Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:4]1[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C@@:5]1([C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[F:32])[CH3:22])[CH:2]=C.C(=O)(O)[O-:34].[Na+].O=O.[BH4-].[Na+]>C(Cl)Cl.CO>[F:32][C:24]1[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=1[C@:5]1([CH3:22])[C@H:4]([CH2:1][CH2:2][OH:34])[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6]1
Reactant: O=C([O-])O
Reactant: C=CC[C@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: O=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)[C@H](CCO)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl ((5R,6S)-6-allyl-5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (250 mg, 0.532 mmol) (cis-isomer from Step 1) in DCM (4 ml) and MeOH (1.3 ml), was added sodium bicarbonate (89 mg, 1.065 mmol) and the mixture was cooled to −78° C. The resulting mixture was ozonolized for about 10 min or until analysis showed no starting material present. The stream of oxygen was passed through the solution for 5 min, then solid sodium borohydride (40.3 mg, 1.065 mmol) was added to the mixture. The flask was removed from the bath and allowed to reach RT and stirred for 30 min. The reaction was quenched with saturated NH4Cl solution (caution: there is evolution of gas), diluted with water to dissolve solids and extracted into EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to afford tert-butyl ((5R,6S)-5-(2-fluoro-5-nitrophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate which was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:35])[C:8]([C:30]([O:32]CC)=[O:31])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([NH:20]C(OC(C)(C)C)=O)[C:17]([F:28])=[CH:16][C:15]=2[F:29])=[CH:5][C:4]=1[F:36]>O>[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:35])[C:8]([C:30]([OH:32])=[O:31])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([F:28])=[CH:16][C:15]=2[F:29])=[CH:5][C:4]=1[F:36]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c(N)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: Cc1c(N)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 25 °C
Yield: 54.1 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to ethyl 7-amino-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (170 mg), and the mixture was heated under reflux for 5 hours. After the reaction mixture was cooled back to room temperature, water (2 ml) was added thereto. Solids deposited were collected by filtration and then washed successively with water, ethanol and diethyl ether to obtain the title compound (68 mg) as a pale yellow powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([CH:10]2[CH:14]([O:15]C(=O)C3C=CC=CC=3)[CH2:13][CH:12]([O:24][CH2:25][P:26]([O:31]CC)([O:28]CC)=[O:27])[O:11]2)[N:6]=1)=O.Br[Si](C)(C)C.[N:39]1C(C)=CC=CC=1C.N>CC#N>[C:3]([C:5]1[N:9]=[CH:8][N:7]([CH:10]2[O:11][CH:12]([O:24][CH2:25][P:26](=[O:27])([OH:28])[OH:31])[CH2:13][CH:14]2[OH:15])[N:6]=1)(=[O:2])[NH2:39]
Reactant: CCOP(=O)(COC1CC(OC(=O)c2ccccc2)C(n2cnc(C(=O)OC)n2)O1)OCC
Reactant: Cc1cccc(C)n1
Agent: C[Si](C)(C)Br
Agent: N
Solvent: CC#N
Product: NC(=O)c1ncn(C2OC(OCP(=O)(O)O)CC2O)n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The 1-[3-benzoyloxy-5-(diethoxy-phosphorylmethoxy)-tetrahydrofuran-2-yl]-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (60 mg. 0.124 mmol) was dissolved in MeCN (1.5 mL). Bromotrimethylsilane (0.164 mL, 1.24 mmol) and 2,6-lutidine (0.043 mL, 0.372 mmol) were added and the mixture stirred at ambient temperature for 10 h. The solvents were removed in vacuo and the product isolated by C-18 HPLC. To this was then added ammonia (7 N in MeOH, 4 mL) and the mixture stirred overnight. The title compound was isolated by C-18 HPLC. 1H NMR (300 MHz, D2O) ppm 8.65 (s, 1H), 5.95 (d, 1H, J=2.4 Hz), 5.49-5.52 (m, 1H), 4.81-4.89 (m, 1H), 3.47-3.70 (m, 2H), 2.27-2.32 (m, 2H). 31P NMR (121.4 MHz, D2O) ppm 15.0. LRMS (ESI) M-H C8H12N4O7P requires 307.0 Found 307.0.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[CH3:27]>O1CCCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:25])=[O:24])=[CH:19][C:18]=1[CH3:27]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(S(=O)(=O)N2CCOCC2)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylethylamine (8.25 mL, 46.4 mmol) was added at 0° C. to a stirred solution of morpholine (1.62 g, 18.5 mmol) in tetrahydrofuran (40 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-3-methyl-benzenesulfonyl chloride (5.0 g, 19 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 4-(4-bromo-3-methyl-benzenesulfonyl)-morpholine, which was used in subsequent reactions without further purification. MS cald. for C11H14BrNO3S [M+] 320.2, obsd. 321.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:13])[CH2:9][CH2:10][NH:11][CH3:12].Br[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1>CN(C=O)C>[CH3:7][N:8]([CH3:13])[CH2:9][CH2:10][N:11]([CH3:12])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CNCCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
Potassium carbonate (2.0 g) and N,N,N′-trimethylethylenediamine (1.1 g) were added to a DMF solution (20 mL) of 2-bromo-5-nitropyridine (2.0 g), and stirred at 80° C. for 2 hours. The solvent was evaporated off under reduced pressure from the reaction liquid, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=500/5 to 500/10) to obtain N-[2-(dimethylamino)ethyl]-N-methyl-N-(5-nitro-2-pyridinyl)amine (1.35 g) as an yellow oily substance.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])=[O:10]
Reactant: O=C(O)CCCCCCCBr
Reactant: COCCOCCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)CCCCCCCBr
Yield: 78.4 %

Procedure:
8-Bromooctanoic acid (22.3 g), 2-(2-methoxyethoxy)-ethanol (14.08 g) and p-toluenesulphouic acid (0.1 g) were added to toluene (250 ml ) and the resulting soution heated at reflux temperature for 16 hours. Ethyl acetate (500 ml) was then added and the solution washed with aqueous K2CO3 solution and water, dried and evaporated. The residual oil was distilled to give 2-(2-methoxyethoxy)-ethyl 8-bromooctanoate (25.5 g), 77%) as a colourless oil, b.p. 126°-128° C./0.08 mm Hg.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][N:82]([CH2:85][CH3:86])[CH2:81][CH2:80]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][CH:79]5[CH2:84][CH2:83][N:82]([CH2:85][CH3:86])[CH2:81][CH2:80]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:32])([F:33])[F:34])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(C(F)(F)F)c2)CC1
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.0880 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0299 g (0.233 mmole) of 4-amino-1-ethylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0459 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-trifluoromethyl-benzamide (I-206) as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:12][C:11](=[O:24])[C:10]=1[C:25](=O)[CH2:26][CH3:27]>C(O)C>[CH2:2]([O:4][N:5]=[C:25]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:12][C:11]=1[OH:24])[CH2:26][CH3:27])[CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Ethoxyamine hydrochloride (0.45 g) and then aqueous 1% sodium hydroxide (18.4 ml) were added to a solution of 3-hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (1.2 g; 4.2 mmole) in anhydrous absolute ethanol (200 ml). The mixture was stirred at room temperature for a period of 4 hours and then the ethanol was removed by evaporation under reduced pressure using a rotary evaporator. The residue was treated with dichloromethane and the organic phase was washed twice with dilute aqueous hydrochloric acid and twice with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.25 g; 93%), as a pale yellow oil.
Reaction SMILES: [C:1]1([Mg]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]1(=[O:17])[CH2:16][CH2:15][CH2:14]1.Cl>C(OCC)C>[OH:17][C:13]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCC1
Reactant: Br[Mg]c1cccc2ccccc12
Agent: Cl
Solvent: CCOCC
Product: OC1(c2ccc3ccccc3c2)CCC1

Procedure:
To a mixture of 23.1 g. of naphthyl magnesium bromide and 250 ml. of diethyl ether, 7 g. of cyclobutanone are slowly added. After the addition, the mixture is refluxed for one hour, cooled, acidified with aqueous hydrochloric acid and filtered. The product is isolated by methylene chloride extraction to furnish 2-(1'-hydroxycyclobutyl)-naphthalene. The product is hydrogenated in 200 ml. of ethanol with a molar equivalent of hydrogen in the presence of 50 g. of Raney nickel; the reaction mixture is filtered after the hydrogenation and evaporated to furnish 2-cyclobutylnaphthalene.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc(O)c1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(OCc2ccc(-c3cc(C(N)=O)on3)cc2)c1
Temperature: 85 °C
Yield: 57.6 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 3-methoxyphenol (21 μL, 0.19 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 85° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(3-methoxy-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (20 mg, 58%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.91 (d, J=8.1 Hz, 2H), 7.54-7.62 (m, 3H), 7.18 (t, J=7.9 Hz, 1H), 6.47-6.64 (m, 3H), 5.16 (s, 2H), 3.26-3.33 (m, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:19][C@H:20]([CH3:34])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CO>[CH3:33][O:32][C:30]([CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C@H:20]([NH:19][CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:34])=[CH:24][CH:25]=1)=[O:31]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2cccc(Cl)c2)cc1

Procedure:
Following a procedure similar to that described in Preparation 29, but using 5.2 g of (R)-α-t-butyldimethylsilyloxy-α-(3-chlorophenyl)acetaldehyde (prepared as described in Preparation 49), 4.24 g of methyl 4-[2(R)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 27), 50 ml of absolute methanol and 3.4 g of sodium cyanoborohydride, the title compound was obtained having an Rf=0.20 (thin layer chromatography over silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent). [α]D23 -34.7° (c=1.024, chloroform).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:10]([C:11]2[S:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28]Cl)[CH:20]=3)=[N:14][N:15]=2)=[N:9][O:8][N:7]=1)=O.[NH2:33][CH:34]1[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]1.CCO>O>[NH:37]1[CH2:38][CH2:39][CH:34]([NH:33][CH2:28][CH2:27][CH2:26][O:25][C:21]2[CH:20]=[C:19]([CH2:18][C:17]([NH:16][C:13]3[S:12][C:11]([C:10]4[C:6]([NH2:5])=[N:7][O:8][N:9]=4)=[N:15][N:14]=3)=[O:30])[CH:24]=[CH:23][CH:22]=2)[CH2:35][CH2:36]1
Reactant: O=C(Cc1cccc(OCCCCl)c1)Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O
Solvent: CCO
Product: Nc1nonc1-c1nnc(NC(=O)Cc2cccc(OCCCNC3CCNCC3)c2)s1

Procedure:
N-Trifluoroacetyl-4-(5-(3-(3-chloro-propoxy)-phenylacetyl)amino-[1,3,4]thiadiazol-2-yl)-furazan-3-ylamine (0.05 g, 0.1 mmol), 4-amino-N-Boc-piperidine (0.082 g, 0.4 mmol) and EtOH (0.3 mL) were heated by microwave irradiation at 120° C., 10 minutes; 150° C., 10 minutes; and 150° C., 30 minutes. The reaction was diluted with water and purified by preparative HPLC. Yield: 0.02 g (43%). 1H-NMR (MeOD) δ 7.27–7.30 (t, 1H), 6.96–6.98 (m, 2H), 6.88 (d, 1H), 4.14 (t, 2H), 3.87 (s, 2H), 3.50–3.60 (m, 3H), 3.07–3.10 (m, 2H), 2.36–2.39 (m, 2H), 2.17–2.20 (m, 2H), 1.82–1.90 (m, 2H), 1.30–1.35 (m, 2H). LCMS 459.0 (M+1), HPLC Method B Rt 1.7 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27]\[OH:28])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ncccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ncccc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-3-(3-methyl-pyridin-2-yl)-1-(2-methyl-pyridin-4-yl)-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound which contains less than 6% of the Z isomer as a colorless oil, MS (ESI+): m/z=410.0872 ([M+H]+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:14][C@H:10]([C:8]2[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]3[CH:21]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11][O:12][CH3:13])[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 80.4 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (69 mg, 0.24 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (37 mg, 0.24 mmol) and DIPEA (0.21 mL, 1.2 mmol) in IPA (1 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-20% DCM in EtOAc) to afford 271 as a yellow solid (78 mg, 80%). LCMS (Method K): RT 3.52 min [M+H]+ 405.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.68-8.64 (1H, m), 8.11 (1H, td, J=7.76, 1.94 Hz), 7.84 (1H, s), 7.79-7.73 (2H, m), 7.66 (1H, d, J=7.94 Hz), 7.56 (1H, ddd, J=7.52, 4.87, 0.98 Hz), 7.30-7.13 (4H, m), 6.03-5.95 (1H, m), 3.83 (2H, d, J=6.59 Hz), 3.19 (3H, s)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])=[CH:16][C:15]([Br:25])=[CH:14][CH:13]=2.ClCCl.C(N(CC)CC)C>O>[Br:25][C:15]1[CH:14]=[CH:13][C:12]2[N:11]=[CH:10][C:9]3[N:8]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:19]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[C:18]=3[C:17]=2[CH:16]=1
Reactant: CC(C)(O)CNc1c(N)cnc2ccc(Br)cc12
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2cnc3ccc(Br)cc3c2n1CC(C)(C)O
Reaction time: 16 h

Procedure:
Ethoxyacetyl chloride (6.2 g, 50.5 mmol) was added dropwise to a solution of crude 1-[(3-amino-6-bromoquinolin-4-yl)amino]-2-methylpropan-2-ol, dichloromethane (500 mL), and triethylamine (7 mL, 50.5 mmol). After stirring for 16 hours, water was added and the mixture was stirred for an additional 2 hours. The fractions were separated. The organic fraction was washed with water, concentrated under reduced pressure and redissolved in ethanol (500 mL). Water (150 mL) and potassium carbonate (10.5 g) were added and the mixture was heated at reflux temperature for 3 hours. The ethanol was removed under reduced pressure. The remaining aqueous fraction was extracted with ethyl acetate (2×500 mL). The organic fractions were combined, washed with water followed by saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile provided 10.4 g of 1-[8-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a tan powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][CH2:23][CH2:24][C:25]([O:27]CC3C=CC=CC=3)=[O:26])=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:14]2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(CCCc1cn(S(=O)(=O)c2cccc([N+](=O)[O-])c2)c2ccccc12)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCc1cn(S(=O)(=O)c2cccc([N+](=O)[O-])c2)c2ccccc12
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of benzyl 4-[1-(3-nitrobenzenesulfonyl)indol-3-yl]butyrate (1.95 g) in 1,4-dioxane (15 ml) was added 1N-sodium hydroxide (8 ml). The mixture was stirred for 2 hours and poured into diluted hydrochloric acid. The organic layer was extracted with ethyl acetate (30 ml) and washed with water (30 ml×3). The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was crystallized with diisopropyl ether to give a yellow solid of 4-[1-[3-nitrobenzenesulfonyl)indol-3-yl]butyric acid (1.45 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: CCCCCBr
Reactant: O=S(=O)(NCCCCCO)c1ccc(-c2ccccc2)cc1
Product: CCCCCN(CCCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a method analogous to that described in Example 4, with biphenyl-4-sulfonic acid-(5-hydroxypentyl)-amide and bromopentane, reacted at 60° C. for 3 hours, the title compound was obtained as an amorphous white solid. δC (CDCl3, 62.9 MHz): 14.0, 22.3, 22.9, 28.4, 28.6, 28.9, 32.2, 48.2, 48.4, 62.7, 127.3, 127.6, 128.4, 129.1, 138.6, 139.4 and 145.2.