Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][CH:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][CH:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(CCN)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
Acetic anhydride (0.084 mL, 0.89 mmol) was added dropwise to tert-butyl 3-amino-1-(4-chlorophenyl)propylcarbamate (Intermediate 25) (203 mg, 0.71 mmol) and N,N-diisopropylethylamine (0.248 mL, 1.43 mmol) in DCM (5 mL) at 20° C. The resulting solution was stirred at 20° C. for 16 hours. The reaction mixture was quenched with NaHCO3 (2M) (10 mL) and water (10 mL) and extracted with DCM (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2.5% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 3-acetamido-1-(4-chlorophenyl)propylcarbamate (142 mg, 61.0%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ1.36 (9H, s), 1.67-1.82 (2H, m), 1.79 (3H, s), 2.97 (2H, q), 4.50 (1H, d), 7.32 (2H, d), 7.38 (2H, d), 7.43-7.45 (1H, m), 7.79 (1H, s). m/z (ESI+) (M+H)+=327; HPLC tR=2.03 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>>[Br:9][C:10]1[CH:11]=[C:12]([CH2:13][O:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1cccc(Br)c1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1cccc(COc2cccc(Br)c2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-bromophenol (13.8 g, 80 mmol), 3-bromobenzyl bromide (10 g, 40 mmol), K2CO3 (16.6 g. 120 mmol) and 12 hours. The reaction mixture was cooled to rt, concentrated in vacuo and partitioned between Et2O (300 mL) and water (300 mL). The organic phase was washed with aqueous NaOH (1 M, 300 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 3-[(m-bromophenyl)methoxy]bromobenzene as a clear oil. MS (APCI) m/z 339 (M+−3, 50%), 341 (M+−1, 100%), 343 (M++3, 50%), 13C NMR (50 MHz, CDCl3); δ 68.9, 113.4, 117.9, 122.5, 122.6, 124.1, 125.6, 129.9, 130.0, 130.4, 130.9, 138.4, 158.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[CH3:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[CH:23][C:22]=1[CH3:28]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1cc(N)ccc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Benzyloxycarbonylpiperidine-4-carboxylic acid (1.00 g, 3.80 mmol) and 4-chloro-3-methyl-aniline (0.592 g, 4.18 mmol) in CH2Cl2 (5 mL) were treated with HOBT (0.582, 3.80 mmol) and EDC (1.46 g, 7.60 mmol), and stirred at rt for 16 h. The mixture was directly purified on SiO2 (50 to 100% EtOAc, hexanes) to afford the title compound. HPLC/MS: 387.2/389.1 (M+1); Rt=1.22 min (LC2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.Cl[C:47]([O:49][CH3:50])=[O:48]>C(Cl)Cl>[CH3:50][O:49][C:47](=[O:48])[O:35][C:32]1[CH:33]=[CH:34][C:29]([N:7]([CH2:6][C:5]2[CH:36]=[CH:37][CH:38]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[CH2:10][CH2:9]2)=[CH:30][CH:31]=1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of COMPOUND 117 (43 mg, 0.083 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by methyl chloroformate (14 μL, 0.19 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 139 as a white solid (41 mg, 86%) following work-up and purification. 1H NMR (CDCl3) δ 0.91-1.14 (m, 2H), 1.00 (d, 3H, J=6.0 Hz), 1.50-1.55 (m, 1H), 1.70-1.74 (m, 3H), 2.15 (t, 1H, J=12.0 Hz), 2.31 (s, 6H), 2.55 (t, 1H, J=10.8 Hz), 2.74-2.91 (m, 3H), 3.24-3.32 (m, 1H), 3.57-3.63 (m, 1H), 3.78 (s, 2H), 3.86 (s, 3H), 3.86-3.90 (m, 1H), 6.51 (d, 2H, J=8.1 Hz), 6.92-7.05 (m, 5H), 7.43-7.53 (m, 4H), 8.37-8.38 (m, 1H). 13C NMR (CDCl3) δ 13.80, 19.54, 29.34, 30.72, 31.34, 40.23, 43.96, 48.84, 52.54, 55.68, 57.14, 60.94, 112.96, 114.36, 119.30, 122.04, 127.69, 128.78, 129.65, 130.33, 130.94, 131.25, 134.49, 139.04, 142.38, 143.01, 146.78, 155.24, 170.23. ES-MS m/z 569 (M+H). Anal. Calcd. for C34H40N4O4.0.5H2O: C, 70.69; H, 7.15; N, 9.70. Found. C, 70.64; H, 7.02; N, 9.65.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17](O)=[C:16]([Cl:22])[C:15]=1[OH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([O:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:16]([Cl:22])[C:15]=1[OH:23]
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1O
Reactant: CN1CCN(CCO)CC1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)c(OCCN2CCN(C)CC2)c(Cl)c1O
Reaction time: 16 h

Procedure:
To a solution of 2-(4-methylpiperazin-1-yl)ethanol (14.42 g) and 3,5-dichloro-2,4-dihydroxybenzoic acid methyl ester (52.15 g) in chloroform (400 ml) were added triphenylphosphine (28.85 g) and azodicarboxylic acid diisopropyl (21.7 ml) at room temperature, and the mixture was stirred for 16 hours. 1N Hydrochloric acid (300 ml) was added to the reaction mixture for extraction to give a crude product of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:39])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]3[N:34]=[CH:33][C:32]4[O:35][CH2:36][CH2:37][O:38][C:31]=4[CH:30]=3)C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[N:4][CH:3]=1.[ClH:40].C(O)C>>[ClH:40].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:39])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][CH2:28][C:29]3[N:34]=[CH:33][C:32]4[O:35][CH2:36][CH2:37][O:38][C:31]=4[CH:30]=3)[CH2:18][CH2:19]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(Br)cc32)CC1
Agent: Cl
Solvent: CCO
Product: O=c1ccc2ncc(Br)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 59 h

Procedure:
To 0.51 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate, 18 mL of a 2 mol/L hydrogen chloride/ethanol solution was added at room temperature, the mixture was stirred at room temperature for 59 hours, and at 50° C. for 9 hours, and then, the generated solid was filtered off. Subsequently, the solid was suspended in 3 mL of chloroform, thereto was added 5 mL of trifluoroacetic acid, the mixture was stirred at room temperature for 100 minutes, and then the solvent was distilled off under reduced pressure. The residue was charged with 10 mL of chloroform and 3 mL of water and adjusted to pH 10 with a 2 mol/L aqueous sodium hydroxide solution, and then the organic layer was separated. The aqueous layer was extracted with chloroform twice, and combined with the organic layer, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 2 mL of ethyl acetate and 3 mL of ethanol, and 10 mL of a 2 mol/L hydrochloric acid/ethanol solution was added thereto, the mixture was stirred for 15 minutes, and the solvent was distilled off under reduced pressure. To the residue, 4 mL of ethyl acetate was added and suspended, and the solid was filtered off to obtain 0.41 g of 7-bromo-1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one hydrochloride as a slightly yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: Cc1ccc(CC(=O)O)cn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccc(C)nc3)nc12

Procedure:
From (6-methyl-pyridin-3-yl)-acetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 400 (M+H+, 100).
Reaction SMILES: C([Li])CCC.[C:6]1([S:12][C:13]2[C:14]3[CH:25]=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]4)=[CH:18][C:15]=3[S:16][CH:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:26]I>C1COCC1>[C:6]1([S:12][C:13]2[C:14]3[CH:25]=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]4)=[CH:18][C:15]=3[S:16][C:17]=2[I:26])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(Sc2csc3cc4ccccc4cc23)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1sc2cc3ccccc3cc2c1Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Under nitrogen atmosphere, n-butyl lithium (1.63 M (solvent: hexane), 0.46 ml, 0.75 mmol) was dripped into a THF solution (5 ml) of 3-(phenylsulfenyl)naphtho[2,3-b]thiophene (146 mg, 0.5 mmol) at 0° C. After the mixture was stirred for 1 hour at room temperature, iodine (190 mg, 0.75 mmol) was added thereto at 0° C. and the mixture was stirred for further 6 hours at room temperature. Subsequently an aqueous solution of Na2S2O5 was added thereto, and the mixture was extracted with CH2Cl2 (50 ml×3) and washed with saline (15 ml×3). The extract liquid was dried with magnesium sulfate, and concentrated. Purification was implemented by column chromatography (silica gel, CHCl3, Rf: 0.9), so that 3-(phenylsulfenyl)-2-iodonaphtho[2,3-b]thiophene was produced as an orange solid (138 mg, 0.3 mmol, yield: 66%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.[H-].[Na+].I[CH3:18].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:6]2[CH3:18]
Reactant: CI
Reactant: COC(=O)c1cc2c(F)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(F)cccc2n1C
Yield: 105.2 %

Procedure:
To methyl 4-fluoro-1h-indole-2-carboxylate (1.211 mmol, 234 mg) in N,N-dimethylformamide (10 ml) at 0° C. was added sodium hydride (1.817 mmol, 72.7 mg). The reaction mixture was stirred for one hour at room temperature before iodomethane (1.817 mmol, 0.113 ml, 258 mg) was added. After stirring for three hours water was added and the product was extracted with dichloromethane and concentrated in vacuo to give methyl 4-fluoro-1-methyl-1H-indole-2-carboxylate (264 mg). The latter compound was dissolved in ethanol (5 ml). Then 2 N aqueous sodium hydroxide (5.84 mmol, 2.92 ml) and potassium hydroxide (1.168 mmol, 65.5 mg) were added and the reaction mixture was stirred at 80° C. over night. 2N Hydrochloric acid was added to the reaction mixture and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated to give 4-fluoro-1-methyl-1H-indole-2-carboxylic acid (189 mg).
Reaction SMILES: [C:1]([C:4]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[C:25]([CH3:28])[CH:24]=[C:23]4[N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[C:10]=2[Cl:34])[CH:6]=[CH:7][CH:8]=1)(O)=[O:2].Cl.C([N:38]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[C:1]([C:4]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[C:25]([CH3:28])[CH:24]=[C:23]4[N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[C:10]=2[Cl:34])[CH:6]=[CH:7][CH:8]=1)(=[O:2])[NH2:38]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C(=O)O)c3Cl)c2n1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C(N)=O)c3Cl)c2n1
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
To a solution of 2-carboxy-1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]pyrrole (80 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.3 mg) and 1-hydroxybenzotriazole (30.7 mg) at ambient temperature, and the mixture was stirred for 1.5 hours at the same temperature. To the mixture was added conc. ammonia solution (12 mg) at ambient temperature, and the mixture was stirred for 2 days at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The separated organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=20:1, V/V) to give 2-carbamoyl-1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]pyrrole (31 mg) as amorphous powder.
Reaction SMILES: [CH3:1][N:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[N:19]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][NH:13][C:14](OC)=[O:15])=[O:11])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].CO>C1COCC1>[CH3:1][N:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[N:19]=1)[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10](=[O:11])[NH:12][NH:13][C:14]2=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)NNC(=O)Nc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(N(C)c2ccc(-n3c(=O)[nH][nH]c3=O)cc2)c2ccccc2n1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2-[({4-[methyl(2-methylquinazolin-4-yl)amino]phenyl}amino)carbonyl]hydrazine carboxylate 0.150 g (0.4 mmol) in THF 5 mL was added K2CO3 0.138 g (1.0 mol), and the reaction mixture was stirred for 48 h under reflux. Due to the incompletion of the reaction, the reaction was further heated under microwave irradiation at 120° C. for 20 min. The reaction mixture was filtrated with a short silica-get column using methanol, and methanol was evaporated under reduced pressure to obtain a crude product, which was purified with preparative HPLC to give the titled compound in pure form. 1H NMR (CD3OD, 400 MHz): δ 8.21, 8.19 (dd, 1H, J=8.0, 1.2 Hz), 7.87-7.83 (m, 2H), 7.79-7.75 (m, 1H), 7.71, 7.69 (dd, 1H, J=8.4, 0.8 Hz), 7.65-7.59 (m, 2H), 7.59-7.53 (m, 1H), 7.30-7.26 (m, 1H), 6.98 (d, 1H, J=8.4 Hz), 3.87 (s, 3H), 2.80 (s, 3H). m/e: 349.30 (M+1), 347.25 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10]C(C)=O.C(=O)=O.S(Cl)(Cl)=O>CO>[CH3:10][O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: NCCCCCC(=O)O
Reactant: CC(C)=O
Agent: O=C=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6-aminohexanoic acid (20 g, 0.15 mol) was suspended in methanol (80 mL), the mixture was cooled to −20° C. (acetone/dry ice) and thionyl chloride (14 mL, 0.2 mol) was added dropwise maintaining a temperature below −10° C. After addition of all thionyl chloride the cooling bath was removed and the mixture stirred for 90 minutes at room temperature. The mixture was refluxed shortly (5 minutes) and the solvents removed in vacuum. The residue was redissolved in methanol (60 mL). The product was precipitated by addition of diethyl ether (200 mL) with cooling on an ice bath. The product was collected by filtration as a white solid (22 g, 81%). The product was shown to be pure by TLC. R1(methanol)=0.13. Melting point 123-124° C. Mass spectroscopy (FAB+): 146.1 (MH+). 1H-NMR (DMSO-d6) δ: 8.1 (br. s, 3H), 3.60 (s, 3) 2.75 (t, 2H), 2.30 (t, 2H), 1.50 (qn, 4H), 1.30 (qn, 2H).
Reaction SMILES: C([C:4]1[S:5][C:6](Cl)=[CH:7][C:8]=1[O:9][CH2:10][C:11]([OH:13])=[O:12])(O)=O.N1C2C(=CC=CC=2)C=CC=1.C(=O)=O.[ClH:28]>[Cu].O>[Cl:28][CH:10]([O:9][C:8]1[CH:7]=[CH:6][S:5][CH:4]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)COc1cc(Cl)sc1C(=O)O
Reactant: Cl
Agent: [Cu]
Agent: O=C=O
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=C(O)C(Cl)Oc1ccsc1

Procedure:
A mixture of 1.63 g of the product of Step C, 3.5 ml of quinoline and 0.24 g of Gattermann copper was heated to 200° C. under nitrogen during which 165 ml of carbon dioxide gas evolved for the water and the mixture was then poured into iced water. 5.6 ml of 10N hydrochloric acid were added thereto and the mixture was extracted with ether. The ether phase was dried and evaporated to dryness and the residue was effloresced with petroleum ether (Bp -60°-80° C.) to obtain 1.2 g of 2-chloro-4-thienyloxy-acetic acid melting at 119° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13]CC2C=CC(OC)=CC=2)[CH2:10][C@@H:9]1[C@H:23]1[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C@H:23]1[O:27][C:26]([CH3:28])([CH3:29])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CO[C@@H]2C[C@H]([C@H]3OC(C)(C)N(C(C)=O)[C@H]3Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To an ice cold solution of (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluorobenzyl)-2,2-dimethyloxazolidin-5-yl]-4-(4-methoxy-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.48 g, 13.0 mmol) in 20:1 dichloromethane:water (130 mL) add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.71 g, 20.74 mmol). Stir 4 h in an ice bath and wash with saturated aqueous sodium bicarbonate (3×300 mL), saturated aqueous sodium chloride, dry magnesium sulfate and purify on silica gel with dichloromethane/ethyl acetate mixtures to give the title compound as a foam (5.288 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[C:13]1([CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Pt]=O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:22][CH2:21][CH2:20][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CC(C)NCCC(c2ccccc2)c2ccccc2)cc1

Procedure:
The starting material is prepared as follows: the mixture of 246.3 g of p-methoxyphenylacetone, 317 g of 3,3-diphenylpropylamine and 1,000 ml of anhydrous ethanol is hydrogenated at 20° and 3.4 atm. over 5 g of platinum oxide. After the theoretical amount of hydrogen has been absorbed (ca 4,000 ml), the mixture is filtered and the filtrate evaporated at 60°, to yield the 1-(4-methoxyphenyl)-2-(3,3-diphenylpropylamino)-propane as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[CH2:26][CH2:27]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(c4ccncc4)CC3)cc21
Temperature: 125 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
A mixture of 0.31 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.33 g of (4-pyridyl)piperazine and 2 ml of pyridine was stirred at 125° C. for 1 hour. After cooling, the reaction mixture was added to ice water to cause crystallization. The resulting crystal was collected by filtration, washed with ethyl ether and then recrystallized from ethanol to yield 0.1 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:14][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 7-nitro-1,2,3,4-tetrahydroquinoline (4.5 g, 25.25 mmol) in DMF (50 mL) was added potassium carbonate (15 g) followed by iodomethane (5.54 g, 39.0 mMol) and the mixture was agitated overnight at ambient temperature. The mixture was poured onto water and extracted with ether (3×200 mL). The combined ethereal extracts were washed with brine, dried and concentrated to give the crude product which was purified by column chromatography on silica-gel to obtain the title compound as an orange liquid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19]>>[OH:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:12][C:13]2[S:14][C:15]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:16][C:17]=2[C:18]([NH2:20])=[O:19])=[N:7][CH:6]=1)([CH3:10])[CH3:9]
Reactant: NC(=O)c1cc(-c2ccccc2)sc1N
Reactant: CC(C)(O)c1ccc(Br)nc1
Product: CC(C)(O)c1ccc(Nc2sc(-c3ccccc3)cc2C(N)=O)nc1

Procedure:
2-{[5-(1-Hydroxy-1-methylethyl)pyridin-2-yl]amino}-5-phenylthiophene-3-carboxamide was prepared using 2-(6-bromopyridin-3-yl)propan-2-ol (79.3 mg, 0.367 mmol) (for preparation, see WO 2004/050024 A2 Example 120 Step A) and 2-amino-5-phenylthiophene-3-carboxamide (80 mg, 0.367 mmol) as the starting materials according the general procedure in Example 1.
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:13][OH:14]>>[N:1]1[C:10]2[C:9](=[N:13][OH:14])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2cccnc21
Reactant: NO
Agent: Cl
Product: ON=C1CCCc2cccnc21
Yield: 96 %

Procedure:
According to the reported procedure (J. Het. Chem. 1978, 15, 249-251), 6,7-dihydro-5H-quinolin-8-one was reacted with hydroxylamine hydrochloride to afford the title compound (2.40 g, 96%) as a white solid after drying in vacuo: MS (ES) m/e 163 (M+H)+.