Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:2]([C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]([S:23]([CH3:26])(=[O:24])=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:10][CH:9]=1)(=[O:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1ccc(CN(CCCCCCC(=O)O)S(C)(=O)=O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(CN(CCCCCCC(=O)O)S(C)(=O)=O)cc1
Yield: 108.3 %

Procedure:
A solution of 7-{[4-(1-hydroxy-hexyl)-benzyl]-methanesulfonyl-amino}-heptanoic Acid (88 mg, 0.21 mmol) and Dess-Martin reagent (145 mg, 0.34 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 72 h. Sodium thiosulfate solution was added and the reaction mixture was stirred until all solids were dissolved. The aqueous layer was extracted with CH2Cl2 (2×), and the organic solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification by radial chromatography (CH2Cl2 to 5% MeOH/CH2Cl2) provided the title compound (93.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, 2H), 7.43 (d, 2H), 4.40 (s, 2H), 3.15 (t, 2H), 2.95 (t, 2H), 2.85 (s, 3H), 2.28 (t, 2H), 1.71 (m, 2H), 1.50 (m, 4H), 1.15-1.40 (m, 8H), 0.85-0.95 (m, 3H).
Reaction SMILES: C([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([Cl:16])[CH:6]=1)(=O)C.C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>ClCCl>[Cl:16][C:7]1[C:8]([C:9]([NH:33][CH:30]2[CH2:32][CH2:31]2)=[O:11])=[CH:12][C:13]([O:14][CH3:15])=[C:5]([OH:4])[CH:6]=1
Reactant: COc1cc(C(=O)O)c(Cl)cc1OC(C)=O
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CC2)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-acetoxy-2-chloro-5-methoxybenzoic acid (8.6 g, 35.2 mmol) and triethylamine (8.9 g, 88 mmol) in dry dichloromethane (100 ml) was cooled to 0° C. and ethylchloroformate (7.6 g, 70 mmol) was added at such a rate that the temperature stayed below 5° C. After 1 h cyclopropylamine (6.0 g, 105 mmol) was added. After stirring overnight at room temperature the organic phase was washed with water (2×200 ml). Drying over magnesium sulfate was followed by reduction of the solvent volume to half. Petrol ether was added and the product was filtered off. Yield 570 mg, 6.7%, mp 214-216° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cccnc3)c2n1C
Temperature: 140 °C
Yield: 65.4 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 3-pyridylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 min, then heated for 30 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 425 as a white solid (0.066 g, 66%). LCMS (Method K): RT 2.50 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.72-8.64 (2H, m), 8.22-8.03 (1H, m), 7.97-7.90 (1H, m), 7.75-7.65 (2H, m), 7.57-7.53 (1H, m), 7.30 (2H, s), 7.21-7.17 (1H, m), 5.63 (1H, m), 3.19-3.17 (3H, m), 1.58 (3H, d, J=6.72 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:22][OH:23]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:22][OH:23])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Solvent: CCO
Product: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
7.0 g (23.4 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile are stirred at boiling temperature for 1.5 hours together with about 1.0 g of freshly prepared hydroxylamine in 90 ml of ethanol. By cooling, filtering off the precipitated material, washing with ether and drying there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime of melting point 249°-250°. By chromatography of the residue from the mother liquor on silica gel and subsequent crystallization from ethyl acetate there is obtained a second portion of the desired amidoxime.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:28]O)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:50][CH2:28][C:6]1[CH:7]=[CH:8][C:9]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][CH2:21]2)[N:13]=3)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1cc(CO)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reaction time: 1 h

Procedure:
To a nearly clear solution of (3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methanol (0.394 g, 0.977 mmol) and triphenyl phosphine (0.294 mL, 1.27 mmol) in 10 mL DCM at 0° C. was added carbon tetrabromide (0.114 mL, 1.17 mmol) in one portion. The reaction mixture was allowed to stir 1 h, then was treated with 3.5 g silica gel and dried. Purification by silica gel chromatography, 40 g, 0-30% EA/hexanes gave 2-(4-(bromomethyl)-2-nitrophenyl)-5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridine as an orange-yellow solid. MS (ESI) m/z: Calculated: 467.0; Observed: 467.6 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(N(CC)CC)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:31][CH2:30][CH:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[CH2:29][CH2:28]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:12][CH:13]=1
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1NCC1CCN(c2ccncc2)CC1
Yield: 20.2 %

Procedure:
Using a similar procedure to that described in Example 8, Part B, 2-chloro-N-(4-chlorophenyl)pyridine-3-carboxamide (125 mg, 0.47 mmol), 1-(4-pyridyl)piperidin-4-ylmethylamine (90 mg, 0.47 mmol), and triethylamine (0.07 mL) yielded 40 mg (24%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:24]=[CH:23]C=[CH:21][C:13]3=[C:14]([CH:19]=[O:20])[CH:15]=2)[N:10]=[CH:9]1.[NH2:25]C1C2C(=CC=CC=2)C(Br)=CC=1C(OC)=O>>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:24]=[CH:23][N:25]=[CH:21][C:13]3=[C:14]([CH:19]=[O:20])[CH:15]=2)[N:10]=[CH:9]1
Reactant: O=Cc1cc2c(=O)n([C@H]3CCCC[C@@H]3O)cnc2c2ccccc12
Reactant: COC(=O)c1cc(Br)c2ccccc2c1N
Product: O=Cc1cc2c(=O)n([C@H]3CCCC[C@@H]3O)cnc2c2ccncc12

Procedure:
3-[(1S,2S)-2-Hydroxycyclohexyl]-4-oxo-3,4-dihydropyrido[3,4-h]quinazoline-6-carbaldehyde was prepared by the procedure described for the synthesis of 3-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazoline-6-carbaldehyde in Example 2, substituting methyl 5-amino-8-bromoisoquinoline-6-carboxylate for methyl 1-amino-4-bromo-2-naphthoate.
Reaction SMILES: [N+:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]>C(O)(=O)C>[N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: CC(=O)O
Product: Nc1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C
Yield: 84.4 %

Procedure:
Compound 5,6-dinitrobenzo[d][1,3]dioxole (6.0 g, 28.3 mmol) was added to stirred glacial acetic acid (120 mL) under N2 atmosphere. After the mixture was heated to boiling, the heat source was removed and iron powder (4.75 g) added with vigorous stirring. Quick spontaneous boiling occurred, the mixture turned dark and the exothermic reaction subsided (2-5 min). The mixture was refluxed for 10 min and poured into ice/water. The orange-red product was isolated by filtration, dissolved in glacial acetic acid, and the solution filtered while hot. The filtrate was poured into ice-cold water. The orange-red solid product was isolated by filtration and dried to provide compound 6-nitrobenzo[d][1,3]dioxol-5-amine (4.35 g, 84%). LCMS: 183 [M+1]+; 1H NMR (DMSO-d6) δ 6.06 (s, 2H), 6.51 (s, 1H), 7.36 (s, 1H), 7.73 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>COCCOC>[F:21][C:20]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH3:22])=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:35]3[CH:34]=[N:33][N:32]([CH2:31][CH2:30][O:29][CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][O:23]4)[CH:36]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Solvent: COCCOC
Product: Cn1ncc2cc(Cc3cnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nn34)c(F)cc21

Procedure:
6-Chloro-3-(6-fluoro-1-methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazine (Stage 281.2, 268 mg, 849 μmol) was introduced in a microwave reactor together with 1-[2-(tetrahydropyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 410 mg, 1.273 mmol) and DME (5 mL). The mixture was purged with Argon for 5 min. Tetrakis-(triphenylphosphine)-palladium (39.2 mg) and 2 M Na2CO3 (1.528 mL) were added and the mixture was flushed with argon before being sealed. The RM was submitted to microwave irradiation at 150° C. 30 min. The RM was diluted with EtOAc and washed with water, brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 40 g RediSep® silica gel column, DCM/MeOH=100:0->94:6 in 45 min). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound as an oil (tR 1.13 min (conditions 2), MH+=476)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:32][CH2:33][CH3:34])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:31]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:47].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:47][C:9]1[C:8]2[N:31]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:32][CH2:33][CH3:34])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]3)=[CH:12][C:11]=2[N:10]=1
Reactant: CCCn1c(COCC)nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyl 4-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (5.17 g, 10.5 mmol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (3.62 g, 10.5 mmol, based on 50% purity). After 30 minutes, concentrated ammonium hydroxide (50 mL) was added and the mixture was stirred for 30 minutes. p-Toluenesulfonyl chloride (2.00 g, 10.5 mmol) was added in 3 portions and the mixture was stirred for 16 hours. The layers were separated and the organic fraction was sequentially washed with 5% aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Recrystallization from acetonitrile afforded 2.58 g of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a reddish-tan crystalline solid, mp 194-195° C.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[N:19]=1.O>CN(C=O)C>[F:14][CH:2]([F:1])[C:3]1[N:7]([C:18]2[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[N:19]=2)[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COc1cccc2nc(C(F)F)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(Cl)n1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
2-Difluoromethyl-4-methoxybenzimidazole (9.03 g, 45.6 mmol) was dissolved in DMF (100 ml), 60% NaH (1.82 g, 45.6 mmol) was added, and stirred for 30 minutes. The reaction mixture was added to a solution obtained by dissolving 2,4,6-trichloropyrimidine (15.7 g, 92.1 mmol) into DMF (100 ml) while cooling with ice, and stirred on an ice bath for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, precipitated crystals were filtered, and washed well with hexane and ether, then air-dried to afford 2-(2-difluoromethyl-4-methoxybenzimidazol-1-yl)-4,6-dichloropyrimidine (12.3 g, yield 78%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)O[C:5](=O)[C:4]=1[C:15]([O:17][CH3:18])=[O:16].[C:19]1([N:25]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30]C3=O)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:26]=3)[C:5]=2[C:4]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Reactant: COC(=O)c1c(SC)cc(-c2cccs2)oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2cccs2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.8 %

Procedure:
A mixture of methyl 4-(methylthio)-2-oxo-6-(thiophen-2-yl)-2H-pyran-3-carboxylate (282 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 6 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 211 mg of (49%) of methyl 8-(methylthio)-2-phenyl-6-(thiophen-2-yl)-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: F[C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([OH:15])=[O:14].[F:16]C1C=C(F)C=C2C=1CCC2(CC(O)=O)O>>[F:16][C:10]1[CH:2]=[C:3]2[C:7](=[CH:8][CH:9]=1)/[C:6](=[CH:12]/[C:13]([OH:15])=[O:14])/[CH2:5][CH2:4]2
Reactant: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Reactant: O=C(O)CC1(O)CCc2c(F)cc(F)cc21
Product: O=C(O)/C=C1\CCc2cc(F)ccc21
Yield: 68 %

Procedure:
This compound was prepared in an analogous manner to (E)-2-(4,6-difluoro-1-indanylidene)acetic acid in Example 5e by substituting 2-(5-fluoro-1-hydroxy-1-indanyl)acetic acid (14.70 g, 0.069 mol) for 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid. Recrystallization from acetonitrile:2-propanol mixtures gave 9.05 g (68%) of (E)-2-(5-fluoro-1-indanylidene)acetic acid as a white solid: m.p., 240-242° C.;
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCC(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure O and Scheme W using 3,3-diphenyl-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:2].[H-].[Na+].[CH3:16]I.O>O1CCCC1>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([CH:1]=[O:2])[C:4]1=[O:13]
Reactant: CI
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)c(C=O)cc2ccccc21
Temperature: 25 °C

Procedure:
2.7 Grams of 3-formylcarbostyril was dissolved in 150 ml of tetrahydrofuran, then 0.8 g of oil 50%-sodium hydride was added thereto at a room temperature with stirring. Next, 4.5 g of methyl iodide was added dropwise at a room temperature for 3 hours. The reaction mixture was concentrated under a reduced pussure, the residue thus obtained was poured into water and the crystals precipitated were collected by filtration. Recrystallized from ethanol to obtain 1.7 g of 1-methyl-3-formylcarbostyril in the form of yellow-brownish needle-like crystals.
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:7]=1)[CH2:3][C:4]#[N:5].CO>C1COCC1>[NH2:5][CH2:4][CH2:3][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:7]=1)[OH:1]
Reactant: N#CC[C@@H](O)c1cccc(OCC2CCOCC2)c1
Solvent: C1CCOC1
Solvent: CO
Product: NCC[C@@H](O)c1cccc(OCC2CCOCC2)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
BH3-DMS (0.56 g, 7.4 mmol) was added dropwise to a solution of hydroxynitrile (14) (0.65 g, 2.4 mmol) in dry THF (50 mL). The reaction mixture was refluxed 18 h at 65° C. After completion of the reaction (as monitored by TLC) the MeOH (15 mL) was added to the reaction mixture which was stirred at rt for an additional 1 h. The mixture was then concentrated under reduced pressure followed by purification by column chromatography (100-200 silica mesh, 4-6% MeOH in DCM) to give Example 1 as a white solid. Yield (0.75 g, 99%); 1H NMR (400 MHz, DMSO-d6) δ 7.80 (bs, 3H), 7.24 (t, J=8.0 Hz, 1H), 6.89-6.87 (m, 2H), 6.82-6.80 (m, 1H), 5.54 (bs, 1H), 4.65 (bs, 1H), 3.87 (dd, J=11.4, 2.8 Hz, 2H), 3.81 (d, J=6.4 Hz, 2H), 3.37-3.30 (m, 2H), 2.87-2.79 (m, 2H), 2.02-1.96 (m, 1H), 1.88-1.80 (m, 2H), 1.69-1.65 (m, 2H), 1.34-1.27 (m, 2H); RP HPLC tR=1.10 min, 94.5% (AUC); ESI MS m/z 266.27 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[OH:12])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[OH:12]
Reactant: CCc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(N)c(O)c1
Yield: 85.4 %

Procedure:
To a solution of 2-nitro-5-ethylphenol(1 g, 6.4 mmol) in methanol(250 mL) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(750 mg, 91%). 1H NMR (CD3OD): d 6.41-6.17 (m, 3H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCCCCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(CCCCCCl)C(C)=O
Yield: 101.1 %

Procedure:
A mixture of ethyl acetoacetate [VI-1] (260.2 g, 2.0 mol), methyl isobutyl ketone (300 g) and 1-bromo-5-chloropentane [V-1] (311.0 g, 1.68 mol) is heated to 80°-90° C. Thereto is added anhydrous potassium carbonate (300 g), and the mixture is reacted at 80°-90° C. for 12 hours. To the reaction mixture is added potassium carbonate (341.4 g), and the mixture is reacted for additional 6 hours. After completion of the reaction, the methyl isobutyl ketone layer is washed with water, and concentrated under reduced pressure to give crude ethyl 7-chloro-2-(1-oxoethyl)heptanoate [II-1] (398.6 g, content; 70.8%, yield; 72.6%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1)[CH3:50]>CN(C=O)C>[CH2:49]([O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1)[CH3:50]
Reactant: CCOc1ncccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ncccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
DIEA (0.013 mL, 0.077 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-Ethoxy-pyridin-3-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 61% yield: LCMS (ESI) m/z 403 (MH+).