Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Br[C:13]1C(C)=C(C=CC=1)C(O)=O.CI.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 60:40 mixture of 5-bromo-2-methyl benzoic acid and 3-bromo-2-methyl benzoic acid (8.0 g, 0.037 mol) was dissolved in N,N′-dimethylformamide (130 mL). Methyl iodide (2.28 mL, 2.3 mol) and potassium carbonate (5.11 g, 0.037 mol) were added in sequence at room temperature. The mixture was stirred at room temperature for 2 hours at which point the reaction was determined to be complete by HPLC. The solvent was removed under high vacuum and the resulting residue was passed through a silica gel column using 5% ethyl acetate in hexanes as the eluent. The mixture of isomers was obtained as an oil and then separated by preparative normal phase HPLC using 0.5% isopropyl alcohol in hexanes as the eluent. The title compound was obtained as a white solid (1.38 g, 29%). 1H NMR (300.132 MHz, CDCl3) δ 8.04 (d, J=2.2 Hz, 1H), 7.50 (dd, J=8.2, 2.2 Hz, 1H), 7.12 (d, J=8.2 Hz, 1H), 3.89 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1.[CH3:22]C1NC2C(C=1C(Cl)=O)=CC=CC=2>>[CH3:22][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH2:13][C:14]13[CH2:15][CH2:16][N:17]([CH2:20][CH2:21]1)[CH2:18][CH2:19]3)=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: Cc1[nH]c2ccccc2c1C(=O)Cl
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: Cc1[nH]c2ccccc2c1C(=O)OCC12CCN(CC1)CC2

Procedure:
Quinuclidin-4-ylmethyl 2-methyl-1H-indole-3-carboxylate was prepared in a similar manner to (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate, substituting 2-methyl-1H-indole-3-carbonyl chloride as the electrophile.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7][Br:8])=[CH:4][CH:3]=1.CO.Cl.[CH3:15][O:16][NH2:17].[Br-].[Li+]>CC(C)=O>[CH3:15][O:16][N:17]=[C:6]([C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:7][Br:8]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CON
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CO
Solvent: CC(C)=O
Product: CON=C(CBr)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
A 2.0 L round bottom flask was charged with 4-fluorophenacyl bromide (97.6 g, 450 mmol), then methanol (750 mL), then O-methylhydroxylamine hydrochloride (75.1 g, 899 mol), and the mixture was heated to 65° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure, charged with acetone (750 mL), and lithium bromide (195 g, 2.25 mol), and heated to 60° C. for 15 hours. The reaction mixture was then concentrated under reduced pressure, suspended in 1.0 L methylene chloride, and washed with 3×200 mL water. The aqueous extracts were then pooled and back-extracted with 2×200 mL methylene chloride. All organic extracts were then pooled, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield O-methyloxime 30. Yield of 30: 92.3 g (83%). 1H NMR (500 MHz, CDCl3) δ 4.10 (s, 3H), 4.35 (s, 2H), 7.11 (t, J=8.8 Hz, 2H), 7.72 (m, 2H). MS (ESI+) 246.0.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](O)(=[O:11])[CH:8]([CH3:10])[OH:9].C(O)(C)C>O>[C:7]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:11])[CH:8]([CH3:10])[OH:9]
Reactant: CC(O)C(=O)O
Reactant: CN(C)CCO
Solvent: CC(C)O
Solvent: O
Product: CC(O)C(=O)OCCN(C)C

Procedure:
A dimethylethanolamine lactate was prepared by mixing 13.3 parts of dimethylethanolamine and 18.0 parts of lactic acid (85 percent solution in water). The mixture was held at 40° C. to 60° C. for a short time and there was then added 7.2 parts of isopropanol. The final composition comprised 75 percent solids and contained 7.1 percent water.
Reaction SMILES: [F:1][C:2]1[C:3]([C:27]([OH:29])=O)=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.[CH2:30]([O:32][CH2:33][CH2:34][NH2:35])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:32][CH2:33][CH2:34][NH:35][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:22])([F:24])[F:23])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:29])[CH3:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Reactant: CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Yield: 59.4 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (52 mg) was prepared by following General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-ethoxyethylamine (17 mg), HBTU (80 mg), and DIEA (46 uL). LC/MS: m/z 498.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.35 (bs, 1H), 8.14 (d, 1H), 7.92 (s, 1H), 7.89 (d, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.37 (s, 1H), 3.60 (bs, 3H), 3.56-3.41 (m, 6H), 1.14 (t, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]1([C:19]#[C:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[OH:38][C@@H:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]#[C:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:22]=1)[C:28]([OH:30])=[O:29]
Reactant: O=Cc1ccccc1
Reactant: O=C(O)Cc1cccc(C#Cc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)[C@@H](c1cccc(C#Cc2ccccc2)c1)[C@@H](O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To diisopropylamine (0.241 mL, 1.693 mmol) in tetrahydrofuran (10 mL) under nitrogen at −78° C. was added n-BuLi (0.677 mL, 1.693 mmol). After 60 min, the colorless solution was warmed to −20° C. and a solution of 2-(3-(phenylethynyl)phenyl)acetic acid (200 mg, 0.847 mmol; Araldi, G. L.; Liao, Y.; Brugger, N. Hydrazide Deriviatives as Prostaglandin Receptor Modulators. WO 2005/012232 A2, 2005) in tetrahydrofuran (5 mL) was added resulting in a red solution which was allowed to stir for 45 min as the cooling bath temperature rose to 5° C. The reaction was recooled to −30° C., benzaldehyde (0.103 mL, 1.016 mmol) was added dropwise resulting in immediate disappearance of the red color and the cooling bath was removed. After 48 h, the reaction mixture was quenched with 1N HCl (20 mL), extracted with ethyl acetate (3×20 mL), washed with brine, dried over MgSO4, filtered and concentrated providing (2S,3R)-3-hydroxy-3-phenyl-2-(3-(phenylethynyl)phenyl)propanoic acid as an amber oil which was used in the next step without further purification or characterization.
Reaction SMILES: C(OC[C:10]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:22]=[C:23]([NH:30][CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=2)=[CH:16][CH:15]=1)[CH3:13])=[O:11])C1C=CC=CC=1.C[CH2:36][OH:37]>[Pd]>[CH:31]1([NH:30][C:23]2[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([N:12]([CH3:13])[C:10](=[O:11])[O:37][CH3:36])=[CH:19][CH:18]=3)[N:22]=2)[CH2:32][CH2:33][CH2:34]1
Reactant: CCO
Reactant: CN(C(=O)COCc1ccccc1)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Agent: [Pd]
Product: COC(=O)N(C)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-benzyloxy N-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (0.012 g, 0.026 mmol) in EtOH (0.4 mL) was added Pd/C (10 mg), and was charged with H2 (1 atm). After stirring for 15 h at room temperature, it was purified by preparative HPLC to give N-(4-(4-(cyclobutyllamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-2-hydroxy-N-methylacetamide (MS calcd for C19H22N6O2 366.2, found [MH] 367.0; UV 208.7, 272.4, 304.5 nm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>>[C:2]1([C:15]2([OH:18])[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Product: OC1(c2ccccc2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 1-bromo-benzene and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=O>CN(C1C=CN=CC=1)C.ClCCl>[C:22]([C:27]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:3][C:2]=2[N:1]=1)([CH3:26])([CH3:23])[CH3:21]
Reactant: COC(=O)Nc1ccc(NCC2CCCCC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl {3-amino-4-[(cyclohexylmethyl)amino]phenyl}carbamate (950 mg, 3.43 mmol) and DMAP (100 mg, 0.858 mmol) were dissolved in 25 mL of dichloromethane. Trimethylacetyl chloride (0.460 mL, 3.77 mmol) was added in dropwise and the solution was stirred at rt for 1 h. The solvent was concentrated. The residue was divided in two portions and each of them was dissolved in 3 mL of glacial AcOH in a sealed tube. The solutions were heated at 150° C. using a Personal Chemistry Smith Synthesizer microwave instrument for three intervals of 30 min (3×30 min). The contents of the two tubes were combined and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 3:1/dichloromethane:diethyl ether. Yield: 656 mg (56%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.08 (m, 2H), 1.18 (m, 3H), 1.54 (s, 9H), 1.65 (m, 1H), 1.69 (m, 2H), 1.73 (dd, J=5.96, 3.22 Hz, 2H), 2.02 (m, 1H), 3.78 (s, 3H), 4.10 (d, J=7.42 Hz, 2H), 6.64 (m, 1H), 7.25 (d, J=8.79 Hz, 1H), 7.39 (m, 1H), 7.59 (d, J=1.76 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>O1CCOCC1>[OH:21][CH2:20][CH2:19][N:18]([C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:22][CH2:23][OH:24]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: OCCNCCO
Solvent: C1COCCO1
Product: COC(=O)c1cc([N+](=O)[O-])c(N(CCO)CCO)c([N+](=O)[O-])c1
Yield: 81.1 %

Procedure:
A solution of methyl 4-chloro-3,5-dinitrobenzoate (XIV) (10.0 g, 0.036 mol) and diethanolamine (7.66 g, 0.073 mol) in p-dioxane (60 mL) was stirred at 50° C. for 5 h. Volatiles were removed under reduced pressure, and the residue was adsorbed directly onto silica gel and chromatographed. Elution with EtOAc/petroleum ether (1:10) gave foreruns, and subsequent elution with EtOAc/petroleum ether (3:2) gave methyl 4-[N,N-bis(2-hydroxyethyl)amino]-3,5-dinitrobenzoate (XV: X=OH, Z=OMe) (9.61 g, 80%), mp (CHCl3 /petroleum ether) 101°-103° C. 1H NMR (CDCl3) δ 8.52 (s, 2 H, ArH-2,6), 3.97 (s, 3 H, COOCH3), 3.76 (dxt, J=6.5, 4.7 Hz, 4 H, CH2OH), 3.26 (t, J=4.7 Hz, 4 H, NCH2), 2.76 (t, J=6.5 Hz, 2 H, OH). 13C NMR δ 163.14 (COOCH3), 145.50 (C-4), 142.54 (C-3,5), 131.19 (C-2,6), 123.59 (C-1), 59.16 (CH2OH)1, 54.58 (CH2N), 53.14 (OCH3). Anal. (C12H15N3O8) C,H,N.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:6][CH:5]=1.[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH3:17][C:18]1[C:19]([N:25]2[CH2:26][CH2:27][N:28]([C:3]([C:4]3[CH:9]=[CH:8][C:7]([N:10]4[CH2:14][CH2:13][O:12][C:11]4=[O:15])=[N:6][CH:5]=3)=[O:16])[CH2:29][CH2:30]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: COC(=O)c1ccc(N2CCOC2=O)nc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)c(C)c1
Yield: 22.1 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using 6-(2-oxooxazolidin-3-yl)nicotinic acid methyl ester (250 mg) described in Preparation Example 138 and 1-(3,5-dimethylpyridin-2-yl)piperazine (233 mg) described in Preparation Example 47, the title compound (95 mg) was obtained.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=O)=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20]C#N)[CH:17]=[CH:18][CH:19]=1.O>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:9]=1)=[C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=1)[O:12][N:10]=2
Reactant: N#CCc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Sodium hydroxide (0.62 mol) was dissolved in methanol (100 ml) and the mixture was cooled till room temperature. 1-bromo-4-nitro-benzene (0.124 mol), followed by 3-chloro-benzeneacetonitrile (0.223 mol) were added dropwise, the temperature raised till 50° C. and the mixture was stirred at room temperature for one night. The mixture was poured into water and ice, the precipitate was filtered off, washed with water and extracted with CH2Cl2 and CH3OH. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The residue was taken up in Et2O, filtered off and dried, yielding 13.2 g (34.8%) of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole, mp. 163° C. (intermediate 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[C:5]([CH3:20])[CH:4]=1.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:15]1[C:16]2[C:11](=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:20])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:19]
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)c(C)c1

Procedure:
The title compound was prepared by reacting 6-(4-methoxy-2-methylphenyl)-2-naphthol (800 mg, 3.03 mmol) and NCS (485 mg, 3.61 mmol) in THF (30 mL) according to method A to yield 640 mg (71%) of yellow solid: 1H NMR (DMDO-d6): δ 2.26 (3H, s), 3.79 (3H, s), 6.86 (1H, dd, J=8.36 Hz, J=2.63 Hz), 6.91 (1H, d, J=2.51 Hz), 7.22 (1H, d, J=8.34 Hz), 7.31 (1H, d, J=8.89 Hz), 7.56 (1H, dd, J=8.71 Hz, J=1.71 Hz), 7.79–7.83(2H, m), 8.04 (1H, J=8.91 Hz), 10.46 (1H, s); 13C NMR (DMDO-d6): δ 20.54, 55.07, 111.48, 112.21, 115.71, 118.73, 121.94, 127.92, 128.15, 128.35, 129.34, 130.12. 130.87, 133.26, 136.14, 136.36, 150.99, 158.49; MS (ESI) m/z 297/299 (M−H)−.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1([CH3:27])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[O:14]1>>[CH3:18][C:17]1([CH3:19])[C:13]([CH3:12])([CH3:27])[O:14][B:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N+:9]([O-:11])=[O:10])=[CH:22][CH:21]=2)[O:16]1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(OCc3ccccc3[N+](=O)[O-])cc2)OC1(C)C
Yield: 62 %

Procedure:
Alkylation of 1-Bromomethyl-2-nitro-benzene with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A for Example 3.32 to give 4,4,5,5-Tetramethyl-2-[4-(2-nitro-benzyloxy)-phenyl]-[1,3,2]dioxaborolane in 62% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 5.5 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (dd, J=7.8, 1.0 Hz, 1 H) 8.2 (dd, J=8.1, 1.3 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:8]=2)[NH:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccc2ccccc2n1
Solvent: ClCCl
Product: O=c1ccc2cc(S(=O)(=O)Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.9 %

Procedure:
To an ice bath cooled stirred slurry of 2-hydroxyquinoline (30.5 g, 0.210 mol) in dichloromethane (300 cm3) was added chlorosulphonic acid (70 cm3, 1.05 mol) in 4 equal sized batches. This was left to stir at room temperature for 2 days then slowly poured onto crushed ice. Large amount of a white solid formed in the lower chlorinated layer. This was filtered off and dried in vacua to yield 2-Oxo-1,2-dihydro-quinoline-6-sulfonyl chloride as a dry white solid (36.3 g); δH (300 MHz; D6 DMSO) 6.51–6.59 (1H, m, 1×Ar—H), 7.29–7.34 (1H, m, Ar—H), 7.71–7.79 (1H, m, Ar—H), 7.90–7.96 (1H, m, Ar—H) and 8.00–8.06 (1H, m, Ar—H); LCMS retention time ˜3.43 min, m/z (FIANEG) 241.9 [Cl35(M)−, 100%] and 244.0 [Cl37(M)−, 33%]. NMR and LCMS showed that this material contained some starting material as a minor impurity but no further purification was performed.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[Cl:10][CH2:11][C:12](O)=O.[OH-].[NH4+]>Cl>[Cl:10][CH2:11][C:12]1[NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1
Reactant: O=C(O)CCl
Reactant: Cc1cccc(N)c1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc2nc(CCl)[nH]c12
Temperature: 25 °C

Procedure:
A solution of 1.83 g (15 m mol) of 3-methyl-1,2-phenylenediamine in 20 ml of 4N aqueous hydrochloric acid was stored at room temperature overnight. To the solution was added 2.13 g (22.5 m mol) of monochloroacetic acid and refluxed for 3 hours. The reaction solution was cooled to room temperature, rendered alkaline by addition of ammonium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from ethyl ether to give 0.8 g (29.52%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].C1COCC1.[P:12](Cl)([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][P:12]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([O:17][CH2:18][CH3:19])=[O:13])[CH3:16]
Reactant: [Li]c1cccs1
Reactant: CCOP(=O)(Cl)OCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cccs1
Temperature: 25 °C

Procedure:
A solution of 2-thienyllithium in THF (1 mmol) was added to a solution of diethyl chlorophosphate (1 mmol) at −78° C. under nitrogen. After 2 h the reaction was warmed to room temperature and quenched with brine. Extraction and chromatography afforded 2-diethylphosphonothiophene as a yellow oil. TLC: Rf=0.37, 50% EtOAc-hexane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[C@H:14]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:26]([BH3-])#N.[Na+].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[CH3:26][N:12]1[CH2:11][C@@H:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:14]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H]1CNC(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1C[C@@H](CNC(=O)OC(C)(C)C)[C@H](CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 145 mg (0.44 mmol) of trans-3,4-bis(tert-butoxycarbonylaminomethyl)pyrrolidine synthesized by the process described above in acetonitrile (1.5 ml) were added 0.20 ml (2.7 mmol) of a 37% aqueous solution of formaldehyde and 46.9 mg (0.75 mmol) of sodium cyanoborohydride. The mixture was stirred for 20 minutes at room temperature. Acetic acid was then added to the resultant solution to adjust its pH to about 5. The solution was stirred for an additional 30 minutes at room temperature. A 1N aqueous solution of sodium hydroxide was added to the reaction mixture to adjust the pH of the reaction mixture to about 10, and extraction was then conducted with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 90.1 mg (yield: 60%) of crude crystals of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:40])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:22])[CH3:40])=[CH:29][CH:28]=1)[C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: COc1ccc(NCc2ccc(N(C)C)cc2)cn1
Product: COc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 73.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(4-dimethylaminophenyl)methyl](6-methoxypyridin-3-yl)amine (0.91 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.35 g) was obtained. By the reaction and treatment in the same manner as in Example 105 using this compound, N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.34 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].Br[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:21]([CH2:20][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:17][CH:16]=1)#[N:22]
Reactant: N#CCBr
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OCC#N)cc1
Yield: 84.3 %

Procedure:
To 150 ml of acetone were added 14.58 g of ethyl 2-ethoxycarbonyl-2-(4-hydroxyphenyl)acetate, 8.8 g of bromoacetonitrile and 9.6 g of anhydrous potassium carbonate. After refluxing under heating for 5 hours, insoluble materials were removed by filtration, and the resulting filtrate was concentrated to dryness. The residue thus obtained was purified by silica gel column chromatography using toluene as an elution solvent, thereby obtaining 14.2 g of ethyl 2-[4-(cyanomethoxy)phenyl]-2-ethoxycarbonylacetate in the form of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2)=[O:13].Cl.Cl.[CH3:26][N:27]([CH3:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([N:27]([CH3:35])[CH3:26])[CH:29]=2)=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2)=[O:13]
Reactant: O=C(Cl)c1ccc(Cl)c(NC(=O)c2ccc3ncccc3c2)c1
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Product: CN(C)c1cccc(NC(=O)c2ccc(Cl)c(NC(=O)c3ccc4ncccc4c3)c2)c1

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-3-(6-quinolylcarbonylamino)benzoyl chloride was reacted with 3-dimethylaminoaniline dihydrochloride to give the title compound; NMR Spectrum: (DMSOd6) 3.04 (s, 6H), 6.5 (d, 1H), 7.08-7.20(m, 3H), 7.61-7.64 (m, 1H), 7.74 (d, 1H), 7.92 (d, 1H) 8.1-8.2 (m, 2H), 7.31 (d, 1H), 8.58 (d, 1H), 8.72 (s, 1H), 9.02 (s, 1H) 10.13 (s, 1H), 10.5 (s, 1H); Mass Spectrum: Mass Spectrum: M+H+ 445 and 447.