Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[Cl:47][CH2:48][CH2:49][CH2:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[Cl:47][CH2:48][CH2:49][CH2:50][S:51]([NH:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)(=[O:53])=[O:52]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(=O)(=O)CCCCl)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 12 °C
Reaction time: 16 h
Yield: 104.4 %

Procedure:
To a solution of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (70 mg, 0.13 mmol) and Et3N (0.1 mL) in CH2Cl2 (2 mL) was added 3-chloropropane-1-sulfonyl chloride (140 mg, 0.92 mmol) dropwise at 0° C. The reaction mixture was stirred at 12° C. for 16 hours. The reaction mixture was concentrated to provide 6-(3-chloropropylsulfonamido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (90 mg, yield: 100%), which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)n1ccc2cc(OCCCCBr)ccc21
Solvent: CN(C)C=O
Product: CCN(CC)CCCCOc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Yield: 84.3 %

Procedure:
4.8 g (13 mmol) 5-(4-Bromo-butoxy)-indole-1-carboxylic acid tert-butyl ester in 5 ml DMF were treated with 5 ml (48.1 mmol) diethylamine at 50° C. for 5 h. The solution was concentrated and extracted with ether and water. The combined organic phases were dried over Na2SO4 to yield 3.95 g (85%) 5-(4-Diethylamino-butoxy)-indole-1-carboxylic acid tert-butyl ester as yellow oil, MS: 361 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C:25]2([CH2:35][O:34][C:33]3[CH:36]=C4C(=C[C:32]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[O:34]1[CH2:35][CH2:25][CH2:32][C@@H:33]1[CH2:36][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: mp 174-176° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.32-7.25 (m, 1H), 7.16-7.00 (m, 3H), 6.49 (s, 1H), 6.24 (s, 1H), 4.88 (d, J=8.7 Hz, 1H), 4.63 (d, J=8.7 Hz, 1H), 4.31-4.22 (m, 1H), 4.21-4.17 (m, 2H), 4.14-4.09 (m, 2H), 3.99-3.67 (m, 4H), 2.09-1.82 (m, 3H), 1.78-1.66 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.1, 177.9, 155.3, 144.6, 143.0, 142.9, 138.4, 132.4, 132.3, 128.9, 128.8, 123.8, 123.7, 123.3, 121.4, 121.3, 111.7, 111.6, 109.8, 109.5, 99.4, 80.29, 80.26, 77.1, 76.8, 68.4, 68.3, 64.6, 64.0, 58.10, 58.08, 44.7, 29.4, 29.1, 25.9, 25.7; MS (ES+) m/z 380.2 (M+1).
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.N>O.CO>[NH2:6][C:5]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNc1ccccc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Nc1c(N=O)cnn1-c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 2.32 g (21 mmol) of phenylhydrazine with a purity of 98% by weight, 10 ml of methanol and 3.0 ml (36 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for one hour. After completion of the reaction, 10 ml of water was added to the mixture to cool the same up to 10° C., then, 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower for 30 minutes. Precipitated crystals were collected by filtration, and the crystals were washed with 5 ml of cold water and dried under reduced pressure to obtain 3.19 g of 5-amino-4-nitroso-1-phenylpyrazole (Isolation yield: 63.4%) as an ocherous solid with a purity of 74.9% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH2:8]O)=[CH:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[S:3]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1COCC1>[CH3:1][N:2]1[C:7]([CH2:8][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[S:3]1
Reactant: CN1Sc2sccc2C=C1CO
Reactant: C1COCCN1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1Sc2sccc2C=C1CN1CCOCC1
Yield: 84 %

Procedure:
To a solution of the product from Step C (0.79 g, 3.42 mmol) and triethylamine (1.04 g, 10.3 mmol) in anhydrous THF (30 mL) at ambient temperature was added methanesulfonic anhydride (0.89 g, 5.13 mmol) with stirring. After 30 min morpholine (2 mL) was added and the mixture stirred for 1 h at ambient temperature and then heated at reflux temperature for 1 h. The volatiles were evaporated and a saturated aqueous solution of sodium bicarbonate (80 mL) was added. This mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts were dried (MgSO4) and evaporated to give a viscous oil which was purified by column chromatography (silica, 30 to 50% ethyl acetate/hexane) to give a white solid (0.82 g, 84%): mp 104°-106° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:20])[CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([O:18][CH3:19])[C:14]=1[N+:15]([O-:17])=[O:16])[O:20][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(OC)c([N+](=O)[O-])c(OCc2ccccc2)c1
Yield: 84.7 %

Procedure:
In DMF (10 ml), 3-benzyloxy-5-methoxy-4-nitrophenol (1.43 g, 5.20 mmol), potassium carbonate (1.08 g, 7.79 mmol) and methyl bromoacetate (591 μl, 6.24 mmol) were stirred at room temperature for 2 days. The reaction mixture was poured in water (200 ml), followed by extraction with ether (200 ml). The extract was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (20:1) eluate fractions, the title compound (1.53 g, 85%) was obtained as a yellow crystalline solid.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccsc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 2 g of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4]diazepine in 20 ml of ethyl alcohol and 20 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography to give the desired product.
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([CH2:15][P:16]([S:22][CH:23]([CH3:25])[CH3:24])([S:18][CH:19]([CH3:21])[CH3:20])=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[CH2:30](OCC)C>C(O)(=O)C>[CH2:5]([N:4]([CH2:15][P:16]([S:22][CH:23]([CH3:25])[CH3:24])([S:18][CH:19]([CH3:21])[CH3:20])=[S:17])[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCC(C(=O)O)N(CP(=S)(SC(C)C)SC(C)C)C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(SC(C)C)SC(C)C
Reaction time: 0.08 h

Procedure:
Ethyl-N-[bis(isopropylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (4.0 g.) was dissolved in 10 ml. of 35% hydrobromic acid in acetic acid for one hour. Diethyl ether was added and a viscous oil precipitated. The ether was decanted and the precipitate washed with diethyl ether an additional three times. The precipitate was dissolved in acetonitrile and excess propylene oxide added. After about 5 minutes, the solution was concentrated in vacuo to yield ethyl-N-[bis(isopropylthio)phosphinothioylmethyl]glycine (0.95 g.) as an oil, ND25 =1.5524. The compound gave the following analysis.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:23]([C:22]3[CH:21]=[C:20]([CH:28]=[CH:27][CH:26]=3)[CH2:19][NH:18][C:16](=[O:17])[O:15][C:11]([CH3:14])([CH3:12])[CH3:13])[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: N
Product: CC(C)(C)OC(=O)NCc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-((tert-butoxycarbonylamino)methyl)benzoic acid (Fluka). 1H NMR (300 MHz, DMSO-d6) δ 1.42 (s, 9H), 4.27 (d, J=6.1 Hz, 2H), 7.51-7.72 (m, 4H), 8.01-8.17 (m, 2H), 8.45 (dt, J=8.1, 1.9 Hz, 1H), 8.82 (dd, J=5.1, 1.7 Hz, 1H), 9.26 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:12]O.N1C=CC=CC=1.P(Br)(Br)[Br:21]>ClCCl>[Br:21][CH2:12][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(CO)cccc1[N+](=O)[O-]
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(CBr)cccc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
A solution of 14.7 g of (2-methoxy-3-nitro-phenyl)-methanol dissolved in 140 ml of dichloromethane and 5.5 ml of pyridine was cooled in an ice bath and slowly added 6.48 ml of phosphorus tribromide. After 45 minutes at 5° C., the reaction mixture was diluted with dichloromethane, washed with water, dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (5:95) giving 7.3 g of 1-bromomethyl-2-methoxy-3-nitrobenzene as a yellow solid. ##STR158##
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3](O)=[O:4].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>ClCCl>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([Cl:23])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCC(C)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-methylundecanoic acid (0.40 g, 2.0 mmol) in anhydrous dichloromethane (20 ml) and a catalytic amount of DMF (approximately 0.02 ml) was added oxalyl chloride (0.4 mL, 4.6 mmol). The resulting mixture was stirred vigorously for 2 hours at room temperature. The organic solvent was evaporated under reduced pressure and the residue (80) was used in the next step.
Reaction SMILES: N1C=CN=C1.[C@@H:6]1([N:14]2[CH:21]=[CH:20][C:18](=[O:19])[NH:17][C:15]2=[O:16])[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:7]1.[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].O>CN(C=O)C>[CH:22]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:12][CH2:11][C@H:10]1[O:13][C@@H:6]([N:14]2[CH:21]=[CH:20][C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH2:7][C@@H:8]1[OH:9])([CH3:24])[CH3:23]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Imidazole (0.183 g, 2.69 mmol) was added to a solution of 2′-deoxyuridine (0.272 g, 1.19 mmol) in dry DMF (5 mL) under nitrogen. The mixture was cooled in an ice-salt bath before drop-wise addition of triisopropylsilyl chloride (0.28 mL, 1.31 mmol) via a syringe. The reaction mixture was kept at 0° C. for 3 h, allowed to warm up to room temperature and then stirred at room temperature for 22 h. After addition of water (5 mL), the crude mixture was extracted with CHCl3 (2×10 mL). The organic layers were combined and dried over MgSO4. Removal of the solvent under reduced pressure afforded a crude transparent oil which was further purified by flash chromatography eluting the column (ISOLUTE SI) a gradient of 0→10% CH3OH in CHCl3. The title compound was obtained from the fractions with Rf=0.25 (10% CH3OH in CHCl3) as a crystalline white solid (0.366 g, 74%). M.p. 152-153° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH:6]([O:8][CH3:9])[O:5][CH:4]1[O:10][CH3:11].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:11][O:10][CH:4]1[CH:3]([CH2:2][NH:1][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7][CH:6]([O:8][CH3:9])[O:5]1
Reactant: COC1CC(CN)C(OC)O1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1CC(CNC(=O)c2ccccc2)C(OC)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
10 g (62 mmol) of 3-aminomethyl-2,5-dimethoxytetrahydrofuran and 17 ml (123 mmol) of triethylamine were dissolved in 100 ml of anhydrous tetrahydrofuran. At 0° C., 7.2 ml (62 mmol) of benzoyl chloride were added dropwise and the mixture was stirred at 0° C. for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. 17 g of crude product were obtained and were immediately reacted further.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[H][H].O>CO.[Pt]>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: Nc1cccnc1-c1ccccc1
Agent: [Pt]
Agent: Cl
Solvent: O
Solvent: CO
Product: N[C@H]1CCCN[C@H]1c1ccccc1
Yield: 87.3 %

Procedure:
In a bottle were placed 2.65 g (15.6 mmol) of 3-amino-2-phenylpyridine, 10.6 g of 5% platinum/carbon and 106 mL of 1.5 M HCl in methanol. The mixture was shaken under an atmosphere (ca. 40 p.s.i.) of hydrogen for 2.5 hours. Water was added to the system, the mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ca. 700 mL of water. The filtrate was made basic with solid sodium hydroxide and extracted with two portions of dichloromethane. The combined organic fractions were washed with water, dried (sodium sulfate) and concentrated with a rotary evaporator to obtain 2.4 g of the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][S:34]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:36])=[O:35]
Reactant: CC(C)CCS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Product: CC(C)CCS(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
[(R)-1-(3-Methyl-butane-1-sulfonyl)-pyrrolidin-3-yl]-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and 3-methyl-butane-1-sulfonyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([O:16]CC)=O)[CH:8]=2)[NH:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=[N:29]O)[NH2:28])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[N:28]=[C:14]([CH2:13][O:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH2:11][CH2:10]4)[O:16][N:29]=2)=[CH:24][CH:25]=1
Reactant: NC(Cc1ccc(Cl)cc1)=NO
Reactant: CCOC(=O)COc1ccc2c(c1)CCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(OCc3nc(Cc4ccc(Cl)cc4)no3)ccc2N1
Temperature: 110 °C
Yield: 27 %

Procedure:
To a stirred solution of ethyl 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate (0.1 g, 0.4 mmol) in dry toluene (2 mL), 2-(4-chlorophenyl)-N′-hydroxyacetimidamide (0.073 g, 0.4 mmol) and potassium carbonate (0.1 g, 8 mmol) were added and heated to 110° C. in a microwave oven for 30 min. Solvent was removed under vacuum. Water (5 mL) was added to the residue, and the solid which formed was filtered, dried, and recrystallized using a mixture of ACN/Ethanol to afford 6-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as an off-white solid (40 mg, 27%). 1H NMR: 400 MHZ, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.82 (t, J=7.60 Hz, 2H), 4.14 (s, 2H), 5.39 (s, 2H), 6.78-6.83 (m, 2H), 6.89 (d, J=2.40 Hz, 1H), 7.33 (d, J=8.40 Hz, 2H), 7.40 (d, J=8.40 Hz, 2H), 9.95 (s, 1H). LCMS: RT 1.85 min. LCMS (ES-API), m/z 370.0 (M+H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Br)([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=O)C.C1COCC1.[NH3:23]>C(O)C>[NH2:23][C:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: N
Reactant: COC(=O)C(C)(Br)c1ccc(OC(C)=O)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)C(C)(N)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
10 g of methyl 2-(4-acetoxyphenyl)-2-bromopropionate, 50 mL of THF and 30 mL of ethanol are introduced into a Woulff bottle at ambient temperature. The mixture is saturated with gaseous ammonia and stirred for one night at ambient temperature. The insoluble matter is filtered and purified over a silica column with 90/10 dichloromethane/methanol to yield the product (5 g; Yd=77%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:4][C:3]=1[CH3:25].[OH:26]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:26])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(SCCCCOc2ccc3c(c2)CCC(=O)N3)ccc1Br
Reactant: OO
Product: Cc1cc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)ccc1Br

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-bromo-3-methyl-phenylmercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[O:13][CH2:2][CH2:3][N:4]=2)=[CH:11][CH:10]=1
Reactant: O=C(NCCO)c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Oc1ccc(C2=NCCO2)cc1
Yield: 87 %

Procedure:
To a slurry of 18.0g (0.1 moles) of N-(2-hydroxyethyl)-p-hydroxybenzamide in 100 ml of ethyl acetate was added a solution of 23.80g (0.2 moles) of thionyl chloride in 25 ml of ethyl acetate. Thionyl chloride addition was slow enough to maintain the reaction temperature below 50° C. After 2 hours at room temperature the precipitate was collected by vacuum filtration and then dissolved in 200 ml of water. The solution was neutralized with 5% sodium hydroxide solution. The white precipitate which formed was collected by vacuum filtration and then dried in a vacuum oven at ≈70° C. overnight. This material was identified by NMR and IR spectroscopy as the desired 2-(p-hydroxyphenyl)-oxazoline. An 87% yield was obtained.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:23]=[CH:22][S:21][C:5]=3[C:6](=[O:20])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][Si](C(C)(C)C)(C)C.CC1(C)C(C)(C)OB([C:32]2[CH2:37][CH2:36][CH:35]([NH:38][C:39](=O)OC(C)(C)C)CC=2)O1>>[OH:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:20])[C:5]3[S:21][CH:22]=[CH:23][C:4]=3[C:3]=2[C:2]=1[C:37]1[CH2:32][CH2:39][NH:38][CH2:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: O=c1[nH]c2ccc(O)c(C3=CCNCC3)c2c2ccsc12
Yield: 234.6 %

Procedure:
Following General Procedure B, 9-bromo-8-(tert-butyldimethylsilyloxy)thieno[2,3-c]quinolin-4(5H)-one (80 mg, 0.20 mmol) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enylcarbamate (90 mg, 0.29 mmol) to afford the desired product (140 mg, 23%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.01-7.98 (m, 2H), 7.35 (d, J=8.9 Hz, 1H), 7.12 (d, J=8.9 Hz, 1H), 5.80 (s, 1H), 4.01-3.91 (m, 2H), 3.63-3.60 (m, 2H), 2.88-2.84 (m, 1H), 2.57-2.53 (m, 1H); ESI MS m/z 299 [C16H14N2O2S+H]+; HPLC >99% (AUC), tR=6.70 min.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:20][C:21]1[CH:22]=[C:23]([NH:31][CH2:32][CH:33]([OH:35])[CH3:34])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([N:31]2[CH2:32][CH:33]([CH3:34])[O:35][C:9]2=[O:11])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: CC(O)CNc1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(c2cc(Br)cc(C(F)(F)F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 195.1 %

Procedure:
Add triethylamine (339 mg, 3.35 mmol) and triphosgene (250 mg, 0.838 mmol) to the solution of 1-(3-bromo-5-(trifluoromethyl)phenylamino)propan-2-ol (500 mg, 1.68 mmol) in dichloromethane (8 mL), stir the resulting mixture overnight at ambient temperature. Partition the reaction mixture between dichloromethane and water, separate the organic layer, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product. Purify with flash chromatography (silica gel, PE:EtOAc=1:1) to afford the product (530 mg, 97%). MS: (M+1): 324.0.