Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[NH:8][NH2:9]>CO>[O:4]1[CH2:5][CH2:6][C:2](=[N:9][NH:8][C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: O=C1CCOC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CCOC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 113.1 %

Procedure:
3-oxotetrahydrofuran (10.38 g) was dissolved in methanol (200 mL), and t-butyl carbazate (17.53 g) was added to the solution. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give the title compound (27.3 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.52 (s, 9H), 2.46 (t, J=6.9 Hz, al), 4.10 (t, J=6.9 Hz, 2H), 4.33 (s, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:50]1[CH:55]=[CH:54][C:53]([C@H:56]([NH2:59])[CH2:57][OH:58])=[CH:52][CH:51]=1>>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[O:15][C:14]([C:16]([NH:59][C@H:56]([C:53]3[CH:54]=[CH:55][CH:50]=[CH:51][CH:52]=3)[CH2:57][OH:58])=[O:18])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)O)o2)s1
Reactant: N[C@H](CO)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)N[C@@H](CO)c3ccccc3)o2)s1
Reaction time: 8 h

Procedure:
To 5 mL of the crude 4.49 millimolar solution of 5-(2-acetamido-4-methylthiazol-5-yl)furan-2-carboxylic acid was added 200 mg of TBTU and 1 mL of Hunig's base. To the stirred reaction mixture was then added 200 mg of S-phenylglycinol. The reaction was allowed to stir overnight and was then concentrated to dryness and dissolved in 1 mL of DMSO and filtered. The filtrate was purified via reverse phase chromatography to yield 4.1 mg of (R)-5-(2-acetamido-4-methylthiazol-5-yl)-N-(2-hydroxy-1-phenylethyl)furan-2-carboxamide as a white solid. LC/MS: 386.2 (M+H)/2.0 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: BrCCc1ccccc1
Solvent: CC#N
Product: O=Cc1cc(Cl)ccc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
5 g of 5-chlorosalicylaldehyde was dissolved in 300 ml of acetonitrile. After adding 41.48 g of potassium fluoride/alumina (neutral) (2:3) and 17.45 ml of (2-bromoethyl)benzene, the resulting mixture was stirred at room temperature for 63 hours. Then the potassium fluoride/alumina was removed by filtration under sucking and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=10:1) and recrystallized from isopropyl ether to give 5.58 g of 5-chloro-2-(2-phenylethoxy)benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 122.9 %

Procedure:
A solution of 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (0.600 g, 1.45 mmol) in DME (10.0 mL) was reacted with 4-trifluoromethylbenzene boronic acid (0.55 g, 2.91 mmol), Pd(PPh3)4 (0.70 g, 0.14 mmol), and Na2CO3 (2.0N, 3.50 mL, 3.64 mmol) by the general procedure D to give 0.850 g of 2-(2-amino-5-chloro-benzoylamino)-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH3:12][CH:13]([N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(N(C(C)C)C(C)C)C>ClCCl>[CH3:12][CH:13]([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:17][CH2:16]1)[CH3:14]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(C)N1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCCN(C(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (209 mg, 1.21 mmol) in dichloromethane (4.00 ml) was added to a stirred solution of 1-propan-2-yl-1,4-diazepane (172 mg, 1.21 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.523 ml, 3.02 mmol) in dichloromethane (4.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (267 mg, 79%) as a cream oil which crystallised on standing. This was used directly with no further purification.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:14]=[N:13][C:12]=1[O:23][CH3:24].[CH2:25]([Sn](CCCC)(CCCC)C=C)[CH2:26]CC.[F-].[K+].CCOC(C)=O>[Cl-].C([N+](CC)(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][O:23][C:12]1[N:13]=[N:14][C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:16][C:11]=1[C:3]1[NH:4][C:5]2[C:10]([C:2]=1[CH:25]=[CH2:26])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1c(-c2cc(-c3ccncc3)nnc2OC)[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of 430 mg 3-Iodo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole, 490 mg tributyl(vinyl)tin, 165 mg tetraethylammonium-chloride and 35 mg bis(triphenylphosphine)palladium(II) chloride in DMF is stirred at 80° C. for 40 min. After cooling to room temperature, 15 ml aqueous potassium fluoride solution (30%) are added and the mixture stirred for 30 min at room temperature before extraction with EtOAc. The organic layer is dried over MgSO4 and the solvent evaporated ion prior to purification of the crude product by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% HCOOH).
Reaction SMILES: [CH3:1]S(O)(=O)=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=[CH:10]2>CO.C(OCC)(=O)C>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:1])=[O:18])=[CH:12][CH:11]=[CH:10]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: CS(=O)(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2cc(O)ccc12
Temperature: 25 °C
Yield: 478.6 %

Procedure:
Methanesulfonic acid (18 mL, 0.28 mol) was added to a stirred solution of 6-hydroxy-1-naphthoic acid (262 g, 1.39 mol) in methanol (1 L) under N2 and the reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and concentrated to give a purple solid. The solid was dissolved in ethyl acetate (1 L), washed with water (3×300 mL), saturated sodium bicarbonate solution (2×300 mL), water (500 mL), brine (300 mL) and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated to give 271 g of the product as a pink solid. 1H NMR (400 MHz, d6-DMSO): δ 9.94 (s, 1H), 8.58 (m, 1H), 7.93 (d, J=8 Hz, 1H), 7.86 (d, J=7.0 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.22-7.19 (m, 2H), 3.88 (s, 3H). ESI-LCMS m/z 203 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([Br:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OCc2ccccc2)cc1Br
Reaction time: 1 h
Yield: 49 %

Procedure:
To a suspension of 4-benzyloxyphenol (30 g, 150 mmol) in chloroform (400 ml) was added, dropwise, a solution of bromine (24 g, 150 mmol) in chloroform (150 ml). After stirring for 1 hour the mixture was washed with 0.1M NaHSO3 (500 ml), then water (500 ml). The chloroform layer was separated, dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5, 10, 20% ethyl acetate/hexane. Recrystallisation from hexane afforded the title compound (20.5 g, 49%); δH (250MHz, CDCl3) 4.98 (2H, s, OCH2), 6.82--6.99 (2H, m, ArH), 7.09-7.12 (1H, d, J 2.75Hz, ArH), 7.30-7.42 (5H, m).
Reaction SMILES: Cl[O-].[Na+].[CH3:4][O:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:15])[CH2:12][CH2:13][OH:14].C(O)(C)C>C(O)(=O)C>[CH3:4][O:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:15])[CH2:12][CH2:13][OH:14]
Reactant: COC(=O)CCCCC(O)CCO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COC(=O)CCCCC(=O)CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
100 ml of aqueous sodium hypochlorite solution (10-13% active chlorine) were added dropwise at room temperature, over a period of 45 minutes, to 16.6 g (87 mmol) of 6,8-dihydroxyoctanoic acid methyl ester in 200 ml of glacial acetic acid. After stirring for a further 3 hours at room temperature, 180 ml of isopropanol were added in order to destroy excess sodium hypochlorite, and stirring was carried out for 10 minutes. The reaction mixture was then added to 1200 ml of water and extracted several times with methylene chloride. The combined organic phases were washed with cold-saturated sodium hydrogen carbonate solution. After drying over sodium sulfate, the solvent was distilled off using a rotary evaporator. 13.0 g (80%) of 8-hydroxy-6-oxo-octanoic acid methyl ester were obtained.
Reaction SMILES: N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH:43]([CH3:45])[CH:42]([OH:46])[CH:41]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH:43]([CH3:45])[C:42](=[O:46])[CH:41]([NH:47][C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:40]1)=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC1CN(C(=O)OCc2ccccc2)CC(NC(=O)OC(C)(C)C)C1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CN(C(=O)OCc2ccccc2)CC(NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
Pyridine (0.8 mL, 10 mmol) and Dess-Martin periodinane (1.8 g, 4.4 mmol) were added to a stirred solution of benzyl-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-5-methylpiperidine-1-carboxylate (1.22 g, 3.35 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 h. A solution containing a mixture of NaHCO3 and Na2S2O3 was added and the resulting mixture was stirred for 30 min. The mixture was then extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with 40% EtOAc in hexanes to give the sub-title compound as a colorless oil (1.15 g, 95%). LCMS calc. for C19H26N2NaO5 (M+Na)+ m/z=385.2. found 385.0.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([CH:13]=[CH2:14])[C:9]([F:15])=[C:8]([F:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+](=[CH2:19])=[N-].C(OCC)C.CN(N=O)C(N)=O>C(OCC)C.C1(C)C(C)=CC=CC=1>[CH:13]1([C:10]2[C:11]([F:12])=[C:2]([F:1])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:8]([F:16])[C:9]=2[F:15])[CH2:19][CH2:14]1
Reactant: C=Cc1c(F)c(F)c(C(=O)OC)c(F)c1F
Reactant: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COC(=O)c1c(F)c(F)c(C2CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
In 10 ml of diethyl ether was dissolved 2.0 g of methyl 2,3,5,6-tetrafluoro-4-vinylbenzoate. To the resulting solution was added, with ice-cooling, a diazomethane-diethyl ether solution prepared from 3.0 g of N-methyl-N-nitrosourea. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 15 ml of xylene and the resulting solution was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 2.1 g (yield: 99.1%) of methyl 4-cyclopropyl-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[N+:19]([C:22]1[CH:23]=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]2=[CH:31][CH:32]=1)([O-:21])=[O:20]>C(#N)C>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([N:1]3[C:29](=[O:28])[C:24]4[C:25](=[CH:31][CH:32]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=4)[C:26]3=[O:27])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: CC#N
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 21 %

Procedure:
4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (1.22 g, 5 mmol) was dissolved in refluxing acetonitrile (20 cm3) and a solution of 4-nitrophthalic anhydride (0.96 g, 5 mmol) in acetonitrile (10 cm3) was added dropwise with stirring to precipitate a yellow gum. The mixture was refluxed for a further 2-3 minutes then cooled in ice. The precipitated material was collected and heated in acetic anhydride on a steam bath for 1/2 hour. The solvent was evaporated. Methanol was added to the residue and evaporated to destroy excess acetic anhydride. The residue was then dissolved in very dilute aqueous acetic acid and insoluble material filtered off. The filtrate was basified by addition of conc. ammonia to precipitate a gum, which was triturated with methanol under reflux to give the title compound as a bright orange solid (0.44 g, 21%).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][NH2:21])=[O:16])=[CH:9][CH:10]=2)[CH2:5]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:56][C:57]1[CH:65]=[C:64]([O:66][CH3:67])[C:63]([O:68][CH3:69])=[CH:62][C:58]=1[C:59](O)=[O:60]>CN(C=O)C>[Br:56][C:57]1[CH:65]=[C:64]([O:66][CH3:67])[C:63]([O:68][CH3:69])=[CH:62][C:58]=1[C:59]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15](=[O:16])[NH:14][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][N:4]([CH3:3])[CH2:5]3)=[CH:10][CH:9]=2)[CH:18]=1)=[O:60]
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Reactant: COc1cc(Br)c(C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc(Br)c(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(C)CC4)c2)cc1OC
Yield: 40.9 %

Procedure:
Dissolved 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)benzylamine dihydrochloride (36.8 mg, 0.10 mmol) in DMF (1.0 mL) and added 4-methylmorpholine (0.044 mL, 0.4 mmol). Dissolved HATU (57.0 mg, 0.15 mmol) in 1.0 mL DMF and added to the 2-bromo-4,5-dimethoxybenzoic acid (25.5 mg, 0.12 mmol) and stirred to dissolve. Added the amine to the 2-bromo-4,5-dimethoxybenzoic acid solution and shook at room temperature 48 hours. The solvent was removed under reduced pressure. The residue was dissolved in 10% water/DMSO (900 uL). Purified by prep HPLC to give 22.0 mg of 2-bromo-4,5-dimethoxy-N-[3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide. MS, electrospray, 538 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17]O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:17][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(CO)nn1-c1ncccc1Cl
Solvent: ClCCl
Product: COC(=O)c1cc(CCl)nn1-c1ncccc1Cl
Temperature: 5 °C
Reaction time: 4 h

Procedure:
Methyl 1-(3-chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylate (26.7 g, 0.1 mol) was dissolved in 150 ml of CH2Cl2 and the solution was cooled to 5° C. SOCl2 (0.12 mol) in 30 ml of CH2Cl2 was slowly added dropwise at this temperature. The mixture was stirred at 40° C. for a further 4 h and concentrated under reduced pressure. The product can be used further without purification.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20]C)=[O:19]>CN(C=O)C>[C:18]([CH2:17][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])([OH:20])=[O:19]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
This procedure is different from the literature synthesis, but is easier, gives higher yields, and leaves no unreacted thymine in the product. To a suspension of thymine (3, 40 g, 0.317 mol) and potassium carbonate (87.7 g, 0.634 mmol) in DMF (900 mL) was added methyl bromoacetate (30 mL, 0.317 mmol). The mixture was stirred vigorously overnight under nitrogen. The mixture was filtered and evaporated to dryness, in vacuo. The solid residue was treated with water (300 mL) and 4 N hydrochloric acid (12 mL), stirred for 15 minutes at 0° C., filtered, and washed with water (2×75 mL). The precipitate was treated with water (120 mL) and 2 N sodium hydroxide (60 mL), and was refluxed for 10 minutes. The mixture was cooled to 0° C., filtered, and title compound was precipitated by the addition of 4 N hydrochloric acid (70 mL). The yield after drying, in vacuo over sicapent was 37.1 g (64%). 1H-NMR: (90 MHz; DMSO-d6): 11.33 ppm (s, 1H, NH); 7.49 (d, J=0.92 Hz, 1H, ArH); 4.38 (s, 2H, CH2); 1.76 (d, J=0.92 Hz, T-CH).
Reaction SMILES: [CH2:1]([N:8]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:27][CH2:26][C:21]3(OCC[O:22]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O>Cl>[CH2:1]([N:8]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:27][CH2:26][C:21](=[O:22])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC4(CC3)OCCO4)cc2)cc1OC
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Yield: 709.6 %

Procedure:
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonamide(0.10 g, 0.19 mM) was stirred in 6M HCl (2 ml) and acetone(5 ml) at 60° C. overnight. The reaction mixture was basified with 5N NaOHaq. (until pH>7) and washed with ethyl acetate (3×10 ml). The organic extracts were dried with sodium sulfate, passed through a plug of magnesol, concentrated and triturated with hexanes to afford 0.65 g of the desired product as a white solid. H1 NMR(CDCl3) δ 2.58(t, 4H, J=6.06 Hz), 3.67(s, 3H), 3.74(t, 4H, J=6.12 Hz), 3.81(s, 3H), 4.71(s, 2H), 6.48(m, 3H), 6.67(d, 1H, J=8.46 Hz), 6.93(d, 2H), J=9.9 Hz), 7.20(m, 4H), 7.59(d, 2H, J=4.71 Hz). MS(ES) m/z 481.0; (MH+); HRMS for C26H28SN2O5: 481.1778.
Reaction SMILES: CN(C)C=[O:4].C1(N2C(C3C=CC=CC=3)CC(=O)N2)C=CC=CC=1.[CH:24]1([N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:31]([NH:30][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Agent: O=C1CC(c2ccccc2)N(c2ccccc2)N1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Into 100 ml of dimethylformamide, 23.8 g of Compound (A), 30.1 g of Compound (B) and 0.8 g of 4-dimethylamino-pyridine were dissolved, and thereto an ethyl acetate 20 ml solution containing 20.6 g of dicyclohexylcarbodiimide was added dropwise in an ice bath. After the dropwise addition, the solution was allowed to react at room temperature over night. Into the reaction solution, 200 ml of ethyl acetate was poured, and dicyclohexylurea obtained was separated by filtration. Into the filtrate, 300 ml of water was poured to perform liquid separation operation. Water washing was performed twice, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the oily product obtained was subjected to silica gel column chromatography. As a result, from the methylene chloride/ethyl acetate=10/3 fraction, 43 g of Compound (C) was obtained as a pale yellow oily product. ##STR16## Synthesis of Compound (D):
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:18])[C:13](=[O:17])SCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>[Pd].CC(C)=O>[CH3:18][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:13]=[O:17]
Reactant: CCSC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CC(C)=O
Product: C[C@H](C=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution containing S-ethyl (2R)-2-{[(benzyloxy)carbonyl]amino}-propanethioate (18.9 g, 62.5 mmol), wet 10% Pd/C (1.89 g), and acetone (347 mL) at 0° C. was added triethylsilane (29.9 mL, 187.5 mmol). The resulting mixture was stirred for 30 minutes at 0° C. and then filtered through celite using ethyl acetate to wash the celite thoroughly. The filtrate was concentrated and partitioned between acetonitrile (500 mL) and hexanes (150 mL). The layers were separated, and the acetonitrile phase was washed once with hexane (150 mL) and then concentrated to provide the desired product (59.4 mmol, 95%) which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](CC(F)(F)F)[C:6]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:5]2.OC1C=C2C(=CC=1)NC(C(O)=O)=C2.N1CCOCC1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:16]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:17])=[CH:5]2
Reactant: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Agent: O=C(O)c1cc2cc(O)ccc2[nH]1
Solvent: C1COCCN1
Product: O=C(c1cc2cc(O)ccc2[nH]1)N1CCOCC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 5-hydroxy-1H-indole-2-carboxylic acid (purchased at Fluka, Ref 55355) and morpholine. The desired product was obtained in 86% yield as white solid. MS (m/e): 493.1 (2M+, 100%).