Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 580 mg, 2.56 mmol) was dissolved in DMSO (20 mL). Sodium tert-butoxide (295 mg, 3.07 mmol) was added, followed by 1-(bromomethyl)-4-(methylsulfonyl)benzene (669 mg, 2.69 mmol) to give a brown solution. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with aqueous saturated NH4Cl, diluted with ethyl acetate, and washed with aqueous saturated NH4Cl (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was loaded onto an ISCO® silica gel cartridge (40 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow solid (403 mg, 40%). ESI-MS m/z [M+H]+ calc'd for C17H19ClN4O3S, 395.09; found 395.4.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:9]1([C:8]2[O:15][C:10]3[CH:11]=[CH:7][C:6]([NH2:3])=[CH:14][C:9]=3[CH:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Product: Nc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (63.4 ml, 0.455 mol) is added to 2-hydroxy-5-nitrobenzylphsophonium bromide (50 g, 0.101 mol) in refluxing toluene (600 ml), followed by addition of benzoyl chloride (16.2 ml, 0.140 mol) in toluene (50 ml). The mixture is refluxed for 3 hours, cooled and stirred at room temperature for 2 hours. The resulting mixture is concentrated and the product is recrystallized from 2/1 isopropyl ether/hexane, and the 2-phenyl-5-nitrobenzofuran is filtered off. This product is hydrogenated in THF (300 ml) and methanol (150 ml), with Pd/C (10%; 3.2 g). The catalyst is filtered off and the filtrate is concentrated. The residue is taken up in isopropanol/MeOH/HCl, and the hydrochloride is precipitated. It is suspended in 1M NaOH and extracted with ethyl acetate. The extracts are washed with water and concentrated. The solid is recrystallized from isopropyl ether. Yield: 9.8 g (32%); Elem. anal. C14H11NO; theory C, 80.36; H, 5.30; N, 6.70. found C, 79.78; H, 5.16; N, 6.87. IR (KBr): 3400, 3325, 1595, 1465 cm−1.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20](Br)[C:21]([O:23]C)=[O:22])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>O1CCOCC1>[CH3:19][O:18][C:16]1[CH:15]=[C:14]([CH:20]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]([OH:23])=[O:22])[CH:13]=[C:12]([O:11][CH3:10])[CH:17]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)C(Br)c1cc(OC)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(OC)cc(C(Sc2ccccc2)C(=O)O)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of benzenethiol (5.91 g) and potassium hydroxide (3.48 g) in dioxane (200 ml) was heated at 80° C. for one hour under nitrogen. After cooling down to 20° C., a solution of methyl 2-(3,5-dimethoxyphenyl)-2-bromoacetate (15.0 g) in dioxane (100 ml) was added and the mixture was refluxed for two hours. Additionally potassium hydroxide (1.5 g) was added and the reflux continued for further two hours. After cooling to room temperature, the suspension was filtered and the filtrate concentrated to dryness. The residue was partitioned between dichloromethane (300 ml) and aqueous hydrochloric acid (1M, 300 ml). The organic phase was dried and concentrated to dryness, leaving crude 2-(3,5-dimethoxyphenyl)-2-(phenylsulfanyl)acetic acid. Crystallization from diethyl ether gave the pure compound (7.2 g), m.p. 124-126° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][CH2:11][CH:12](C)CO)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH2:37][CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[CH3:12])[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(CO)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 47.3 %

Procedure:
(3-Hydroxy-2-methyl-propyl)-carbamic acid benzyl ester (5.0 g, 24.0 mmol) was dissolved in THF (175 mL) at 0° C. 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (6.7 g, 24.0 mmol) and triphenylphosphine (7.6 g, 29.0 mmol) were added. Diisopropyl azodicarboxylate (5.75 mL, 29.0 mmol) was added dropwise, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure and purified using silica gel chromatography (25% ethyl acetate in hexanes) to afford the title compound (5.33 g, 47%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH2:12])=[CH:3][CH:2]=1.[C:13](=N)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:27]([O:33][CH2:34][CH:11]([N:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: NCc1ccnc2ccccc12
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCC(N=C(c1ccccc1)c1ccccc1)c1ccnc2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
A Stirred mixture of 1-quinolin-4-ylmethanamine (142 mg, 0.90 mmol, CHEMBRIDGE) and benzophenone imine (163 mg, 0.90 mmol) was heated at 50° C. for 2 hours. The resultant product was dissolved in dichloromethane (4 ml) and added to a solution of chloromethyl pivalate (136 mg, 0.90 mmol) and tetrabutylammonium bromide (150 mg, 0.465 mmol). 50% NaOHaq (0.9 ml) was added to the reaction mixture at 0° C. After the mixture was stirred at 0° C. for 1 hour, the reaction was diluted with dichloromethane (30 ml) and water (30 ml). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified through silica gel column chromatography eluting with Hexane/EtOAc (3:1 to 2:1) to furnish the title compound (142 mg, 36% yield) as colorless oil. MS (ESI) m/z 437 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:14]=[C:13]([C:24]([O-:26])=[O:25])[C:12]=2[CH3:27])[CH3:10])=[CH:4][CH:3]=1.[Li+].[OH-].C1COCC1.Cl>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:14]=[C:13]([C:24]([OH:26])=[O:25])[C:12]=2[CH3:27])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=Cc1ccc(Cl)cc1)c1c(C)c(C(=O)[O-])nn1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=Cc1ccc(Cl)cc1)c1c(C)c(C(=O)O)nn1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.3 %

Procedure:
The mixture of 46e (3.34 mmol, 1.5 g), LiOH (13.3 mmol, 319 mg), THF (7 mL), MeOH (7 mL), and H2O (37 mL) was stirred at room temperature for 4 h. The mixture was acidified with 1N HCl to pH=5 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give 46f (202 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CCO>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH2:5][CH2:6]1
Reactant: Clc1ncccn1
Reactant: O=C1Cc2cc(C3CCNCC3)ccc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1Cc2cc(C3CCN(c4ncccn4)CC3)ccc2N1
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
To a solution of 5-(piperidin-4-yl)indolin-2-one (39.8 mg, 0.184 mmol) in EtOH 3 ml) were added 2-chloropyrimidine (33.7 mg, 0.294 mmol) and iPr2NEt (0.095 ml, 0.551 mmol). After stirring at 80° C. for 6 h, the reaction mixture was concentrated. The residue was purified by column chromatography (CHCl3/MeOH) to give 5-(1-(pyrimidin-2-yl)piperidin-4-yl)indolin-2-one (47.9 mg, 88%).
Reaction SMILES: O=C1[O:7][C:6](=[O:8])[CH2:5][N:4]([CH2:9][CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][C:22](=[O:24])[O:21][C:20](=[O:25])[CH2:19]2)[CH2:12][C:13]([OH:15])=[O:14])[CH2:3]1.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH3:61])=[O:38].C[N:63]([CH:65]=[O:66])[CH3:64]>>[C:13]([CH2:12][N:11]([CH2:10][CH2:9][N:4]([CH2:5][C:6]([OH:7])=[O:8])[CH2:3][C:65](=[O:66])[NH:63][CH2:64][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:38])[NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH3:61])[CH2:16][CH2:17][N:18]([CH2:19][C:20](=[O:25])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:38])[NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH3:61])[CH2:23][C:22]([OH:21])=[O:24])([OH:15])=[O:14]
Reactant: O=C(O)CN(CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Reactant: COCCOCCOCCOCCOCCOCCOCCNC(=O)CCCCCCCCCCN
Reactant: CN(C)C=O
Product: COCCOCCOCCOCCOCCOCCOCCNC(=O)CCCCCCCCCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)NCCCCCCCCCCC(=O)NCCOCCOCCOCCOCCOCCOCCOC)CC(=O)O)CC(=O)O
Reaction time: 0.25 h
Yield: 74 %

Procedure:
N,N-Bis[2-(2,6-dioxo-4-morpholinyl)ethyl]glycine (3.8 g; 10.6 mmol) (commercial product) was added to a suspension of 11-amino-N-(3,6,9,12,15,18,21-heptaoxadocosyl) undecan-amide (11.1 g; 21.1 mmol) in DMF (200 mL). After 15 min the reaction mixture became clear and the conversion was complete. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 and washed with H2O. The organic phase was separated, dried over Na2 SO4 and then evaporated under reduced pressure. The solid was dissolved in H2O and loaded onto an Amberlite® XAD-7 HP resin column (700 mL) and eluted with a CH3CN/H2O gradient. The fraction containing the product was evaporated to give the desired compound (11 g; 7.8 mmol). Yield 74%. HPLC: 85% (area %); K.F. 0.49%. Weight loss (120° C.): 0.45%. The 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: Cl.[NH2:2][OH:3].Cl[C:5](Cl)(Cl)[CH:6]([O:8]CC)O.S([O-])([O-])(=O)=O.[Na+].[Na+].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([O:28][CH3:29])[CH:22]=1>O.Cl>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:6](=[O:8])[CH:5]=[N:2][OH:3])=[C:23]([O:28][CH3:29])[CH:22]=1
Reactant: NO
Reactant: COc1cc(Br)ccc1N
Reactant: CCOC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Br)ccc1NC(=O)C=NO
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
Hydroxylamine hydrochloride (6.67 g, 96 mmol) in water (15 mL) was added to a suspension of 2,2,2-trichloro-1-ethoxyethanol (6.96 g, 36 mmol) and sodium sulfate (38.3 g, 270 mmol) in water (45 mL) and 2N HCl (30 mL). The mixture was stirred at 60° C. for 20 min. 4-Bromo-2-methoxybenzenamine (6.06 g, 30 mol) in 2N HCl (30 mL) was added, and the mixture was heated to 90° C. for 2 h. The mixture was cooled to room temperature. The solid was collected by filtration, washed with water, and air dried to afford the title compound (5.55 g, crude, 68% yield). This material was used in the next step without further purification. MS (ESI) m/e [M+1]+ 273, 275.
Reaction SMILES: C1C[O:4][CH2:3]C1.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:11]([F:23])[C:10]=1[F:24])[CH3:7].C([Li])(CC)C>CN(C=O)C>[CH2:6]([O:8][C:9]1([CH:3]=[O:4])[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:11]([F:23])[CH:10]1[F:24])[CH3:7]
Reactant: C1CCOC1
Reactant: CCOc1ccc(-c2cccc(F)c2F)c(F)c1F
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Product: CCOC1(C=O)C=CC(c2cccc(F)c2F)=C(F)C1F
Temperature: -65 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
THF (400 ml) was added to 4-ethoxy-2,2′,3,3′-tetrafluorobiphenyl (6) (39.25 g) prepared by means of a conventional coupling reaction in a reaction vessel under an atmosphere of nitrogen. The solution was cooled to −65° C. or lower, and sec-butyllithium (1.08 M in cyclohexane and n-hexane; 141.3 ml) was added dropwise. After the reaction mixture had been stirred at −65° C. for another 1 hour, N,N,-dimethylformamide (21.2 g) was added dropwise, and the reaction mixture was warmed slowly to room temperature. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and water (500 ml) was added to give two layers. The water layer was extracted with toluene (200 ml) twice, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was treated with silica gel chromatography (silica gel: 30 g, eluent: toluene) to give 4-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-carboaldehyde (7) (30 g) in 70% yield.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH:12]=[CH2:13].[BrH:15].C(O)(=O)C>ClCCl.[Br-].[Zn+2].[Br-]>[Br:15][CH:11]1[CH2:12][CH2:13][O:7][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:10]1
Reactant: C=CCCO
Reactant: O=Cc1ccc(Br)cc1
Reactant: Br
Agent: [Br-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1ccc(C2CC(Br)CCO2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.8 %

Procedure:
To a solution of 4-bromobenzaldehyde (1.00 g, 5.41 mmol) and 3-buten-1-ol (800 mg, 10.8 mmol) in dichloromethane (20 mL) at room temperature was added zinc (II) bromide (25 mg, 0.11 mmol) followed by 33% hydrobromic acid (2.4 g) in acetic acid (4.9 g, 81 mmol) and stirred at room temperature for 5 hours. Reaction was quenched by aqueous sodium bicarbonate, then extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.00 g) which contained some of 4-bromobenzaldehyde 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (d, 2H) 7.24 (d, 2H) 5.19 (dd, 1H) 4.25 (m, 1H) 4.12 (m, 1H) 3.60 (m, 1H) 2.75 (m, 1H) 2.68 (m, 1H) 2.11 (m, 2H).
Reaction SMILES: [N:1]1(CC(N2CCNCC2=O)=O)[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1cn(CC(=O)N2CCNCC2=O)c(=O)[nH]c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c[nH]c(=O)[nH]c1=O
Yield: 80 %

Procedure:
5.5 g, of N-(thymin-1-ylacetyl)-piperazinone (20.6 mmol) was suspended in 200 mL of dry DCM and treated with 3.77 g (1.5 eq, 30.9 mmol) DMAP, 11.23 g (51.5 mmol, 2.5 eq) Boc-anhydride and 7.2 mL (51.5 mmol, 2.5 eq) of triethylamine. The reaction also results in protection of the secondary amino group on the thymine. The reaction mixture was stirred at room temperature for 3-4 hours, while following the reaction progress by TLC. Upon completion, the reaction mixture was concentrated by rotary evaporation, and the resulting oil was resuspended in DCM. The organic phase was washed successively with 0.1 N HCl solution (2×25 mL), water (2×100 mL) and dried over sodium sulfate. Concentration and purification by recrystallization from diethyl ether afforded 6 g of the Boc-protected thymine PNA precursor (80% yield) as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].FC(F)(F)C(O)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:31]2[N:32]=[C:33]([O:40][C@@H:41]([C@H:43]3[CH2:47][NH:46][C:45](=[O:48])[CH2:44]3)[CH3:42])[C:34]3[N:35]([N:37]=[CH:38][CH:39]=3)[CH:36]=2)[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:31]2[N:32]=[C:33]([O:40][C@@H:41]([C@H:43]3[CH2:47][NH:46][C:45](=[O:48])[CH2:44]3)[CH3:42])[C:34]3[N:35]([N:37]=[CH:38][CH:39]=3)[CH:36]=2)[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:26][CH2:27][N:28]([S:2]([CH3:1])(=[O:5])=[O:3])[CH2:29][CH2:30]1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(S(C)(=O)=O)CC1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Methanesulfonic anhydride (9.5 mg, 0.05 mmol) was added to a solution of (R)-4-((R)-1-(6-(3-methoxy-4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.48 (22.4 mg, 0.04 mmol) and triethylamine (0.05 mL, 0.36 mmol) in dichloromethane (1.8 mL). After two hours, reaction mixture was loaded directly onto silica and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(3-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.50 (19 mg).
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[Br:13][C:14](Br)=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=1[Cl:24].S(=O)(=O)(O)O>CO.C1(C)C=CC=CC=1>[Br:13][C:14]#[C:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=1[Cl:24]
Reactant: CSc1ccc(C=C(Br)Br)c(Cl)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CSc1ccc(C#CBr)c(Cl)c1
Reaction time: 0.25 h
Yield: 12381.4 %

Procedure:
A suspension of Triton B (Reg Trade Mark, N-benzyltrimethylammonium hydroxide, 40% in methanol, 1.8 g) in toluene was added to a solution of 1,1-dibromo-2-[2-chloro-4-(methylsulphenyl)phenyl]ethene (0.96 g) in toluene. The mixture was stirred for 15 minutes. Sulphuric acid (2 m) was added and the resulting layers were separated. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromotography eluted with a mixture of hexane and dichloromethane to give 1-bromo-2-[2-chloro-4-(methylsulphenyl)phenyl]acetylene 90.78 g) as a yellow oil, NMR (CDCl3) 2.5 (s,3H), 7.05(d,1H), 7.2(s,1H), 7.35(d,1H).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2([CH2:16][CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13][CH2:12]2)[O:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[CH:28]([NH2:30])=O.[OH-].[Na+].[H][H]>[Pd]>[NH:14]1[CH2:13][CH2:12][C:11]2([C:2]3[N:1]=[CH:28][NH:30][C:3]=3[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[O:10]2)[CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: NC1C(=O)c2ccccc2OC12CCN(C(=O)OCc1ccccc1)CC2
Reactant: NC=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(c1)OC1(CCNCC1)c1nc[nH]c1-2
Temperature: 180 °C

Procedure:
Benzyl 3-amino-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (600 mg, 1.64 mmol) was added portion-wise to formamide (3.0 mL, 75 mmol) and the mixture was heated at 180° C. for 2 h. After cooling to room temperature, 3 mL of 1N NaOH was added and the resulting solution was extracted with dichloromethane. The organics were combined and washed with brine, dried over sodium sulfate, and evaporated to dryness. The crude material was filtered through silica gel eluting with 0-10% methanol in dichloromethane. The combined fractions were evaporated, and the residue (400 mg) was dissolved in methanol (5 mL). Pd/C (210 mg, 0.20 mmol) was added and the mixture was stirred under a balloon of hydrogen. The reaction was filtered and the filtrate evaporated to give 1H-spiro[chromeno[4,3-d]imidazole-4,4′-piperidine]. ESI-MS m/z calc. 241.3. found 242.5 (M+1)+; Retention time: 0.27 minutes (3 min run).
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1.Br[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1
Reactant: COC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1nc2cc(Cl)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(N(C)c2nc3cc(Cl)ccc3s2)cc1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A mixture of 4-[N-methyl-N-(5-chloro-2-benzothiazolyl)amino]phenol (2.0 g), methyl 2-bromopropionate (1.16 g), potassium carbonate (1.05 g) and dimethylformamide was heated at a temperature of 100° C. for a period of 1 hr with vigorous stirring. After cooling the mixture was poured into water and the aqueous mixture was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was recrystallised from methanol to give methyl 2-{4-[N-methyl-N-(5-chloro-2-benzothiazolyl)amino]phenoxy}propionate (1.55 g) as colourless crystals, mp 120° C.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)[S:7][CH:8]=1.[Li]CCCC.CN([CH:23]=[O:24])C>CCOCC.CCCCCC>[CH3:14][C:9]1([C:6]2[S:7][CH:8]=[C:4]([CH:23]=[O:24])[CH:5]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: CC1(c2cc(Br)cs2)OCCO1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(c2cc(C=O)cs2)OCCO1
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(4-bromo-thiophen-2-yl)-2-methyl-[1,3]dioxolane (1.00 g, 4.01 mmol) in Et2O (36.0 mL) at −78° C. was added dropwise n-BuLi (2.5 mL of a 1.6M solution in hexane, 4.00 mmol) over 15 min. The reaction mixture was then stirred at −78° C. for 15 min before DMF (3.1 mL, 40.14 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 10 min. Sat. aq. NaH4Cl (40 mL) was added and the aqueous layer was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-3-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.84 min. The crude material was dissolved, under inert atmosphere (N2) in MeOH (9.98 mL) and treated at 0° C., portionwise with NaBH4 (284 mg, 7.21 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was poured in water (16 mL) and the aq. layer was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC:rf (50:50 EA-Hept)=0.21. LC-MS-conditions 02: tR=0.71 min; [M+H]+=201.49.