Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[OH:10])[C:5]#[N:6].C.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[C:9]=1[OH:10])[C:5]#[N:6]
Reactant: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Product: N#Cc1cc(N)c(O)c(Br)c1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
To a 22-l, 3-neck round-bottom flask fitted with a stirring paddle, a Claisen adapter fitted with a thermocouple and a condenser blanketed with nitrogen, and an addition funnel capped with a septum was added a mixture of 3-bromo-4-hydroxy-5-nitrobenzonitrile (96.9 g, Step A) in methanol (14 l). To this mixture was added iron (III) chloride (9.3 g) and activated charcoal (38 g, Darco 6-60, 100-mesh powder). The mixture was heated to reflux (65° C.) and stirred for 15 min at this temperature. Hydrazine (80 ml) was added to the refluxing mixture dropwise via addition funnel. Once the addition was complete, the mixture was stirred at reflux for 2 h. The mixture was then allowed to cool, filtered through Celite, washing with methanol, and concentrated to a red oil. A mixture of 300 ml of acetic acid and 700 ml of methanol was added and the mixture was concentrated again and then co-concentrated twice with 800 ml of toluene. The residue was purified by flash chromatography on an Isco Companion XL, 1.5 kg column, eluting with 3 column volumes of 30% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 30 to 60% over 6 column volumes, followed by 2 column volumes of 60% ethyl acetate in hexanes to provide 40 g (55%) of the title compound. Mass spectrum (ESI) 214.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:17]([OH:18])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:21][C@@H:22]1[CH2:26]OS(=O)(=O)[N:23]1C(OC(C)(C)C)=O.Cl>CN(C=O)C.O>[NH2:23][C@H:22]([CH3:26])[CH2:21][O:18][C:17]1[C:2]([Br:1])=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:16]=1
Reactant: C[C@@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: CCOC(=O)N1CCc2cc(O)c(Br)cc2CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2cc(Br)c(OC[C@@H](C)N)cc2CC1
Reaction time: 0.17 h
Yield: 112.5 %

Procedure:
Under an argon atmosphere, to a solution of 1.7 g of ethyl 7-bromo-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 30 ml of DMF was added 283 mg of sodium hydride under ice-cooling, followed by stirring at the same temperature for 10 minutes. Then, 1.54 g of t-butyl (4R)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylate was added thereto, followed by stirring at room temperature for 18 hours. To the reaction mixture was added water and 1 M aqueous hydrochloric acid sequentially, followed by stirring, and the precipitated solid was collected by filtration. To 20 ml of a suspension of the resulting solid in ethanol was added 10 ml of a 4 M hydrogen chloride-ethyl acetate solution under ice-cooling, followed by stirring at 60° C. for 1 hour. The reaction mixture was evaporated under reduced pressure, and to the residue were added chloroform and saturated aqueous sodium bicarbonate. After extraction with chloroform, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.26 g of ethyl 7-{[(2R)-2-aminopropyl]oxy}-8-bromo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as an opaque cream-colored oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[CH3:12][NH:13][CH3:14]>C1COCC1.Cl>[CH3:12][N:13]([CH3:14])[CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)Cc1cccc([N+](=O)[O-])c1

Procedure:
A solution of 3-nitrobenzyl bromide (10, 1.67 g, 7.73 mmol) and N,N-dimethylamine (4.25 mL, 2M in THF) in anhydrous THF (30 mL) was heated at 40° C. overnight. The reaction mixture was diluted with 1N HCl (30 mL, aq.), the aqueous layer separated, and extracted with EtOAc (30 mL). The pH of the aqueous layer was then adjusted to 9 using saturated Na2CO3 (aq.) and the aqueous layer was extracted with EtOAc (50 mL). The organic layer was washed with water (40 mL), brine (40 mL), and dried over Na2SO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 11 (1.2 g).
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36]C(S(Cl)(=O)=O)=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:21][S:22]([C:25]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CN2c3c(cc(F)c(OS(C)(=O)=O)c3CCN2C)C1=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn2c3c(c(OS(=O)(=O)c4ccc(C)cc4)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
304 mg of the compound (168) obtained in Example 45 was added to 2 ml of pyridine, and 260 mg of p-toluene-sulfonyl chloride was added to the solution. The solution was stirred for 2 hours at room temperature. 50 ml of chloroform was added to the solution, and the solution was washed with water and aqueous 5% citric acid solution. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with isopropyl ether to obtain mg of the subject compound (169).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH2:37]>C(Cl)Cl>[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH:37][C:8]([C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1)=[O:10]
Reactant: COC(=O)CN
Reactant: O=C(O)c1cc(I)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc(I)ccn1
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
To a solution of 4-iodo-picolinic acid (1.41 g, 5.66 mmol) in CH2Cl2 (35 mL) at room temperature under N2 is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.62 g, 8.49 mmol) and 1-hydroxybenzotriazole (HOBt) (0.077 g, 0.57 mmol). The solution is stirred for 5 minutes and glycine methyl ester hydrochloride (1.07 g, 8.49 mmol) is added and the reaction is stirred 16 hours. The reaction volume is concentrated under reduced pressure and the crude material was partitioned between EtOAc and 1M K2CO3. The aqueous phase is removed and the organic phase washed with H2O, sat. NaCl, dried (MgSO4), filtered and concentrated under reduced pressure to afford a brown oil which is purified over silica (EtOAc:heptane gradient 1:4) to afford 0.805 g (44% yield) of the desired product as a colorless solid. HPLC-MS: m/z 321 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])(=[O:25])=[O:24]
Reactant: N#CCCCCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCCCCCCC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 15 g. of 12-hydroxydodecanonitrile and 14 ml. of triethylamine in 320 ml. of methylene chloride is stirred at 0° C. while 5.7 ml. of methanesulfonylchloride is added dropwise. The mixture is stirred at 0° C. for 1 hour, diluted with methylene chloride and extracted with water; cold, dilute hydrochloric acid; saturated aqueous sodium bicarbonate; and brine. The solution is dried over anhydrous magnesium sulfate and eaporated to yield 12-(methanesulfonyloxy)dodecanonitrile as a yellow oil
Reaction SMILES: Cl[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][S:11][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]([C:25]3[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=3)=[N:13][C:6]=2[N:7]=1
Reactant: CSc1ncc2cc(-c3ccccc3)c(Cl)nc2n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1

Procedure:
The mixture of 7-chloro-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidine (0.100 g, 0.347 mmol), 4-formylphenylboronic acid (0.13 g, 0.87 mmol), Cesium carbonate (0.34 g, 1.04 mmol) and bis(tri-t-butylphosphine)palladium (0.018 g, 0.035 mmol) in dioxane (5 mL) was heated to reflux overnight. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (20% EtOAc in hexane) to give the title compound. LRMS m/z (M+H) Calcd: 358.4, found: 358.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[N:22]=1.[C:28]1([C@@H:34]([NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:27][C:23]1[N:22]=[C:21](/[CH:39]=[CH:38]/[C:37]([NH:36][C@H:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:35])=[O:40])[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1cccc(Br)n1
Reactant: C=CC(=O)N[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)/C=C/c1cccc(Br)n1)c1ccccc1
Reaction time: 0.08 h

Procedure:
To the solution of triphenylphosphine (0.496 mmol) in DMF (10 mL), a palladium acetate (0.245 mmol) was added at room temperature under argon atmosphere. The mixture was stirred for 5 min then 2,6-dibromopyridine (12.7 mmol) followed by N-((S)-1-phenylethyl)acrylamide (14.0 mmol) and triethylamine (35.9 mmol) were added and the reaction mixture was stirred at 140° C. for 7 hr. The majority of the solvent was removed under diminished pressure. Diluted HCl was added and the product was extracted with ethyl acetate. Organic layers were combined, washed with brine, dried over sodium sulfate. Drying agent and solvent was removed and product was purified by column chromatography using hexanes and hexanes:ethyl acetate 2:1 as eluents, to give pure product with a good yield.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[C:8]([NH:16][CH2:17][CH3:18])=[N:9][C:10]([S:14][CH3:15])=[N:11][C:12]=1[CH3:13])C.N12CCCN=C1CCCCC2>CCN(C(C)C)C(C)C>[CH2:17]([N:16]1[C:8]2[N:9]=[C:10]([S:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]=2[CH:6]=[CH:5][C:4]1=[O:3])[CH3:18]
Reactant: CCNc1nc(SC)nc(C)c1/C=C/C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(=O)ccc2c(C)nc(SC)nc21
Yield: 76.5 %

Procedure:
To a solution of (E)-ethyl-3-(4-(ethylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate (16.8 g, 59.8 mmol) in DIPEA was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.21 g, 119.6 mmol) at room temperature. Then the reaction mixture was heated to reflux and reacted for 15 h. After evaporation of solvent, the residue was triturated with acetone. The product 8-ethyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (10.77 g, 77% yield) was collected by filtration. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J=9.6 Hz, 1H), 6.63 (d, J=9.6 Hz, 1H), 4.5 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.62 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11]Br)[S:7][CH:6]=1)=[O:4].[NH2:14][C:15]([NH2:17])=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[O:13][C:15]([NH2:17])=[N:14][CH:11]=2)[S:7][CH:6]=1)=[O:4]
Reactant: NC(N)=O
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Solvent: CN(C)C=O
Product: COC(=O)c1csc(-c2cnc(N)o2)c1
Temperature: 140 °C
Yield: 100.9 %

Procedure:
5-(2-Bromo-acetyl)-thiophene-3-carboxylic acid methyl ester (0.261 g, 0.99 mmol) was dissolved in DMF (4 mL) and urea (0.131 g, 2.18 mmol) was added. The vessel was purged with nitrogen then sealed and heated by microwave irradiation at 140° C. for 10 minutes. The resultant mixture was diluted with water and extracted with ethyl acetate (×3). The organic phase was washed with lithium chloride (15% aqueous solution) then dried over sodium sulfate, filtered and evaporated to give crude 5-(2-amino-oxazol-5-yl)-thiophene-3-carboxylic acid methyl ester as an orange-brown solid (0.224 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[C:17]([CH2:16][CH2:15][CH2:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:5]=1[C:3]([OH:2])=[O:4])([OH:19])=[O:18]
Reactant: COC(=O)CCCc1c(C(=O)OC)[nH]c2ccccc12
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)CCCc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
3-(3-Carboxy-propyl)-1H-indole-2-carboxylic acid (Lit. 3) was esterified using HCl/MeOH to give the 3-(3-methoxycarbonyl-propyl)-1H-indole-2-carboxylic acid methyl ester. Using general procedure B, 3-(3-methoxycarbonyl-propyl)-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 386.3 ([M−H]−).
Reaction SMILES: C(O)=O.[S:4](Cl)([N:7]=C=O)(=[O:6])=[O:5].[CH3:11][N:12]([CH3:35])[C:13]([C:15]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:17]([OH:33])[C:16]=1[OH:34])=[O:14]>CN1C(=O)CCC1>[CH3:35][N:12]([CH3:11])[C:13]([C:15]1[N:19]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:17]([OH:33])[C:16]=1[O:34][S:4](=[O:5])(=[O:6])[NH2:7])=[O:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Solvent: CN1CCCC1=O
Solvent: O=CO
Product: CCOC(=O)c1c(O)c(OS(N)(=O)=O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
Formic acid (165 μL, 4.31 mmol) was added dropwise to neat sulfurisocyanatidic chloride (374 μL, 4.31 mmol) at 0° C. with stirring. The reaction mixture allowed to warm to RT and stirred for 2 h, after which a solution of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (0.5 g, 1.44 mmol) in NMP (3 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and allowed to warm to RT and stirred for a further 2 h. The reaction mixture was partitioned with brine (30 mL) and EtOAc (25 mL), the aqueous layer was extracted with EtOAc (2×25 mL) the combined organics were dried (MgSO4), filtered and solvents removed in vacuo to give a yellow oil. The compound was purified by preparative HPLC (C-18 column, 21.2 mm i.d.×100 mm, 5 micron particle size, gradient 5-95% MeCN in 0.1% aqueous formic acid over 16 min) to afford ethyl 5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-4-(sulfamoyloxy)-1H-pyrrole-2-carboxylate (UL1-068) (76 mg, 12%) as a white solid: m/z 428 (M+H)+ (ES+); 426 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 1H), 7.92 (s, 2H), 7.16-7.08 (m, 2H), 6.96-6.88 (m, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 2.75 (s, 3H), 2.67 (s, 3H), 1.02 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:30][OH:31])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C@H:9]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][O:31][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][Cl:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCl
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](CO)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)CCCCl)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 0.5 g of (S)-2-O-benzyl-1-O-octadecylglycerine and 0.16 ml of triethylamine in 2 ml of chloroform is added dropwise to a solution, cooled to 0° C., of 0.16 ml of 4-chlorobutyryl chloride in 1 ml of chloroform. The reaction mixture is stirred at room temperature, diluted with 5 ml of chloroform and washed in succession with 5 ml of 1N sodium hydroxide and 3×10 ml of water. The organic phase is dried and concentrated. The residue is chromatographed on silica gel while eluting with hexane-ether (19:1). There is obtained (R)-2-O-benzyl-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in the form of an oily residue.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9]P(=O)(OCC)OCC)([O-:5])=[O:4].O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>O1CCCC1>[N+:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH:9]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)([O-:5])=[O:4]
Reactant: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc([N+](=O)[O-])c2)CC1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A suspension of sodium hydride (10.98 mmol, 0.439 g) in tetrahydrofuran (40 mL) was added to a stirred solution of diethyl 3-nitrobenzylphosphonate (7.32 mmol, 2 g) in tetrahydrofuran (40 mL) at 0° C. and the reaction stirred for 30 minutes. tert-Butyl 4-oxopiperidine-1-carboxylate (7.32 mmol, 1.459 g) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue partitioned between dichloromethane and water. The organic layer was separated, dried and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: 0-2% methanol in dichloromethane) to afford the intermediate tert-butyl 4-(3-nitrobenzylidene)-piperidine-1-carboxylate (2 g).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[CH2:32][OH:33]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH3:25])=[O:23])=[C:3]([CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[CH2:32][OH:33])[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: OC[C@H]1COCCN1
Product: COC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 44.2 %

Procedure:
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.44 g, 44%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.[CH2:12]([C@H:14]1[O:16][CH2:15]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:16]1[CH2:15][C@@H:14]1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: ClC[C@@H]1CO1
Reactant: Cc1nc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Reaction time: 8 h

Procedure:
A mixture of 2-methylbenzothiazol-5-ol, a compound of formula (1) (6.0 g, 36 mmol), (S)-(+)-epichlorohydrin, a compound of formula (2) (20 ml, 182 mmol), and potassium carbonate (20 g, 144 mmol) in acetone (100 ml), was heated to reflux and allowed to stir overnight. The solution was allowed to cool and filtered through Celite 512. The filtrate was evaporated (in vacuo), to yield an oil. The oil was chromatographed on silica gel, eluting with 20% ethyl acetate/hexanes, to yield 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole as a white solid (6.2 g, 28 mmol).
Reaction SMILES: O.[Cl:2][C:3]1[C:4]([Cl:20])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]=[C:9]([N:14]3[CH:18]=[CH:17]N=C3)[NH:8][C:7]=2[CH:19]=1.[CH:21]1(N)CC[CH2:22]1>>[CH:18]1([NH:14][C:9]2[NH:8][C:7]3[CH:19]=[C:3]([Cl:2])[C:4]([Cl:20])=[CH:5][C:6]=3[S:11](=[O:12])(=[O:13])[N:10]=2)[CH2:17][CH2:22][CH2:21]1
Reactant: NC1CCC1
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2cc(Cl)c(Cl)cc21
Solvent: O
Product: O=S1(=O)N=C(NC2CCC2)Nc2cc(Cl)c(Cl)cc21

Procedure:
6,7-Dichloro-3-(imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate was treated with cyclobutylamine according to the general procedure Method D to give the title compound; m.p. 320-326° C.; IR (KBr): 3290, 3163, 3068, 2979, 2952, 1631, 1580, 1556, 1460, 1331, 1251, 1166, 1152, 1137, 1128 cm−1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1F)[CH3:2].[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH2:13][CH3:14])=[CH:5][C:4]=1[N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]2)[CH2:31][CH2:30]1)[CH3:2]
Reactant: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Reactant: CCOc1cc(F)c(CC)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 33.4 %

Procedure:
A mixture of 1-ethyl-4-(ethyloxy)-2-fluoro-5-nitrobenzene (Example 208, step A) (0.80 g, 3.75 mmol), 1-(methylsulfonyl)-4-(4-piperidinyl)piperazine (0.928 g, 3.75 mmol) and K2CO3 (0.622 g, 4.50 mmol) in DMSO (20 mL) was heated at 90° C. for 48 h. The reaction had not progressed sufficiently so the reaction was then heated at 120° C. for an additional 4 h. The reaction was cooled to rt, poured into H2O and extracted exhaustively with DCM. The combined organics were washed with H2O then dried over MgSO4. The resultant solution was concentrated onto silica and purified by flash chromatography to afford 1-{1-[2-ethyl-5-(ethyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (0.551 g, 33%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (s, 1H), 6.74 (s, 1H), 4.19 (q, J=6.93 Hz, 2H), 3.19-3.28 (m, 2H), 3.06-3.14 (m, 4H), 2.87 (s, 3H), 2.52-2.79 (m, 9H), 1.80-1.92 (m, 2H), 1.46-1.67 (m, 2H), 1.33 (t, J=6.97 Hz, 3H), 1.19 (t, J=7.47 Hz, 3H).