Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C:8](=[O:16])[C:7]2[C:17]([CH3:26])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:6]1=2.[Br:32]N1C(=O)CCC1=O.CC(CC(C)C)C#N.C(OC)(=O)C>O>[Br:32][CH2:26][C:17]1[C:7]2[C:8](=[O:16])[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:10][N:5]([CH2:4][C:3]3[C:2]([F:1])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])[C:6]=2[S:19][C:18]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(-c2ccccc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)CC(C)C#N
Solvent: COC(C)=O
Solvent: O
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccccc3)c(CBr)c2c1=O
Reaction time: 2 h
Yield: 89.9 %

Procedure:
7-(2,6-Difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-oxo-2-phenylthieno[2,3-b]pyridine (10 g), N-bromosuccinimide (4.86 g), 2,2′-azobis(2,4-dimethylvaleronitrile (0.56 g) and methyl acetate (100 ml) were mixed and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool with stirring over a period of 2 hours, water (50 ml) was added and then the mixture was stirred with cooling on ice for 1.5 hours. The crystal precipitated was recovered by a filtration, washed with an ice-cooled methyl acetate (30 ml) and water (30 ml), dried in vacuo at 40° C. for 6 hours to obtain the title compound (10.61 g, 87.1%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([F:40])=[CH:16][C:17]3[N:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])[N:19]([CH:36]4[CH2:38][CH2:37]4)[C:18]=3[CH:39]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC[C:50]([N:52]=[C:53]=[O:54])=[O:51]>C1COCC1>[CH:36]1([N:19]2[C:18]3[CH:39]=[C:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]4)[C:15]([F:40])=[CH:16][C:17]=3[N:21]3[C:50](=[O:51])[NH:52][C:53](=[O:54])[CH:22]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=4)=[O:24])[CH:20]23)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(=O)OCc2ccc([N+](=O)[O-])cc2)n3C2CC2)CC1
Reactant: O=C=NC(=O)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)N2C(=O)NC(=O)C(C(=O)OCc4ccc([N+](=O)[O-])cc4)C2N3C2CC2)CC1
Reaction time: 20 h
Yield: 59.7 %

Procedure:
A solution of p-nitrobenzyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benzimidazole acetate (553 mg, 1 mmol) in THF (50 ml) is treated in succession at 0° with triethylamine (300 mg, 3 mmol) and chloroacetyl isocyanate (298 mg, 2.5 mmol). After stirring for 20 hours the solvent is distilled off and the residues is taken up in ethyl acetate and washed in succession with water (50 ml) and 10 percent sodium chloride solution (50 ml). The organic phase is dried over magnesium sulfate and the solvent is evaporated. The residue is recrystallized from ethyl acetate. There are obtained 373 mg (59%) of p-nitrobenzyl 5-cyclopropyl-8-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-7-[4-(tert-butoxycarbonyl)-1-piperazinyl]pyrimido[1,6-a]benzimidazole-4-carboxylate.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH:2]=[CH2:3].[Br:17][CH2:18][CH2:19]Br>CN(C=O)C>[CH2:1]([N:4]([CH2:19][CH2:18][Br:17])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: BrCCBr
Reactant: C=CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: C=CCN(CCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 48.7 %

Procedure:
N-Allyl-2-nitro-benzenesulfonamide (570 mg, 2.35 mmol) is dissolved in DMF (5 mL) and then CsCO3 (920 mg, 2.82 mmol) and 1,2-dibromoethane (884 mg, 4.71 mmol) is added. The mixture is then microwaved for 30 min at 150° C., then filtered and the solid washed with EtOAc (30 mL). The organic is washed with Brine (20 mL) and then dried over Na2SO4 and then concentrated to dryness. HPLC (CH3CN/H2O/0.1% TFA) provides N-Allyl-N-(2-bromo-ethyl)-2-nitro-benzenesulfonamide (400 mg, 48%). MS-ES [M+H]+=351.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23]#[N:24])=[C:19]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=3[CH:17]=[C:16]([CH3:32])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1([O-])O[O:34]1.O.O.O.O.[Na+].C(O)C>[Cl-].[Na+].O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23](=[O:34])[NH2:24])=[C:19]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:18]=3[CH:17]=[C:16]([CH3:32])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C#N)c(Cc3ccccc3)c2c1
Reactant: [O-]B1OO1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C(N)=O)c(Cc3ccccc3)c2c1
Temperature: 130 °C
Yield: 79.4 %

Procedure:
4-(3-Benzyl-2-cyano-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.302 gm, 0.7 mmol), sodium perborate tetrahydrate (0.43 gm, 2.8 mmol), ethanol (8 ml) and water (8 ml) were combined in a vial and heated in a microwave reactor to 130° C. for 10 minutes. The reaction mixture was cooled to room temperature, diluted with brine and water and extracted three times with ethyl acetate. The solution was dried over magnesium sulfate and purified by column chromatography (methanol/dichloromethane gradient) to give 4-(3-benzyl-2-carbamoyl-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.25 gm, 80% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:28]=4[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])[CH:19]=3)[C:14](O)=[O:15])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[C:44]([CH2:43][CH2:42][C:28]1[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:18]2[CH:17]=[C:13]([C:14]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:15])[CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:19]=2)=[CH:32][CH:31]=[CH:30][C:29]=1[O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])([OH:46])=[O:45]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Reactant: C1COCCN1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCOCC3)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)O

Procedure:
The title compound was prepared according to the general procedure described in Example 74 starting from 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid and morpholine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[CH:15][N:14]([C:17]4[S:18][C:19]([C:28](O)=[O:29])=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)[C:13]=3[CH:31]=2)[CH2:4][CH2:3]1.C[N:33](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[CH:15][N:14]([C:17]4[S:18][C:19]([C:28]([NH2:33])=[O:29])=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)[C:13]=3[CH:31]=2)[CH2:6][CH2:7]1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: CN1CCN(Cc2ccc3ncn(-c4nc(-c5ccccc5)c(C(=O)O)s4)c3c2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5ccccc5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a mixture of 0.022 g (0.05 mmole) of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid (I.1b), 0.023 g (0.06 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.004 g of ammonium chloride and 1 mL of dimethylformamide was added 0.026 mL (0.15 mmole) of ethyldiisopropylamine. The mixture was stirred at ambient temperature for 1 hour. Solids were removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 10:90-90:10) to give 0.014 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid amide (I.1) as a white powder. MH+/Z=433.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][CH:34]3[CH2:37][CH2:36][CH2:35]3)=[C:27]([F:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([F:38])[C:28]([O:32][CH2:33][CH:34]5[CH2:37][CH2:36][CH2:35]5)=[C:29]([F:31])[CH:30]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC3CCC3)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCC4CCC4)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[4-(cyclobutylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (139 mg, 0.334 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 44 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 1.82-1.90 (m, 4H), 2.00-2.06 (m, 2H), 2.65-2.70 (m, 1H), 3.17 (s, 3H), 3.39 (s, 3H), 4.07-4.13 (m, 2H), 5.32 (s, 2H), 6.20-6.26 (m, 1H), 7.34 (s, 1H), 7.63 (d, J=8.7 Hz, 2H), 7.77 (s, 1H), 12.67 (br s, 1H); APCI-MS (m/z) 516.11 (M+H)+.
Reaction SMILES: [C:1]([N:5]([C:22](=[O:31])[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[NH:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH2:14][CH:15]([CH:17]=O)[O:16][C:11]=2[C:10]=1[CH3:21])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:40][OH:41]>CO>[C:1]([N:5]([C:22](=[O:31])[C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[NH:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH2:14][CH:15]([CH:17]=[N:40][OH:41])[O:16][C:11]=2[C:10]=1[CH3:21])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C=O)CO3)C(C)(C)C)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C=NO)CO3)C(C)(C)C)c1
Yield: 82.1 %

Procedure:
To a 100 mL round bottom flask, containing 100 mg (0.24 mm) of 3,5-dimethyl-benzoic acid N-tert-butyl-N′-(3-formyl-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide, added 0.50 g of triethylamine, 70 mg (1 mm) of hydroxylamine hydrochloride and 25 mL of methanol. The reaction mixture was refluxed for 1 hour. The methanol was removed on a rotary evaporator and the residue was dissolved with chloroform and dilute HCl and transferred to a separatory funnel. The chloroform extract was dried and evaporated to dryness. The residue was chromatographed on silica and the product eluted with 40% ethyl acetate in hexane. Evaporation of solvent yielded 85 mg of 3,5-dimethyl-benzoic acid N-tert-butyl-N′-[3-(hydroxyimino-methyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl]-hydrazide. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.7 (s, 1H), 7.4 (d, 1H), 7.05 (s, 2H), 6.95 (s, 1H), 6.55 (d, 1H), 6.15 (m, 1H), 4.8 (m, 1H), 4.0–4.4 (m, 4H), 2.248 (s, 6H), 1.915 (s, 3H), 1.574 (s, 9H); TLC: Rf=0.40 (1:1 ethyl acetate:hexane).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]([CH3:25])[N:23]=[N:22][N:21]=1.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O.N>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cn1nnnc1S
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Agent: N
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A 320 ml portion of acetonitrile was added to 54.5 g of 7-ACA and 25,6 g of 5-mercapto-1-methyl-1H-tetrazole, and 296.7 g of DCPA was added to the mixture with stirring and under cooling at -20° to -10° C. After the dissolution, the reaction mixture was stirred at 15° to 17° C. for 40 minutes to allow the reaction to proceed, cooled and poured into 1.8 kg of ice-water. The mixture was allowed to stand at 5° C. overnight, cooled by adding ice under stirring and adjusted to pH 4.0 with 25% aqueous ammonia. The resulting precipitate was recovered by filtration, washed with 480 ml of cold water and 500 ml of acetone successively, and dried, thereby affording 62.2 g (94.7% of yield) of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=1)([O-])=[O:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[CH:5]=[C:6]3[O:10][CH2:9][CH2:8][C:7]3=[CH:11][C:12]=2[N:13]=[C:15]([NH2:16])[N:14]=1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCC2
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)OCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
A mixture of nitroaniline 194 (7.27 g, 40.4 mmol) and cyanamide (6.79 g, 162 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (15 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (200 mL), filtered, washed with water (3×50 mL) and dried. The aqueous fraction was extracted with CHCl3 (3×50 mL), dried and the solvent evaporated. The combined solids were purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give crude amine 195 (1.87 g, 23%) as a yellow powder: mp (MeOH/DCM) 241-246° C. Anal. calcd for C9H8N4O2: C, 52.9; H, 4.0; N, 27.4. Found: C, 53.3; H, 3.8; N, 26.4%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(-c2cccc(Br)c2)c1-c1ccccc1

Procedure:
m-Bromoaniline (5 mmol, 0.9 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate and brine. The organic layer was dried over MgSO4, then the solids were separated and the solvents evaporated under vacuum. The crude product was recrystallized from ethanol to yield the named product (m.p. 117.5° C.-119.2° C.).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccccc1

Procedure:
To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethylamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent: hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[S:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=1>>[C:15]1([C:12]2[N:11]=[C:10]([O:1][CH2:2][C:3]3([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]3)[S:14][N:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1nc(-c2ccccc2)ns1
Reactant: OCC1(CO)CCC1
Product: OCC1(COc2nc(-c3ccccc3)ns2)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 25a from [1-(hydroxymethyl)cyclobutyl]methanol and 5-chloro-3-phenyl-1,2,4-thiadiazole. 1H NMR (300 MHz, CDCl3) δ 8.10 (m, 2H), 7.39 (m, 3H), 4.63 (s, 2H), 3.62 (d, J=6 Hz, 2H), 2.71 (t, J=6 Hz, 1H), 1.88-1.97 (m, 6H). GC-MS m/z 277 (M+H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(Cl)CCl.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:21][CH:20]=1>>[CH3:5][O:4][N:3]([CH3:2])[C:27](=[O:29])[CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1
Reactant: CNOC
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(CCC(=O)N(C)OC)cc1
Reaction time: 15 h
Yield: 85.5 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (5.41 g, 55.5 mmol), EDC (12.77 g, 66.6 mmol), followed by triethylamine (17 mL, 122 mmol) were added to a cooled 0° C. solution of 3-(4-methoxyphenyl)propionic acid (10 g, 55.5 mmol). The reaction mixture was stirred for 15 h under N2 and then concentrated. The residue was partitioned between 1 N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by silica gel chromatography (40% EtOAc in hexanes) to give a clear oil (10.6 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Yield: 83.1 %

Procedure:
A mixture of 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (2 g, 5.594 mmol), morpholine (0.64 mL, 7.27 mmol) and diisopropylethylamine (1.46 mL, 8.392 mmol) in isopropanol (25 mL) was heated at reflux for 50 hours. After cooling to a temperature in the range of 15° C. to 40° C., the precipitated solid was filtered, washed with hexane and dried. The solid was dissolved in ethyl acetate, washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid (1.9 g, 83% yield).
Reaction SMILES: Br[CH2:2][C:3]([C@:5]1([OH:28])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:26])[C:12]4[C:13]([OH:25])=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:27])[C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:29]([O-:32])(=[O:31])[CH3:30].[K+].O>CC(C)=O>[C:29]([O:32][CH2:2][C:3]([C@:5]1([OH:28])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:26])[C:12]4[C:13]([OH:25])=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:27])[C:8]=2[CH2:7][CH2:6]1)=[O:4])(=[O:31])[CH3:30]
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)c3c(c(O)c21)C[C@@](O)(C(=O)CBr)CC3
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1cccc(O)c1C3=O

Procedure:
The entire amount of 9(R)-bromoacetyl-4,6,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione was dissolved in acetone (110 ml). Potassium acetate (270 mg) was added to the above solution and the mixture was allowed to react at room temperature for 2 hours, followed by addition of water (100 ml). The precipitated crystals were collected by filtration to give reddish orange crystals of 9(R)-acetoxyacetyl-4,6,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P. 215°-217° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][OH:13])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)[O:11][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCOC1CCCCO1
Reactant: OCC(O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCC(COCCCCCCOC2CCCCO2)OCCCCCCOC2CCCCO2)cc1
Reaction time: 0.75 h
Yield: 41.2 %

Procedure:
To a cooled solution, 0° C., of 1-benzylglycerol (3.00 g) in dimethylformamide (165 ml) was added sodium hydride (60% dispersion in mineral oil, 3.95 g) and the reaction stirred for 45 minutes. 1-Tetrahydropyran-2-yloxy-6-bromohexane (13.10 g) was added and the reaction stirred at 20° C. for 19 hours. The reaction was quenched by the portionwise addition of methanol(10 ml) over 30 minutes at 0° C. The solvent was removed in vacuo and the residue partitioned between water (125 ml) and dichloromethane(125 ml). The organic layer was washed with brine (150 ml), dried and the solvent removed in vacuo. This was purified by column chromatography on silica gel (Biotage) eluting with 8% ethyl acetate in cyclohexane to give the title compound as a pale yellow oil (3.74 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:10][C:11]1[C:12](=[O:21])[CH:13]=[CH:14][C:15](OC)([O:17]C)[CH:16]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:12]1([OH:21])[CH:13]=[CH:14][C:15](=[O:17])[CH:16]=[C:11]1[Cl:10]
Reactant: c1ccc2scnc2c1
Reactant: COC1(OC)C=CC(=O)C(Cl)=C1
Product: O=C1C=CC(O)(c2nc3ccccc3s2)C(Cl)=C1
Yield: 58 %

Procedure:
The title compound was synthesised according to Method A, described above, from benzothiazole and 2-chloro-4,4-dimethoxycyclohexa-2,5-dien-1-one (see, e.g., McKillop et al., 1993).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[CH:4][N:3]=1.Cl[C:10]([N+]([O-])=O)=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCN2C(=NCCC2)CC1>CCO>[C:12]1([C:11]2[C:7]3[C:6](=[O:8])[NH:5][CH:4]=[N:3][C:2]=3[O:1][CH:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cc(O)ncn1
Reactant: O=[N+]([O-])C(Cl)=Cc1ccccc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1[nH]cnc2occ(-c3ccccc3)c12
Temperature: 60 °C

Procedure:
The title compound 10 was prepared by the method of Dauzonne, D.; Adam-Launay, A. Tetrahedron 1992, 48, 3069-3080. 4,6-Dihydroxypyrimidine (3.3 g, 29.4 mmol) and (2-Chloro-2-nitro-vinyl)-benzene (5.3 g, 26.7 mmol) were combined in EtOH (absolute, 110 mL) and the mixture was heated at 60° C. for 10 min to dissolve 4,6-Dihydroxypyrimidine. DBU (8.06 mL, 53.9 mmol) was then added drop-wise to the reaction. After addition of DBU the deep green-brown solution was heated at reflux for 3 h then at 60° C. over night. The deep red solution was then cooled to room temperature and concentrated to a thick red oil. Purification by flash chromatography (SiO2, gradient eluent: CH2Cl2 to 5% MeOH/CH2Cl2) to afford crude 10 as an orange-red semisolid/oil. This material was triturated with 1.75:1 CH2Cl2/hexanes and solid 10 was isolated by Buchner filtration. Flash chromatography of the mother liquors afforded a second crop of solid 3 (>90% pure). The two crops were combined and concentrated to afford 10.