Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([O:7][CH2:8][C:9]#[N:10])=[O:6].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22]>ClCCl>[CH3:2][N:3]([CH2:4][C:5]([O:7][CH2:8][C:9]#[N:10])=[O:6])[C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22]
Reactant: CNCC(=O)OCC#N
Reactant: C=CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)N(C)CC(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Cyanomethyl 2-(methylamino)acetate hydrochloride (Compound SP703) (3.00 g, 18.3 mmol) and triethylamine (6.34 ml, 45.5 mmol) were dissolved in dichloromethane (30 ml) under a nitrogen atmosphere, and pent-4-enoyl chloride (2.60 g, 22.0 mmol) was added dropwise at 0° C. The reaction solution was stirred at room temperature for 2 hours and 30 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solid was removed by filtration. The solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=1:10→2:7) to afford cyanomethyl 2-(N-methylpent-4-enamido)acetate (Compound SP704) (3.40 g, 88%).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)(=O)C.[O:15]1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:15][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:14])=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(CCC(=O)O)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: OCCCc1ccc(O)cc1
Yield: 65 %

Procedure:
To 3.82 g (17.36 mmoles) of methyl ester of 3-(4-acetylphenyl) propionic acid were added 100 ml of dry tetrahydrofurane. To this solution were slowly added 1.80 g (47.43 mmoles) of lithium aluminium hydride (LiAlH4). The reaction mixture was refluxed in an argon atmosphere for 4 hours. At the end of the reaction, water was carefully added, extraction was performed three times with diethyl ether and the result was vacuum dried over anhydrous sodium sulphate, giving 1.70 g (65% yield) of 3-(4-hydroxyphenyl)-1-propanol. Crystallisation in methanol gave a white crystalline solid m,.p.=52-53° C.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][O-:17].[Na+].O([Si](C)(C)C)[K].Cl>CS(C)=O.O>[CH3:16][O:17][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=c1[nH]cnc2cc(F)c([N+](=O)[O-])cc12
Reactant: C[O-]
Agent: C[Si](C)(C)O[K]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Yield: 75.6 %

Procedure:
7-fluoro-6-nitroquinazolin-4(3H)-one (60 g, 287 mmol) in <Step 3> of Example 3 was dissolved in DMSO (600 mL) and sodium methoxide (46.5 g, 861 mmol) was added dropwise thereto in an ice water bath. Thirty minutes later, KOTMS (147 g, 1150 mmol) was added slowly to the water bath, and the mixture was subjected to a reaction for one day. Then, the mixture was neutralized with a 2N HCl solution. Subsequently, the solid thus obtained was filtered and dried to obtain the title compound (48 g, 76%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]([C@@H:8]2[CH2:12][C@H:11]([S:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10][N:9]2[CH3:23])=[O:7])[CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:35]>C(Cl)Cl.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:13][C@@H:11]2[CH2:10][N:9]([CH3:23])[C@H:8]([C:6]([N:4]3[CH2:5][CH:2]([NH:1][C:34]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=4)=[O:35])[CH2:3]3)=[O:7])[CH2:12]2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(N)C3)N(C)C2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
0.60 g of (2S, 4S)-2-(3-aminoazetidin-1-ylcarbonyl]-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 18 ml of methylene chloride, and 0.38 ml of diisopropylethylamine and 0.46 g of p-nitrobenzyl chloroformate were added to the resulting solution, whilst ice-cooling, after which the mixture was stirred at the same temperature for 30 minutes. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography (silica gel 60 9385, manufactured by Merck, 40 g), to give 0.85 g of the title compound, in the form of an amorphous powder, from the fraction obtained by elution with a 95:5 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[H-].[Na+].[Br-].[Li+].Br[CH2:15][C:16]1[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>COCCOC.CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]#[N:23])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N#Cc1ccccc1CBr
Reactant: O=c1[nH]c(Cl)ncc1Br
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1Cn1c(Cl)ncc(Br)c1=O
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
5-Bromo-2-chloro-3H-pyrimidin-4-one (1.88 g, 9.0 mmol) was stirred in DME (25 mL)/DMF (5 mL) under nitrogen at 0° C. Sodium hydride (95%, 238 mg, 9.4 mmol) was added in portions. After 10 min, lithium bromide (1.56 g, 17.9 mmol) was added and the reaction stirred for 15 min at r.t. α-Bromo-o-tolunitrile (3.5 g, 17.9 mmol) was added, and the reaction stirred at 65° C. for 8 h. The solution was diluted with EtOAc, washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (1:1:1 EtOAc/hexanes/CHCl3) gave 997 mg (34%) of 2-(5-bromo-2-chloro-6-oxo-6H-pyrimidin-1-ylmethyl)-benzonitrile as a white solid. 1H NMR (400 MHz, CDCl3): δ8.11 (s, 1H), 7.73 (dd, 1H, J=7.6, 1.2 Hz), 7.58 (dt, 1H, J=7.6, 1.2 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.16 (d, 1H, J=7.6 Hz), 5.69 (s, 2H). MS (ES) [m+H] calc'd for C12H7N3OBrCl, 324, 326, 328; found 324, 326, 328.
Reaction SMILES: [CH3:1][S-:2].[Na+].CN(C)C=O.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[C:13]#[N:14]>O>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[S:2][CH3:1])[C:13]#[N:14]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(C#N)cc1F
Reaction time: 0.33 h

Procedure:
Sodium thiomethoxide (3.88 g, 55.3 mmol) was added to a dimethylformamide (100 mL) solution of 3,4-difluorobenzonitrile (7.00 g, 50.3 mmol) over 20 minutes under ice water cooling, and the mixture was further stirred for 20 minutes at the same temperature. Water (200 mL) was added to the reaction mixture, and the solid precipitated therefrom was collected by filtration and washed with water. Thus, a crude product of the title compound was obtained. The crude product thus obtained was dissolved in ethyl acetate, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Thus, the title compound (7.30 g, yield: 87%) was obtained.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:7]1[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=1)[CH3:6].O>C1C=CC=CC=1>[Br:2][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:5][CH3:6])[CH:8]=1
Reactant: BrP(Br)Br
Reactant: CCc1cccc(CO)c1
Solvent: O
Solvent: c1ccccc1
Product: CCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorous tribromide (5.3 ml) was added to a solution of the product from step (i) (7.6 g) in benzene (150 ml) at 0° C. After 3 hours, water (40 ml) was added and the mixture warmed to room temperature and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 2% ethyl acetate in isohexane. Yield 8.0 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:31]=1[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]=2[O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:7]=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]=1
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: CCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OC)c1
Yield: 74.6 %

Procedure:
A mixture of 1.5 g (4.86 mmol) of 3-(decyloxy)-5-hydroxybenzoic acid methyl ester, 2.2 g (4.86 mmol) of 1-(6-bromohexyl)-2,3-bis (phenylmethoxy)benzene, 1.3 g (9.7 mmol) of potassium carbonate and 0.73 g (4.86 mmol) of sodium iodide in 50 ml of acetone and 15 ml of DMF was stirred at reflux for 48 hours. After the usual workup, the crude product was purified by HPLC using 10% ethyl acetate-hexane to give 2.47 g (75% yield, mp 45°-46°) of 3-(decyloxy)-5-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]benzoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:14]([CH3:20])[C@@H:15]([O:18][CH3:19])[CH:16]=O)[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[N+](=[C:23](P(=O)(OCC)OCC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C@H:3]([C@@H:14]([CH3:20])[C@@H:15]([O:18][CH3:19])[C:16]#[CH:23])[C@@H:4]([CH3:13])[CH2:5][O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: CO[C@H]([C@@H](C)[C@H](C=O)OC)[C@@H](C)COC(=O)C(C)(C)C
Reactant: CCOP(=O)(OCC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#C[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 2,2-Dimethyl-propionic acid (2S,3S,4R,5R)-3,5-dimethoxy-2,4-dimethyl-6-oxo-hexyl ester (2.0 g, 6.94 mmol) in anhydrous methanol (100 ml) at 0° C. and under an atmosphere of nitrogen was added diethyl 1-diazo-2-oxopropylphosphonate (1.6 ml, 10.4 mmol) and potassium carbonate (1.44 g, 10.4 mmol). The reaction was stirred at 0° C. for 1 hour and then room temperature for 2 hours, after which it was quenched with saturated ammonium chloride and extracted with diethyl ether (3×). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by flash chromatography (SiO2, iHex/EtOAc, 15:1) to afford 1.67 g (85%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 4.22 (dd, J=10.7 Hz, 3.6 Hz, 1H), 4.07 (dd, J=10.7 Hz, 5.8 Hz, 1H), 3.87 (dd, J=9.6 Hz, 2.0 Hz, 1H), 3.46 (s, 3H), 3.44 (m, 1H), 3.40 (s, 3H), 2.48 (d, J=2.0 Hz, 1H), 1.97 (m, 2H), 1.23 (s, 9H), 1.00 (d, J=6.9 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH2:4].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH3:6].[H-].[Na+]>C(OCC)C.O1CCCC1>[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:2][CH2:3][NH:4][C:14]2=[O:15])=[CH:9][CH:8]=1)[CH3:6]
Reactant: NCCCl
Reactant: CCc1ccc(N=C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1ccc(N2CCNC2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.5 %

Procedure:
To a solution of 3.98 g of 2-chloroethylamine in 30 ml of diethyl ether, a solution of 3.68 g of 4-ethylphenyl isocyanate in 15 ml of tetrahydrofuran was added dropwise under ice cooling. After the resultant mixture was stirred at room temperature for 30 minutes, diethyl ether was added, followed by the collection of precipitated crystals by filtration. The crystals so obtained were added under ice cooling to a suspension of 10.8 g of 60%-sodium hydride in 35 ml of tetrahydrofuran, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, to which 1N hydrochloric acid was added. Resulting crystals were collected by filtration and washed with n-hexane, whereby 3.64 g of the title compound were obtained (yield: 89%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:30][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:21]=1)[C:17]([NH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:36]2[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]2)=[CH:7][CH:8]=1)=[O:31]
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Reactant: OC1CCNCC1
Product: O=C(Nc1ccc(OCCCN2CCC(O)CC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 4-hydroxypiperidine according to conditions described in general procedure L. A yellow powder is produced (0.137 g, 80%). MS: 506 (M+1).
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][CH3:32])=[CH:26][C:25]=1[N+:33]([O-:35])=[O:34])(=O)=O>CN(C=O)C>[CH3:32][O:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:25]([N+:33]([O-:35])=[O:34])[CH:26]=1
Reactant: COCc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
A stirred solution of bis(1,1-dimethylethyl) propanedioate (1.672 g, 7.73 mmol) in anhydrous DMF (25 mL) under argon was cooled to 0° C. and treated, portionwise with sodium hydride (0.297 g, 7.42 mmol) which was added over 10 mins. The resultant mixture was stirred at 0° C. for 15 mins and then allowed to warm to rt. After 1 hr the mixture was cooled back to 0° C. and treated with a solution of 4-[(methyloxy)methyl]-2-nitrophenyl trifluoromethanesulfonate D122 (1.95 g, 6.19 mmol) in DMF (5 mL) which was added slowly over 10 mins. After the addition was complete the cooling bath was removed and the mixture allowed to warm to rt. After 1 hr TLC indicated little or no reaction. The mixture was then warmed to 70° C. for 16 hr, then cooled to room temp and the solvent was removed under vacuum. The dark brown oily reside was dissolved in EtOAc (100 mL) and washed thoroughly with water (6×50 mL) and brine (50 mL), dried (MgSO4) and concentrated to dryness under vacuum. The residue was subjected to silica gel chromatography eluting with 0-5% MeOH in DCM to give the title compound as a yellow oil (1.32 g, 55.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:15]=1[NH:14][C:13]1[CH:12]=[N:11][CH:10]=[CH:9][C:8]2=1.[Cl:16]N1C(=O)CCC1=O>C1COCC1>[Cl:16][C:4]1[C:3]([O:2][CH3:1])=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[NH:14]2)=[CH:6][CH:5]=1
Reactant: COc1cccc2c1[nH]c1cnccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COc1c(Cl)ccc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a mixture of 8-methoxy-β-carboline (1.0 g, 5 mmol) in THF (100 ml) was added N-chlorosuccinimide (0.70 g, 5.2 mmol). The reaction was stirred at RT for 4 h before concentrating and washing the residue with 1:1:1 mixture of 10% Na2CO3, hexane, and EtOAc (400 ml). The resulting residue was triturated with xylenes to provide 677 mg of 7-chloro-8-methoxy-β-carboline.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:21][CH:22]2[CH2:26][O:25]C(C)(C)[O:23]2)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:29][CH3:30])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:31])[CH:5]=1.Cl.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([OH:23])[CH2:26][OH:25])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:29][CH3:30])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:31])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC3COC(C)(C)O3)c(Cl)c1Cl)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC(C)=O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC(O)CO)c(Cl)c1Cl)C2
Reaction time: 2 h

Procedure:
A mixture of 165 mg of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate from Example 109, Step A is dissolved in 100 ml. of 0.075 N hydrochloric acid and 20 ml. of acetone and heated, with stirring at 50°-55° C. for 2 hours. The mixture is cooled and neutralized with a solution of sodium bicarbonate. The solution is saturated with sodium chloride and extracted two times with 100 ml. portions of 20% tetrahydrofuran in ether. The extract is dried over Na2SO4. After filtration, the filtrate was concentrated to a yellow oil that solidified on standing. After recrystallization from tetrahydrofuran-ether-petroleum ether, there is obtained 110 mg. of product, m.p. 135°-138° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[N:6][C:7]=1[O:8][CH3:9].[CH3:11][C:12]1(C)[C:16](C)(C)OB(C(C)=C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O.CCOC(C)=O.CCOCC>[CH3:9][O:8][C:7]1[N:6]=[C:5]([NH2:10])[CH:4]=[CH:3][C:2]=1[C:12]([CH3:16])=[CH2:11]
Reactant: COc1nc(N)ccc1Br
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C(C)c1ccc(N)nc1OC
Temperature: 150 °C

Procedure:
To a solution 5-bromo-6-methoxypyridin-2-amine (1.72 g, 8.47 mmol) in dimethylacetamide (26 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.07 mL, 11.0 mmol), palladium tetrakis(triphenylphoshine) (979 mg, 847 μmol) and tribasic potassium phosphate (3.6 g, 16.9 mmol) in water (7.63 mL, 424 mmol). The mixture was sealed in a microwave vial and heated at 150° C. in a microwave for 15 min. Upon cooling, the mixture was diluted with EtOAc and Et2O, washed with water and brine, concentrated on to silica gel, and chromatographed (10% to 40% EtOAc in hexanes) to give 6-methoxy-5-(prop-1-en-2-yl)pyridin-2-amine contaminated with catalyst-derived impurities (−950 mg). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 7.34 (d, J=8.0 Hz, 1H), 6.06 (d, J=8.1 Hz, 1H), 5.19 (m, 1H), 5.09 (m, 1H), 4.29 (br. s, 2H), 3.91 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1.[S:36]1[CH:40]=[N:39][N:38]=[C:37]1[NH2:41].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:41][C:37]4[S:36][CH:40]=[N:39][N:38]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nncs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 8 h
Yield: 60.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-5-fluoro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE GGGGG, 1.233 g, 2.310 mmol) 1,3,4-thiadiazol-2-amine (0.280 g, 2.77 mmol), and cesium carbonate (2.258 g, 6.93 mmol). Acetonitrile (11.55 ml) was added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g SNAP Ultra column, 0-5% MeOH/DCM) to give 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (632 mg, 1.402 mmol, 60.7% yield) as an off-white solid. m/z (ESI) 451.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20]>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:22][C:23]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH3:11])[N:3]=1)=[O:24])(=[O:21])=[O:20]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: CNc1nc(N)nc(OC)n1
Solvent: CC#N
Product: CNc1nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)nc(OC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2.1 g of 2-amino-4-methoxy-6-methylamino-1,3,5-triazine in 60 ml of hot acetonitrile was added, dropwise, 3.3 g of 2-chlorobenzenesulfonylisocyanate in 20 ml of acetonitrile. After stirring for 18 hours at room temperature, the mixture was filtered to yield the product named above melting at 224°-228°.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]([CH3:19])([CH2:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16])[CH3:12]>C(O)C.[Ni]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:10][C:11]([CH3:19])([CH2:13][CH2:14][C:15]([NH:18][CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])([CH3:17])[CH3:16])[CH3:12]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(N)CCC(C)(C)N
Agent: [Ni]
Solvent: CCO
Product: CC(C)(CCC(C)(C)NCc1ccccc1O)NCc1ccccc1O
Yield: 5.3 %

Procedure:
55.0 g of a bisazomethine prepared from 2 mols of salicylaldehyde and 1 mol of 2,5-diamino-2,5-dimethylhexane and with a melting point of 111°-112° C. are hydrogenated for 2 hours in 250 ml of ethanol in an autoclave in the presence of 5.5 g of Raney nickel at 100° C. and under a pressure of 80 atmospheres. The catalyst is filtered off and the filtrate is concentrated. The residue is recrystallised from 220 ml of ispropanol, collected by filtration, washed with n-hexane and dried in vacuo, affording 18.9 g (34% of theory) of N,N'-bis-(2-hydroxybenzyl)-2,5-diamino-2,5-dimethyl-hexane with a melting point of 102°-106° C. Two recrystallisations from a mixture of cyclohexane and ethanol yield 15.2 g of pure product with a melting point of 124°-125° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].ClC1C=CC=C(C(OO)=[O:24])C=1>C(OCC)(=O)C>[O-:24][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccccn1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
tert-Butyl (E)-3-(2-pyridyl)-2-propenoate (2.05 g, 10.0 mmol) was dissolved in ethyl acetate (10 ml), and 3-chloroperbenzoic acid (ca. 70%, 2.35 g, 10.5 mmol) was added thereto. The mixture was stirred at room temperature overnight. The reaction mixture was subjected to a silica gel (100 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (5:1, v/v) were collected and concentrated to give the title compound (2.14 g, 96%).