Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[F:37][C:2]([F:1])([F:38])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCNCC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 2.3 g (4.32 mmol) of tert. butyl 4-{4-[9-(2,2,2-trifluoro-ethylcarbamoyl)-9H-fluoren-9-yl]-butyl}-piperazine-1-carboxylate and 6 ml of trifluoroacetic acid in 50 ml of dichloromethane is stirred for 14 hours at ambient temperature. Dilute sodium hydroxide solution is added cautiously, so that the solution has a pH of 9. The precipitate formed is filtered off, washed with water and dried.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]1[CH2:19][C@H:15]2[O:16][CH2:17][CH2:18][C@@:14]2([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[OH:34])=[O:21])[CH2:13]1.C=O.O.[C:38]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[CH:26][C:25]2[O:34][CH2:38][N:22]([C:20]([C@:14]34[CH2:13][C@H:12]([N:3]5[C:4](=[O:11])[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[C:2]5=[O:1])[CH2:19][C@H:15]3[O:16][CH2:17][CH2:18]4)=[O:21])[CH2:23][C:24]=2[CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C

Procedure:
A solution of the product of Step C (7.97 g, 15.5 mmol, 1 eq), paraformaldehyde (9.28 g, 310 mmol, 20 eq) and p-toluenesulfonic acid hydrate (2.94 g, 15.5 mmol, 1 eq) in toluene (300 mL) was heated to 130° C. for 18 hours in a flask equipped with a Dean-Stark trap. The solution was cooled to rt and concentrated. Purification by chromatography (200 g column) eluting with 25 to 60 to 100% ethyl acetate/heptane afforded the product of Step D. Calculated for C25H21F3N2O5: 487.1 (M+1). found: 487.2.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1(C)C(C)=CC=CC=1>[C:15]([N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:17])[CH3:16]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)N1c2ccccc2Sc2ccccc21
Yield: 93.7 %

Procedure:
The 10-acetylphenothiazine of formula (5) was synthesized by the following method. A 200-ml four-neck flask was loaded with 19.93 g (0.1 mole) of phenothiazine, 15.31 g (0.15 mole) of acetic anhydride, and 40 g of xylene, and the contents were subjected to heating under reflux conditions for 6 hours. The reaction liquid was cooled, the precipitate was separated by filtering, and the product washed with methanol. As a result, 22.6 g of 10-acetylphenothiazine having a molecular weight of 241.3 were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH:15]=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:17].OC1C=C2C(=CC=1)N(C)C(=O)C=C2.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.[BH4-].[Na+]>CO.O>[N:35]1([CH2:34][CH2:33][CH2:32][NH:31][CH2:15][CH2:14][CH2:13][O:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:17])[CH:4]=[CH:5]3)[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: NCCCn1ccnc1
Reactant: Cn1c(=O)ccc2cc(OCCC=O)ccc21
Agent: Cn1c(=O)ccc2cc(O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1c(=O)ccc2cc(OCCCNCCCn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 11.2 %

Procedure:
3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propionaldehyde (127.5 mg) prepared from 6-hydroxy-1-methylquinolin-2(1H)-one and N-(3-aminopropyl) imidazole (82.9 mg) were added to methanol (10 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride (31.4 mg) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (21 mg) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[C:6](Br)[C:5]([Br:10])=[C:4](Br)[C:3]=1[Br:12].[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Br:10][C:5]1[CH:6]=[C:7]([OH:8])[CH:2]=[C:3]([Br:12])[CH:4]=1
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Oc1cc(Br)cc(Br)c1
Yield: 44.4 %

Procedure:
Pentabromophenol (1.0 g, 2.05 mmol) and AlCl3 (4.1 g, 30.75 mmol) were mixed in toluene (20 mL) and heated at reflux temperature under a nitrogen atmosphere overnight. The reaction mixture was cooled, cautiously added to ice, filtered and the filtrate was extracted with EtOAc (3×50 mL). The organics were dried (Na2SO4) and concentrated in vacuo. The residue obtained was purified by chromatography on silica gel with EtOAc:heptane (1:4, v/v) as eluent to afford the title compound as a white solid (230 mg, 0.91 mmol, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]([O:17][C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24](OS(C)(=O)=O)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC>C(#N)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]1[CH2:22][CH2:23][C@@H:24]([O:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([NH2:1])=[N:3][CH:4]=[CH:5]3)[CH2:25][CH2:26]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reactant: Nc1nccc2cc(O)ccc12
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3c(N)nccc3c2)CC1
Temperature: 120 °C
Yield: 7.8 %

Procedure:
A suspension of 1-amino-6-hydroxyisoquinoline (0.08 g, 0.5mmol), methane-sulfonic acid trans-4-tert-butoxycarbonylaminocyclohexyl ester (176 mg) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (270mg, ˜2.2 mmol/g loading) in acetonitrile (2ml) were heated at 120° C. over a period of 15 minutes using the microwave. The excess supported reagent was removed by filtration, washing with acetonitrile followed by methanol, and the filtrate evaporated to dryness under reduced pressure. Purification was achieved by prep-HPLC to give cis-[4-(1-aminoisoquinolin-6-yloxy)cyclohexyl]carbamic acid tert-butyl ester (14 mg).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]([F:16])=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]=1[F:16]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1NCCn2c1cc1c(F)c(F)cc(Br)c12
Product: COc1ccc(-c2cc(F)c(F)c3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, off-white solid (77 mg, 94%), MS (ISP) m/z=329.2 [(M+H)+], mp 227.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8,9-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 4) (75.3 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[C:11]([F:16])[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccccc1F
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cccc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: C1(/C=[N:8]/[C:9]2[N:10]([CH2:14][CH2:15][CH3:16])[CH:11]=[CH:12][N:13]=2)C=CC=CC=1.Cl>>[CH2:14]([N:10]1[CH:11]=[CH:12][N:13]=[C:9]1[NH2:8])[CH2:15][CH3:16]
Reactant: CCCn1ccnc1/N=C/c1ccccc1
Agent: Cl
Product: CCCn1ccnc1N
Temperature: 25 °C
Yield: 55.6 %

Procedure:
A mixture of N-[(1E)-phenylmethylidene]-1-propyl-1H-imidazol-2-amine (0.92 g, 4.31 mmol) and 6N HCl (25 mL) was heated at reflux for 2 h. After cooling to rt, the reaction was concentrated to a residue then taken up in 2M aqueous Na2CO3 and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with CH2Cl2/MeOH/NH4OH (gradient, 950:47:3 to 900:90:10) to give 0.30 g (56%) of brown oil: 1H NMR (400 MHz, CDCl3) δ 6.63, 6.52, 4.00, 3.65, 1.75, 0.95; MS (ESI+) 126.7.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19](Br)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.[NH:34]1[CH2:37][CH:36]([NH:38]C(=O)OC(C)(C)C)[CH2:35]1.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O>CN(C=O)C.C(OC(=O)C)C.ClCCl>[NH2:38][CH:36]1[CH2:37][N:34]([C:19]2[N:20]=[C:21]([C:22]3[O:23][C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[N:25][N:26]=3)[C:16]([NH2:8])=[N:17][CH:18]=2)[CH2:35]1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(N2CC(N)C2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl N-tert butoxycarbonyl-5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-ylcarbamate (200 mg, 0.3858 mmol) and tert-butyl N-(azetidin-3-yl)carbamate (66.44 mg, 0.3858 mmol) and DIPEA (99.72 mg, 134.4 μL, 0.7716 mmol) in DMF (5 mL) was heated at 90° C. After this time, the reaction mixture was cooled to room temperature and diluted with ethylacetate (5 mL), washed with water (5 mL) and concentrated in vacuo to leave a solid. The solid was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1.319 g, 891.2 μL, 11.57 mmol) was added and the resulting solution stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo to leave an oil. The oil was redissolved in dichloromethane and concentrated in vacuo to leave the product, which was used crude in the next step.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15]>N1C=CC=CC=1>[SH:15][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1
Reactant: CC(C)CC(=O)c1ccc(O)nc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC(C)CC(=O)c1ccc(S)nc1
Temperature: 120 °C
Yield: 15 %

Procedure:
Combine 2-hydroxy-5-(3-methyl-butyryl)-pyridine (742 mg, 4.1 mmol) and phosphorus pentasulfide (1.88 g, 4.2 mmol) in pyridine (5 mL). Heat the mixture at 120° C. for 5 h under a nitrogen atmosphere. Cool the mixture to room temperature and partition between water and EtOAc. Collect the aqueous layer, wash with additional EtOAc and DCM. Acidify the aqueous layer with 1M aqueous HCl and extract with DCM (4×30 mL). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound (120 mg, 15%). MS (ES+) m/z: 196.2 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]([CH:17]([NH:23][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)[CH2:27]2)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[N:15][CH:16]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:34][CH2:33][C:32]([N:28]2[CH2:29][CH2:30][CH2:31][C@@H:26]([C:24]([NH:23][CH:17]([C:13]3[CH:14]=[N:15][CH:16]=[C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][F:1])[CH:12]=3)[CH2:18][C:19]([OH:21])=[O:20])=[O:25])[CH2:27]2)=[O:48])[CH2:36][CH2:37]1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2OCCF)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3cncc(-c4ccccc4OCCF)c3)C2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
73 mg (0.11 mmol) tert-butyl 4-(3-{(3R)-3-[(1-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate were dissolved in 13 ml methanol. 344 mg (1.09 mmol) barium hydroxide octahydrate were added. The mixture was stirred at room temperature for 20 hours and then concentrated to give 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}propanoic acid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:1][N:2]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNCCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCNC(=O)OCc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl 2-(methylamino)ethylcarbamate (0.05 g, 0.24 mmol) in CH2Cl2 (5 mL was cooled to 6° C. and treated with triethylamine (0.1 mL, 0.72 mmol) and methanesulfonyl chloride (0.02 mL, 0.24 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction was washed with 10% KHSO4, the organic layer was dried over Na2SO4, filtered and evaporated to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:7]2.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:34][S:35]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:6]1[CH2:7][C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH2:5]1)(=[O:37])=[O:36]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOS(C)(=O)=O)C2
Reaction time: 0.25 h

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octanol (1.95 g) and triethylamine (1.11 ml) in acetonitrile (20 ml) was dropwise added methanesufonyl chloride (0.494 ml) with cooling with ice. After the stirring was continued for 15 min, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (2.36 g) as an oil.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>O>[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[S:1]([Cl:14])(=[O:3])=[O:2])#[N:4]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccccc1S(=O)(=O)Cl
Temperature: 0 °C
Yield: 91.5 %

Procedure:
44 grams(0.24 mole) of saccharin and 100 grams(0.48 mole) of phosphorus pentachloride were stirred at 110° C. to 120° C. for 3.5 hours. The reaction mixture was then poured into 500 milliliters of ice and water, stirred until solidified, filtered, ground with water, re-filtered, and dried to give 44.3 grams of 2-cyanobenzenesulfonyl chloride and pseudosaccharin chloride. Based on saccharin, the per cent yield was 92.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[NH:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:3][C:7]1[N:12]=[N:11][C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1ccc(=O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a mixture of phosphorus oxychloride (20 ml) and acetonitrile (40 ml) heated at reflux was added a solution of n-butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (20 g) in acetonitrile (80 ml). The reaction was heated at reflux for 30 minutes, cooled and added to an ice cooled solution of K2CO3 (87.8 g) in water (600 ml) with vigorous stirring. The product was filtered off, washed with water and dried at 60° C. to give n-butyl 6-chloropyridazine-3-carboxylate (17.5 g, 80% yield), mpt 110°-111° C.
Reaction SMILES: [Cl-].[Li+].O.[CH2:4]([C:11]([CH2:22][CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]>CS(C)=O>[F:36][C:25]([F:37])([C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])[CH2:24][CH2:23][CH2:22][CH:11]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reaction time: 12 h
Yield: 44.5 %

Procedure:
Lithium chloride (985 mg, 23.24 mmol) and water (0.21 ml, 11.62 mmol) were added to a solution of diethyl 2-(6-heptenyl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)malonate (6.0 g, 11.62 mmol) in dimethyl sulfoxide (40 ml) followed by stirring for 12 hours at a temperature of 160° C. to 180° C. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40→1/30) to give ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate (2.3 g, Yield 44%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[N:21]1([CH2:27][C:28]2[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:29]=2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(CN2CCOCC2)c1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2c(c(Nc3cccc(CN4CCOCC4)c3)n1)SCC2
Reaction time: 20 h
Yield: 70.6 %

Procedure:
1.25 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine are placed in 5 ml dimethylformamide, first 1.05 ml diisopropylethylamine, then 0.960 g 3-morpholin-4-ylmethyl-phenylamine (J. Med. Chem. 1990, 33, 327) are added. The reaction mixture is sf 20 hours at 60° C., then after cooling evaporated down. The residue is extracted with dichloromethane and water, the organic phase is dried and evaporated to dryness. The residue is crystallised with petroleum ether/ethyl acetate. 1.28 g of the product are obtained as a powder.
Reaction SMILES: [CH3:1][C:2]1(C)C(C)(C)OB(C=C)O1.Cl[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:20][N:21]=2)[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:1]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:20][N:21]=2)[N:18]=1)=[CH2:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To an argon purged flask were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.65 ml, 45.1 mmol), tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.20 g, 11.3 mmol), cesium carbonate (11.0 g, 33.8 mmol), and PdCl2(dppf)-CH2Cl2 (0.461 g, 0.564 mmol). The mixture was dissolved in 38 mL of dioxane and 4 mL of water (0.25M 10:1) and was heated to 80° C. for 12 h. The mixture was cooled to room temperature, concentrated, and purified directly via MPLC (DCM/MeOH+1% NH4OH) to afford the title compound (3.0 g, 95% yield).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[C:27]([Cl:35])[CH:26]=1.C[Si](N[Si](C)(C)C)(C)C.[Li].CO>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[Cl:35][C:27]1[CH:26]=[C:25]([NH:24][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:30]=[CH:29][C:28]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: CC(=O)Nc1ccc(N)cc1Cl
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
A glass microwave reaction vessel was charged with 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (100 mg, 0.319 mmol) and N-(4-amino-2-chlorophenyl)acetamide (64.8 mg, 0.351 mmol, Aldrich) in THF (5 mL), argon was bubbled in for 2 min and the tube was sealed. The reaction mixture was cooled to 0° C., lithium bis(trimethylsilyl)amine (1 N in THF, 1 mL, 0.957 mmol) was added dropwise. The red solution was stirred at 0° C. for 1 h and then warmed to room temperature. The mixture was diluted with saturated NaHCO3 and extracted with EtOAc (3×).The organic extract was washed with satd. NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (25 g) eluting with a gradient of 2% to 5% 2 M NH3.MeOH in DCM to give N-(2-chloro-4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)acetamide (120 mg, 0.251 mmol, 79% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.84 (s, 1H); 9.74 (dd, J=7.92, 1.86 Hz, 1H); 9.47 (s, 1H); 8.89 (s, 1H); 8.42 (dd, J=4.70, 1.76 Hz, 1H); 8.30 (d, J=2.35 Hz, 1H); 7.55-7.63 (m, 1H); 7.45-7.54 (m, 1H); 7.08 (dd, J=7.82, 4.69 Hz, 1H); 5.85 (dd, J=10.95, 2.15 Hz, 1H); 4.01-4.10 (m, 1H); 3.72-3.85 (m, 1H); 2.92 (s, 3H); 2.24-2.39 (m, 1H); 2.08 (s, 3H); 1.96-2.05 (m, 2H); 1.73-1.91 (m, 1H); 1.56-1.70 (m, 2H). m/z (ESI, +ve ion) 478 (M+H)+.