Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18]C)=[O:17])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCOC(C)=O.O>O1CCOCC1>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([OH:18])=[O:17])=[O:12])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
A solution of methyl 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzoate (2.00 g, 6.25 mmol) in dioxane (30 mL) was treated with 5 N NaOH (12.5 mL). After 1 h, the mixture was poured into EtOAc and water, and the aqueous layer was washed with EtOAc. The pH of the aqueous layer was then adjusted to 2–3 by addition of 5 N HCl and washed with EtOAc (3×). The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated, yielding the title compound; which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:40][C@@H:41]([CH3:57])[CH2:42][N:43]1[CH:47]=[CH:46][C:45]([C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[C:50]([Cl:56])[CH:49]=2)=[N:44]1>CN(C=O)C.O>[Cl:56][C:50]1[CH:49]=[C:48]([C:45]2[CH:46]=[CH:47][N:43]([CH2:42][C@@H:41]([NH:40][C:6]([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[O:8])[CH3:57])[N:44]=2)[CH:55]=[CH:54][C:51]=1[C:52]#[N:53]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Reaction time: 45 h

Procedure:
4-Imidazolecarboxylic acid (1.00 g, 8.9 mmol) was dissolved in dry DMF (35 ml). Dry 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 2.31 g, 12.0 mmol), HOBt (1.84 g, 12.0 mmol), and DIPEA (4.7 ml, 3.46 g, 26.8 mmol) were added at RT. After stirring for 15 min (S)-4-[1-(2-aminopropyl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile of Example 34© (2.44 g, 9.4 mmol) in dry DMF (15 ml) was added to the solution at RT. Then the solution was stirred for 45 h. Water was added and the product was extracted into ethyl acetate. The organic phase was washed with brine and water, dried and evaporated. The crude product was purified by triturating in hot DCM. The product was filtered and washed with heptane. 1H NMR (400 MHz, DMSO-d6): 1.08 (3H, d), 4.30 (1H, distorted dd), 4.41 (2H, m), 6.95 (1H, d), 7.57 (1H, s), 7.75 (1H, d), 7.85 (1H, d), 8.01 (2H, m), 8.21 (1H, s), 8.30 (1H, d), 12.47 (1H, broad s).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15]([NH2:17])=[C:14]1[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:8]2.[C:18](=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:31])[CH:27](Br)[CH2:28][CH3:29]>CN(C)C=O.O>[OH2:2].[NH2:17][C:15]1[C:16]2[C:7]([N:8]=[C:9]3[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH:27]([CH2:28][CH3:29])[C:26]([O:25][CH2:24][CH3:18])=[O:31]
Reactant: CCC(Br)C(=O)OC
Reactant: O=C([O-])[O-]
Reactant: Nc1c2c(nc3cccc(O)c13)CCCC2
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1cccc2nc3c(c(N)c12)CCCC3
Reaction time: 1 h

Procedure:
To a solution of 8-hydroxy-1,2,3,4-tetrahydro-9-acridinamine hydrochloride (23.08 g) in dry dimethylformamide was added potassium carbonate (28.75 g), with stirring. After one hr, methyl-2-bromobutyrate (15.89 ml) was added dropwise and stirring was continued overnight. The reaction mixture was diluted with water (1.5 l), and extracted with ethyl acetate (2 l). The organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was flash chromatographed (ethyl acetate, 5% triethylamine/ethyl acetate) to yield 30.34 g of ethyl α-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]butyrate hydrate.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21]=3[CH:20]=[CH:19][N:18]=[C:17]4SC)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>ClCCl.O>[C:42]([NH:46][C:17]1[N:16]2[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]=3)=[C:21]2[CH:20]=[CH:19][N:18]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)N
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)Nc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (40 mg, 0.095 mmol) in dichloromethane (2 mL) was added 3-chloroperoxybenzoic acid (12 mg, 0.14 mmol) and the reaction mixture stirred at room temperature for 1 hour. t-Butylamine (3 mL) was added and heated to reflux for 3 hours. The reaction was allowed to cool and diluted with water. The mixture was extracted with ethyl acetate and the organic phase washed with brine before being concentrated under vacuum. The residue was purified by silica gel chromatography eluting with SO/5 acetone in dichloromethane to yield a 1:1 mixture of starting material and product. The residue was dissolved in dichloromethane (2 mL) and 3-chloroperoxybenzoic acid (18 mg, 0.21 mmol) was added. The mixture was stirred for 2 hours and then t-butylamine (3 mL) was added. The reaction mixture was stirred for 3 hours, diluted with water, extracted with ethyl acetate, washed with brine, concentrated, and the residue purified by silica gel chromatography eluting with 5% acetone in dichloromethane to yield N-(tert-butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine (6 mg, 14%), 1H NMR (CDCl3): δ 8.02 (d, 1H), 7.72 (d, 1H), 7.60 (dd, 2H), 7.47 (d, 1H), 7.13 (t, 2H), 6.42 (s, 1H), 6.25 (d, 1H), 5.14 (bs, 1H), 4.28 (m, 1H), 2.04 (m, 2H), 1.45–1.78 (m, 15H). MS m/z 446 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:22]1[CH:23]=[C:15]2[C:16]([C:17](=[O:19])[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[C:12](=[O:13])[NH:14]2)=[CH:20][CH:21]=1
Reactant: O=C=NS(=O)(=O)c1ccc(F)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccc(F)cc1
Yield: 26.8 %

Procedure:
1.72 g (8.57 mmol) of 4-fluorobenzenesulfonylisocyanate and 1.47 g (8.57 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 815 mg of the above-identified compound (yield 26.8%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 7.12 (1H,s), 7.23 (1H,d), 7.49-7.55 (2H,m), 7.86 (1H,d), 8.23-8.28 (2H,m), 11.90 (1H,br).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][N:3]=1.Cl[CH:28]([C:31]1([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][CH:38]=[CH:37]3)[CH2:33][CH2:32]1)[CH:29]=O>C(O)(C)C.CO>[N:40]1[C:41]2[C:36](=[CH:35][C:34]([C:31]3([C:28]4[N:7]5[CH:6]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([N:14]7[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]7)=[N:12][CH:13]=6)[CH:4]=[N:3][C:2]5=[N:1][CH:29]=4)[CH2:33][CH2:32]3)=[CH:43][CH:42]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N)nc3)cn2)CC1
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cn2)CC1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
A mixture of tert-butyl 4-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]piperazine-1-carboxylate (0.120 g, 0.337 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.0827 g, 0.337 mmol) in isopropyl alcohol (2.0 mL) was heated at 100° C. overnight. The mixture was diluted with methanol and purified by RP-HPLC (pH 10.0) to give the desired product (80 mg, 43.4%). LCMS: (M+H)=548.2.
Reaction SMILES: O.[Cl:2][C:3]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:4]=1[CH:5]=[O:6].[CH2:23](O)[CH2:24][OH:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:17][C:16]1[C:12]([C:8]2[CH:7]=[C:4]([CH:5]3[O:25][CH2:24][CH2:23][O:6]3)[C:3]([Cl:2])=[CH:10][C:9]=2[F:11])=[N:13][N:14]([CH3:22])[C:15]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C3OCCO3)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Yield: 61.2 %

Procedure:
In an apparatus equipped with a Dean-Stark trap for azeotropic removal of water, 2.4 g (7.0 mmoles) 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzaldehyde, 0.4 mL (7.7 mmoles) ethylene glycol and a catalytic amount of p-toluene-sulfonic acid in 50 mL toluene was heated to reflux for 24 hours. The resultant mixture was concentrated and the residue purified by chromatography to give 1.65 g (61%) of 4-chloro-3-(4-chloro-5-(1,3-dioxolan-2-yl)-2-fluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a clear colorless oil; nD25 1.5348.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=[O:8])=[C:5](Br)[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[CH:9][C:6]=2[CH:7]=[O:8])[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(Br)c(C=O)cc1OC
Reactant: COc1cccc(B(O)O)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2cc(OC)c(OC)cc2C=O)c1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.36 g) was added to a solution of 4,5-dimethoxy-2-bromobenzaldehyde (2.5 g) in toluene (20 ml) and ethanol (20 ml), followed by addition of 2M aqueous sodium carbonate (20 ml). To this mixture was added 3-methoxyphenylboronic acid (1.7 g), and the mixture was heated to reflux. After 1 hour, the reaction was partitioned between water (150 ml) and ethyl acetate (300 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (150 ml) and brine (150 ml), dried over magnesium sulfate and concentrated. Chromatography (silica, 20-30-40% ethyl acetate/hexanes) afforded 2.7 g (98%) of 2-(3-methoxyphenyl)-4,5-dimethoxybenzaldehyde as a yellow oil which solidified upon standing.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH:12]([NH:14][C:15]1[C:16]([S:21]([NH2:24])(=[O:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([N:35](C2C=CC=CC=2)[C:36](=O)[O-:37])[N:28]=1.Cl>C(#N)C.O>[CH3:34][O:33][C:31]1[CH:32]=[C:27]([O:26][CH3:25])[N:28]=[C:29]([NH:35][C:36]([NH:24][S:21]([C:16]2[C:15]([NH:14][CH:12]=[O:13])=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:23])=[O:22])=[O:37])[N:30]=1
Reactant: COc1cc(OC)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1ncccc1NC=O
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2NC=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
0.75 g (0.0049 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is added to a solution of 0.5 g (0.0019 mol) of 3-formylamino-2-pyridinesulfonamide and 0.68 g (0.0025 mol) of N-(4,6-dimethoxypyrimidin-2-yl)phenylcarbamate in 40 ml of acetonitrile. The solution is stirred for 16 hours at room temperature, 20 ml of water are subsequently added, and the pH is brought to 4 using 2-normal hydrochloric acid. The mixture is extracted with dichloromethane, the organic phase is dried over MgSO4, and n-heptane is added. Filtration gives 0.64 g (89% of theory) of N-[(4,6-dimethoxy-pyrimidin-2-yl)-aminocarbonyl]-3-formylamino-2-pyridinesulfonamide of melting point 172° C. (decomp.).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]#[N:22])=[CH:16][C:15]=1[O:30][CH3:31].[CH3:32][CH2:33][O:34][C:35](C)=[O:36]>C1COCC1>[CH2:33]([O:34][C:35](=[O:36])[C:20]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:21]#[N:22])[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[C:15]([O:30][CH3:31])[CH:16]=1)[CH3:32]
Reactant: CCOC(C)=O
Reactant: COc1cc(C(C#N)Cc2ccccc2)ccc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)(Cc1ccccc1)c1ccc(F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a −78° C. cooled solution of diisopropylamine (5.11 ml, 35.8 mmol) in THF was added n-butyllithium (22.40 ml, 35.8 mmol) and stirred for 1 h while the reaction mixture was allowed to warm up <−40° C. 2-(4-Fluoro-3-methoxyphenyl)-3-phenylpropanenitrile (6.1 g, 23.89 mmol) dissolved in THF was added followed by ethyl chloroformiate (3.42 ml, 35.8 mmol). The reaction mixture was stirred over night and was allowed to heat up to room temperature. Evaporated solvents and redissolved in EtOAc, washed with 10% citric acid, water and brine and the combined organic layers were dried over MgSO4, filtered and evaporated to obtain 7.2 g of a yellow oil, that was purified by flash chromatography on 330 g SiO2 using 20% EtOAc in cyclohexene to obtain 18.26 g of the desired product as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)=[O:4].[CH2:22](Br)[C:23]#[CH:24].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[OH:4][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:17])([F:18])[F:19])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)([C:2]([F:20])([F:1])[F:21])[CH2:24][C:23]#[CH:22]
Reactant: N#Cc1cc2nc(C(=O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Reactant: C#CCBr
Agent: Cl
Agent: [In]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C#CCC(O)(c1nc2cc(C#N)c(C(F)(F)F)cc2[nH]1)C(F)(F)F

Procedure:
2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile (0.31 g; 0.94 mmol), propargyl bromide (80% in toluene; 1.1 mL; 12.3 mmol) and indium (1.08 g; 9.5 mmol) were suspended in THF (12 mL) and 0.03 M HCl (10 mL) and stirred vigorously overnight. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude material. The crude material was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:28][CH2:29][CH3:30])[C:14]([C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:19]([O:21]CC)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.C(O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:28][CH2:29][CH3:30])[C:14]([C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:19]([OH:21])=[O:20])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN(CCCCOCc1ccccc1)C(=O)c1cc(C)cc(C(=O)OCC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCN(CCCCOCc1ccccc1)C(=O)c1cc(C)cc(C(=O)O)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of ethyl 3-{[[4-(benzyloxy)butyl](propyl)-amino]carbonyl}-5-methylbenzoate (1.75 g, 4.25 mmol) in THF/ethanol/water (1/2/1, 30 mL) is added lithium hydroxide (0.31 g, 12.76 mmol). The reaction mixture is stirred for 2 h and then acidified to pH=3 with concentrated hydrochloric acid (0.5 mL). The reaction mixture is extracted with ethyl acetate (2×30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-{[[4-(benzyloxy)butyl](propyl)-amino]carbonyl}-5-methylbenzoic acid (IX, 1.63 g), ESI-MS (m/z) [M+H]+=384.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51]1>CN(C=O)C>[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51]1
Reactant: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(c4)OCO5)c3)c(=O)oc12
Temperature: 25 °C
Yield: 79.1 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 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-Benzo[1,3]dioxol-5-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 0.023 g of product in 77% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][O:16][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Li])CCC.[C:22](=[O:24])=[O:23]>O1CCCC1.CCCCCC>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([C:22]([O:24][CH3:17])=[O:23])[O:16][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCc3ccoc3C2)cc1
Reactant: O=C=O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cc2c(o1)CN(Cc1ccccc1)CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.683 g (3.202 mmol) of 6-benzyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 30 ml of tetrahydrofuran, 4.0 ml (6.4 mmol) of 1.6 M n-butyl lithium in hexane was added under ice-cooling, followed by stirring for 0.5 hours. After the reaction mixture was cooled to -78° C., crushed dry ice was added; while the mixture was stirred vigorously, the mixture was allowed to warm to room temperature. After the solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of about 10% hydrogen chloride in methanol, followed by overnight stirring at room temperature. After the solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added, followed by 3 extractions with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9](S(O)(=O)=O)[CH:8]=[CH:7]2.[NH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]=[C:24]([OH:27])[CH:23]=[CH:22]2.[H-].[Na+].CI>CN(C)C=O.O>[NH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]=[C:24]([OH:27])[CH:23]=[CH:22]2.[CH3:24][O:27][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[NH2:1])=[CH:7][CH:8]=1
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Agent: Nc1cccc2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc2cccc(N)c2c1
Reaction time: 4 h

Procedure:
8-Amino-naphthalen-2-ol was prepared from 8-amino-2-naphthalenesulphonic acid (commercially available) according to the literature (J. Org. Chem. 1949, p351). To a solution of 8-amino-naphthalen-2-ol (8.00 g) in dry N,N-dimethylformamide (80 mL) was added sodium hydride (60% dispersion in mineral oil, 3.2 g) carefully. After stirring for 4 hours the reaction mixture was cooled in an ice bath and methyl iodide (3.13 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 3 days. Water (10 mL) was then added and the volatiles were removed in vacuo. The residue was dissolved in chloroform, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield a dark oil. This was purified using flash chromatography (chloroform) to yield 7-methoxy-naphthalen-1-ylamine as a dark brown liquid (2.92 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[N:37]=[C:36]([N:38]([CH3:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:35]=[C:34]([C:46](=[NH:49])[NH:47]O)[N:33]=1.NC1N=C(N(C)C2C=CC=C(C)C=2)N=C(C(NO)=N)N=1>N1C=CC=CC=1>[CH3:45][N:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]1[N:37]=[C:32]([NH2:31])[N:33]=[C:34]([C:46]2[N:47]=[C:14]([C:11]3[CH:12]=[N:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:1])([F:18])[F:17])=[CH:9][CH:10]=3)[O:16][N:49]=2)[N:35]=1
Reactant: O=C(O)c1ccc(OCCOCC(F)(F)F)nc1
Reactant: CN(c1ccccc1)c1nc(N)nc(C(=N)NO)n1
Agent: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(OCCOCC(F)(F)F)nc3)n2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
6-[2-(2,2,2-Trifluoroethoxy)ethoxy]pyridine-3-carboxylic acid (Intermediate 242, 0.133 g, 0.50 mmol) and 1,1′-carbonyldiimidazole (0.081 g, 0.50 mmol) were combined in pyridine (3 mL) and stirred at room temperature for 3 h. 4-Amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1, 0.100 g, 0.39 mmol) was added and the mixture stirred at room temperature for 4 h before being heated to 80 C for 16 h. Pyridine was removed under vacuum and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was dried over sodium sulfate and concentrated to yield an orange solid. This was purified by FCC, using a gradient of 30-70% EtOAc in heptane to afford the title compound as a white solid (0.116 g, 61%). Method A HPLC-MS: MH+ requires m/z=489 Found: m/z=489, Rt=4.58 min (100%). 1H NMR (500 MHZ, CDCl3) δ ppm 9.06 (1H, s), 8.41 (1H, d), 7.47 (2H, m), 7.34 (3H, m), 6.96 (1H, d), 5.34 (2H, br s), 4.64 (2H, t), 4.04 (2H, t), 3.97 (2H, q) and 3.65 (3H, s).