Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[C:6]=2[N:13]=1)[CH3:2].[S:23]([N:33]=[C:34]=[O:35])([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C>C(Cl)Cl>[CH2:1]([C:3]1[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:34]([NH:33][S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:35])=[CH:18][CH:19]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[C:6]=2[N:13]=1)[CH3:2]
Reactant: CCc1nc2c(C)nc(C)cc2n1-c1ccc(CCN)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: CCc1nc2c(C)nc(C)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 41.1 %

Procedure:
To a clean and dry 12 L 3-neck round-bottom flask were charged 2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethanamine (422 g, 1.43 moles) and CH2Cl2 (3.37 L). Tosyl isocyanate (217 mL, 1.43 moles) dissolved in CH2Cl2 (851 mL) was added to the reaction keeping the temperature below 21° C. and was stirred for at least 90 minutes. The reaction was deemed complete by HPLC and activated charcoal (DARCO KB-B, 4.2 g) was added. The resulting slurry was filtered through a 0.5-micron filter into a speck free 5 L 3-neck round-bottom flask and the filter washed with CH2Cl2 (421 mL). The reaction was atmospherically concentrated to a minimum stirable volume and displacement continued with speck freed acetone until an internal temperature of 58° C. to 62° C. was achieved and final volume was ˜1.3 L. The reaction was cooled to at least 30° C. and seed of N-[({2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide Polymorph Form A was added. The reaction was allowed to granulate between 20° C. and 25° C. for at least 10 hours. After cooling reaction to 0° C. to 5° C. and granulating for at least 2 hours, the reaction was filtered on a speck free filter. The solids were washed two times with speck free acetone (1.68 L) cooled to 0° C. to 5° C. The wet-cake was returned to a speck free 12 L 3-neck round-bottom flask and speck free ethyl acetate (4.4 L) was added. The slurry was heated to at least 75° C. and held for at least 2 hours. The reaction was cooled to at least 30° C. and the solids were filtered on a speck free filter. The solids were washed with speck free ethyl acetate (1.6 L). The wet-cake was returned to the same speck free 12 L 3-neck round-bottom flask and speck free ethyl acetate (4.4 L) was added. The slurry was heated to at least 75° C. and held for at least 2 hours. The reaction was cooled to at least 30° C. and the solids were filtered on a speck free filter. The solids were washed with speck free ethyl acetate (1.6 L). The product was dried at 45° C. to 50° C. for at least 24 hours to yield 289 g the title product, Polymorph Form A (41.4% yield, 98.68% purity by HPLC).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[CH2:28](O)[CH3:29].O>>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)[O:18][CH2:28][CH3:29])[CH:12]=[C:11]([CH3:27])[C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CCO
Reactant: CSc1ccc(C(O)CCc2cc(C)c(OC(C)(C)C(=O)O)c(C)c2)cc1
Solvent: O
Product: CCOC(CCc1cc(C)c(OC(C)(C)C(=O)O)c(C)c1)c1ccc(SC)cc1

Procedure:
This compound was prepared following the general procedure E, using 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-hydroxypropyl]phenoxy]-2-methylpropanoic acid at reflux in a 2/3:1/3 ethanol/water mixture for 72 hours;
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2S(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
Into a suspension of methyl 7-[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (327.4 mg) in THF/methanol (4/2 ml) was added at room temperature an aqueous solution (1.0 ml) of potassium carbonate (240 mg), and the resulting mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, 1 N hydrochloric acid (5 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (241 mg) as light yellow crystals.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Br:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:12][CH:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[CH:9]=2>>[Br:5][C:6]1[N:7]([CH2:3][CH2:2][C:1]#[N:4])[C:8]2[C:13]([C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:12][CH:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[CH:9]=2
Reactant: C=CC#N
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCC#N)c2c1
Temperature: 100 °C
Yield: 71.5 %

Procedure:
Acrylonitrile (10 mL of 1.52 M in 1,4-dioxane, 30.4 mmol) was added to methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (840 mg, 2.5 mmol) in a microwave vial. The vial was sealed and Triton® B (500 □L1.1□mol) was added via syringe. The vial was heated in a microwave apparatus for 1 hr at 100° C. The solution was cooled and poured to precipitate the crude product. The granular solid was collected, washed with water and dried. Recrystallization from ethanol gave the product as a colorless solid (696 mg, 74%). MS m/z 390 (MS+); 1H NMR (300 MHz, DMSO-D6) δ ppm 1.27–1.49 (m, 3 H) 1.60–2.01 (m, 7 H) 2.77–2.90 (m, 1 H) 2.98 (t, J=6.40 Hz, 2 H) 3.87 (s, 3 H) 4.62 (t, J=6.59 Hz, 2 H) 7.67 (dd, J=8.42, 1.46 Hz, 1 H) 7.83 (d, J=8.42 Hz, 1 H) 8.25 (s, 1 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:28]1[CH2:29][CH2:30][C:25]([F:31])([F:24])[CH2:26][CH2:27]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Reactant: FC1(F)CCNCC1
Product: O=C(O)c1c(N2CCC(F)(F)CC2)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and 4,4-difluoro-piperidine. Yellow foam. MS (ESI): 437.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:5]2C.[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH2:32]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])=[C:5]2[NH:32][CH2:31][CH:30]([O:33][CH3:34])[O:29][CH3:28]
Reactant: COC(CN)OC
Reactant: Cc1c(C(=O)C(C)C)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)c(OS(=O)(=O)O)c12
Product: COC(CNc1c(C(=O)C(C)C)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12)OC
Yield: 73 %

Procedure:
6-Chloro-3-isobutyryl-4-methylsulfoxy-8-trifluoromethyl-2-quinolinone (379 mg, 1 mmol) and 2,2-dimethoxyethylamine (105 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (307 mg, yield: 73%).
Reaction SMILES: C([O:3][C:4]([CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]2[CH:19]=[N:20][CH:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)=[O:5])C.[OH-].[Na+]>CO>[C:4]([CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]2[CH:19]=[N:20][CH:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C=CCCCCCc1cccc2cncn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=CCCCCCc1cccc2cncn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.8 g of 5-(7-ethoxycarbonyl- hept-6-enyl)imidazo[1,5-a]pyridine in 30 ml of methanol is added 15 ml of 1 N sodium hydroxide. The reaction is stirred at room temperature for 3 hours. The methanol is evaporated under reduced pressure and the residue diluted with 30 ml of water and the solution adjusted to pH 7 with 1 N hydrochloric acid. The solution is extracted with 2×50 ml of ethyl acetate. The combined ethyl acetate extracts are dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield 5-(7-carboxyhept-6-enyl)-imidazo-[1,5-a]pyridine melting at 110°-111°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([F:21])[CH:18]=[C:19]([F:20])[C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[F:21][C:17]1[CH:18]=[C:19]([F:20])[C:14]2[O:13][CH2:12][C:11](=[O:22])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCN2C(=O)COc3c(F)cc(F)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5c(F)cc(F)cc54)CC3)nc2N1
Yield: 8.7 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6,8-difluoro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 71) (1 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (220 mg, 1.24 mmol) and sodium cyanoborohydride (130 mg, 2.1 mmol) were reacted as described for Example 21 to give 41 mg (8%) product as a dry film.
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].[CH3:21]C1C=C(C=CC=1[N+]([O-])=O)C(O)=O>>[CH3:21][C:17]1[CH:2]=[C:3]([CH:14]=[CH:15][C:16]=1[N+:18]([O-:20])=[O:19])[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2F)CC1
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
3-methyl-N-(1-methyl-4-piperidyl)-4-nitro-benzamide was prepared in a manner analogous to Intermediate 62 utilising 3-Methyl-4-nitrobenzoic acid, available form Aldrich, as the starting Nitro acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[N+:22]([CH2:25][CH3:26])([O-:24])=[O:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:10])[CH:25]([N+:22]([O-:24])=[O:23])[CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1cccc(Br)c1
Reactant: CC[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C(O)Cc1cccc(Br)c1)[N+](=O)[O-]
Reaction time: 3 h
Yield: 43.8 %

Procedure:
To a solution of 2-(3-bromophenyl)acetaldehyde (5.0 g, 0.025 mol) and DBU (7.6 mL, 0.05 mol) in THF (300 mL), Nitroethane (1.0 g, 0.03 mol) was added at 0° C. over 10 min. The reaction mixture was stirred for 3 h, quenched by the addition of H2O (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with H2O (2×30 mL) and brine (1×20 mL), dried over Na2SO4, filtered and concentrated to afford 1-(3-bromophenyl)-3-nitrobutan-2-ol (3.0 g, 44%) as a yellow oil. MS (ES+) C10H12BrNO3 requires: 273, 275 found: 274, 276 [M+2+H]+(1:1).
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.F[C:21](F)(F)C(OC(=O)C(F)(F)F)=O.C[O-].[Na+].Cl.N1C=CC=CC=1>N1C=CC=CC=1.CO>[NH2:17][C:16]1[N:18]=[C:19]2[C:12]([N:11]=[CH:10][N:9]2[C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[C:13]([O:14][CH3:21])[N:15]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1nc(N)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To 2 mmol of deoxyguanosine, dried by evaporation of pyridine and suspended in 10 mL of dry pyridine was added dropwise 2.3 mL (16 mmol) of trifluoroacetic anhydride, with cooling in an ice both. After ten minutes a suspension of 4.3 g of sodium methoxide in 300 mL of methanol was added dropwise. After a further 24 hrs, the mixture was treated with a solution of pyridine hydrochloride (12 mL of pyridine/4 mL conc HCl). The excess acid was destroyed by addition of 2 g of sodium bicarbonate and the mixture was evaporated to dryness. The residue was dissolved in water and purified on a Dynamax reversed-phase hplc column using a gradient of 2-5% acetonitrile in water in 45 min at a flow rate of 6 mL/min. Evaporation of appropriate fractions gave 0.36 g (60%) of pure 2-amino-6-methoxy-9-(2-deoxy-Beta-D-erythro-pentofuranosyl)purine. A crystalline sample was obtained by crystallization from water, mp 155°-7°. UVmax (MeOH) 281 nm; UVmin 281 nm; 1H NMR (DMSO-d6) delta (ppm) 8.07 (s, 1,H8), 6.43 (br s, 2, NH2), 6.20("t", 1, Japp =6.9 Hz, H1'), 5.27 (d, 1, J=3.8 Hz, 3'-OH), 4.98 (t, 1, J=5.5 Hz, 5'-OH) , 4.35 (m,1,H3'), 4.00 (s, 3, OCH3), 3.82 (m, 1, H4'), 3.53 (m, 2, H5',5'), 2.57 & 2.22 (m & m, 1 & 1, H2' & H2"). Anal. Calcd. for C11H15N5O4.H2O: C, 44.15; H, 5.72; N, 23.40. Found: C, 44.15; H, 5.83; N, 23.43.
Reaction SMILES: [O:1]=[C:2]([CH3:18])[CH2:3][C:4]([O:6][C@@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([Cl:11])([Cl:10])[Cl:9])=[O:5].[Cl:19][C:20]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>C1C=CC=CC=1.C(O)(=O)CCCCC.N1CCCCC1>[Cl:19][C:20]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:3]([C:2](=[O:1])[CH3:18])[C:4]([O:6][C@@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([Cl:9])([Cl:10])[Cl:11])=[O:5]
Reactant: CC(=O)CC(=O)O[C@@H](c1ccccc1)C(Cl)(Cl)Cl
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CCCCCC(=O)O
Product: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)O[C@@H](c1ccccc1)C(Cl)(Cl)Cl

Procedure:
(S)-2,2,2-Trichloro-1-phenylethyl 3-oxobutanoate (8.6 g 27.5 mmoles) and 2,3-dichlorobenzaldehyde (4.82 g, 27.5 mmoles) in dry benzene (100 ml) were heated at reflux for 5 hours with hexanoic acid (25 drops) and piperidine (8 drops) in a Dean and Stark apparatus. The solvent was evaporated and the residue dissolved in ethyl acetate (200 ml), washed with saturated sodium bicarbonate, 2% aqueous sodium bisulphite solution and brine, dried (MgSO4) and the solvent removed in vacuo. The sub-title compound was obtained as a yellow oil. HPLC and nmr indicate 2:1 mixture of geometric isomers.
Reaction SMILES: [N+](C1C=CC=CC=1N)([O-])=O.ICl.C(OC=C(C(OCC)=O)C(OCC)=O)C.[NH2:28][C:29]1[CH:47]=[C:46]([I:48])[CH:45]=[CH:44][C:30]=1[NH:31][CH:32]=[C:33]([C:39]([O:41]CC)=O)[C:34]([O:36]CC)=O.OC1C2C(=C([N+]([O-])=O)C=C(I)C=2)N=CC=1C(OCC)=O.NC1C=C(I)C=C2C=1N=CC(C(OCC)=O)=C2O.[Cl:87][C:88]1[CH:95]=[CH:94][C:91]([CH2:92][NH2:93])=[CH:90][CH:89]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>[NH2:28][C:29]1[CH:47]=[C:46]([I:48])[CH:45]=[C:44]2[C:30]=1[N:31]=[CH:32][C:33]([C:34]([NH:93][CH2:92][C:91]1[CH:94]=[CH:95][C:88]([Cl:87])=[CH:89][CH:90]=1)=[O:36])=[C:39]2[OH:41]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=CNc1ccc(I)cc1N)C(=O)OCC
Agent: CCOC(=O)c1cnc2c(N)cc(I)cc2c1O
Agent: CCOC(=O)c1cnc2c([N+](=O)[O-])cc(I)cc2c1O
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1cc(I)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12

Procedure:
6-Oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamides The preparation of specific examples of heterocycle W1.1 is described in Chart A. 2-Nitroaniline is iodinated with iodine monochloride to afford A.1 (Wilson, et.al., Aust. J. Chem., 1983, 36, 2317-2326) which is heated with diethyl ethoxymethylenemalonate in a mixture of diphenyl ether/biphenyl, initially at 150° C. to generate diethyl 2-[(2-amino-4-iodoanilino)methylene]malonate and then at 240° C. to cyclize this intermediate to ethyl 4-hydroxy-6-iodo-8-nitro-3-quinolinecarboxylate (A.2). Stannous chloride reduction of A.2 affords ethyl 8-amino-4-hydroxy-6-iodo-3-quinolinecarboxylate A.3 which reacts with 4-chlorobenzylamine to give 8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide A.4. Intermediate A.4 reacts with ethyl orthoformate to give N-(4-chlorobenzyl)-8-iodo-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide (A.5). Palladium mediated carbonylation of A.5 in presence of tributyl tin hydride or trioctylsilane (Kotsuki et. al., Synthesis 1996, 470) affords A.6 which is reductively aminated with morpholine and sodium cyanoborohydride to give A.7. Specific examples in which G=3-hydroxypropyl or 3-hydroxy-1-propynyl are prepared as described in Chart B. Palladium catalyzed coupling of A.5 with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) gives B.1 (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. or Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula B.2 (Z=CH2OH).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].C(N(C(C)C)CC)(C)C.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].C(OCC)(=O)C>C(#N)C.Cl.CCCCCCC>[CH2:24]([S:26]([N:6]1[CH2:5][C:4](=[CH:3][C:1]#[N:2])[CH2:7]1)(=[O:28])=[O:27])[CH3:25]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 1000 g, 5.2 mol) was diluted with acetonitrile (7 L) and 3 N aqueous HCl (7 L). This resulting reaction mixture was stirred at room temperature for 18 h. When TLC showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residual solids were then suspended in acetonitrile (12 L) and cooled to 5° C. Diisopropyethyl amine (2.7 L, 15. 6 mol, 3 equiv) was slowly added to the suspension while keeping the temperature<15° C. The homogeneous solution was allowed to cool to 5° C. and ethanesulfonyl chloride (730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the reaction temperature<15° C. The resulting solution was allowed to slowly warm to room temperature and stirred at room temperature for overnight. The additional amount of ethanesulfonyl chloride (100 ml, 1.05 mol, 0.2 equiv) was added and the reaction mixture was stirred for an additional 2 h at room temperature. After the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure to a volume of about 4 L. This solution was then placed in a 50 L separatory funnel, diluted with dichloromethane (10 L) and washed with half saturated brine (10 L). The aqueous phase was extracted with dichloromethane (5 L). The combined organic layers were dried over sodium sulphate and absorbed onto silica gel (1 Kg) under reduced pressure. The material was then loaded onto a silica gel column (2.5 Kg) and eluted with 20% ethyl acetate in heptane (40 L), 40% ethyl acetate in heptane (80 L) and finally 60% ethyl acetate in heptane (40 L) to afford pure 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (4, 567 g, 968.4 g theoretical, 58.6% yield) as a off-white solid. For 4: 1H NMR (300 MHz, CDCl3) δ1.38 (t, 3H), 3.05 (q, 2H), 4.72 (m, 2H), 4.79 (m, 2H), 5.41 (m, 1H); MS: m/z calcd. 187.05. found: 187.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:14]=2)[CH:11]=1)=[CH2:5])C.O.[Br:25]N1C(=O)CCC1=O>O1CCCC1.ClCCl>[Br:25][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:14]=2)[CH:11]=1)=[O:5]
Reactant: C=C(OCC)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 42 %

Procedure:
To a solution of 123 mg of 6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 4 mL of tetrahydrofuran are added 1 mL of water and then, after cooling to 0° C., 71 mg of N-bromosuccinimide. The reaction mixture is stirred for 2.5 hours at room temperature and then diluted with 80 mL of dichloromethane. The organic phase is washed with water and then dried and concentrated to dryness under reduced pressure to give 60 mg of crude 6-(2-bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid (containing small amounts of 6-acetyl derivative and dibromo derivative) that is used without further purification.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:15]=1[C:16](Cl)=O.C[SiH](O)C.C[Si](C)(C)C.C[Si](O)(C)C>ClCCl.O>[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:15]=1[CH2:16][C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Agent: C[SiH](C)O
Agent: C[Si](C)(C)O
Agent: [Al+3]
Solvent: O
Solvent: C[Si](C)(C)C
Solvent: ClCCl
Product: COc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: -3 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A 250 mL of 4-neck flask equipped with an internal thermometer and a condenser were added anisole (5.7 g, 52.0 mmol) and dichloromethane (17 mL) and the mixture was cooled to −3° C. Aluminum (III) chloride (7.4 g, 55.0 mmol) was added to the above solution over 1 h while maintaining the internal temperature below 5° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 0.05 mol) in dichloromethane (15 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. PMHS (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (100 mL) was added slowly dropwise over 1 hour with stirring. Note: A severe exotherm would occur upon addition of the first portion of water. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (30 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was recrystallized from absolute ethanol (58 mL) to give 12.0 g of 1-chloro-4-iodo-2-(4-methoxybenzyl)benzene as a white solid (yield, 67%, HPLC-0002: 98.7%). Note: The purity can be increased by doing a second recrystallization of 1-chloro-4-iodo-2-(4-methoxybenzyl)benzene, HPLC purity could be up to 99.5% with 75˜80% yield. 1H NMR (CDCl3, 400 MHz): δ 7.50 (d, J=8.4 Hz, 2H), 7.10˜7.13 (m, 3H), 6.88 (d, J=8.4 Hz, 2H), 4.00 (s, 2H), 3.82 (s, 3H). MS ESI (m/z): 357 [M+1]+. 13C NMR (CDCl3, 100 MHz): δ 158.3, 141.5, 139.5, 136.6, 134.2, 131.2, 130.6, 129.9, 114.1, 91.71, 55.29, 38.09.