Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]([O:11][C:12](=[O:18])[C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[CH:7]1[CH2:10][O:9][CH2:8]1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].CO.Cl>O1CCCC1.O>[C:4]([CH:6]([O:11][C:12](=[O:18])[C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[CH:7]1[CH2:10][O:9][CH2:8]1)([OH:5])=[O:3]
Reactant: C=CC(C)(C)C(=O)OC(C(=O)OCC)C1COC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)(C)C(=O)OC(C(=O)O)C1COC1
Yield: 66.7 %

Procedure:
To a stirred solution of 2,2-dimethyl-but-3-enoic acid ethoxycarbonyl-oxetan-3-yl-methyl ester (207 mg, 0.808 mmol) in tetrahydrofuran (81 mL) was added a solution of potassium carbonate (123 mg, 0.888 mmol) in water (20.25 mL) followed by methanol (4.05 mL). The reaction mixture was heated to reflux for 7 h and then allowed to cool. Hydrochloric acid (2 M, 400 μL) was added (pH 7) and the solvents were evaporated. The residue was extracted with dichloromethane (2×) and the washes discarded. The aqueous was acidified with hydrochloric acid (2 M) to pH 5, extracted with dichloromethane (2×) and the combined organic extracts passed through a hydrophobic frit and evaporated. To the aqueous layer was added hydrochloric acid (about 5 drops) and the mixture was extracted with dichloromethane (2×) and the combined organic extracts passed through a hydrophobic frit, evaporated and combined with previous material to give the title compound (123 mg, 67%) as a yellow/green oil. 1H NMR (300 MHz, CDCl3) δ 1.39 (s, 3H), 1.40 (s, 3H), 3.54-3.67 (m, 1H), 4.67-4.75 (m, 2H), 4.81-4.92 (m, 2H), 5.14 (d, J=10.9 Hz, 1H), 5.15-5.32 (m, 2H), 6.08 (dd, J=17.5, 10.5 Hz, 1H), 9.30 (br s, 1H). LCMS (m/z) 229.1 [M+H] Tr=1.67 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.[OH-].[Na+]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22])=[N:3][N:4]=[CH:5]2
Reactant: Cc1ccccc1B(O)O
Reactant: Clc1ccc2c(Cl)nncc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccccc1-c1nncc2cc(Cl)ccc12
Temperature: 78 °C

Procedure:
A mixture of 1,6-dichlorophthalazine (1.04 g, 5.21 mmol), tetrakis(triphenylphosphine)palldium (0.30 g, 0.26 mmol), o-tolylboronic acid (0.57 g, 4.2 mmol) in 2 N aq. sodium carbonate (5 mL), 1,4-dioxane (5 mL) and ethanol (2.5 mL) was heated in a Personal Chemistry microwave at 78° C. for 45 min. The mixture was treated with 1 N sodium hydroxide (10 mL), extracted with ethyl acetate (2×35 mL). The combined ethyl acetate layers were dried and concentrated. Purification on an ISCO column (40 g, eluted with 30-75% ethyl acetate in hexanes) provided 6-chloro-1-o-tolylphthalazine as a brown amorphous solid. MS (ESI, pos. ion.) m/z: 255 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7]Cl.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]>CN(C)C=O>[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]
Reactant: ClCCCCCl
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1CCCCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (3.87 g of 50% dispersion in oil, 0.0807 mole) was suspended and stirred in 80 ml of dry dimethylformamide. A solution of 1,4-dichlorobutane (44 ml, 0.404 mole) and 2-piperidone (8 g, 0.0807 mole) in 100 ml of dimethylformamide was added dropwise over 1 hour, maintaining the temperature at 25°-30° C. by use of a water bath. The reaction mixture was stirred for 16 hours at room temperature, then byproduct salt removed by filtration and the mother liquor evaporated in vacuo to one-tenth volume. The resulting concentrate was distributed between 100 ml of water and 100 ml of hexane. The lower, oily phase of three phases was separated, diluted with 50 ml of methylene chloride, dried over magnesium sulfate, filtered and evaporated to yield 1-(4-chloro-1-butyl)-2-piperidone as an oil [14.3 g; pnmr(CDCl3)delta 1.4-1.83 (4H, m), 3.03-3.72 (6H, m), 4.10-4.43 (2H, t, J=7)].
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH3:14])[CH:5]=1)=[CH2:3].[Li]C(C)(C)C.[CH:20]([CH:22]=[CH2:23])=[O:21]>>[CH2:13]([O:12][C:6]1[CH:5]=[C:4]([CH:2]=[CH:3][CH:20]([OH:21])[CH:22]=[CH2:23])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH3:14]
Reactant: C=CC=O
Reactant: C=C(Br)c1ccc(OC)c(OCC)c1
Agent: [Li]C(C)(C)C
Product: C=CC(O)C=Cc1ccc(OC)c(OCC)c1
Yield: 86.2 %

Procedure:
According to the General Procedure C, 1-Bromo-1-(3-ethoxy-4-methoxyphenyl)ethene (1.40 g, 5.44 mmol), t-BuLi (8.00 ml, 13.60 mmol) and acrolein (914 mg, 16.32 mmol) are converted to give after workup and chromatography [SiO2, PE/EE gradient from 5:1 to 2:1, Rf (PE/EE=2:1)=0.31] the title compound (1.10 g, 4.69 mmol) as a colorless oil;
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:21][CH2:22][CH2:23][CH:24]([CH3:28])[C:25](Cl)=[O:26]>CC(=O)C>[ClH:21].[Cl:21][CH2:22][CH2:23][CH:24]([CH3:28])[C:25]([N:3]1[CH2:4][CH2:5][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH:2]1[CH3:1])=[O:26]
Reactant: CC(CCCl)C(=O)Cl
Reactant: CC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(CCCl)C(=O)N1CCN(Cc2ccccc2)CC1C
Product: Cl
Reaction time: 0.75 h
Yield: 45.5 %

Procedure:
To a stirred mixture of 20 parts of 2-methyl-4-(phenylmethyl)piperazine, 11.13 parts of sodium carbonate and 120 parts of 2-propanone were added dropwise 16.28 parts of a 4-chloro-2-methylbutanoyl chloride. Upon completion, stirring was continued for 45 minutes. The precipitated product was filtered off and taken up in dichloromethane. Water and sodium carbonate were added. The organic layer was separated, dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried in vacuo at 40° C., yielding 16.5 parts (45.5%) of 1-(4-chloro-2-methyl-1-oxobutyl)-2-methyl-4-(phenylmethyl)piperazine monohydrochloride (int. 25).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>ClCCl.CN(C)C=O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=4)[NH:9][N:8]=3)[CH2:5][CH2:6]2)=[CH:29][CH:28]=1
Reactant: Clc1ccc(-c2cc(C3CCNCC3)n[nH]2)cc1
Reactant: ClCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(CN2CCC(c3cc(-c4ccc(Cl)cc4)[nH]n3)CC2)cc1

Procedure:
A solution of 3-(4-piperidinyl)-5-(4-chlorophenyl)pyrazole (1.50 g), triethylamine (1.60 cm3) and 4-chlorobenzyl chloride (0.92 g) in 3:1 dichloromethane-dimethylformamide (20 cm3) was stirred at room temperature for 4.5 hours. Dichloromethane was removed by evaporation and the crude product was partitioned between water (25 cm3) and ethyl acetate (2×25 cm3). The combined organic extracts were washed with saturated brine (20 cm3), dried (MgSO4), filtered and evaporated to dryness to give an off-white solid. Recrystallisation from ethanol-water yielded the title compound as fine, white needles (0.575 g, 26%), m.p. 179°-181° C. (from EtOH/H2O); (Found: C, 65.19; H, 5.24; N, 10.86. C21H21N3Cl2 requires C, 65.29; H, 5.48; N, 10.88%.); δH (360 MHz; CDCl3) 1.71 (2H, apparent qd, J=12 and 3, 2×NCH2CHAHB), 1.84 (2H, apparent d, J=11, 2×NCH2CHAHB), 1.92 (2H, apparent t, J=11, 2×NCHAHB), 2.41-2.55 (1H, m, NCH2CH2CH), 2.84 (2H, apparent d, J=11, 2×NCHAHB), 3.44 (2H, s, NCH2Ar), 6.21 (1H, s, N=C--CH=C), 7.30-7.21 (6H, m, 6×ArH), 7.61 (2H, d J=8.1, 2×ArH) and 11.6-12.0 (1H, br s, NH); δC (90 MHz; CDCl3) 31.9 (t), 33.8 (d), 53.3 (t), 62.5 (t), 99.5 (d), 126.9 (d), 128.6 (d), 128.9 (d), 130.3 (d), 132.8 (s), 133.5 (s) and 136.8 (s). 3 quaternary carbons not observed; m/z (CI+ ; NH3) 386 (M+ +H; 30%), 262 (22), 228 (18), 210 (10), 196 (17), 179 (28), 162 (28), 154 (40), 142 (67), and 140 (100); m/z (CI- ; NH3) 420 (M- +Cl; 2%); 385 (M- ; 10), 259 (10), 178 (27) and 127 (20).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[C:6]([OH:12])[CH:5]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([O:12][CH3:14])[C:7]([CH3:11])=[C:8]([OH:10])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(C)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(O)c(C)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.1 g (28.2 mmol) of 3,5-Dihydroxy-4-methyl-benzoic acid methyl ester was dissolved in 100 ml of DMF and treated at 0° C. with 7.8 g (56.4 mmol) of potassium carbonate and 4.0 g (28.2 mmol) of methyl iodide. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The compound was purified by preparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% trifluoroacetic acid).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=O)C.[CH3:28][NH2:29]>C(O)CCC>[CH3:28][NH:29][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:3]
Reactant: CCOC(=O)CCCCCCCn1c(-n2ccnc2)c(C)c2ccccc21
Reactant: CN
Solvent: CCCCO
Product: CNC(=O)CCCCCCCn1c(-n2ccnc2)c(C)c2ccccc21

Procedure:
A solution of 4 g of 1-(7-ethoxycarbonylheptyl)-3-methyl-2-(1-imidazolyl)indole in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evaporated to dryness to yield 1-[7-(N-methylcarbamoyl)heptyl]-3-methyl-2-(1-imidazolyl)indole.
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:17])C=CC=CC=1.C([N:29]([CH2:32]C)CC)C>C1(C)C=CC=CC=1>[N:29]([C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)=[C:32]=[O:17]
Reactant: O=C(O)c1ccncc1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of isonicotinic acid (0.369 g, 3 mmol) (Aldrich) in toluene (15 mL) was added diphenylphosphoryl azide (0.958 g, 3.5 mmol) (Aldrich), followed by the addition of triethylamine (0.35 g, 3.6 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes and the mixture became clear. Then the mixture was heated at 80° C. for 2 hours. The mixture was cooling down to room temperature to give crude 4-isocyanato-pyridine as 0.2 M solution of toluene and used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25]([OH:27])=O.C(OC(Cl)=O)C(C)C.Cl.[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH2:42])[CH3:38]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH:42][C:25]([C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:8][CH:7]=1)=[O:27])[CH3:38]
Reactant: CCOC(=O)CN
Reactant: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1cnc(C(=O)c2cccc(OC)c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Yield: 6.3 %

Procedure:
A solution of 6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (30.0 mg, 81.65 mmol) in dry, N,N-dimethylformamide (2 mL) chilled in an ice-bath under argon. With stirring, triethylamine (14.4 uL, 102 mmol) and isobutylchloroformate (13.4 uL, 102 mmol) were added. The solution was stirred for 30 min and then solution of glycine ethyl ester hydrochloride (227 mg, 1,633 mM) in 4 mL of dimethylformamide and triethylamine (0.229 mL, 1.633 mM) were added and the reaction was allowed to warm to room temperature with stirring for 1 hr. and then diluted with ethyl acetate (30 mL), The ethyl acetate solution was washed sequentially with saturated sodium bicarbonate solution (2×5 mL), water (5 mL), and saturated sodium chloride solution (5 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 46 mg solid. This crude material was purified by flash chromatography, eluting with 50% ethyl acetate in hexanes (containing 1% acetic acid) and then increasing gradually to 80% ethyl acetate in hexanes After tlc analysis, fractions were pooled and evaporated to yield 36 mg (79.4%) of white, powder as an acetate salt: APCI-MS m/e calcd for C24H24N2O7 (M+H) 453.5, found 453; H NMR (300 MHz) compatible
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CC(C)=O>[CH2:17]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCOc1ccc(C=O)cc1

Procedure:
Anhydrous potassium carbonate (55.5 g, 0.4 mol) was added to a stirred solution of 4-hydroxybenzaldehyde (24.5 g, 0.2 mol) in acetone (300 cm3), over a period of 30 min at room temperature. 1-Bromoheptane (40.3 g, 0.225 mol) was added dropwise and the resulting mixture heated under reflux (12 h). The solution was poured into water (1000 cm3), the product extracted into diethyl ether (2×300 cm3), and the combined ethereal extracts dried (MgSO4). The solvent was removed in vacuo and the product isolated as a colourless oil by distillation under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.Cl[C:16]([O:18][CH3:19])=[O:17].O>C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)Cl
Reactant: Nc1ccccc1F
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
2-Fluoroaniline (10.0 mL, 0.104 mol) was dissolved in ethyl acetate (40 mL) to prepare a solution. Pyridine (10.0 mL, 0.124 mol) was added to the solution, and the mixture was cooled under ice cooling. A solution of methyl chloroformate (8.80 mL, 0.114 mol) in 10 mL of ethyl acetate was added dropwise to the cooled mixture over a period of 30 min. The reaction solution was warmed to room temperature followed by stirring for 3 hr. The disappearance of 2-fluoroaniline from the reaction solution was confirmed by high performance liquid chromatography. Thereafter, 20 mL of water was added thereto under ice cooling to stop the reaction. Next, 50 mL of ethyl acetate and 50 mL of water were added to the reaction mixture to carry out extraction. The organic layer was washed with 40 mL of water and 30 mL of a saturated sodium hydrogencarbonate solution and was then dried over an hydrous magnesium sulfate. The solvent was then removed from the organic layer by distillation to give 16.5 g of 2-fluoro-N-methoxycarbonylaniline as a substantially single product (yield 94.4%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].Cl[C:35](=[O:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][CH2:36][C:35]([NH:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:4]2[N:3]=[C:2]([NH2:1])[N:6]([C:7](=[O:16])[C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[N:5]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26])=[O:43])[CH3:42]
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Reactant: CCOC(=O)CCC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)NS(=O)(=O)c1ccc(Nc2nc(N)n(C(=O)c3c(F)cccc3F)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (1.0 g, 2.5 mmol) and THF (100 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (2.8 mL, 1.0 M solu in THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then ethyl 4-chloro-4-oxobutyrate (0.46 g in 10 mL THF, 2.8 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. After being concentrated, the residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/9:1) to afford the desired product (200 mg, 15%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.72 (d, 2H), 7.70 (m, 1H), 7.50 (d, 2H), 7.15 (t, 2H), 4.20 (q, 2H), 3.32 (s, 2H), 2.71 (s, 2H), 1.25 (t, 2H); MS (ESI) m/z: 523 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(Cl)Cl.[CH2:18]1[C:20]2([CH2:25][N:24]([C:26]3[N:27]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:28]4[C:33]([N:34]=3)=[C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:31]=[C:30]([C:41]3[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=3)[N:29]=4)[CH2:23][CH2:22][NH:21]2)[CH2:19]1>C(Cl)Cl.CO>[C:8]([N:21]1[CH2:22][CH2:23][N:24]([C:26]2[N:27]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:28]3[C:33]([N:34]=2)=[C:32]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[N:31]=[C:30]([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[N:45][CH:46]=2)[N:29]=3)[CH2:25][C:20]21[CH2:19][CH2:18]2)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNC5(CC5)C4)n(CC(F)(F)F)c3n2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
Triethylamine (56.8 μl, 0.41 mmol) and acetic anhydride (19.2 μl, 0.20 mmol) were added to a methylene chloride solution (3.0 ml) of 5-[8-(4,7-diazaspiro[2.5]oct-7-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (83.3 mg, 0.17 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then the reaction mixture was poured into methylene chloride-methanol (10:1), 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 (44.0 mg, 49%) as a light brown solid.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.C(C1C=C([CH:18]([C:20]2[N:21]([CH3:31])[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)O)C=CC=1)C.C(N([CH:38]([CH3:40])[CH3:39])CC)(C)C.[NH2:41][C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][C:43]=1[F:50]>C(Cl)Cl>[CH2:27]([C:26]1[CH:25]=[C:23]([N:41]([CH2:18][C:20]2[N:21]([CH3:31])[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][C:43]=2[F:50])[CH:40]=[CH:38][CH:39]=1)[CH3:28]
Reactant: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc(N)c(F)c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: CCc1cccc(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(C#N)cc2F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.8 %

Procedure:
Methansulfonic anhydride (77 mg, 0.44 mmol) was added to a solution of Intermediate 370.2 (81 mg, 0.28 mmol) and diisopropylethylamine (0.2 mL, 1.16 mmol) in CH2Cl2 (2.5 mL) at 0° C. The mixture was stirred for 1 h at 0° C. and then 4-amino-3-fluorobenzonitrile (136 mg, 1 mmol) was added. The mixture was stirred for 1 h at ambient temperature, diluted with CH2Cl2 (40 mL), washed with sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (EtOAc, hexanes) afforded 65 mg of Intermediate 382.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.11 (t, J=7.58 Hz, 3H) 2.54 (q, J=7.58 Hz, 2H) 3.69 (s, 3 H) 5.60 (d, J=5.87 Hz, 1H) 6.10-6.16 (m, J=1.96 Hz, 1H) 7.06-7.24 (m, 6H) 7.27-7.39 (m, 3H) 7.99-8.04 (m, 2H).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:10])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccccc21
Reactant: BrCc1ccccc1
Product: O=C1CC(Cc2ccccc2)c2ccccc21

Procedure:
This compound was prepared according to the method described by B. M. Trost and L. H. Latimer in J. Org. Chem. 42 (1977) 3212. The starting compounds were 1-indanone and benzyl bromide.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.P([O-])([O-])(O)=O.[Na+].[Na+].[NH2:17][C:18]1[C:31]2[C:30](=[O:32])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:33])[C:22]=2[C:21]([C:34]2[C:39]([CH3:40])=[C:38]([S:41]([OH:44])(=[O:43])=[O:42])[C:37]([CH3:45])=[C:36]([NH2:46])[C:35]=2[CH3:47])=[CH:20][C:19]=1[S:48]([OH:51])(=[O:50])=[O:49].[OH-].[Na+].[CH2:54]([NH2:57])[CH2:55][NH2:56]>O>[NH2:17][C:18]1[C:31]2[C:30](=[O:32])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:33])[C:22]=2[C:21]([C:34]2[C:39]([CH3:40])=[C:38]([S:41]([OH:44])(=[O:43])=[O:42])[C:37]([CH3:45])=[C:36]([N:46]([NH:56][CH2:55][CH2:54][NH2:57])[C:8]3[N:1]=[CH:2][N:4]=[C:5]([Cl:6])[N:7]=3)[C:35]=2[CH3:47])=[CH:20][C:19]=1[S:48]([OH:51])(=[O:50])=[O:49]
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1-c1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Reactant: NCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(-c2cc(S(=O)(=O)O)c(N)c3c2C(=O)c2ccccc2C3=O)c(C)c(S(=O)(=O)O)c(C)c1N(NCCN)c1ncnc(Cl)n1
Temperature: 40 °C

Procedure:
19 parts of cyanuric chloride are stirred vigorously into 50 parts of water, with addition of a wetting agent and 5 parts of disodium hydrogen phosphate, at a temperature of 0° C. A neutral solution of 53 parts of 1-amino-4-(3-amino-2,4,6-trimethyl-5-sulfophenyl)anthraquinone-2-sulfonic acid in 450 parts of water is added dropwise; during this procedure, the pH is kept at a value of 4.5 by addition of sodium hydroxide solution. When the reaction has ended, 6 parts of ethylenediamine in 54 parts of water are added dropwise such that the temperature remains below 15° C. and the pH remains at a value of 7. The pH is then increased to and kept at a value of 8.5. To bring the conversion to completion, the mixture is heated to a temperature of 40° C. towards the end of the reaction. A solution of 1-amino-4-{3-[(2-aminoethylamino)-6-chloro- 1,3,5-triazin-2-ylamino]-2,4,6-trimethyl-5-sulfophenyl}anthraquinone-2-sulfonic acid (solution 1) is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>ClCCCl>[Cl:9][CH2:10][C:11]([NH:8][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(N)ncn1
Solvent: ClCCCl
Product: Cc1cc(NC(=O)CCl)ncn1
Temperature: 80 °C

Procedure:
6-Methyl-pyrimidin-4-yl amine (545 mg) was suspended in DCE (5 mL) and chloroacetylchloride (0.4 mL) was added dropwise. The reaction was heated in a microwave at 80° C. for 5 mins. The reaction mixture was cooled, filtered and a solid obtained. The reaction was repeated a second time and both batches of solid were combined, washed with dichloromethane then suspended in dichloromethane and sat. NaHCO3 (aq.) was added. The organic phase was collected and the aqueous layer extracted with dichloromethane (×2). The combined organic layer was dried over sodium sulphate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the sub-titled compound as a yellow solid (120 mg).