH2:4][NH:3][CH2:2]1.Cl.[CH3:21][NH2:22].CN>C1COCC1>[CH3:21][NH:22][C:15]([CH:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][NH:3][CH2:4]1)=[O:17]
Reactant: CN
Reactant: CCOC(=O)C1CNCCc2c1[nH]c1ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)C1CNCCc2c1[nH]c1ccccc21
Temperature: 80 °C
Yield: 65.8 %

Procedure:
Ethyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (1.29 g, 5 mmol; European Patent No. EP 064 317 B1) and methylamine hydrochloride (0.67 g, 10 mmol) were added to a solution of methylamine in THF (2 M, 15 mL) and the suspension was heated to 80° C. in a sealed tube under nitrogen stirring for 72 hours. Solvent was evaporated to give a crude product, which was purified by chromatography on silica gel eluting with MeOH-DCM (1:9 to 1:4) to give the title compound (0.8 g); 1H-NMR (CDCl3): δ 8.46 (1H, br s), 8.24 (1 H, s), 7.48 (1H, d)), 7.30 (1H, d), 7.16 (1H, m), 7.10 (1H, m), 3.70 (1H, d), 3.66 (1H, dd), 3.46 (1H, dd), 3.08 (2H, m), 2.87 (2H, m), 2.73 (3H, d), 1.9 (1H, br s); MS (ES): 244 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH:19][C:20](N)=[O:21])=[O:18].C(N(C(C)C)CC)(C)C.C([O-])(=O)CCC([O-])=O>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:20]([NH:19][C:17]([C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)=[O:18])=[O:21])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: NC(=O)NC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])CCC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(NC(=O)c1ccco1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 14b, from 3-aminoquinuclidine dihydrochloride (1.0 g, 5 mmol), 2-furoylurea (0.77 g, 5 mmol), and diisopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml). The product (0.58 g) was converted to the 1:1 succinate mp 156°-159° C.
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:3]=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:5][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:1])[CH2:3][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCNC1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CN2CCCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (22 mg), pyrrolidine (0.02 ml), acetic acid (0.01 ml) in methylene chloride (1 ml) was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (28 mg) was added. The mixture was stirred at room temperature for at least two days. The mixture was quenched with diluted NaOH and extracted with methylene chloride. The organic layer was separated, concentrated to dryness and the residue was purified by silica gel column chromatography using 35% to 65% ethyl acetate in hexane as eluent to give the title compound. The title compound was prepared as the corresponding HCl salt by adding HCl/doxane, followed by concentration to give a solid. LC_MS retention time 2.0 min M+1=480.0.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:4].C(O)C.[C-:16]#[N:17].[Na+]>O>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([CH2:2][C:16]#[N:17])=[O:4]
Reactant: [C-]#N
Reactant: COc1ccccc1C(=O)CBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C(=O)CC#N

Procedure:
A 10.0 g. portion of α-bromo-o-methoxyacetophenone is suspended in 50 ml. of ethanol. A solution of 6.4 g. of sodium cyanide in 30 ml. of water is added as described in Example 8. Following the procedure of Example 8, there is obtained o-methoxybenzoylacetonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:25][C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 2-bromoacetophenone (25 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 7 mg of white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:29])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>ClCCl.CO>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: OC1CCN(c2ccnc(Cl)n2)CC1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Nc2nccc(N3CCC(O)CC3)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 1-(2-chloropyrimidin-4-yl)-4-piperidinol (120 mg, 0.534 mmol) and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (109 mg, 0534 mmol) using in analogous manner the procedure described in example 43b). Obtained after trituration in dichloromethane/methanol (19:1 v/v) as a white solid (117 mg, 57%). MS ISP (m/e): 381.1 [(M+1-1)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.24 (s, 1H), 7.97 (d, 1H), 7.84 (d, 1H), 7.63 (s, 1H), 7.26 (dd, 1H), 7.18 (d, 1H), 7.03 (s, 1H), 6.31 (d, 1H), 4.77 (d, 1H), 4.07 (m broad, 2H), 3.78 (s, 3H), 3.77 (m, 1H), 3.25 (m broad, 2H), 2.14 (s, 3H), 1.78 (m broad, 2H), 1.36 (m broad, 2H). Mp 197-200° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:38][CH2:39][CH2:40][CH3:41])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1>>[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:38][CH2:39][CH2:40][CH3:41])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:2](=[O:3])[O:4][CH2:5][CH:6]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 70.8 %

Procedure:
Using the general method of Example 55, 9-fluorenylmethyl chloroformate (0.085 g, 0.33 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.105 g, 0.33 mmol) to provide 0.125 g of 9H-9-fluorenylmethyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder. Analysis: Calculated for C32H34N6O2+¼H2O: % C, 71.29; % H, 6.45; % N, 15.59; Found: % C, 70.99; % H, 6.35; % N, 15.55.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:15]=[C:16]([CH3:17])[C:10]=3[N:9]=2)=[C:6]([O:24][CH3:25])[N:5]=[C:4]([O:26][CH3:27])[N:3]=1.C(N(CC)CC)C.Cl.[NH2:36][CH2:37][C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=1)[OH:39]>C(#N)C>[Cl:46][C:42]1[CH:41]=[C:40]([CH:38]([OH:39])[CH2:37][NH:36][C:2]2[C:7]([C:8]3[NH:12][C:11]4[CH:13]=[C:14]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[CH:15]=[C:16]([CH3:17])[C:10]=4[N:9]=3)=[C:6]([O:24][CH3:25])[N:5]=[C:4]([O:26][CH3:27])[N:3]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: COc1nc(Cl)c(-c2nc3c(C)cc(N4CCOCC4)cc3[nH]2)c(OC)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nc(NCC(O)c2cccc(Cl)c2)c(-c2nc3c(C)cc(N4CCOCC4)cc3[nH]2)c(OC)n1

Procedure:
To a solution of 2-(4-chloro-2,6-dimethoxy-pyrimidin-5-yl)-4-methyl-6-morpholin-4-yl-1H-benzoimidazole (0.075 g, 0.192 mmol) in acetonitrile (5 mL) was added triethylamine (134 μl, 0.962 mmol) and (S)-2-Amino-1-(3-chloro-phenyl)-ethanol hydrochloride (42 mg, 0.202 mmol). The crude material was purified on silicagel dry colomn using AcOEt: Hex (8:2) to give the title compound as a beige solid. (0.055 g, 55%). HPLC 98%. LCMS 20 (+ESI, M+H+) m/z 525. IR (KBr, cm−1) 3446, 2955, 1595, 1472, 1367. 1H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 11.1 (m, 1H), 7.54 (s, 1H), 7.41-7.28 (m, 3H), 6.87 (d, J=2.0 Hz, 1H), 6.78 (s, 1H) 5.85 (s. 1H), 4.88 (m, 1H), 4.05 (s, 3H), 3.91-3.84 (m, 4H), 3.79-3.77 (m, 4H), 3.73-3.69 (m, 1H), 3.09-3.07 (m, 4H), 2.50 (3H, s). HRMS calcd for C26H29ClN6O4:525.2017; found 525.2008.
Reaction SMILES: [Br:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH3:13])=[CH:9][C:10]=1C)=[O:4].BrC1C(C)=C[C:19]([O:22]C)=NC=1>>[Br:1][CH:2]([CH3:14])[C:3]([C:5]1[C:6]([O:22][CH3:19])=[N:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=1)=[O:4]
Reactant: COc1cc(C)c(Br)cn1
Reactant: COc1cc(C)c(C(=O)C(C)Br)cn1
Product: COc1ccc(C(=O)C(C)Br)c(OC)n1

Procedure:
This compound is prepared analogously to 2-bromo-1-(6-methoxy-4-methyl-pyridin-3-yl)-propan-1-one (Intermediate DA) by replacing 5-bromo-2-methoxy-4-methyl-pyridine with the appropriate starting compound. MS: m/z 274 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCC(=CC#Cc3cccc(C)n3)CC2)cc1
Yield: 64.6 %

Procedure:
A solution of the Compound of Example 3 (60 mg, 0.283 mmol), p-toluenesulfonyl chloride (80.9 mg, 0.425 mmol), TEA (0.425 mmol) in 5 mL of CHCl3 was stirred at r.t. for 1 h. The chloroform solution was washed with NaOH 0.1 N, water, dried over Na2SO4 and evaporated to dryness in vacuo. Purification by flash chromatography (EtOAc—Petroleum Ether 1:1), afforded 67 mg of the title product.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].C([CH:16]1[C:29](=[O:30])[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[CH:23][CH:22]=[N:21]3)[N:18]=[CH:17]1)(O)=O>CN(C=O)C>[N:8]1([C:1]([CH:16]2[C:29](=[O:30])[C:28]3[C:19](=[C:20]4[C:25](=[CH:26][CH:27]=3)[CH:24]=[CH:23][CH:22]=[N:21]4)[N:18]=[CH:17]2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(O)C1C=Nc2c(ccc3cccnc23)C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1c2ccc3cccnc3c2N=CC1C(=O)n1ccnc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
1,1'-Carbonyldiimidazole (30.4 g) was added to a stirred mixture of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline (18 g) and DMF (400 ml). The mixture was stirred at 100° C. for 2.5 hours, and then cooled to ambient temperature. The resulting solid was filtered to give 3-(imidazol-1-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline in 92% yield.
Reaction SMILES: OCCN[N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH2:24])[CH3:20].O1CCOCC1>O>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH:24][N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1)[CH3:20]
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCCO)S1
Reactant: CCOC(CN)OCC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(CNN1NC=C(c2ncc([N+](=O)[O-])n2C)S1)OCC

Procedure:
A mixture composed of 9.8 g. of 2-(2-chloro-5-thiadiazole)-1-methyl-5-nitroimidazole, (Example 16), 11.0 g. of 2,2-diethoxyethylamine, and 250 ml. of dioxane is stirred and heated on the steam bath for 12 hours. It is then diluted with 500 ml. of cold water, cooled, and the precipitated yellow solid collected and dried. Recrystallization from 50% aqueous ethanol gives the pure compound melting at 154°-155° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1.C(O)(=O)C>O>[O:1]=[CH:2][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCCC3OCCO3)cc2)S1
Solvent: O
Solvent: CC(=O)O
Product: O=CCCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 40.4 %

Procedure:
A solution of 6.30 g of 5-{4-[2-(1,3-dioxolan-2-yl)ethoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Preparation 106) in 50 ml of a 4:1 mixture of acetic acid and water was stirred at 60° C. for 6 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.20 g of the title compound, melting at 48-51° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[Br:11][CH2:12][C:13](Br)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:11][CH2:12][C:13]1[S:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COc1ccc(N)c(S)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2nc(CBr)sc2c1

Procedure:
7.75 g (50 mmol) of 2-amino-5-methoxy-thiophenol are dissolved in 150 ml methylene chloride and 14.1 g (70 mmol) of bromoacetylbromide are added whilst cooling with ice. Then the mixture is heated for 1 hour to reflux temperature. After cooling solid potassium carbonate is added until foaming ceases, the mixture is filtered and the filtrate is evaporated down. The evaporation residue is purified by column chromatography on neutral aluminium oxide (eluant: petroleum ether/ethyl acetate=3:1). Yield: 6.8 g (52.7 of theory), Melting point: 90-91° C.
Reaction SMILES: [F:1][C:2]([F:7])([CH2:5][OH:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:4][CH2:3][C:2]([F:7])([F:1])[CH2:5][O:6][S:16]([CH3:15])(=[O:18])=[O:17])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)(F)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 5 g (44.6 mmol) 2,2-difluoropropane-1,3-diol (prepared as described in J. Med. Chem. 1994, 37, 1857-1864) in DCM (50 mL) was added triethylamine (18.6 mL, 133.83 mmol) and methane sulphonyl chloride (6.9 mL, 89.22 mmol) at 0° C. and stirred for 1 h at 0° C. Thereafter the reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 2,2-difluoropropane-1,3-diyl dimethanesulfonate (9 g, 84%) which was used immediately in the next step.
Reaction SMILES: N[C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:27]([O:26][CH2:25][C:13]1[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:5][C:4]=3[N:3]=[CH:2][C:11]=2[N:12]=1)[CH3:28]
Reactant: OB(O)c1cccnc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOCc1nc2cnc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)OC(C)(C)C
Yield: 51.4 %

Procedure:
tert-Butyl [2-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (21.80 g, 46.94 mmol) and 3-pyridylboronic acid (6.64 g, 54.0 mmol) were coupled according to the method described in Part J of Example 1. Palladium (II) acetate was added as a 5 mg/mL solution in toluene. The reaction was terminated after 4.5 hours, and the work-up procedure described in Part F of Examples 125-135 was followed. The crude product was recrystallized from acetonitrile (12 mL/g) to provide 10.80 g of tert-butyl {2-[2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}carbamate as a white solid.