Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]1[N:21]=[C:20]([C:22]#[N:23])[C:19]([C:24](OC)=[O:25])=[C:18]([NH:28][C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>[Pd].CCO>[O:25]=[C:24]1[C:19]2[C:18]([NH:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)=[N:17][C:16]([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:21][C:20]=2[CH2:22][NH:23]1
Reactant: COC(=O)c1c(C#N)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cccc(Nc2nc(N3CCCCC3CNC(=O)OC(C)(C)C)nc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
A mixture of methyl 2-(2-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)-4-cyano-6-(m-tolylamino)pyrimidine-5-carboxylate (310.1 mg, 0.645 mmol), palladium on carbon (72.4 mg, 0.680 mmol) in EtOH (8 mL), and 1N HCl (4 mL) was stirred at RT for 16 h. The mixture was filtered to remove the catalyst. The filtrate was treated with saturated aq NaHCO3 (20 mL) for 3 h. The mixture was concentrated under reduced pressure and the residue was extracted with EtOAc (2×40 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (213.4 mg, 73%). 1H-NMR (DMSO-d6) δ ppm 1.28 (s, 9H), 1.35 (br s, 1H), 1.49-1.56 (m, 2H), 1.67-1.69 (m, 3H), 2.31 (s, 3H), 3.06 (br s, 1H), 3.24 (br s, 2H), 4.16 (s, 2H), 4.67 (br s, 1H), 5.08 (br s, 1H), 6.77 (br s, 1H), 6.87 (d, 1H, J=7.0 Hz), 7.23-7.25 (m, 1H), 7.53 (br s, 2h), 8.07 (s, 1H), 8.55 (s, 1H). [M+H] calc'd for C24H33N6O3, 453; found, 453.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=1)[NH:10][CH2:9][CH2:8][CH2:7]2)([O-])=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=1)[NH:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1NCCC2
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cc2c(c(C(=O)O)c1)NCCC2
Yield: 95.6 %

Procedure:
A solution of 6-nitro-1,2,3,4-tetrahydroquinoline-8-carboxylic acid (4.5 g) in DMF (200 ml) was hydrogenated in the presence of 10% palladium on charcoal (1 g) for 5 hours. After removal of the catalyst by filtration, solvent was distilled away to give the title compound (3.72 g, 96.8%). This compound was recrystallized from DMF-ethanol to give brown crystals, mp 207-208° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:14]([O:18][C:19]([NH:21][C:22]1([C:37](O)=[O:38])[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[C:10]([C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:37]([C:22]2([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:23][CH2:24][N:25]([C:28]3[C:29]4[CH:36]=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:26][CH2:27]2)=[O:38])[CH2:3][CH2:4][OH:5])=[CH:13][CH:12]=1)#[N:11]
Reactant: N#Cc1ccc([C@@H](N)CCO)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
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: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(C#N)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
(S)-4-(1-amino-3-hydroxypropyl)benzonitrile (Intermediate 46) (195 mg, 1.11 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (400 mg, 1.11 mmol) and DIPEA (0.580 mL, 3.32 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (463 mg, 1.22 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 4-(1-(4-cyanophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (267 mg, 46.4%) as a white solid. (S)-tert-butyl 4-(1-(4-cyanophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (267 mg, 0.51 mmol) was suspended in dioxane (5.00 mL) and 4M hydrogen chloride in dioxane (0.769 mL, 22.14 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-cyanophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (70.0 mg, 15.1%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]([CH2:32][OH:33])[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[S:24]([N:27]=[CH:28][N:29]([CH3:31])[CH3:30])(=[O:26])=[O:25])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH2:21][C:19]1[CH:18]=[CH:17][C:16]([S:24]([N:27]=[CH:28][N:29]([CH3:30])[CH3:31])(=[O:26])=[O:25])=[C:15]([O:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:32][OH:33])[CH:20]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCCCC(CO)Nc1nc(Cl)ncc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C=NS(=O)(=O)c1ccc(N)cc1OCCC[C@@H](CO)Nc1nc(Cl)ncc1Br
Reaction time: 2 h

Procedure:
A solution of 145 mg (0.30 mmol) of 2-[4-(5-bromo-2-chloro-pyrimidin-4-ylamino)-5-hydroxy-pentyloxy]-N-dimethylaminomethylene-4-nitro-benzenesulfonamide in 20 ml of THF is mixed under argon at room temperature with 2.0 ml of an approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid. After 2 hours, the reaction solution is mixed again with 0.3 ml of Ti(III)Cl solution, and it is stirred for another 18 hours. The batch is diluted with ethyl acetate and made basic with 1N NaOH solution. The phases are separated, and the aqueous phase is extracted again from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/methanol 9:1; Flashmaster II). 90 mg (0.17 mmol, corresponding to 56% of theory) of the product is obtained.
Reaction SMILES: [OH-].[Ca+2].[OH-].O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12]>>[CH:11]1([OH:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:5][CH2:7][CH2:6][CH2:5][CH:10]=[CH:12]1
Reactant: CC(=O)c1ccccc1O
Agent: [Ca+2]
Agent: [OH-]
Product: OC1C=CCCCCCCCCC1
Temperature: 215 °C

Procedure:
A mixture of 180 parts of trans-1,2-epoxidodecane, 6 parts of calcium hydroxide and 0.3 parts of o-hydroxyacetophenone was refluxed at 210-220° C. for 3 hours in a three-necked flask equipped agitator, Dean-Stark trap, and temperature probe. After cooling and filtration 175 parts of the mixture containing 15% starting epoxide and 74% cyclododec-2-en-1-ol (85% conversion, 87% selectivity) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([O-])(=[O:11])=[O:10])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([Cl:22])(=[O:11])=[O:10])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])Cc1ccc(F)c(Oc2ccccc2)c1
Agent: [Na+]
Product: O=S(=O)(Cl)Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 0 °C

Procedure:
The sodium sulfonate obtained in step 1 is mixed with phosphorous pentachloride at room temperature for two days. An ice-water mixture is added and the aqueous solution is extracted with methylene chloride. The organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain (4-fluoro-3-phenoxyphenyl)methanesulfonyl chloride as a syrup (2.05 g).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 67.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (760 mg, 2.4 mmol) was reacted with (S)-tert-butyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate (1.3 g, 3.7 mmol) to afford the desired product (730 mg, 66%) as a light yellow solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C(OC(Cl)(Cl)Cl)([O:15][C:16](Cl)(Cl)[Cl:17])=O>O1CCCC1>[C:16]([Cl:17])(=[O:15])[O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N:4]([CH3:12])[CH3:3])[CH:6]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1cccc(OC(=O)Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (130 mg, 3.25 mmol, 1.11 equiv, 60%) was added in several batches to a solution of 3-(dimethylamino)phenol (400 mg, 2.92 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). The mixture was stirred at 0° C. for 30 min then ditrichloromethyl carbonate (296.74 mg, 1.00 mmol, 0.34 equiv) was added in several batches to the mixture at 0° C. The resulting solution was stirred for 4 h at 50° C. and used in the next step without any purification
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[OH:21])([CH3:10])([CH3:9])[CH3:8].C1(S(O[C@@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])(=O)=O)C=CC=CC=1>CS(C)=O>[C:7]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[O:21][C@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@H](C)OS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)[C@@H](C)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Potassium carbonate (5.66 g, 41 mmol) and 2,4-di-t-butylphenol (8.87 g, 43 mmol) were dissolved in dimethyl sulfoxide (175 mL) at 25° C. and allowed to stir overnight under a nitrogen atmosphere to ensure complete anion formation. A solution of 10.0 g (41 mmol) of methyl (2S)-2-(phenylsulfonyl)oxypropanate (12) in dimethyl sulfoxide (50 mL) was added to the anion at 25° C. and the reaction mixture was allowed to stir overnight. The reaction was quenched with water (200 mL) and the phases were separated. The aqueous phase was extracted with perchloroethylene (3×200 mL). The combined organic extracts were washed with water (3×300 mL), a saturated aqueous sodium chloride solution (1×300 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM silica gel 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 7 cm diameter×18 cm length) using hexane and ethyl acetate (29:1) afforded 10.1 g (77%) of methyl (2R)-2-(2,4-di-t-butylphenyloxy)propanate (17) as a thick oil: 1H NMR (CDCl3) δ1.29 (s, 9 H), 1.43 (s, 9 H), 1.60-1.65 (d, 3 H), 3.73 (s, 3 H), 4.75-4.82 (q, 1 H), 6.54-6.57 (d, 1 H), 7.08-7.12 (d, 1 H), 7.33 (s, 1 H); 13C NMR (CDCl3) δ172.9, 153.7, 143.0, 137.2, 124.2, 123.1, 110.5, 71.7, 52.0, 5.0, 34.2, 31.5, 29.9, 18.6; IR (neat) 2962 (vs), 1764 (s), 1740 (s), 1497 (s), 1235 (vs) cm-1.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.[CH:45]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH2:55])[CH:53]=2)[CH:48]=[CH:47][N:46]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCOCC1.[NH4+].[Cl-]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]3[C:2]([NH:55][C:52]4[CH:53]=[C:54]5[C:49]([CH:48]=[CH:47][N:46]=[CH:45]5)=[CH:50][CH:51]=4)=[N:3][CH:4]=[C:5]([CH2:34][N:35]4[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]4)[CH:6]=3)[N:9]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: Nc1ccc2ccncc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4ccncc4c3)n2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
A glass microwave reaction vessel was charged with 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (400 mg, 0.643 mmol) and isoquinolin-7-amine (139 mg, 0.965 mmol)(Ark Pharm, Inc, Libertyville, Ill.) in dioxane (2 mL) and the reaction mixture was cooled at 0° C. To this solution, sodium bis(trimethylsilyl)amide (1.0 N in THF, 2 mL, 2 mmol) was mixed. The red solution was stirred at 0° C. for 1 h and 25° C. for 16 h. The reaction mixture was diluted with saturated NH4Cl and extracted with EtOAc (3×). The organic extract was washed with saturated NaCl and dried over MgSO4. The solution was filtered and concentrated under a vacuum. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 5% 2M NH3-MeOH in DCM, to provide N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoquinolin-7-amine (150 mg, 31.3% yield) as a yellow solid. m/z (ESI, positive ion): 746 (M+H)+. 1H NMR (400 MHz, DMSO-d6): 6 ppm 2.63 (s, 3H) 2.82 (s, 3H) 3.06-3.10 (m, 4H) 3.57 (s, 2H) 3.70 (s, 3H) 3.75 (s, 3H) 4.86 (s, 4H) 6.84-6.97 (m, 4H) 7.30 (t, J=6.85 Hz, 4H) 7.72 (d, J=5.48 Hz, 1H) 7.74-7.79 (m, 1H) 7.82-7.88 (m, 1H) 8.35 (d, J=5.67 Hz, 1H) 8.39 (d, J=2.35 Hz, 1H) 8.58 (d, J=1.76 Hz, 1H) 8.75 (d, J=2.35 Hz, 1H) 9.13 (s, 1H) 12.19 (s, 1H).
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([CH:19]([SH:23])[C:20]([O-:22])=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH2:11]([CH:19]([SH:23])[C:20]([O-:22])=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18].[CH2:11]([CH:19]([SH:23])[C:20]([O-:22])=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18].[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Agent: CC(C)CCCCCC(S)C(=O)[O-]
Product: CCCC[Sn+2]CCCC
Temperature: 110 °C

Procedure:
A suitable reactor was charged with 248.7 grams (1.0 mole) of dibutyltin oxide and 425.4 grams (2.05 moles) of isooctylthioglycolate of commercial purity. The reaction mixture was heated under vacuum, with agitation, to about 110° C. while distilling off water of reaction. On cooling and filtering, 656.1 grams of dibutyltin bis(isooctylthioglycolate) was obtained as an oily liquid.
Reaction SMILES: [C:1](=[O:15])([O-])[O:2][C:3]1([C:12]#[N:13])[CH:8]=CC=C[CH:4]1C(C)C.[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:12]([C:3]([CH3:4])([O:2][C:1]([N:20]1[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]1)=[O:15])[CH3:8])#[N:13]
Reactant: CC(C)C1C=CC=CC1(C#N)OC(=O)[O-]
Reactant: OC1CCNCC1
Product: CC(C)(C#N)OC(=O)N1CCC(O)CC1
Yield: 98.1 %

Procedure:
50 g of 1-cyano-1-methylethylphenyl carbonate and 25 g of 4-hydroxypiperidine were heated at 130° C. After completion of the reaction, the resulting product was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1-1:2-0:1), thereby obtaining 50.5 g of the intended compound.
Reaction SMILES: [OH-].[Li+].[CH3:3][N:4]([CH3:28])[C:5]([CH2:7][C:8]1[N:12]2[CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[O:6]>O1CCCC1.C(Cl)(Cl)Cl.CO>[CH3:28][N:4]([CH3:3])[C:5]([CH2:7][C:8]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:6]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C)cc3)c(CC(=O)N(C)C)n2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc3ccc(C(=O)O)cn3c2CC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1M lithium hydroxide (84 ml, 15.4 mmol) was added dropwise to a solution of 6 (3.0 g, 8.53 mmol) in tetrahydrofuran (THF) (100 ml) and the solution stirred at room temperature overnight. Solvent was removed and the aqueous phase washed with chloroform, neutralized to pH 7 with 1M HCl and evaporated to dryness. The solid obtained was suspended in chloroform:methanol (9:1) (100 ml) and stirred for 1 h. The solid was removed by filtration, dried and purified by chromatography (chloroform:methanol, 9:1) to give hapten-I (1.67 g, 58%). NMR 13C(CD3OD) (d, ppm): 172.48, 171.05, 146.92, 146.09, 139.64, 132.69, 130.77, 130.01, 128.91, 127.9, 125.43, 117.55, 115.7, 38.27, 36.64, 30.53 and 21.71. MS: Mass formula (338.1503); Calc. Mass (338.1505).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[N:18][C:19]([N:22]4[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]4)=[N:20][CH:21]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:31].[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][CH:2]([F:36])[O:3][C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:21]=[N:20][C:19]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:29])[CH2:24][CH2:23]4)=[N:18][CH:17]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:31]
Reactant: CS(N)(=O)=O
Reactant: Cc1nc2ccc(-c3cnc(N4CCC(C(=O)O)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc2ccc(-c3cnc(N4CCC(C(=O)NS(C)(=O)=O)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Yield: 23.8 %

Procedure:
A solution of Example 23 (0.138 g, 0.28 mmol) in DCM (6 mL) was treated with methanesulphonamide (0.1 g, 1.0 mmol 1), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.2 g, 1.0 mmol) and 4-(dimethylamino)pyridine (0.033 g, 0.28 mmol) and the mixture was heated to reflux for 3 days. The reaction mixture was concentrated in vacuo and the crude residue was partitioned between DCM (20 mL) and water (10 mL). The organic layer was concentrated in vacuo, and the crude residue purified by FCC on silica gel (eluting with 0-10% MeOH/DCM), to give the title compound (38 mg, 24%) as a white solid. HPLC-MS (pH 10): MH+ m/z 571.7 [M+H]+, RT 1.49 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=1)=[CH:9][CH:8]=[C:7]([Br:29])[CH:6]=2.C(N(CC)CC)C.[CH2:37]([O:39][CH2:40][C:41](Cl)=O)[CH3:38]>ClCCl>[C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][C:17]1[CH:27]=[CH:28][C:14]([CH2:13][N:12]2[C:11]3[C:10]4[CH:9]=[CH:8][C:7]([Br:29])=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=[C:38]2[CH2:37][O:39][CH2:40][CH3:41])=[CH:15][CH:16]=1)([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNc2c(N)cnc3cc(Br)ccc23)cc1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
tert-Butyl {4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]benzyl}carbamate (8.46 g, 18.5 mmol), triethylamine (2.25 mL) and dichloromethane (92 mL) were combined. Ethoxyacetyl chloride (2.92 g, 24 mmol) was added dropwise to the mixture. The reaction was stirred for an additional 1.5 hours and then concentrated under reduced pressure. Ethanol (92 mL) and triethylamine (10.31 mL) were added to the residue and the reaction was heated at reflux temperature for 1.5 hours. A precipitate formed. The reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed sequentially with water and saturated aqueous sodium chloride. The organic fraction was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. An initial purification by flash column chromatography eluting with a gradient of CMA in chloroform (2–10%) was followed by recrystallization from acetonitrile to provide 3.4 g of tert-butyl[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylmethyl)benzyl]carbamate as yellow-orange crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].O>C1(C)C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 83 %

Procedure:
6.0 g (29.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 9b), 4.2 g (45.4 millimoles) of propionyl chloride and 100 ml of anhydrous toluene are kept at 80° C. for 6 hours. The product is then filtered off at 10° C., washed first with toluene and then with water, and dried under reduced pressure at 50° C. 6.5 g (83% of theory) of 2-(p-propionylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, hydrated with one mole of water per four moles of compound, are obtained as almost colorless crystals, of melting point 252°-253° C. after recrystallization from a dimethylformamide/water mixture.