Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].C[O:3][C:4]1C=[CH:8][C:7](N([S:12]([O-:15])(=[O:14])=[O:13])N)=[CH:6][CH:5]=1.[Na+].[N+](C1OC(C(Cl)=O)=CC=1)([O-])=[O:18]>O.C(O)(C)(C)C>[C:4]([OH:3])(=[O:18])[CH2:5][CH2:6][C:7]([CH3:8])=[O:1].[S:12](=[O:13])(=[O:18])([OH:14])[OH:15]
Reactant: COc1ccc(N(N)S(=O)(=O)[O-])cc1
Reactant: O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(=O)CCC(=O)O
Product: O=S(=O)(O)O
Temperature: 25 °C

Procedure:
25.8 G. (0.1-mole) of sodium p-methoxyphenyl-hydrazine-sulphonate monohydrate are dissolved in a mixture of 112 ml of water and 48 ml of tert. butanol, then 17.4 g. (0.1 mole) of 5-nitro-furan-2-carboxylic acid chloride are poured into the solution, and the mixture is stirred for an hour at room temperature and consecutively for another hour on a water-bath of 70°-80°C. Subsequently, without isolating the product, 17 ml of levulinic acid and 4.5 ml of concentrated sulphuric acid are added dropwise, the mixture is stirred at 80°-85°C for an hour, cooled and 80 ml of water are added. The precipitated 1-(5-nitro-2-furoyl)-2-methyl-5-methoxy-indole-3-yl acetic acid is filtered by suction, and washed consecutively with 80 ml of 60% acetic acid and 100 ml of water. The crude product is recrystallized from 170 ml of 88% tert. butanol, clarified with 5% of active carbon "Norit", recrystallized on cooling, filtered by suction, washed with 20 ml of 88% tert. butanol, and dried to afford 17.7 g. of 1-(5-nitro-2-furoyl)-2-methyl-5-methoxy-indole-3-yl acetic acid. Yield 73.5%, m.p. 178°-180°C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1.ClCCl>[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)(=[O:36])=[O:35]
Reactant: Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1n[nH]c2cc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)ccc12)c1ccsc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
A solution of 1.72 g of 6-(4-aminophenyl)-3-[(thiophen-3-yl)carbonylamino]-1H-indazole hydrochloride in 69 mL of pyridine is admixed at 0° C. with a solution of 1.14 g of 2,3-dichlorobenzenesulfonyl chloride in 23 mL of dichloromethane. The reaction mixture is stirred for 3 hours at a temperature in the region of 20° C. and then concentrated under reduced pressure. The dry residue is diluted in ethyl acetate, washed with water and then washed with saturated sodium chloride solution and concentrated under reduced pressure. The foam obtained is purified by flash chromatography, eluting with a dichloromethane/methanol/acetonitrile (96/2/2 by volume) mixture, to give 0.69 g of 3-thiophenecarboxylic acid {6-[4-(2,3-dichlorobenzenesulfonylamino)phenyl]-1H-indazol-3-yl}amide, whose characteristics are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH:31]1([NH2:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:41][CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: NC1CCCc2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]([C:15]([O:17][CH3:18])=[O:16])[NH:3]1.[H-].[Na+].C1(P(C2C=CC=CC=2)(O[NH2:30])=O)C=CC=CC=1>CN(C=O)C>[NH2:30][N:3]1[C:2](=[O:1])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CC(=O)N1N
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(tert-Butyl) 3-methyl 5-oxo-1,3-piperazinedicarboxylate (4.5 g) was dissolved in DMF (90 ml) and combined with sodium hydride (0.84 g, in oil) with cooling on ice. After stirring at 50° C. for 1 hour, O-diphenylphosphinyl hydroxylamine (4.5 g) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was combined with aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried and concentrated to obtain 1-(tert-butyl) 3-methyl 4-amino-5-oxo-1,3-piperazinedicarboxylate as a yellow oil. A solution of this material and 1-(4-pyridinyl)-4-piperidone (3.1 g) in ethanol (90 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 15 hours. The reaction mixture was concentrated to obtain a residue, which was dissolved in methanol (90 ml) and combined with acetic acid (2.1 ml) with cooling on ice,followed by sodium cycanoborohydride (2.2 g) and then stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried, concentrated and purified by a column chromatography on a basic silica gel (ethyl acetate:methanol=20:1) to obtain the title compound (3.8 g) as a pale yellow non-crystalline powder.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[NH2:43][CH2:44][CH2:45][O:46][C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[C:50]#[N:51]>ClCCl.O>[C:50]([C:49]1[CH:48]=[C:47]([CH:54]=[CH:53][CH:52]=1)[O:46][CH2:45][CH2:44][NH:43][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:12][CH:11]=1)#[N:51]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: N#Cc1cccc(OCCN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Reaction time: 18 h

Procedure:
283 mg (1.73 mmol) of 4-isopropylbenzoic acid was dissolved in 10 ml of dichloromethane. 1.2 ml (8.65 mmol) of triethylamine, 363 mg (1.90 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 256 mg (190 mmol) of 1-hydroxybenzotriazole and 342 mg (1.24 mmol) of 3-(2-aminoethoxy)benzonitrile hydrochloride were added to the solution, and they were stirred for 18 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with water, 1 N sodium hydroxide and saturated aqueous NaCl solution successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>C1COCC1>[CH2:14]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: OCc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
To a THF (200 ml) solution of 2-iodo-benzyl alcohol (25 g, 107 mmol), at r.t., was added the NaH (5.12 g, 128 mmol) in small portions. After complete addition of the NaH the allyl bromide (11.1 ml, 128 mmol) was added via syringe. The mixture was stirred overnight at room temperature. The resulting white heterogeneous mixture was quenched with H2O (100 ml) and diluted with 300 ml of Et2O followed by washing with H2O (2×100 ml) and brine (1×100 ml). The organic layer was dried over MgSO4 and concentrated in vacuo to yield 31 g of 1-[(allyloxy)methyl]-2-iodobenzene as a faint yellow oil. HRMS (ESI+) calcd for C10H11IO m/z 273.9857 (M+H)+. Found 273.9855.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1-c1ccc(F)cc1

Procedure:
By following a procedure analogous to Example 27 starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluorophenylboronic acid, 2-(4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=64%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1.CC[Mg+].[Br-].[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[CH2:21]([Sn:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Cn1cnc(I)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-iodo-1-methylimidazole (0.424 g, 2.04 mmol) in CH2Cl2 at rt was added EtMgBr (3.0 M in Et2O, 0.75 mL, 2.25 mmol) and the resulting solution was allowed to stir for 30 min at rt. To this solution was then added Bu3SnCl (0.60 mL, 2.21 mmol) and the mixture was stirred for another 7 h. The resulting mixture was then washed (sat. NH4Cl, H2O, brine), dried (Na2SO4) and evaporated to give the title compound, which was used directly in the following step without further purification:
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F-].[Cs+]>>[CH2:6]([O:13][CH2:1][C@@H:2]([OH:3])[CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC[C@H]1CO1
Reactant: OCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: OC[C@H](O)COCc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
A mixture of (S)-glycidol (77) (20 g, 0.27 mol), benzyl alcohol (27.9 mL, 0.27 mol) and CsF (0.82 g, 5.40 mmol) was heated with stirring at 120° C. for 16 h. Unreacted benzyl alcohol was removed using a rotary evaporator attached to a high vacuum line. The product was partitioned between EtOAc and water, and the organic extract was evaporated and chromatographed on silica. Elution with petroleum ether gave fore fractions, and then further elution with EtOAc/petroleum ether (3:7) gave (2S)-3-(benzyloxy)-1,2-propanediol (78) (9.52 g, 19%) as a viscous oil: [α]19 −3.64° (c, 6.59, CHCl3); 1H NMR (CDCl3) δ 7.38-7.28 (m, 5H), 4.56 (s, 2H), 3.92-3.87 (m, 1H), 3.71 (dd, J=11.4, 3.9 Hz, 1H), 3.64 (dd, J=11.4, 5.4 Hz, 1H), 3.61-3.57 (m, 2H), 2.60 (br, 1H), 2.22 (br, 1H). APCI MS m/z 183 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:22]([NH:23]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:21](=[O:43])[N:12]2[C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:22]([NH2:23])[C:21](=[O:43])[N:12]2[C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Reaction time: 18 h

Procedure:
t-Butyl 3-benzyl-7-triphenylmethylamino-3-cephem-4-carboxylate (929 mg) was dissolved in acetone (2 ml) and the solution cooled to -20°. p-Toluene sulphonic acid (330 mg) in acetone (2 ml) was added dropwise over 2 - 3 minutes and the solution left at 0° for 18 hours. The crystalline product was filtered, washed with a little cold acetone and dried (493 mg) m.p. 175°-177°. The mother liquors were taken up in ethyl acetate, washed with dilute aqueous sodium bicarbonate and brine, dried and evaporated. Chromatography on silica gave crystalline t-butyl 3-benzyl-7-amino-3-cephem-4-carboxylate (V). ##SPC11##
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[CH:6]=[N:5][N:4]=1.S(Cl)([Cl:13])=O>>[ClH:13].[Cl:13][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[CH:6]=[N:5][N:4]=1
Reactant: CCCn1cnnc1CO
Reactant: O=S(Cl)Cl
Product: CCCn1cnnc1CCl
Product: Cl

Procedure:
To 3-hydroxymethyl-4-propyl-4H-1,2,4-triazole (5.95 g), thionyl chloride (40 ml) was slowly added at 0° C. The mixture was heated to reflux for 1 hour, and concentrated under reduced pressure. To the residue was added ethanol, and the mixutre was further concentrated. To the residue were added ethyl acetate and small amount of ethanol, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate, to give 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (5.43 g) as pale yellow crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:7])[CH3:6].[C:16](Cl)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:5]([C:9]1[CH:14]=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
Aluminum chloride (44.4 g, 333 mmol) was cooled to −45° C., and toluene (1.25 L) was added followed by 2-tert-Butylphenol (50.0 g, 333 mmol). The sample was then stirred for 2 hours. In addition, acetyl chloride (26.1 g, 333 mmol) was added dropwise, followed by 2.5 hours of stirring. The reaction solution was added dropwise to ice-cold water (250 mL), and then this was stirred at room temperature. Crystals were collected by filtration and dried under reduced pressure (50° C.) to give 48.7 g of the subject compound as white crystals (yield: 76.1%, HPLC purity: 99.8%).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11]O>CCOCC.C(Cl)Cl>[Br:2][CH2:11][C:10]1[O:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][C:6]=1[CH3:5]
Reactant: BrP(Br)Br
Reactant: Cc1nc(-c2ccccc2)oc1CO
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)oc1CBr
Reaction time: 4 h

Procedure:
80 mL (0.67 mmol) of PBr3 is added slowly to a solution of 104 mg (0.57 mmol) of (4-methyl-2-phenyl-oxazol-5-yl)-methanol in 0.5 mL of Et2O and 1.5 mL of CH2Cl2 at 0° C. The cooling bath is removed, and the reaction mixture is stirred for 4 h. The reaction mixture is then partitioned between saturated aqueous NaHCO3 solution and Et2O. The organic phase is separated and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to produce 5-bromomethyl-4-methyl-2-phenyl-oxazole as a solid; 1H NMR (250 MHz, CDCl3) δ7.90-7.99 (m, 2H), 7.32-7.40 (m, 3H), 4.50 (s, 2H), 2.16 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.N1C=CC=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)Nc1cccc(O)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(Oc2cccc(NC(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Hydroxyphenyl)urea (2.00 g), p-tolylboronic acid (3.57 g), and Cu(OAc)2 (2.63 g) were dissolved in 150 mL of THF, and 5.32 mL of pyridine was added. The reaction was stirred at room temperature overnight, then filtered through Celite with the aid of 200 mL EtOAc. The filtrate was washed with water, 0.2N CuSO4, 0.5N NaOH, and brine, and dried over Na2SO4 The solution was concentrated to a solid that was taken up in 200 mL of dichloromethane and stirred at room temperature for about 1 hour, after which time it was filtered to give 1-(3-(p-tolyloxy)phenyl)urea as white solid. The material was used in Step B without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](OC)(OC)OC.[N-:19]=[N+:20]=[N-:21].[Na+]>C(O)(=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([N:1]2[CH:12]=[N:21][N:20]=[N:19]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(OC)OC
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A suspension of 2-amino-5-chloro-benzoic acid (5.0 g, 0.029 mol), trimethyl orthoformate (9.5 mL, 0.087 mol) and sodium azide (5.6 g, 0.087 mol) in glacial acetic acid (105 mL) was stirred at room temperature for 2 h. Filtration and concentration from toluene gave 5-chloro-2-(1H-tetraazol-1-yl)benzoic acid (4.0 g, 62%); 1H NMR (400 MHz, CD3OD): δ 9.47 (s, 1H), 8.16 (d, J=2.5 Hz, 1H), 7.83 (dd, J=2.5, 8.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: Cc1c(F)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1c(F)cccc1C(=O)Cl

Procedure:
A solution of 2.87 g of 3-fluoro-2-methylbenzoic acid in 25 ml of thionyl chloride is refluxed for 1.75 hour and the excess thionyl chloride removed under vacuum. To the residue is added toluene (several 5 times) and the toluene removed under vacuum after each addition to give 3-fluoro-2-methylbenzoyl chloride.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>O1CCCC1>[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:8]2[N:9]=[C:10]([NH:12][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:11][C:7]=2[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCc2nc(N)sc2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC1CCc2nc(NC(=O)c3ccccc3)sc2C1

Procedure:
To a solution of 4.2 g (0.02 Mol) of 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzthiazole in 100 ml of absolute tetrahydrofuran are added 2.2 g (0.022 Mol) of triethylamine and 3.1 (0.022 Mol) of benzoylchloride and the mixture is refluxed for 3 hours. The reaction mixture is mixed with water and extracted with ethyl acetate. The organic phase is concentrated by evaporation. The residue is recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([I:18])=[C:12]([CH2:14][C:15]([OH:17])=O)[CH:13]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:23]1[CH:27]=[CH:26]N=C1)=O.O.C[N:35]([CH:37]=[O:38])C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([I:18])=[C:12]([CH2:14][C:15]([NH:23][C@@H:27]([CH3:26])[C:37]([NH2:35])=[O:38])=[O:17])[CH:13]=2)=[CH:19][CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1cc(OCc2ccc(F)cc2)ccc1I
Reactant: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1I)C(N)=O
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A mixture of (5-(4-fluoro-benzyloxy)-2-iodo-phenyl]-acetic acid (example 45a, 355 mg, 0.919 mmol) and 1,1′-carbonyl-diimidazole (164 mg, 1.01 mmol) in N,N′-dimethylformamide (2 mL) was stirred at 50° C. for 1.5 h. H-L-alanine-NH2HCl (145 mg, 1.16 mmol) was added and the mixture was stirred at 50° C. overnight. Water was added and the product precipitated. The solid was filtrated (368 mg, 88%). MS: m/e=457.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:17]([Li])CCC.C[N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([N:23]3[CH2:24][CH2:25][CH:26]([OH:29])[CH2:27][CH:28]3[CH3:17])=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(=O)CC1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CC(O)CCN1c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -40 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (288 mg) in anhydrous tetrahydrofuran (10 ml), with stirring at −78° C., was added 2.5M n-butyllithium in hexanes (541 μL). The reaction mixture was warmed gradually to −40° C. over 1 hour and then cooled to −78oC 1-methyl-4-piperidone (138 μL) was then added. The reaction mixture was gradually warmed to room temperature and then left to stir for 3 days. The reaction mixture was then quenched with water the precipitate formed filtered. This crude product was then purified using flash chromatography to yield 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methyl-piperidin-4-ol (135 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[NH:14][CH:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[CH3:28][NH2:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:29][CH3:28])[C:12]=2[CH:11]=[CH:10]1
Reactant: CN
Reactant: Cc1cc(F)ccc1N1CCC2=C1c1cccc(OC(F)(F)F)c1NC2Cl
Product: CNc1nc2c(OC(F)(F)F)cccc2c2c1ccn2-c1ccc(F)cc1C
Temperature: 180 °C

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-trifluoromethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(394 mg, 1.0 mmol) was dissolved in aqueous solution of methylamine (40%, 10 ml) in the pressure tube. The reaction mixture was refluxed at 180° C. for 3 hours. After removing the reaction solvent of the above mixture, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 301 mg of desired compound as solid in 77% of yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]([CH2:22][CH2:23][CH3:24])[CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH2:20][CH3:21])=[C:12]([C:16]([NH2:18])=[O:17])[CH:13]=2)[CH2:8]1)[CH2:4][CH3:5].Br[CH2:26][CH2:27][F:28]>CCCCCC.CN(C=O)C>[CH2:22]([N:6]([CH2:3][CH2:4][CH3:5])[CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH2:20][CH3:21])=[C:12]([C:16]([NH:18][CH2:26][CH2:27][F:28])=[O:17])[CH:13]=2)[CH2:8]1)[CH2:23][CH3:24]
Reactant: FCCBr
Reactant: CCCN(CCC)C1Cc2cc(OCC)c(C(N)=O)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCN(CCC)C1Cc2cc(OCC)c(C(=O)NCCF)cc2C1
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.05 g, 1.2 mmol) was washed with hexane under nitrogen and suspended in DMF (5 mL). 2-(Dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide (81, 0.15 g, 0.5 mmol) in DMF (5 mL) was added dropwise at 0-5° C. over 30 min and the mixture stirred 30 min. 1-Bromo-2-fluoroethane (0.26 g, 2 mmol) in DMF (5 mL) was added and the resulting mixture was stirred 3 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer is washed with water, brine, dried (MgSO4), filtered and concentrated to give crude product. Chromatographic purification yielded pure product 85 as an oil that was converted into the HCl salt and crystallized from EtOAc/hexane/MeOH to give a white solid (m.p. 158-159° C.).