Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:10](=[O:19])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.C(OC(=O)C)(=O)C>O1CCOCC1>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[CH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:10](=[O:19])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1
Reactant: Cc1ccccc1-n1c(C)nc2nccnc2c1=O
Reactant: O=Cc1ccccc1F
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-n1c(C=Cc2ccccc2F)nc2nccnc2c1=O
Yield: 55.4 %

Procedure:
A mixture of fused zinc chloride (0.17 g, 1.25 mmol), dioxane (15 mL), 2-methyl-3-(2-methyl-phenyl)-3H-pteridin-4-one (0.174 g, 0.69 mmol, preparation 8), and 2-fluorobenzaldehyde (0.22 mL, 2.07 mmol), and acetic anhydride 0.195 mL, 2.07 mmol) was refluxed overnight. The reaction was cooled and concentrated. The residual material was partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The layers were carefully shaken and separated. The organic layer was washed with brine, dried and concentrated. The residue was flash chromatographed on silica gel (0.75×4 inches) with elution proceeding as follows: 50% ethyl acetate/hexane (300 mL), forerun; 60% ethyl acetate/hexane (400 mL). 2-[2-(2-Fluoro-phenyl)-vinyl]-3-o-tolyl-3H-pteridin-4-one (0.137 g, 55%) was isolated as a yellow crystalline solid. A sample was recrystallized from ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:4][CH:5]=2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=[N+]([O-])c1cccc(C=Cc2ccccc2)c1

Procedure:
Using the procedure of Example 5 benzyltriphenylphosphonium chloride and 3-nitrobenzaldehyde are reacted to give 3-nitrostilbene which is selected to 3-aminostilbene. The 3-aminostilbene is sulfonylated to give 3-(2'-phenethyl)trifluoromethanesulfonanilide, m.p. 64.5°-66° C.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13].N1CCCCC1>CO>[CH:1](=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:13])[CH3:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC=O
Solvent: CO
Solvent: C1CCNCC1
Product: CC=C1C(=O)Nc2ccccc21

Procedure:
0.85 mL (15 mmol) acetaldehyde were added dropwise to 2.0 g (15 mmol) indolin-2-one and 0.20 mL piperidine in 20 mL methanol. The reaction mixture was refluxed for 3 h and then evaporated down. The residue was triturated in diisopropylether and suction filtered.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][O:10][CH3:11])[C:4](=[O:12])[CH:3]=1.[I:13][C:14]1[N:15]=[C:16]([CH3:19])[NH:17][CH:18]=1>>[CH3:11][O:10][CH2:9][CH2:8][N:5]1[C:4](=[O:12])[CH:3]=[C:2]([N:17]2[CH:18]=[C:14]([I:13])[N:15]=[C:16]2[CH3:19])[CH:7]=[N:6]1
Reactant: COCCn1ncc(Cl)cc1=O
Reactant: Cc1nc(I)c[nH]1
Product: COCCn1ncc(-n2cc(I)nc2C)cc1=O

Procedure:
The title compound, light yellow oil, MS: m/e=361.1 (M+H+), was prepared in accordance with the general method of example 23b from 5-chloro-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 4-Iodo-2-methyl-1H-imidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([SH:10])=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH3:20])=O>>[CH2:20]([S:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[C:18]#[CH:17]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCSc1ccc([N+](=O)[O-])cn1

Procedure:
7 g of 5-nitro-pyridine-2-thiol are suspended in acetone, and 5 g of potassium carbonate are added. There are then added 6 g of 3-bromopropine-1, and, after the exothermic reaction has finished, the reaction mixture is refluxed for about 30 minutes. The solution obtained is poured onto ice, and the precipitate occurring is filtered off. The crude product is purified by recrystallisation from methanol to yield 2-propargylthio-5-nitropyridine, m.p. 98°-99.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:17]=[C:18]=S.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[NH:31][CH3:32])[C:24]([O:26][CH3:27])=[O:25]>>[C:10]([O:9][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[C:3]([NH:17][C:18]2[N:31]([CH3:32])[C:30]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[N:20]=2)[CH:4]=1)=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Product: COC(=O)c1ccc2c(c1)nc(Nc1cc(CNC(=O)OC(C)(C)C)ccc1Cl)n2C

Procedure:
The sub-title compound was prepared from tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (see Example 2d) and methyl 3-amino-4-methylaminobenzoate according to Example 3, step (g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][N:18]([C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][N:18]([C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(C(=O)O)cc1

Procedure:
The titled compound was prepared following the procedure F using ethyl 4-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexanoyl)amino]benzoate and NaOH 5M as a yellow powder (75%). 1H NMR (CDCl3, 300 MHz) δ 8.06 (d, J=8.7 Hz, 2H). 7.42 (s, 2H), 7.40 (s, 2H), 7.16 (s, 2H), 7.13 (s, 21), 4.91 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.09 (t, J=7.5 Hz, 2H), 1.68-1.52 (m, 5H), 1.42-1.29 (m, 2H), 1.27-1.11 (m, 5H), 0.91 (t, J=7.3 Hz, 3H), 0.82 (t, J=7.1 Hz, 3H). M− (ESI): 480.5; M+ (ESI): 482.4. HPLC, Rt: 5.76 min (Purity: 99%).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].COC(=O)C1C=CC(C(OC)=O)=CC=1OC1C=CC=CC=1OC>>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[CH:13][C:4]2[C:3](=[O:22])[C:20]3[C:15]([O:14][C:5]=2[CH:6]=1)=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=3)=[O:9]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2Cl)c1
Agent: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2OC)c1
Product: COC(=O)c1ccc2c(=O)c3cccc(Cl)c3oc2c1

Procedure:
Using an adaptation of the method described in Procedure 15, substituting 2-(2-chlorophenoxy)-terephthalic acid dimethyl ester, 1i for 2-(2-methoxyphenoxy)-terephthalic acid dimethyl ester, 1c, the title compound 5-chloro-9-oxo-9H-xanthene-3-carboxylic acid methyl ester, 2i was obtained. MS m/z (MH+) 289.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccc(F)cc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 39.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.067 g, 0.61 mmol), the title compound (0.023 g, 39%) was obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C@@H:11]1[C@@H:16]([NH2:17])[CH2:15][C@@H:14]2[CH2:18][C@H:12]1[C:13]2([CH3:20])[CH3:19].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[CH3:10][C@@H:11]1[C@@H:16]([NH:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:15][C@@H:14]2[CH2:18][C@H:12]1[C:13]2([CH3:19])[CH3:20]
Reactant: N#Cc1ccccc1F
Reactant: C[C@H]1[C@H]2C[C@@H](C[C@@H]1N)C2(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@@H](Nc2ccccc2C#N)C[C@@H]2C[C@H]1C2(C)C
Temperature: 130 °C

Procedure:
2-Fluorobenzonitrile (100 mg), (1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (380 mg), triethylamine (1.5 mL) were dissolved in anhydrous dimethylsulfoxide (5 mL) and heated at 130° C. overnight. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column purification with 0-5% methanol/dichloromethane to afford the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=O)[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[CH3:27][NH:28][O:29][CH3:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)(Cl)Cl.O>[CH3:30][O:29][N:28]([CH3:27])[C:23]([CH:20]1[CH2:21][CH2:22][N:18]([C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH2:19]1)=[O:25]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
Triethylamine (1.68 mL, 12.0 mmol) was added dropwise to 1-[(benzyloxy)carbonyl]pyrrolidine-3-carboxylic acid (1.00 g, 4.01 mmol), N,O-dimethylhydroxylamine hydrochloride (782 mg, 8.02 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.54 g, 8.02 mmol) and 1-hydroxybenzotriazole (1.08 g, 8.02 mmol) in chloroform (20 mL), and the reaction mixture was stirred at room temperature for 16 hours. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→3/7 (v/v)) to give the title compound as a yellow oil (1.11 g, yield 95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.[C:11](#[N:17])[CH:12]([CH2:14][C:15]#[N:16])[OH:13].N1CCCCC1>CCO>[CH3:10][C:2]1([CH3:1])[CH2:3][C:4](=[O:5])[CH2:6][C:7](=[C:14]([C:15]#[N:16])[CH:12]([OH:13])[C:11]#[N:17])[CH2:9]1
Reactant: N#CCC(O)C#N
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1(C)CC(=O)CC(=C(C#N)C(O)C#N)C1
Yield: 70.7 %

Procedure:
To a stirred solution of dimedone (98.0 g, 700.0 mmol) and malonitrile (46.2 g, 700.0 mmol) in EtOH (400 mL) at r.t. was added piperidine (8.5 g, 9.9 mL, 100.0 mmol) dropwise over 15 minutes. The reaction mixture was then heated to reflux for 3 days before cooling. The solvent was removed in vacuo and the residue was re-dissolved in EtOAc (500 mL) and dried (MgSO4). Filtration and concentration in vacuo gave a black oil that was purified by column chromatography (SiO2, 1:6 MeOH/DCM) to give the title compound as a yellow solid (108.0 g, 82%). δH (DMSO-d6) 8.31 (2H, br. s), 2.51 (2H, t, J 1.8 Hz), 2.30 (2H, s), 1.04 (6H, s). LCMS (ES−) 187.3 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g. 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS116 (MH+-boc)
Reaction SMILES: [NH2:1][CH:2]([C:19]1[C:20]2[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=2[N:22]=[CH:23][N:24]=1)[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[CH3:36]OC(OC)N(C)C>>[CH3:33][Si:32]([CH3:35])([CH3:34])[CH2:31][CH2:30][O:29][CH2:28][N:25]1[C:21]2[N:22]=[CH:23][N:24]3[CH:36]=[N:1][C:2]([CH:3]4[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)=[O:10])[CH2:4]4)=[C:19]3[C:20]=2[CH:27]=[CH:26]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(C(N)C3CCCN(C(=O)OCc4ccccc4)C3)ncnc21
Reactant: COC(OC)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c1ncn1cnc(C3CCCN(C(=O)OCc4ccccc4)C3)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Benzyl 3-[amino(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperidine-1-carboxylate (63 mg, 0.13 mmol) in N,N-dimethylformamide dimethyl acetal (1 mL) was stirred at 170° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in 1,3-dimethylimidazolidin-2-one (1 mL) and stirred at 230° C. for 1.5 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel thin layer chromatography (hexane/ethyl acetate=1/1→1/2 (v/v)) to give a brown oil containing the title compound (45.2 mg). The resulting mixture was used for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].C([O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])C.O>C1COCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16](=[O:15])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: CCOC(=O)c1ccccc1Cl
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 113.7 %

Procedure:
To a solution of (4-chlorophenyl)acetonitrile (15.1 g, 100 mmol) in THF (250 ml) was added NaH (60% dispersion in oil, 8.0 g, 200 mmol) in 3 portions over 5 minutes. To this was added a solution of 2-chlorobenzoic acid ethyl ester (18.3 g, 100 mmol) in THF (50 ml), dropwise over 10 minutes. The mixture was then heated at 60° C. overnight. After cooling to room temperature, water was added (2×10 ml, bubbling observed), and the reaction was concentrated, in vacuo, to ½ volume. The mixture was diluted with water (125 ml) and methylene chloride (125 ml), adjusted to pH=7 with 3 N aqueous HCl, and the aqueous layer separated and extracted with additional methylene chloride. The combined organics were dried (MgSO4) and concentrated, in vacuo, to give a brown oil (33 g) that began to solidify on standing. After stirring the residue overnight in diisopropyl ether (250 ml), the solid product was collected by vacuum filtration to afford, after drying, in vacuo, title product I-3A-1a (15.2 g, 52%) as a tan solid: −ESI MS (M−1) 288.0; 1H NMR (400 MHz, CD2Cl2) δ 7.74 (d, J=8.30 Hz, 1H), 7.60–7.25 (m, 7H), 5.65 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].[N:16]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:16])=[O:15])=[CH:9]2)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reaction time: 0.33 h
Yield: 73.3 %

Procedure:
To a mixture of 7-nitro-1H-indole-2-carboxylic acid (4.40 g), 1H-1,2,3-benzotriazol-1-ol (3.45 g) and N,N-dimethylformamide (80 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (4.90 g) at room temperature, and the mixture was stirred for 20 min and 28% aqueous ammonia (7.8 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (3.21 g, yield 73%) as yellow crystals. melting point 297-298° C. (decomposition).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8]O.[CH2:10]([NH2:17])[CH2:11][S:12]S(O)(=O)=O>C(O)(=O)C>[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][S:12][CH2:11][CH2:10][NH2:17]
Reactant: NCCSS(=O)(=O)O
Reactant: Cc1nc[nH]c1CO
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc[nH]c1CSCCN
Yield: 86.1 %

Procedure:
9.0 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 10.2 g of 2-aminoethanethiolsulfuric acid are heated at reflux for 80 minutes in 50 ml of acetic acid, and the reaction mixture is concentrated, passed through 250 ml of a strongly basic anion exchange resin (trade name: Amberlite IRA-410[OH- ]) and eluted with water. The eluate is concentrated under reduced pressure and dried to yield 8.93 g of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole as an oily product (yield: 86.2%).
Reaction SMILES: [N:1]1([C:7](=[O:9])[CH3:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][N:4]6[CH2:5][CH2:6][N:1]([C:7](=[O:9])[CH3:8])[CH2:2][CH2:3]6)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CC(=O)N1CCNCC1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: CC(=O)N1CCN(Cc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)CC1

Procedure:
The title compound was prepared from 1-piperazin-1-yl-ethanone and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 163-180° C.; LC-MS: 483 (MH+); HPLC RT: 4.24 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[N:26]=2)[CH:12]=[C:13]([C:15]2[S:19][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:17][CH:16]=2)[CH:14]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=2)[CH:12]=[C:13]([C:15]2[S:19][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:17][CH:16]=2)[CH:14]=1
Reactant: CCOC(=O)c1cn2cc(-c3cnc(CC(C)C)s3)cc(-c3ccc(F)cc3F)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cc1ncc(-c2cc(-c3ccc(F)cc3F)c3nc(C(=O)O)cn3c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of ethyl 8-(2,4-difluorophenyl)-6-(2-isobutylthiazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylate (47.7 mg, 0.108 mmol) in MeOH (2 mL) and THF (2 mL) was added 1N NaOH (2 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with EtOAc (10 mL), washed with water (5 mL) and concentrated. The residue was purified by prep HPLC to give a white solid as a TFA salt form (32 mg, 56% yield). LCMS (Conditions C): Tr 3.55 min; (M+H)+=414.29 (100%), 415.37 (20%), 416.26 (10%). 1H NMR, 400 MHz, CDCl3: 8.37 (d, J=1.5 Hz, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.88 (m, 1H), 7.61 (s, 1H), 7.13-7.03 (m, 2H), 2.96 (d, J=7.1 Hz, 2H), 2.18 (m, 1H), 1.06 (d, J=6.6 Hz, 6H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH3:23].[Br:24]C(Cl)(Cl)C(Cl)(Cl)Br>C1COCC1>[Br:24][C:17]1[N:18]([CH3:23])[C:19]2[C:15]([N:16]=1)=[C:14]([Cl:13])[N:22]=[CH:21][N:20]=2
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: Cn1cnc2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1c(Br)nc2c(Cl)ncnc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a dry flask was added diisopropyl amine (1.6 mL, 11.42 mmol) and THF (15 mL). The solution was cooled to −78° C. and n-butyllithium (2.5M in hexanes, 4.5 mL, 11.25 mmol) was added dropwise. After stirring for 10 minutes at −78° C., the solution was warmed to 0° C. and allowed to stir for an additional 10 minutes. The solution was cooled back to −78° C. and 6-chloro-9-methyl-9H-purine (1.5 g, 8.9 mmol) was added as a suspension in THF (20 mL). After stirring for 20 minutes −78° C., 1,2-dibromotetrachloroethane was added (5.7 g, 17.5 mmol), and after an additional 20 minutes the reaction was quenched with the addition of sat. aq. NH4Cl (15 mL). Upon warming to room temperature, the solution was diluted with ethyl acetate (75 mL) and the aqueous layer was discarded. The organics were washed with brine and dried using magnesium sulfate. The solvent was removed in vacuo to provide a brown solid that was purified by column chromatography (25-50% ethyl acetate in hexanes) to yield 1.493 g tan solid product. 1H NMR (400 MHz, DMSO-d6): δ 8.84 (d, J=72.7 Hz, 1H), 3.76 (s, 3H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].C(O)(=O)C.N(OC(C)(C)C)=O>>[CH3:23][O:22][C:15]1[CH:14]=[C:13]2[C:12](=[C:21]3[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]3)[NH:11][S:8](=[O:10])(=[O:9])[C:3]1[C:2]2=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2N)c2ncccc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: COc1cc2c(c3ncccc13)NS(=O)(=O)c1ccccc1-2
Yield: 13.1 %

Procedure:
In a similar fashion using route 16 general procedure 31, 2-amino-N-(5-methoxyquinolin-8-yl)-benzenesulfonamide (Intermediate 177) (200 mg, 0.61 mmol), acetic acid (36 mg, 0.61 mmol), tert-butyl nitrite (93 mg, 0.91 mmol) gave the title compound (25 mg, 13%) after purification by column chromatography using silica basified by TEA with DCM/MeOH (1:0-499:1) as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([O:32]CC)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:35])=[C:22]2[CH3:36])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:35])=[C:22]2[CH3:36])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Temperature: 100 °C

Procedure:
A mixture of ethyl 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylate (3.72 g, 7.69 mmol) and NaOH (7.7 mL, 2 N, 15.4 mmol) in EtOH (30 mL) was refluxed at 100° C. for 2 h. The completion of the reaction was monitored by anal. HPLC. The reaction mixture was cooled to rt, then acidified to pH˜4 with 2 N HCl solution. The mixture was evaporated in vacuo to obtain the crude, which was precipitated from water and filtered to obtain the title compound. ESI-MS (m/z): 456 [M+H]+.