Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][C:18](OC)=[O:19])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:22]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18][OH:19])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:22]=1
Reactant: COC(=O)Cc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2cc(CCO)ccc2Nc2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
A mixture of Example 6D (6.32 g, 20 mmol) in 100 mL of THF was treated with 1.0 M LiAlH4 in THF (35 mL, 35 mmol) at 0° C. The reaction mixture was stirred for additional 30 min., quenched with MeOH, and concentrated under vacuum. The residue was partitioned between ethyl acetate and pH=3 water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:9 hexanes/ethyl acetate to provide 5.18 g (90%) of the desired product. MS (DCI) m/e 289 and 291 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.96 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.5, 2.0 Hz, 1H), 6.81-6.84 (m, 3H), 4.59 (t, J=6.0 Hz, 1H), 3.51-3.53 (m, 2H), 2.58 (t, J=6.9 Hz, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([O:34][C:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=O)[CH2:23]OP(OCC(O)CO)(O)=O)=O.CCCCCCCC/C=C\CCCCCCCC(OC[C@@H](OC(CCCCCCC/C=C\CCCCCCCC)=O)COP(OC[CH2:83][N+:84](C)([CH3:86])[CH3:85])([O-])=O)=O.C1(=O)NC(=O)C=C1.CCCCCCCCC=CCCCCCCCC(OCC(OC(CCCCCCCC=CCCCCCCCC)=O)COP(OCC(O)CO)(O)=O)=O.CCCCCCCC/C=C\CCCCCCCC(OC[C@@H](OC(CCCCCCC/C=C\CCCCCCCC)=O)COP(OCC[N+](C)(C)C)([O-])=O)=O.C(Cl)(Cl)[Cl:223]>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:20][CH2:21][CH:22]([O:34][CH2:35][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:23][N+:84]([CH3:86])([CH3:85])[CH3:83].[Cl-:223]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OCC(COP(=O)(O)OCC(O)CO)OC(=O)CCCCCCCC=CCCCCCCCC
Reactant: ClC(Cl)Cl
Agent: O=C1C=CC(=O)N1
Product: CCCCCCCC/C=C\CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC/C=C\CCCCCCCC
Product: [Cl-]

Procedure:
DOPG/DOPC sonicated vesicles containing maleimide-PE were prepared by dissolving 16 mg DOPG, 24 mg DOPC and 0.4 mg maleimide-PE in chloroform and removing the solvent by drying under a stream of nitrogen gas. This dried film was placed under vacuum overnight to remove traces of solvent. The film was then suspended in 0.8 ml water with vigorous shaking and sonicated in a bath type sonicator for 30 minutes until clear producing DOTMA/DOPPC SUV's at a concentration of 50 mg/ml.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.BrC1C=CC=C2C=1C=CN=C2.[ClH:23].BrC1C=CC=C2C=1C=C[N+]([O-:35])=C2>>[ClH:23].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:35])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc2c(Br)cccc2c1
Reactant: Brc1ccc2ccncc2c1
Agent: Brc1cccc2cnccc12
Agent: Cl
Product: [O-][n+]1ccc2ccc(Br)cc2c1

Procedure:
Compound 37a was prepared from 7-bromoisoquinoline (Tyson, F. L., J. Am. Chem. Soc. 61, 183 (1939), this procedure gave a mixture of 7-bromoisoquinoline and 5-bromoisoquinoline) using the procedure described for 1a. The title compound was contaminated with the 5-bromoisoquinoline N-oxide hydrochloride. M.p. 107.0-112.5° C.
Reaction SMILES: [NH2:1]C1C=CN=CC=1.C(N(CC)CC)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:15]([NH2:1])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Yield: 122.4 %

Procedure:
To a solution of 4-aminopyridine (3.00 g, 31.9 mmol) in CH2Cl2 (50 mL) at 0° C. was added triethylamine (6.70 mL, 47.9 mmol) and benzoyl chloride (3.70 mL, 31.9 mmol). The ice bath was removed and the resulting mixture was allowed to warm tort over 1.5 h. The reaction was quenched with saturated aqueous NaHCO3, extracted with CH2Cl2, washed with brine, dried (MgSO4) and concentrated. The crude product was recrystallized from EtOAc/hexanes to give 4.73 g (75% yield) of pure benzamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[CH3:23][O:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1.ClC(Cl)C>[CH3:23][O:24][CH2:25][C:26]([O:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])=[O:27]
Reactant: COCC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)CCCO)s1
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COCC(=O)OCCCS(=O)(=O)c1ccc(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(3-hydroxypropane sulfonyl)thiophene-2-sulfonamide (1.2 g, 4.2 mmol) in 75 ml of THF was added 0.4 ml of pyridine and 0.5 g of methoxyacetyl chloride. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The oily residue was dissolved in ethyl acetate and the ethyl acetate was washed with water and then brine. After drying over sodium sulfate the ethyl acetate was concentrated under vacuum, giving an oily residue. A crystalline product was obtained by dissolving the oil in hot dichloroethane and then cooling to 0° C. The yield was 0.8 g. m.p. 93°-95° C. 1H-NMR, δ (DMSO, d6) 8.00 (2H, s); 7.80 (1H, d, J=3); 7.63 (1H, d, J=3); 4.12 (2H, t, J=6); 4.00 (2H, s); 3.55 (2H, m); 3.27 (3H, s); 1.91 (2H, m).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.Cl.Cl[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)([O-])N.Cl>C(O)(C)C.CO.O1CCOCC1>[N:23]1[CH:24]=[CH:25][C:20]([N:2]2[CH2:3][CH2:4][C:5]3([CH2:6][CH2:7][NH:8][CH2:9][CH2:10]3)[CH2:1]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Reactant: Clc1ccncc1
Agent: Cl
Agent: NC(=O)[O-]
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CO
Product: c1cc(N2CCC3(CCNCC3)C2)ccn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The reaction was performed under an N2 atmosphere. tert-Butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (869 mg, 3.62 mmol), 4-chloropyridine hydrochloride (1.08 g, 7.20 mmol) and TEA (2.5 ml, 18 mmol) were suspended in isopropanol (10 ml). The mixture was heated to 80° C. and stirred overnight at 80° C. Then the solvent was removed in a rotary evaporator. The residue was taken up in DCM and concentrated to small volume again. This process was repeated twice more. The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2). The product obtained still contained impurities and was used in the next stage in that condition. 2. The reaction was performed under an N2 atmosphere. The carbamate (1.034 g, max. 3.26 mmol) was dissolved in MeOH (5 ml) and mixed with 4 M HCl in dioxane (5 ml). The reaction batch was stirred for 2 h at RT. Then the solvent was removed. The crude product was purified by column chromatography (silica gel, DCM/7M NH3 in MeOH, 98:2→95:5→9:1). Yield: 455 mg, 58% over 2 stages.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9]C)=[CH:7][C:5]([NH2:6])=[C:4]([O:11][CH3:12])[CH:3]=1.C[O:14][C:15]1[CH:23]=[CH:22][C:18](C(Cl)=O)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]2[N:6]=[C:12]([C:18]3[CH:22]=[CH:23][C:15]([OH:14])=[CH:16][CH:17]=3)[O:11][C:4]=2[CH:3]=1
Reactant: COc1cc(Cl)c(OC)cc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Product: Oc1ccc(-c2nc3cc(O)c(Cl)cc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 16, from 4-chloro-2,5-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as an off-white solid, m.p. 260-262° C.; MS m/e 260 (M−H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:16])[CH3:15].Br[CH2:18][C:19]([CH3:21])=[CH2:20]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[N:13]([CH2:20][C:19]([CH3:21])=[CH2:18])[C:14](=[O:16])[CH3:15]
Reactant: C=C(C)CBr
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A suspension of NaH (2 g) (95% powder) in 100 mL anhydrous DMF was cooled to −78° C., and N-(2-bromo-5-nitrophenyl)acetamide (Step A, 7 g) in 50 mL dry DMF was added to the mixture under N2. After the mixture was warmed to 0° C., 3-bromo-2-methylpropene (7.3 g in 20 dry DMF) was added to the mixture. The mixture was stirred at RT overnight. The mixture was poured into a container of ice and extracted between saturated NaHCO3 solution and EtOAc. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 7:2 Hexane:EtOAc to afford a yellow gum. MS: 314 (M+1). Calc'd. for C12H13BrN2O3−313.1.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8]O>[Ti].O>[C:1]1([C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])[OH:7].[C:1]1([CH:6]=[CH:5][C:4]([OH:8])=[CH:3][CH:2]=1)[OH:7]
Reactant: OO
Reactant: Oc1ccccc1
Agent: [Ti]
Solvent: O
Product: Oc1ccc(O)cc1
Product: Oc1ccccc1O

Procedure:
A 10-liter reactor as for the previous Example is charged with 4,255.8 g of phenol, 813 g of water and 42 g of titanium silicalite. As the system has reached its thermal equilibrium, there are added 675.2 g of 60% H2O2. After three hours of reaction there are obtained 250 g of pyrocatechol, 318 g of hydroquinone and 157 g of tarry by-products.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[CH:50]=[CH:49][NH:48][C:47]=1[C:51](O)=[O:52].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:50]=[CH:49][NH:48][C:47]=1[C:51]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:52]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1[nH]ccc1Cl
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: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]ccc3Cl)c2F)c1
Reaction time: 2 h
Yield: 26.6 %

Procedure:
HATU (0.061 g, 0.16 mmole) was added to a DMF (2 ml) solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.16 mmole) and 3-chloro-1H-pyrrole-2-carboxylic acid (0.023 g, 0.16 mmole) in DMF. DIPEA (0.021 g, 0.16 mmole) was added and the solution stirred for 2 h. The mixture was partitioned between EtOAc and water. The organic layer was separated and washed with 15% NaHCO3 and dried over MgSO4 and the EtOAc evaporated. The residue was purified on silica with EtOAc and Hexanes to afford the title compound (0.0187 g, 26%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 10.93 (br. s., 1H), 7.62-7.67 (m, 1H), 7.56-7.62 (m, 1H), 7.37-7.48 (m, 4H), 7.02 (t, 1H), 6.23 (t, 1H), 4.72 (d, 2H). MS: m/z 438.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[OH:26])([O-])=O.C1(C)C=CC=CC=1.[OH-].[Na+].[H][H]>[C].[Pd].O.CC(O)C>[OH:26][C:13]1[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Yield: 73 %

Procedure:
35.5 g (0.1 mol) of 2-nitro-2'-hydroxy-3',5'-di-t-butylazobenzene, 0.125 g of 5% palladium carbon, 100 ml of toluene, 100 ml of IPA, 100 ml water and 8.3 g of caustic soda were charged into a 500-ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. Reaction was effected in the same way as that employed in Example 1. After the reaction had been completed, the catalyst was filtered off. When part of the filtrate was subjected to quantitative analysis using GC, it was found that the yield of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)benzotriazole is 82%. After the solvent had been distilled off from the filtrate, the residual solid was crystallized by IPA, washed with IPA and then dried to obtain 23.6 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)benzotriazole (yield, 73%; melting point, 150° to 152° C.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[CH3:25][C:26](=O)[CH2:27][C:28](=[O:30])[CH3:29]>O1CCCC1>[C:28]([C:27]1[CH:21]([C:20]2[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)[NH:12][C:10](=[O:11])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:26]=1[CH3:25])(=[O:30])[CH3:29]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
30 g (147 mmol) N-[3-(trifluoromethyl)phenyl]urea, 19.3 g (147 mmol) 4-cyanobenzaldehyde and 14.7 g (147 mmol) 2,4-pentanedione are suspended in 300 ml of tetrahydrofuran, and 90 g polyphosphoric acid ethyl ester are added. The mixture is stirred at reflux for 4 hours. After cooling down to room temperature, the solvent is removed in vacuo, the remainder is dissolved in ethyl acetate and sequentially washed with saturated aqueous sodium hydrogencarbonate and sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude product is purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[O:49][CH2:50][CH:51]([OH:66])[CH2:52][N:53]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)[CH2:54]1>CN1C(=O)CCC1.N1C=CC=CC=1>[Cl:65][C:62]1[CH:61]=[CH:60][C:59]([O:58][CH:55]2[CH2:56][CH2:57][N:53]([CH2:52][CH:51]([OH:66])[CH2:50][O:49][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[NH:42][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:54]2)=[CH:64][CH:63]=1
Reactant: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Reactant: O=C(O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 80 uL 0.2M 2-thiophenecarboxylic acid in NMP were HBTU (80 uL, 0.2M/NMP), HoBT (80 uL, 0.2M/NMP), DIEA (30 uL, 0.5M/NMP) and pyridine (30 uL, 0.5M/NMP) added and stirred for 30 minutes before 1-[(2-aminophenyl)oxy]-3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-propanol (75 uL, 0.2M/NMP) was added. The mixture was stirred overnight at room temperature before it was concentrated under reduced pressure to dryness. The product was diluted with 1000 uL dichloromethane and washed with with sat.NaHCO3/aq (800 uL), 1.81% HCl/aq(800 uL) and sat. NaCl/aq. The organic layer was concentrated under reduced pressure to dryness and used without further purification. Yield 3.6mg, 51%
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:20]([OH:22])=O)=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[CH3:26][C:25]1[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:28][CH3:27])=[CH:18][C:17]=1[NH:16][CH2:15][C:12]1[N:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:10][CH:11]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1NCc1cnc(NC(=O)OC(C)(C)C)cn1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(NCc2cnc(NC(=O)OC(C)(C)C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 3-((5-(tert-butoxycarbonylamino)pyrazin-2-yl)methylamino)-4-methylbenzoic acid (30 mg, 0.08 mmol) in DMF (1 mL) were added HATU (95 mg, 0.25 mmol), DIEA (74 □L, 0.42 mmol) and methylamine hydrochloride (9 mg, 0.13 mmol). The reaction mixture was stirred for overnight at room temperature after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product (29 mg, 93% yield) was used without further purification. MS m/z: 372 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:14][CH2:13][CH2:12][O:6]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: OCCO
Reactant: COc1ccc(C=O)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C2OCCO2)cc1Br
Yield: 92.6 %

Procedure:
A solution of 53.0 g of 3-bromo-4-methoxy benzaldehyde, 18.4 g of ethylene glycol, and 4.24 g of p-toluene sulfonic acid/1 hydrate in benzene was refluxed for 5 hours while taking water out of the system. After the mixture was cooled, the reaction solution was poured into a saturated aqueous solution of NaHCO3, liquid separation was performed, and the aqueous layer was extracted with benzene. The combined organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (Chromatorex NH; mobile phase: EtOAc/n-hexane=1/9; v/v) to obtain 59.1 g of the title compound (colorless oil) was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([CH2:45][CH2:46][OH:47])[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:37]([CH2:45][CH2:46][OH:47])[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of Intermediate 96c (160 mg, 0.41 mmol), Intermediate 110b (142 mg, 0.41 mmol) and DIPEA (142 μL, 0.82 mmol) in dioxane (5 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-8% MeOH in DCM followed by MDAP (Method 7) purification, to afford the title compound (86 mg, 32%) as a glassy white solid. LCMS (Method 5): Rt 4.32 min, m/z 601 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.2 Hz), 0.58 (3H, d, J=6.2 Hz), 1.17 (9H, s), 1.35-1.55 (3H, m), 1.63-1.69 (2H, m), 1.73-1.79 (1H, m), 1.82-2.00 (2H, m), 2.00-2.13 (2H, m), 3.09-3.19 (2H, m), 3.62 (2H, br s), 3.90 (2H, t, J=5.9 Hz), 4.82 (1H, td, J=8.6, 5.7 Hz), 4.92-4.98 (1H, br s), 5.50 (1H, t, J=4.2 Hz), 6.02 (1H, s), 7.04 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=9.8, 2.3 Hz), 7.20-7.25 (1H, m), 7.30-7.36 (3H, m), 7.62 (1H, dd, J=9.7, 0.6 Hz), 7.86 (1H, d, J=2.1 Hz), 8.14 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:16]1([S:22][C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Sc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (1.0 g, 0.005 mol) in dry toluene (5 ml) was treated with thiophenol (0.55 g, 0.005 mol) and a catalytic amount of p-toluenesulfonic acid monohydrate (25 mg). The mixture was heated at 60° C. for 2 h and then at 80° C. for a further 5 h. The reaction was diluted with diethyl ether and washed with 5% NaOH (3×10 ml) followed by water (10 ml) and brine (10 ml). The organic phase was dried over Na2SO4 and concentrated in vacuo to give an oil (1.4 g) which was purified on a silica gel column using CH2Cl2 as eluant. Pooling of fractions containing the major slower running component afforded the title compound as a colourless solid (0.74 g), m.p. 60.5°-62° C. (from n-pentane/diethyl ether).
Reaction SMILES: [C:1]1([CH2:11][C:12]2[C:13]([NH2:18])=[N:14][NH:15][C:16]=2[NH2:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:19](OC)(=[O:25])[CH2:20][C:21](OC)=[O:22].C[O-].[Na+]>CO>[NH2:18][C:13]1[C:12]([CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[C:16]2[NH:17][C:19](=[O:25])[CH2:20][C:21](=[O:22])[N:15]2[N:14]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1n[nH]c(N)c1Cc1cccc2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nn2c(c1Cc1cccc3ccccc13)NC(=O)CC2=O
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1-naphthalenylmethyl)-1H-pyrazole-3,5-diamine (2.18 g, 9.15 mmol), dimethyl propanedioate (3.63 g, 27.4 mmol) in Methanol (30 mL) was added sodium methoxide (1.68 g, 31.1 mmol). The reaction mixture was stirred at 65° C. for 18 h. After the reaction mixture was cooled down, the solvent was evaporated. Water (10 mL) was added in. The solid precipitated. The mixture was neutralized with 1 N HCl. The precipitated product was filtered and dried in vacuo (2.7 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.65 (s, 2H) 4.21 (s, 2H) 5.59 (br. s., 2H) 7.08 (d, J=6.82 Hz, 1H) 7.27-7.45 (m, 1H) 7.48-7.66 (m, 2H) 7.79 (d, J=8.34 Hz, 1H) 7.88-8.00 (m, 1H) 8.16 (d, J=8.34 Hz, 1H) 11.34 (s, 1H). LC/MS: MS (ES+) m/e 307.0 [M+H]+.