Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:24][CH2:25][CH3:26])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:2].[CH2:27]([O:34][C:35](ON1C(=O)CCC1=O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[CH2:27]([O:34][C:35]([N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:24][CH2:25][CH3:26])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(CNCCCCCCOCCCCc1ccccc1)OCC
Solvent: CC(C)=O
Product: CCOC(CN(CCCCCCOCCCCc1ccccc1)C(=O)OCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of 2,39 g (6,55 mmol) N-diethoxyethyl-6-(4-phenylbutoxy)hexylamine in 25 ml acetone is added 1.59 g (7.07 mmol) N-(benzyloxycarbonyloxy)succinimide. After allowing the mixture to stir for 2 hr at room temperature, acetone is removed by evaporation and 30 ml AcOEt are added thereto. The resulting mixture is washed three times with 30 ml H2O. Once separated, the AcoEt phase is dried on anhydrous Na2SO4 and evaporated to dryness, thereby yielding 3.28 g (99%) N-benzyloxycarbonyl-N-diethoxyethyl-6-(phenylbutoxy)hexylamine as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][C:6]=1[CH3:23])=O.[NH2:24][C:25]([NH2:27])=[S:26]>CCO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:24]=[C:25]([NH2:27])[S:26][CH:2]=3)=[C:6]([CH3:23])[CH:7]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)c2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(S(=O)(=O)c2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 64.7 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(4-methoxyphenylsulfonyl)-2,6-dimethylphenyl)ethanone (1.33 g, 3.4 mmol, 1.0 equiv) and thiourea (254.8 mg, 3.4 mmol, 1.0 equiv) in EtOH (5.0 mL) was heated at reflux for 1.0 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The resultant solids were washed with hexanes to give 4-(4-(4-methoxyphenylsulfonyl)-2,6-dimethylphenyl)thiazol-2-amine (839.2 mg, 2.2 mmol) as yellow solids in 65% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.89 (d, J=8.9 Hz, 2 H), 7.61 (s, 2 H), 7.13 (d, J=8.9 Hz, 2 H), 6.95 (brs, 2 H), 6.43 (s, 1 H), 3.83 (s, 3 H), 2.16 (s, 6 H); ESI-MS: m/z 375.6 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:60]=[CH:59][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[CH2:12][N:13]([CH:48]2[CH2:50][CH2:49]2)[C:14]([C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][C:32]4[C:37]([Cl:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=4[Cl:40])=[CH:24][CH:23]=3)[CH2:20][CH2:19][N:18]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:17]2)=[O:15])=[CH:5][CH:4]=1)#[N:2].[N:61]([Si](C)(C)C)=[N+:62]=[N-:63].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH:48]1([N:13]([CH2:12][C:11]2[CH:10]=[C:9]([O:8][CH2:7][C:6]3[CH:59]=[CH:60][C:3]([C:1]4[NH:63][N:62]=[N:61][N:2]=4)=[CH:4][CH:5]=3)[CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=2)[C:14]([C@@H:16]2[C@@H:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][O:31][C:32]4[C:33]([Cl:40])=[CH:34][C:35]([CH3:39])=[CH:36][C:37]=4[Cl:38])=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:17]2)=[O:15])[CH2:50][CH2:49]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(C#N)cc2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(-c3nnn[nH]3)cc2)c1
Temperature: 105 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-([[3-[(4-cyanobenzyl)oxy]-5-(3-methoxy-propyl)benzyl](cyclopropyl)amino]carbonyl}-4-{4-[2-(2,6-dichloro-4-methylphen-oxy)ethoxy]phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in toluene (0.04 M) was added azido(trimethyl)silane (3 eq.) and dibutyltin oxide (0.25 eq.). The reaction was heated to 105° C. and stirred for 16 h. The volatiles were removed in vacuo and the crude product was purified by flash column chromatography (SiO2, 95.9:3.9:0.2 (v/v/v) DCM/MeOH/AcOH) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@@H:15]([CH2:16][C:7]=2[CH:6]=[CH:5][CH:4]=1)[NH:14][CH2:13][CH2:12][CH2:11]3.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH2:24][CH3:25]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][C@@H:10]3[C@@H:15]([CH2:16][C:7]=2[CH:6]=[CH:5][CH:4]=1)[N:14]([CH2:23][CH2:24][CH3:25])[CH2:13][CH2:12][CH2:11]3
Reactant: COc1cccc2c1C[C@H]1CCCN[C@@H]1C2
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1CCC[C@@H]2Cc3c(cccc3OC)C[C@H]21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3 g of trans-1,2,3,4,4a,5,10,10a-octahydro-6-methoxybenzo[g]quinoline are dissolved in 100 ml of dimethylformamide. 3.8 g potassium carbonate and 1.8 ml of n-propyl iodide are subsequently added and the obtained suspension is stirred for 2 days at room temperature.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].[CH3:21][N:22]1[C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:24]=[C:23]1[CH:40]=[O:41].C(N(CC)CC)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:40]([C:23]1[N:22]([CH3:21])[C:26]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:9]=2[NH:10][C:11]2[C:12]([CH3:20])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[C:7]#[N:8])=[CH:25][N:24]=1)=[O:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C=O)n1C
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1c(Nc2c(C#N)cncc2-c2cnc(C=O)n2C)ccc2[nH]ccc12
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture of 5-iodo-4[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (250 mg, 0.67 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole-2-carbaldehyde (see e.g., U.S. Pat. No. 6,521,618) (401 mg, 1.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (24 mg, 0.034 mmol), and triethylamine (74.9 mg, 0.74 mmol) in dioxane (6 mL) was heated at the reflux temperature for 22 h, cooled to room temperature, and concentrated in vacuo. The residue was suspended in CH2Cl2 and filtered and the solid was washed with CH2Cl2. The combined filtrate and washings were concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/CH2Cl2, 20% to 90%; MeOH/ethyl acetate, 5%) to provide 103 mg (43%) of 5-(2-formyl-1-methyl-1H-imidazol-5-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 537 as a dark yellow solid. MS: 355.2 (M+H); melting range: 200-202° C.; and HRMS: 357.1458.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[CH:6]2.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2nc(Cl)ccc2c1
Temperature: 95 °C

Procedure:
A suspension of 6-methoxy-1H-quinolin-2-one of Step B (5.136 g, 29.2 mmol) in toluene (100 mL) is treated with phosphorous oxychloride 913.8 mL) and heated at 95° C. under nitrogen for 2 hours. The crude mixture is poured into ice water and basified with 50% aqueous sodium hydroxide. The solution is extracted with ethyl acetate, the extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is pre-absorbed on silica gel Merck-60 and flash chromatographed using a gradient of ethyl acetate (10–20%) in hexane to provide the title compound (5.25 g) as a white crystalline solid, m.p. 105–107° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1N=C[N:13](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([NH2:13])=[O:10])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](C(N)=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-4-methylcyclohexane carboxylic acid (1.00 g, 7.03 mmol) in EtOAc (15 mL) was treated with CDI (1.425 g, 8.79 mmol) and stirred at RT for 20 minutes. Ammonium hydroxide (˜14M, 5.00 mL, ˜70.0 mmol) was added, the mixture stirred for 20 minutes, then concentrated to dryness. The material was treated with satd. NaHCO3 and the solids collected via filtration and dried to afford trans-4-methylcyclohexanecarboxamide (842 mg, 85%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.13 (s, 1H), 6.61 (s, 1H), 1.94 (m, 1H), 1.70 (m, 4H), 1.25 (m, 3H), 0.84 (m, 5H); MS (ESI) m/z: 142.1 (M+H+).
Reaction SMILES: [NH:1]([C:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6]([C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)N.[CH:15]([C:18]([CH3:20])=O)([CH3:17])[CH3:16]>CC(O)=O>[CH3:20][C:18]1[C:15]([CH3:17])([CH3:16])[C:4]2[C:3](=[C:8]3[CH:9]=[CH:10][S:11][C:7]3=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=2)[N:1]=1
Reactant: CC(=O)C(C)C
Reactant: NNc1ccc(C(=O)O)c2sccc12
Solvent: CC(=O)O
Product: CC1=Nc2c(cc(C(=O)O)c3sccc23)C1(C)C
Temperature: 25 °C

Procedure:
A solution of 4-hydrazinyl-1-benzothiophene-7-carboxylic acid CC (208 mg, 1.0 mmole) and methyl isopropyl ketone (457 mg, 5.3 mmole) in 5 mL HOAc was heated at 120° C. for 1.5 hr and cooled down to 25° C. HOAc was removed in vacuo the product was purified with CombiFlash silica gel column chromatography (eluted with CH2Cl2/MeOH stepping gradient 100:0 to 80:20). The yield of the desired product CD was 210 mg (81%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=[N:12][NH:13]C(OC(C)(C)C)=O)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S:21](Cl)(Cl)=O>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:12]=[N:13][S:21][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(=NOC)C(C)=NNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOC)c1csnn1
Temperature: 50 °C
Reaction time: 0.05 h

Procedure:
A mixture of ethyl 2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate (a mixture of syn and anti isomers) (28.7 g.) and thionyl chloride (30 ml.) was warmed with stirring on a water bath of 50° C. for 3 minutes and then stirred for 5 minutes at ambient temperature to give black solution. To the reaction mixture was added ethyl acetate (200 ml.) and the mixture was poured into ice-water (300 ml.). The ethyl acetate layer was separated, washed in turn with water, with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the ethyl acetate solution was treated with activated charcoal and concentrated to give black oil. The oil was purified by column chromatography on silica gel using a mixture of benzene and ethyl acetate (19:1) as an eluent to give ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (anti isomer) (4 g.).
Reaction SMILES: [C:1](Cl)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:1]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NCCc1ccc(O)cc1
Reactant: CCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-tridecanoyl tyramine was prepared by adding dropwise about 2.80 ml of tridecanoyl chloride to a cooled solution comprising about 1 g of tyramine and about 1.52 ml of triethylamine in THF. The reaction mixture was stirred at room temperature for 48 hours. The mixture was then poured into about 70 ml of a 10% HCl solution and the mixture extracted with ethyl acetate (3×50 ml). The ethyl acetate layer was separated, dried (Na2SO4) and concentrated under reduced pressure to yield about 2 g of crude N-tridecanoyl tyramine. The product was purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (30:1). About 1 g of N-tridecanoyl tyranine was added to a stirred solution comprising about 152 mg of N-tridecanoyl tyramine, sodium hydroxide in 20 ml anhydrous DMF at 0° C. under nitrogen. The solution was stirred for 30 minutes; about 1 g of chlorosulfonamide was slowly added in one portion. The solution was then stirred at room temperature for 24 hours. After this time, the mixture was poured into a cold saturated sodium bicarbonate solution and the resulting solution was extracted with methylene chloride (3×50 ml). The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure to yield about 677 mg of product, which was then purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (20:1). The product produced is (p-o-sulfamoyl)-N-tridecanoyl tyramine.
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F-].[Cs+].C[O:14][CH2:15][CH2:16][O:17][CH3:18]>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.CO>[F:10][C:4]1[CH:3]=[C:2]([C:2]2[CH2:8][CH2:7][C:18]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:4][CH:3]=2)[C:8]([CH3:9])=[CH:7][C:5]=1[NH2:6]
Reactant: Cc1cc(N)c(F)cc1Br
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: Cc1cc(N)c(F)cc1C1=CCC2(CC1)OCCO2
Temperature: 130 °C

Procedure:
A mixture of 4,4,4,4-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (532.0 mg, 2.0 mmol), 4-bromo-2-fluoro-5-methylaniline (406.0 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (231.1 mg, 0.2 mmol), cesium fluoride (912.0 mg, 6.0 mmol), 1,2-dimethoxyethane (4 mL) and methanol (2 mL) was degassed for 5 min and then heated at 130° C. in a microwave reactor for 15 min. The reaction was concentrated in vacuo, and purified by silica chromatography (EtOAC/Hexanes:3/7) to afford 2-fluoro-5-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline; ESMS m/z 264.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1[CH:12]=[CH2:13].[NH3:15]>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:2])[NH:15][CH2:13][CH2:12][C:5]=2[N:6]=1
Reactant: C=Cc1nc(OC)ccc1C(=O)OC
Reactant: N
Solvent: CO
Product: COc1ccc2c(n1)CCNC2=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
A mixture of 6-methoxy-2-vinyl-nicotinic acid methyl ester (130 g, 674 mmol) in 7M solution of NH3 in MeOH (500 mL) was added to a sealed vessel. The mixture was stirred at 100° C. for 24 h. The solvent was evaporated in vacuo. The crude product was diluted with MeOH and the mixture was stirred at rt. The solid was filtered and dried in vacuo to yield 2-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one (75 g, 63%) as a solid.
Reaction SMILES: O[C:2]1[C:7]([C:8](=[O:18])[CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=[CH:4][C:3]=1[O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CCOCC>ClCCl>[N:12]1([C:10]2[O:11][C:2]3[C:7]([C:8](=[O:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=C(CC(=O)N1CCOCC1)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=c1cc(N2CCOCC2)oc2c(OS(=O)(=O)C(F)(F)F)cccc12
Temperature: 25 °C

Procedure:
Trifluoro-methanesulfonic acid 2-hydroxy-3-(3-morpholin-4-yl-3-oxo-propionyl)-phenyl ester [D] (1.06 g, 2.7 mmol) in dichloromethane (30 ml) was treated with trifluoromethanesulphonic anhydride and stirred over night at room temperature. The reaction mixture was then concentrated, re-dissolved in methanol and stirred for a further 2 hours. The solution was diluted with water and basified to pH8. It was then extracted three times with dichloromethane. The extracts were combined, washed with brine, dried with magnesium sulphate and evaporated to give the crude product as a brown oil. Trituration with ether gave trifluoro-methanesulfonic acid 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl ester [E] as a brown solid. Yield 210 mg, 20%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@H:9]1[NH:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=2)[N:19]=3)[CH2:10]1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([N:14]1[C@@H:9]([CH3:8])[CH2:10][N:11]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([C:31]2[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=2)[N:19]=3)[CH2:12][C@H:13]1[CH3:15])(=[O:45])[CH3:44]
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1[C@H](C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
Triethylamine (73.8 μl, 0.53 mmol) was added to a methylene chloride solution (9.0 ml) of 5-[8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (108.7 mg, 0.22 mmol) at room temperature followed by the addition of acetic anhydride (25.0 μl, 0.26 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 3 days followed by the addition of acetic anhydride (8.3 μl, 0.09 mmol) and the resulting mixture was stirred for 1 day. Acetic anhydride (4.2 μl, 0.04 mmol) was further added to the resulting mixture, the resulting mixture was stirred for 1 day, and the reaction mixture was poured into methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (109.8 mg, 93%) as a pale yellow solid.
Reaction SMILES: C([NH:8][C:9]([N:18]1[CH:22]=[CH:21][CH:20]=N1)=[N:10]C(OC(C)(C)C)=O)(OC(C)(C)C)=O.NCCC[CH2:27][CH2:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[CH:32][CH:33]=[C:34]2[C:39]=1[O:38][C:37](=[O:40])[CH:36]=[C:35]2[NH:41][C:42]1[C:47]([Cl:48])=[CH:46][N:45]=[CH:44][C:43]=1[Cl:49].FC(F)(F)C(O)=O>ClCCl>[Cl:49][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([Cl:48])[C:42]=1[NH:41][C:35]1[C:34]2[C:39](=[C:30]([O:29][CH2:28][CH2:27][CH2:20][CH2:21][CH2:22][NH:18][C:9]([NH2:8])=[NH:10])[C:31]([O:50][CH3:51])=[CH:32][CH:33]=2)[O:38][C:37](=[O:40])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCNC(=N)N
Reaction time: 0.5 h

Procedure:
N,N′-Di-Boc-1H-pyrazole-1-carboxamidine (40 mg, 0.13 mmol) was added to a mixture of 8-(5-aminopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (40 mg, 0.09 mmol, Example 68) and dichloromethane (3 mL). After stirring for 30 min, trifluoroacetic acid (0.3 mL) was added. After an additional 19 h, the reaction was concentrated and purified by reverse-phase HPLC (1:9→3:2; acetonitrile:water) to give to give 1-(5-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)pentyl)guanidine: 1H NMR (400 MHz, DMSO-d6; HCl salt): δ 9.60 (s, 1H), 8.82 (s, 2H), 7.98 (d, 1H), 7.57 (t, 1H), 7.50-6.70 (br, 4H), 7.21 (d, 1H), 4.63 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 3.11 (m, 2H), 1.70 (m, 2H), 1.52 (m, 4H); MS (ESI): 479.9.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CS(C)=O.O>[CH2:4]([N:11]1[CH2:16][CH2:15][O:14][CH:13]([CH2:17][C:1]#[N:2])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CN(Cc2ccccc2)CCO1

Procedure:
The mixture of finely ground sodium cyanide (39.6 g.) and 4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine (144.4 g.) in dimethyl sulphoxide (600 ml.) is stirred and heated at 60°-65° C. for 3.5 hours. The mixture is cooled, diluted with water (6 1.) and extracted with ether (3 × 2 1.). The ether extracts are combined and washed with brine (2 × `1.) and dried over anhydrous magnesium sulphate and the solvent removed by evaporation in vacuo. The residue is recrystallised from petroleum ether (b.p. 40°-60° C.) to give 4-benzyl-2-cyanomethylmorpholine, m.p. 62° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=2)[N:11]=1.[OH-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(benzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (160 mg, 0.43 mmol, 1.00 equiv) in methanol (20 mL), sodium hydroxide (85 mg, 2.12 mmol, 4.99 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (2.5 M). The resulting solids were collected by filtration. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, XbridgePrep Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (58% CH3CN up to 78% in 8 min, up to 100% in 2 min); Detector, UV 220 254 nm. This resulted in 70 mg (45%) of 2-(benzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][NH2:10].[CH2:11]([N:13]1[C:18](S(C)=O)=[C:17]([C:22]#[N:23])[C:16](=[O:24])[N:15]2[N:25]=[CH:26][CH:27]=[C:14]12)[CH3:12]>C(O)C>[NH2:23][C:22]1[C:17]2[C:16](=[O:24])[N:15]3[N:25]=[CH:26][CH:27]=[C:14]3[N:13]([CH2:11][CH3:12])[C:18]=2[N:9]([CH3:8])[N:10]=1
Reactant: CCn1c(S(C)=O)c(C#N)c(=O)n2nccc12
Reactant: CNN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c2c(c(N)nn2C)c(=O)n2nccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Triethylamine (1.44 g) and methylhydrazine (1.44 g) were added to a solution of 3.2 g of 4-ethyl-5-methanesulfinyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile in 100 ml of ethanol and stirred at 60° C. for 30 minutes. The reaction mixture was cooled and the crystals precipitated were collected by filtration and sequentially washed with ethanol, methanol and diethyl ether to provide 1.9 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.