Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:6]1[C:5]2[NH:1][N:2]=[N:3][C:4]=2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=1)([O-:15])=[O:14]
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c2[nH]nnc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
1H-Benzotriazole-5-carboxylic acid (1 g, 6 mmol) was dissolved, in conc. sulphuric acid (20 ml) and cooled to 0° C. on an ice bath. Nitric acid (20 ml, excess) was added drop wise to the cooled solution over a period of 20 minutes. Stirring was continued for another 15 minutes at 0° C. and then at 90° C. for 2 hours, by which time TLC (A) indicated the conversion of starting material. The solution was cooled to room temperature and poured over ice to precipitate a white solid. The solid was collected by filtration and washed with copious amounts of water until neutral to afford [21] in 48% yield. Rf (A) 0.53; δH(400 MHz; DMSO-d6) 8.77 (1H, s, BT) 9.01 (1H, s, BT) 13.75 (1H, br s, OH) 16.90 (1H, s, NH); m/z (EI−HR) 208.02288 [(M) calc. for C7H4N4O4 208.02325].
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[C:20]([CH2:22][OH:23])[C:5]2[N:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.N1C=CC=C[CH:25]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:6]2[C:5]3[C:20]([CH2:22][O:23][CH3:25])=[CH:21][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][C:4]=3[O:9][C:8]([CH3:11])([CH3:10])[C:7]2=[O:12])=[CH:18][CH:17]=1.[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:6]2[C:5]3[C:20]([CH2:22][OH:23])=[CH:21][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][C:4]=3[O:9][C:8]([CH3:11])([CH3:10])[C:7]2=[O:12])=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: CC1(C)Oc2cc(N)cc(CO)c2N(c2ccc(F)cc2)C1=O
Solvent: ClCCl
Solvent: O
Product: CC1(C)Oc2cc(NS(C)(=O)=O)cc(CO)c2N(c2ccc(F)cc2)C1=O
Product: COCc1cc(NS(C)(=O)=O)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To solution of 7-amino-4-(4-fluorophenyl)-5-(hydroxymethyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 175(3), 117 mg) and pyridine (0.12 mL) in dichloromethane (5 mL) was added dropwise methanesulfonyl chloride (0.085 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was dissolved in methanol (4 mL) and the solution was refluxed for 15 hours. The reaction mixture was concentrated in vacuo, and the resultant residue was purified by column chromatography on silica gel (Solvent; chloroform→chloroform/methanol=85/15) to give N-[4-(4-fluorophenyl)-5-(methoxymethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide as a pale yellow powder (40 mg, MS (APCI) m/z; 409 [M+H]+) and N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide as a pale brown powder (52 mg, MS (APCI) m/z; 409 [M+H]+), respectively.
Reaction SMILES: [Cl:1][C:2]1[C:9](Cl)=[C:8]([Cl:11])[C:7]([Cl:12])=[C:4]([C:5]#[N:6])[C:3]=1[C:13]#[N:14].[C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>CCCCCC.ClCCl>[C:21]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][C:9]1[C:2]([Cl:1])=[C:3]([C:13]#[N:14])[C:4](=[C:7]([Cl:12])[C:8]=1[Cl:11])[C:5]#[N:6]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: ClCCl
Product: N#Cc1c(Cl)c(Cl)c(Oc2ccccc2-c2ccccc2)c(Cl)c1C#N

Procedure:
3,4,5,6-tetrachlorophthalonitrile (5 g), 2-phenylphenol (3.201 g), K2CO3 (3.898 g) and acetonitrile (50 ml) are put in a 100 ml flask and then heated and refluxed. When the reaction is complete, the resultant is filtered with tetrahydrofuran (THF) to obtain a solid, the solid is added to a small amount of dichloromethane and dissolved therein, and hexane is added thereto, obtaining a crystallized solid (4-(biphenyl-2-yloxy)-3,5,6-trichlorophthalonitrile). Herein, the obtained solid is washed several times, filtered and vacuum-dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[C:3]=1[Cl:11].C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.C(Cl)(=O)C>C(OCC)C>[Cl:11][C:3]1[C:4]([O:9][CH3:10])=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1c(Cl)ccc(Br)c1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)Cl
Product: COc1c(Cl)ccc(B(O)O)c1Cl
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 1-bromo-2,4-dichloro-3-methoxybenzene (5.12 g, 20 mmol) in diethyl ether cooled to −70° C. was added 2.5M n-butyl lithium (8.8 mL, 22 mmol) in portions keeping the temperature below −60° C. The resulting reaction mixture was then stirred for 10 minutes before triisopropylborate (6.9 mL, 30 mmol) was added in portions keeping the temperature below −60° C. The reaction mixture was then allowed to warm to room temperature and acetyl chloride (60 mmol) was added. The reaction mixture was stirred for an hour at room temperature and concentrated. The residue was partitioned between ethyl acetate and 1N NaOH (40 mL) and the organic phase was extracted with additional 1N NaOH (10 mL). The sodium hydroxide extracts were combined, ice was added, and the solution was acidified to pH 3-4 with concentrated HCl. The product was then extracted with ethyl acetate and the organic phase was dried and concentrated to yield 2,4-dichloro-3-methoxyphenylboronic acid (3.27 g, 14.8 mmol): 1H NMR (CDCl3): δ 8.44 (br s, 2H), 7.42 (d, 1H), 7.15 (d, 1H), 3.8 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[C:20]1([C:26]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34]O)[O:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:34][CH2:33][CH2:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:30]=2)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: OCCCCc1cc(-c2ccccc2)no1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(CCCCc2cc(-c3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.8 %

Procedure:
3-Butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.354 mmol) and 4-(3-phenyl-5-isoxazolyl)-1-butanol (77 mg, 0.355 mmol) were dissolved in dry THF (4 ml) under nitrogen. A solution of dibenzyl azodicarboxylate (94%, 224 mg, 0.708 mmol) in dry THF (2 ml) was added. The mixture was cooled to 0° C. and a solution of triphenylphosphine (185 mg, 0.708 mmol) in dry THF (1 ml) was added. The mixture was stirred for 20 min at 0° C. then at room temperature overnight. The mixture was degassed then stirred with morpholine (0.308 ml) and tetrakis(triphenylphosphine)palladium(0) (82 mg) for 4.5 h. A further 60 mg of tetrakis(triphenylphosphine)palladium(0) was added and stirring continued overnight. The reaction was worked up by partition between EtOAc and 2M HCl, the organic phase evaporated and purified by aminopropyl SPE (5 g) washing with THF-MeOH (1:1), MeOH and eluting with DCM-MeOH (1:1) containing 5% AcOH. Further purification by MDAP afforded the title compound (56 mg).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[CH:24]=1>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:2]2[CH2:3][CH:4]3[CH2:8][N:7]([C:27]([C:26]4[CH:30]=[CH:31][C:23]([F:22])=[CH:24][C:25]=4[N:32]4[N:36]=[CH:35][CH:34]=[N:33]4)=[O:28])[CH2:6][CH:5]3[CH2:1]2)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Reactant: O=C(O)c1ccc(F)cc1-n1nccn1
Product: CN(C)c1nc(N2CC3CN(C(=O)c4ccc(F)cc4-n4nccn4)CC3C2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and Intermediate 4. MS (ESI): mass calculated for C22H22F4N8O, 490.46; m/z found 490.9 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.84-7.64 (m, 3H), 7.45-7.36 (m, 1H), 7.20-7.07 (m, 1H), 5.87 (br s, 1H), 4.04-2.79 (m, 16H).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(N(C)C)=O.CCOCC>[I:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(I)c1O
Agent: [Cs+]
Solvent: CCOCC
Solvent: CI
Solvent: CC(=O)N(C)C
Product: COc1c(I)cccc1C=O
Reaction time: 4.75 h

Procedure:
To a solution of 3-iodo-2-hydroxy-benzaldehyde (4.0 g, 16.06 mmol) in DMA (32 mL) was added cesium carbonate (5.85 g, 18 mmol) followed by methyl iodide (1.12 mL, 18 mmol). The resulting mixture was stirred for 4.75 hours then diluted with ether, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (50 g silica; eluted with 0-20% ethyl acetate in hexanes) to give the title compound as an oil.
Reaction SMILES: CC1OC[C:5]([CH2:25][OH:26])([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[N:6]=1.[ClH:27].[CH2:28]([OH:30])[CH3:29]>>[ClH:27].[NH2:6][C:5]([O:30][CH2:28][CH3:29])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:14]=1)[CH2:25][OH:26]
Reactant: CCO
Reactant: CC1=NC(CO)(CCc2ccc(OCCOc3ccccc3)cc2)CO1
Agent: Cl
Product: CCOC(N)(CO)CCc1ccc(OCCOc2ccccc2)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in DMF (5 ml) was added Cs2CO3 (1.2 g, 3.83 mmol) and 2-phenoxyethyl bromide (770 mg, 1.27 mmol). The reaction mixture was stirred at 85° C. for 4 hours. AcOEt and water were then added, the organic layer was separated and the aqueous phase was extracted with AcOEt (3×50 ml). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/Hx 9:1) afforded (2-Methyl-4-{2-[4-(2-phenoxy-ethoxy)phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol as colorless oil. To a solution of (2-methyl-4-{2-[4-(2-phenoxy-ethoxy)phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol (50 mg, 0.14 mmol) in ethanol (2 ml) was added conc. HCl (2 ml). The reaction mixture was stirred at 85° C. for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford 2-amino-4-{4-[2-phenoxy-ethoxy]-phenyl}-2-ethoxy-butan-1-ol hydrochloride as a colorless powder. ESI+MS: m/z=332.3 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([CH2:11]Br)=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[C:13]1([C:19]([NH2:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([N:32]1[CH2:2][C:3]2[C:4]([C:5]#[N:6])=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc(CBr)c1CBr
Product: N#Cc1cccc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 2,3-Bis-bromomethyl-benzonitrile (CAS: 66126-18-9) and triphenylmethylamine. Yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:10]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:10][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[OH:9].[Br:10][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([OH:9])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(O)ccc1Br
Product: COc1ccc(Br)c(O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24 %
Yield: 49 %

Procedure:
To a solution of 3-methoxy-phenol (1 g, 8.055 mmol) in tetrahydrofuran (30 mL) at room temperature was added N-bromosuccinimide (1.478 g, 8.055 mmol) in several portions. The yellow reaction mixture was stirred at room temperature for 12 h. Sodium bicarbonate solution (5 mL) was added and the product was extracted with diethyl ether (2×100 mL). The organic layers were washed with brine (1×20 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 10-30% ethyl acetate in hexanes yielded 2-bromo-5-methoxy-phenol (0.801 g, 49%) and 4-bromo-5-methoxy-phenol (0.396 g, 24%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH3:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH2:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2)[CH3:16]
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cc(CC)ccc2[nH]1
Product: CCc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-ethyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale brown solid. MS: 328.3 ([M−H]−).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:16]([NH2:28])[CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:16]([NH:28][C:36](=[O:38])[CH3:37])[CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)c2ccccc2)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(-c2cc(C(=O)NC3CC3)ccc2C)ccc1C(=O)c1ccccc1
Reaction time: 6 h
Yield: 85.1 %

Procedure:
To a solution of the 3′-Amino-4′-benzoyl-6-methyl-biphenyl-3-carboxylic acid cyclopropylamide from Example 14 (21 mg, 0.057 mmol) and triethyl amine (29 mg, 0.284 mmol) in 1.5 mL methylene chloride was added acetic anhydride (8.7 mg, 0.085 mmol) at room temperature. The reaction mixture was stirred at that temperature for 6 hours. The mixture was diluted with 50 mL of ethyl acetate and was washed with sat. aqueous NaHCO3 (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, and the solvents were evaporated. The residue was purified by preparative TLC sheet (ethyl acetate:hexanes=1:1) to give a colorless solid (20 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7](=[O:18])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.O.[Cl-].[NH4+:23]>CO>[NH3:6].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7](=[O:18])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=2[NH:15][CH2:7][CH:8]2[CH2:13][CH2:12][N:23]([CH:2]([CH3:20])[CH3:3])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccc(O)c1[N+](=O)[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C)N1CCC(CNc2c(O)cccc2C(=O)Nc2ccc(Cl)cc2)CC1
Product: N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4′-Chloro-3-hydroxy-2-nitrobenzanilide (1.43 g) was suspended in 50 ml of methanol, then 5 ml of distilled water, 2.80 g of reduced iron and 530 mg of ammonium chloride were added thereto and the mixture was stirred at 60° C. for 2 hours. The reaction was filtered through Celite and concentrated in vacuo. To the resulting residue was added a saturated saline solution and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting residue and 320 mg of 1-isopropylpyridine-4-carbaldehyde were suspended in 14 ml of toluene, then 37 mg of p-toluene sulfonic acid hydrate were added thereto and the mixture was heated to reflux for 24 hours together with removal of water by an azeotropic operation. This was concentrated in vacuo, to the resulting residue were added 14 ml of acetic acid and 350 mg of a boran-trimethylamine complex and the mixture was stirred at 70° C. for 17 hours. This was concentrated in vacuo, a 5% aqueous solution of sodium bicarbonate was added to the resulting residue and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by means of a silica gel column chromatography using chloroform:methanol:saturated aqueous ammonia (100:10:1) as an eluate to give 380 mg of crudely purified 4′-chloro-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzanilide. The crudely purified product (380 mg) was purified by means of an ODS column chromatography using 0.001N hydrochloric acid:methanol (10:3) as an eluate and then freeze-dried to give 162 mg of 4′-chloro-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzanilide hydrochloride.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7](C(O)=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:14].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18]C1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:38]1CC[O:41][CH2:40][CH2:39]1>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:14].[NH:38]1[CH2:18][CH:19]([C:20]([NH2:16])=[O:21])[O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C1CCc2cc(C(=O)O)ccc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: NC(=O)C1CNCCO1
Product: O=C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
2-Tetralone-6-carboxylic acid, ethylene ketal (395 mg, 2.07 mmol) was co-dissolved in CH2Cl2 (50 mL) with N-hydroxysuccinimide (260 mg, 2.76 mmol) at 0° C. and treated with a slight excess of 1,3-dicyclohexylcarbodiimide (502 mg, 2.50 mmol). The mixture was allowed to warm to ambient temperature over 30 minutes, during which time a fine white precipitate formed. Morpholine (0.91 mL, 10.4 mmol, d=0.998) was added and the solution stirred at ambient temperature for 16 hours. The suspended urea was filtered away and the solution concentrated in vacuo to a colorless oil. The oil was applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 323 mg (51%) of 2-tetralone-6-morpholinamide, ethylene ketal as a slowly crystallizing solid, clean by NMR, TLC.
Reaction SMILES: [CH3:1][N:2]([C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[P:38](OCl)([O:43]CC)([O:40]CC)=[O:39].Br[Si](C)(C)C>ClCCl.CO>[P:38]([OH:43])([OH:40])([O:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([S:10]([CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:8][CH2:7]2)(=[O:12])=[O:11])[CH2:14]1)=[O:39]
Reactant: CCOP(=O)(OCl)OCC
Reactant: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](O)C2)CC1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](OP(=O)(O)O)C2)CC1
Reaction time: 8 h

Procedure:
(3R)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]piperidin-3-ol (100 mg, 0.24 mmol) was suspended in dichloromethane (5 mL). Diisopropylethylamine (0.05 mL, 0.3 mmol) was added followed by diethyl chloro phosphate (0.036 mL, 0.24 mmol). The reaction mixture was stirred under nitrogen overnight. Methanol (1 mL) was added to the flask and the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL) and bromotrimethylsilane (2 mL, 14.4 mmol) was added. The reaction mixture was stirred under nitrogen at room temperature for 18 hours and then was concentrated in vacuo. The residue was purified by reverse phase HPLC. (2 mg, 5%). 1H NMR (400 MHz, DMSO-d6) ppm 1.28 (br. s., 1H) 1.50 (br. s., 1H) 1.63-1.72 (m, 2H) 1.86 (d, J=2.56 Hz, 1H) 2.02 (d, J=10.98 Hz, 1H) 2.83 (s, 1H) 2.94 (td, J=14.46, 6.59 Hz, 2H) 3.14 (s, 2H) 3.47 (br. s., 9H) 3.52 (br. s., 11H) 6.51 (br. s., 1H) 7.09 (d, J=2.93 Hz, 1H). LCMS m/z 488.8 (M+H calcd for C19H30N6O6PS requires 487.5). LCMS (C-18 column, gradient elution 5 minute chromatograph, 95:5 to 5:95 water/acetonitrile, retention time 1.23 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[ClH:24].[NH2:25]O.O>C(O)C>[ClH:24].[NH2:25][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])=[CH:9][CH:10]=1)[CH2:15][CH3:16]
Reactant: NO
Reactant: CCC(=O)c1ccc(CC(=O)OC(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(N)c1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To tert-butyl(4-propionylphenyl)acetate (1 g) in ethanol (20 ml) solution, sodium acetate (0.7 g) and hydroxylamine hydrochloride (0.44 g) were added and the mixture was stirred at 90° C. for 3 hours. Distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over with anhydrous sodium sulfate, then concentrated. Ethanol (22 ml) and 10% palladium carbon (0.6 g) were added to the residue, and the mixture was stirred under hydrogen atmosphere at 5 atm for 40 hours. The insoluble compound was filtered out, then a 4N hydrochloric acid/ethyl acetate solution was added to the filtrate and the mixture concentrated. Hexane/ethyl acetate was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (0.74 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1c(CCl)cccc1OC
Product: COCCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cccc1OC

Procedure:
Analogously to Method D, 0.417 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.278 g of 1-chloromethyl-3-methoxy-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.17 (1:2 EtOAc-heptane); Rt=6.19.