Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([O:15]C(=O)C)[CH2:12][N:11]2[C:10](=[O:19])[N:9]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:8]3=[O:28])=[CH:4][CH:3]=1.O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:19])[N:9]([C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:8]3=[O:28])=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@H](O)CN12
Reaction time: 4 h
Yield: 47.4 %

Procedure:
To a solution of (5S,7S)-5-(4-bromobenzyl)-3-(3,5-dichloro-phenyl)-7-acetoxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.10 g) in THF (5 mL), MeOH (0.10 mL), and water (0.10 mL) was added 2N LIOH (0.11 mL). After 4 hours, the mixture was quenched with acetic acid (0.10 mL) and concentrated. Purification by chromatography (Silica gel: 4% methanol/CH2Cl2, Chromatotron) afforded the titled compound (0.0435 g). MS (m/z) 469 (MH+), mp 88.3° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[N:7]3[CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:4][CH:3]=2)=[CH:34][CH:35]=1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Reactant: OB(O)c1ccc(Cl)nc1
Product: Clc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1

Procedure:
Compound 49a was prepared from compound 15a and 2-chloro-5-pyridineboronic acid using the methods described in Example 1, Step G. Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H21ClN6O2: 473.1 [M+H]. found 473.2
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1>>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:15][C:6]1=2
Reactant: O=C1CNc2ncc(I)cc2N1Cc1c(Cl)cccc1Cl
Reactant: OB(O)c1cccnc1
Product: O=C1CNc2ncc(-c3cccnc3)cc2N1Cc1c(Cl)cccc1Cl

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (150 mg) was reacted with pyridine-3-boronic acid as in General Procedure 4B to give the title compound as a brown solid. M.p.>200° C., LCMS: m/z=385.48 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.06 (2H, s), 5.45 (2H, s), 7.07 (1H, s), 7.45 (5H, m), 7.85 (1H, d, J=7.8 Hz), 8.01 (1H, s), 8.49 (1H, d, J=4.8 Hz), 8.67 (1H, s) (NMR and LCMS indicate presence of triphenylphosphine impurity)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: COc1cccc(C=O)c1
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2cccc(OC)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-methoxybenzaldehyde gave the title compound as white crystals m.p.:146° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1.Cl.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH:18]1[C:23](O)=[O:24].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([CH:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)[C:23](=[O:24])[CH:18]3[CH2:19][O:20][CH2:21][CH2:22][N:17]3[C:6]=2[N:7]=1
Reactant: Clc1ncc(NC2CCSCC2)c(Cl)n1
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCSCC1
Temperature: 95 °C
Reaction time: 4 h
Yield: 7.5 %

Procedure:
To a mixture of 2,4-dichloro-N-(tetrahydro-2H-thiopyran-4-yl)pyrimidin-5-amine (864 mg, 3.27 mmol) and morpholine-3-carboxylic acid hydrochloride (822 mg, 4.91 mmol) in DMSO (15 ml) was added diisopropylethylamine (2.29 ml, 13.1 mmol), and the reaction mixture was stirred at 95° C. for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude solid. The solid was chromatographed by silica gel (hexane/ethyl acetate, 19:1 to 3:2) to afford partially purified 2-chloro-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (83.6 mg, 0.245 mmol, 7.5% yield) as a white solid. MS [M+H] found 341.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](=[S:5])[S-:4].C[NH2+]C.C(=S)=S.[N+:13]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:15])=[O:14]>CO>[CH3:1][N:2]([CH3:6])[C:3](=[S:4])[S:5][CH:17]([CH2:16][N+:13]([O-:15])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: C[NH2+]C
Solvent: S=C=S
Solvent: CO
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccccc1
Yield: 51 %

Procedure:
Dimethylammonium dimethyldithiocarbamate (16.6 grams, 0.10 mole), carbon disulfide (7.6 grams, 0.10 mole), and β-nitrostyrene (14.9 grams, 0.10 mole) were dissolved in methanol (50 ml.). A rapid exothermic reaction ensued and the product precipitated. The reaction temperature was held to 35° C. with ice cooling. After several hours at 25° C., the product was filtered off, washed with methanol, and dried in air. The crude product melted at ca. 103° - 110° C. and weighed 22.9 grams (85%). Recrystallizations from hot methanol and from acetone-2-propanol solution (without heating) gave 13.8 grams of α-(nitromethyl)-benzyl dimethyldithiocarbamate melting at 104° - 108.5° C. (prior sintering). The infrared spectrum was essentially identical to the spectrum of analytically pure material.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:40])[C:29]3[N:33]=[C:32]([C@@H:34]4[CH2:38][CH2:37][CH2:36][O:35]4)[NH:31][C:30]=3[CH:39]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][C:28]1[C:29]2[N:33]=[C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[NH:31][C:30]=2[CH:39]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:27]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2[nH]c([C@@H]3CCCO3)nc12

Procedure:
59 mg (0.23 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 70 mg (0.21 mmol) (S)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 0.12 mL (0.70 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)(O)[O-].[Na+].II.CC1(C)N([O])C(C)(C)CCC1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: II
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)ccc1C=O
Temperature: 5 °C
Reaction time: 72 h

Procedure:
Following the general method of R. A. Miller and R. S. Hoerrner, Org. Lett., 5, 285 (2003), a solution of 2.5 g (14.1 mmol based on 97% purity) of 4-chloro-2-methoxybenzyl alcohol in 35 mL of toluene was treated with 35 mL of water and 3.54 g (42.3 mmol) of sodium bicarbonate. The resulting two-phase mixture was stirred at ambient temperature as 7.2 g (28.2 mmol) of iodine was added, followed by 0.223 g (1.41 mmol) of 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO). After 3 days, the dark mixture was cooled to 5° C. and quenched by addition of a solution of 1.8 g of sodium sulfite in 18 mL of water. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with brine. The organic phase was then dried over anhydrous sodium sulfate. The supernatant was concentrated to a volume of approximately 5 mL and kept at 5° C. for 1 h. The solid that separated was collected on a filter, washed twice with small volumes of cold toluene, and dried in vacuo to yield the title compound as a white solid. LC-MS 171 (M+1).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][NH:8][N:7]=1)([O-:5])=[O:4].[CH3:11][O:12][C:13]([C:15]1[O:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=1)=[O:14].C([O-])([O-])=O.[K+].[K+].[Br-]>CC(C)=O>[CH3:11][O:12][C:13]([C:15]1[O:16][C:17]([CH2:20][N:8]2[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)=[CH:18][CH:19]=1)=[O:14]
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-nitro-2H-[1,2,3]triazole (1.50 g, 13.15 mmol) in acetone (26.3 mL) was treated with 5-chloromethyl-furan-2-carboxylic acid methyl ester (2.66 g, 14.47 mmol) followed by K2CO3 (9.18 g, 65.75 mmol) and TBA bromide (848 mg, 2.63 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure, water (50 mL) was added and the product was extracted with EA (3×30 mL) and 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 hept-EA)=0.22. LC-MS-conditions 02: tR=0.90 min.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:15]3=2)[CH:10]=[C:9]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[CH3:5][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:15]3=2)[CH:10]=[C:9]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cc2ccc3sc4ccccc4c3c2[nH]1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccc3sc4ccccc4c3c2n1C

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 1H-[1]benzothieno[2,3-g]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a quantitative yield of ethyl 1-methyl-1H-[1]benzothieno[2,3-g]indole-2-carboxylate, mp 85°-86°, (PhCH3), (C,H,N).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:22](=[O:24])[NH:21][C:20]([CH3:25])=[N:19][C:18]=3[N:17]=[C:16]([S:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[S:31][CH:32]=3)[C:15]=2[C:40]#[N:41])=[CH:10][CH:9]=1)(=O)C.O1CCOCC1.[OH-].[Li+]>O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[S:31][CH:32]=[C:28]([CH2:27][S:26][C:16]3[C:15]([C:40]#[N:41])=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:9][CH:10]=4)[C:23]4[C:22](=[O:24])[NH:21][C:20]([CH3:25])=[N:19][C:18]=4[N:17]=3)[N:29]=2)=[CH:34][CH:35]=1
Reactant: CC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc3nc(C)[nH]c(=O)c23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c(-c3ccc(OCCO)cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
24 mg (0.04 mmol) of the compound from Example 8A were initially charged in 2.3 ml of a 2:1 mixture of dioxane and water, and 1.9 mg (0.08 mmol) of lithium hydroxide were added. The reaction mixture was stirred at RT for 4 h. A further 1.9 mg (0.08 mmol) of lithium hydroxide were added, and the mixture was stirred for another 4 h. 2 ml of water were added to the reaction. The mixture was extracted three times in total with in each case 4 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][N:14]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C>C(Cl)Cl.O>[CH:12]([CH:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:16][CH2:15][N:14]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.8 %

Procedure:
A solution of DMSO (0.54 mL, 7.66 mmol) in CH2Cl2 (1 mL) was added to a solution of oxalyl chloride (0.33 mL, 3.8 mmol) in CH2Cl2 (8 mL) at −60° C. After 5 min, a solution of di-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (1.10 g, 3.48 mmol) in CH2Cl2 (3 mL) was added. After 15 min, triethylamine (2.4 mL, 17 mmol) was added, and the reaction mixture was allowed to warm to rt. After 1 h, water (25 mL) was added, the organics were separated, and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organics were washed with brine (3×50 mL), 1% HCl (3×50 mL), water (50 mL), and 5% NaHCO3 (3×50 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (10 to 20% EtOAc in Hexanes gradient), yielding 0.873 g (80%) of the desired product as a white solid. Rf=0.70 in 50% EtOAc/Hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][NH:17][C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[BH4-].[Na+]>CC#N.CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]2[C:12]([CH2:15][CH2:16][NH:17][CH:18]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=CNC(=O)Cc2ccc(Cl)c(Cl)c2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(cc1OCc1ccccc1)C(Cc1ccc(Cl)c(Cl)c1)NCC2
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a suspension of N-[2-(4-benzyloxy-3-methoxy-phenyl)-vinyl]-2-(3,4-dichloro-phenyl)-acetamide (13.3 g, 30 mmol) in CH3CN (100 mL) at rt is added dropwise phosphoroxychloride (8.1 mL, 13.5 g, 88 mmol). The resulting white suspension is heated to reflux, and the resulting yellow solution is heated at reflux for 3 h. The dark yellow solution is allowed to cool and is evaporated to a yellow oil. The oil is taken up in MeOH (100 mL) and evaporated to yield an orange solid. The material is redissolved in MeOH (100 mL) and the solution is cooled to 0° C. NaBH4 (3.61 g, 95 mmol) is added in portions with gas evolution and a strong exotherm. The resulting white suspension is stirred at rt for 16 h. The reaction mixture is partitioned between EtOAc (200 mL) and water (200 mL), and the aqueous phase is extracted with EtOAc (3×200 mL). The combined organic phase is washed with water and brine, and evaporated to provide the title compound as a faint yellow oil which is used without further purification.
Reaction SMILES: [K+].[OH:2][CH2:3][CH2:4][C:5]([CH3:10])([CH3:9])[C:6]([O-:8])=[O:7].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>>[CH2:11]([O:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4][CH2:3][OH:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(CCO)C(=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)(CCO)C(=O)OCc1ccccc1
Yield: 67.5 %

Procedure:
Step B To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid monopotassium salt (60 mmol) and benzyl bromide (8.55 mL, 72 mmol) were added NaI (10.8 g, 72 mmol) and K2CO3 (8.29 g, 60 mmol). The reaction mixture was stirred at reflux for 18 h. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash column chromatography (EtOAc: hexanes=1:2) to give 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester as a colorless oil (9 g, 67%)
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3].[CH3:19][Si:20]([CH3:28])([C:22]([CH3:27])([CH3:26])[CH:23]([CH3:25])[CH3:24])Cl.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:20]([CH3:28])([CH3:19])[C:22]([CH3:27])([CH3:26])[CH:23]([CH3:25])[CH3:24])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O)c1C=O
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Reaction time: 4 h
Yield: 92.4 %

Procedure:
To a solution of 75.1 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid allyl ester in 0.6 l of N,N-dimethylformamide were added 81.0 g of dimethyl-(1,1,2-trimethyl-propyl)-chlorosilane and 45.5 g of triethylamine. The mixture was stirred for 4 h at rootn temperature and then evaporated in vacuo. The residue was taken up in 2 l of ethyl acetate, and the mixture was successively washed with 1N hydrochloric acid and with brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from hexane to give 108.8 g of 2-formyl-5-methoxy-6-methyl-3-[dimethyl-(1,1,2-trimethyl-propyl)silanyloxy]-benzoic acid allyl ester as white crystals of m.p. 81°-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:7]1[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: Cc1[nH]cnc1CSCCN
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C

Procedure:
To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) [prepared according to the procedure described in J. Org. Chem., 40, 2743 (1975)] in 200 ml of methanol at ambient temperature was added a solution of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 2.73 g; 11.2 mmoles) [prepared according to Belgian Patent 779,775] in 25 ml of methanol. After stirring for 30 minutes, a methanolic solution of the title compound was produced. The TLC [Silica/CH2Cl2 :CH3OH (90:10)] gave Rf=0.44.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.CN(C=O)C.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(N(C(C)C)CC)(C)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[N:8]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: BrCCCCCCCCCCBr
Reactant: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1oc2ccc(Cl)cc2c(=O)n1CCCCCCCCCCBr
Yield: 49.9 %

Procedure:
A slurry of 9.77 g of 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione (50 mmol) and 60 ml of DMF was treated with a solution of 1,10-dibromodecane (52.52 g, 0.175 mol) and DMF (60 ml) was added. Diisopropylethylamine (9.6 ml, 55 mmol) was added dropwise. A thermometer and condenser were attached, and the flask was placed in an oil bath. The reaction was heated to 60 C for approximately 3 hrs, cooled to 47 C and hexanes (150 ml) were added. The mixture was diluted with water (175 ml). The resulting solids were removed by filtration. The aqueous layer was washed with warm hexanes. The resulting solids were filtered from the hexane layer and recrystallized from warm hexanes to give 10.39 g of 6-chloro-3-(10-bromodecyl)-2H-1,3-benzoxazine-2,4(3H)-dione.
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16]C)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=3[C:2]1=2.[OH-].[Na+].O.O1CCCC1CO>CO.C(OCC)C.ClCCl.CO>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([OH:16])=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=3[C:2]1=2
Reactant: COC(=O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCC1CCCO1
Solvent: CO
Product: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1

Procedure:
A 250 mL single-necked, round-bottomed flask was equipped with a magnetic stirrer and stir bar, 125 mL addition funnel, and a nitrogen inlet. To the flask was added a solution of methyl 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoate (6.0 g, 18.84 mmol) in methanol (60 mL). The stirred batch was treated drop-wise over 10 minutes with a solution of 3 N aqueous sodium hydroxide (38 mL) and methanol (30 mL). A yellow precipitate appeared and re-dissolved. The batch was stirred at ambient temperature for 18 hours. Solvent was removed under reduced pressure and the stirred aqueous residue was acidified to pH 6-7 with 3 N aqueous hydrochloric acid (˜38 mL). The resulting slurry was stirred at 23° C. for 2 hours. The solid was collected on a filter and rinsed with water (4 mL). More product was extracted from the filtrate with a 2:1 (v/v) mixture of 2-methyltetrahydro-furan-tetrahydrofuran (30×300 mL). The combined organic extracts were concentrated in vacuo to provide a residue. This residue was transferred to a small fritted glass funnel where it was swished consecutively with water (5 mL), 4:1 (v/v) tetrahydrofuran-methanol (20 mL), 8:1 (v/v) dichloromethane-methanol (8 mL), and 5:1 (v/v) dichloro-methane-methanol (9 mL), sucking the solvent through the frit each time. This material was then thoroughly mixed with the first crop and placed in a small fritted glass funnel. An final swish with diethyl ether (25 mL) was performed and the solid was dried at 23° C. in a vacuum oven to constant weight. In this way the title compound was obtained as a bright yellow solid (4.7 g, 83% yield) of >99 A % purity by HPLC analysis.