Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)[N:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1>Cl>[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:32][CH:33]=3)[N:19]=2)[CH2:14][CH2:13]1
Reactant: Nc1nccn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: Cl
Product: NC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1
Temperature: 25 °C

Procedure:
trans-{4-[8-Amino-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-carbamic acid benzyl ester (50.00 mg, 0.091 mmol) was dissolved in concentrated HCl (2.00 mL) at 0° C. The resulting mixture was stirred at rt. overnight. The solution was washed with EtOAc (4×20 ml), the aq. solvent was then removed under reduced pressure to give a crude product which was further purified by flash chromatography (5% MeOH in DCM). 1H NMR (400 MHz, MeOD) δ 1.28-1.46 (m, 2H), 1.74-1.92 (m, 3H), 1.98-2.07 (m, 2H), 2.11-2.20 (m, 2H), 2.90 (d, J=7.1 Hz, 2H), 3.26-3.31 (m, 1H), 7.02-7.28 (m, 6H), 7.40-7.49 (m, 2H), 7.64-7.73 (m, 2H), 7.92 (d, J=5.8 Hz, 1H). MS (ES+): m/z: 414.00 [MH+]. HPLC: tR=1.92 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH:11][C:12]([CH2:14][O:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:17]1)=[O:13].[C:49](Cl)(=[O:51])[CH3:50]>ClCCl.C(N(CC)CC)C>[C:49]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH:11][C:12]([CH2:14][O:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:17]1)=[O:13])(=[O:51])[CH3:50]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)NCc2ccccc2CCN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)NCc2ccccc2CCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 0.49 g of tert-butyl 3-({[2-(2-aminoethyl)phenyl]methylcarbamoyl}methoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 10 ml of dichloromethane and 0.22 ml of triethylamine is admixed at 0° C. with 0.15 ml of acetyl chloride and stirred at room temperature over 17 hours. The reaction mixture is diluted with dichloromethane, washed with 1N HCl (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.09 (EtOAc); Rt=5.10.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]3)[CH:18]=1)[C:3]([C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:30]N1C(=O)CCC1=O>>[Cl:30][C:27]1[CH:28]=[C:19]([C:17]2[CH:18]=[C:13]([CH2:12][N:2]([CH3:1])[C:3]([C:5]3[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][N:6]=3)=[O:4])[CH:14]=[N:15][CH:16]=2)[CH:20]=[C:21]2[C:26]=1[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2
Reactant: CN(Cc1cncc(-c2ccc3c(c2)CCC(=O)N3)c1)C(=O)c1ncccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Product: CN(Cc1cncc(-c2cc(Cl)c3c(c2)CCC(=O)N3)c1)C(=O)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 203, 3-chloro-pyridine-2-carboxylic acid methyl-[5-(2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 215) was reacted with N-chloro-succinimide to give the title compound as a light brown solid. MS: 441.5 (M+H+).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Mn]([O-])(=O)(=O)=[O:24].[K+]>O.C(Cl)Cl>[CH2:6]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:13]([OH:24])=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC(CO)CCCCCC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCC)C(=O)O
Temperature: 25 °C

Procedure:
Concentrated sulphuric acid (100 g) was diluted with water (750 ml) and this solution was cooled to room temperature and added to a solution of 2-hexyldecanol (242 g) in methylene chloride (600 ml). The solutions were stirred together beneath a reflux condenser and solid potassium permanganate was added in portions during 5 hours so as to maintain gentle boiling of the methylene chloride. The mixture was filtered to remove precipitated manganese dioxide, and the organic layer was separated and washed with water. The solvent was distilled leaving 2-hexyldecanoic acid (222 g) as a nearly colourless oil.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][C@H:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Reactant: CCCOC1CCNCC1
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)CCc3ccccc32)CC1
Reaction time: 20 h
Yield: 38.1 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.493 g, 1.5 mmol) and 4-propoxypiperidine (0.430 g, 3.0 mmol) in MeCN (2 mL) and shaken at 60° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, EtOAc/MeOH 4:1) to give the title compound (107LH48) (0.197 g, 38%). 1H NMR (CD3OD) δ 7.26-7.19 (m, 3H), 7.03-6.98 (m, 1H), 3.96 (d, J=7.0 Hz, 2H), 3.40 (t, J=6.7 Hz, 2H), 2.90-2.86 (m, 2H), 2.74-2.71 (m, 1H), 2.65-2.54 (m, 3H), 2.26-1.99 (m, 6H), 1.87-1.84 (m, 2H), 1.59-1.49 (m, 4H), 0.91 (t, J=7.4 Hz, CH3), 0.85 (d, J=6.6 Hz, CH3); 13C NMR (CD3OD) δ 173.0, 140.3, 129.1, 128.4, 128.4, 124.3, 116.8, 76.3, 70.7, 64.5, 53.2, 52.8, 32.9, 32.4, 32.4, 30.3, 26.2, 24.3, 17.1, 11.0.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[CH:10][C:6]=2[C:5](=[O:21])[CH2:4][S:3]1(=[O:23])=[O:22].C(N(CC)CC)C.[Cl:31][C:32]1[CH:41]=[CH:40][C:35]([CH2:36][N:37]=[C:38]=[O:39])=[CH:34][CH:33]=1>CS(C)=O.Cl>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:36][NH:37][C:38]([C:4]2[S:3](=[O:22])(=[O:23])[N:2]([CH3:1])[C:7]3[S:8][C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)=[CH:10][C:6]=3[C:5]=2[OH:21])=[O:39])=[CH:40][CH:41]=1
Reactant: O=C=NCc1ccc(Cl)cc1
Reactant: CN1c2sc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1c2sc(C#CCOC3CCCCO3)cc2C(O)=C(C(=O)NCc2ccc(Cl)cc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a stirring solution of 1-methyl-6-(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)-1H-thieno[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide (Preparation 35, 0.64 g) and triethylamine (0.27 g) in DMSO (15mL) at ambient temperature is added 4-chloro-benzylisocyanate (0.45 g). The resulting red solution is stirred overnight at ambient temperature and diluted with 10% aqueous HCl (20 mL). The aqueous layer is extracted with EtOAc (3×25 ml). The combined organic layers are dried over MgSO4 and concentrated in vacuo. The residue is dissolved in EtOAc (15 mL) and allowed to stand at ambient temperature overnight. The resulting solid is collected by filtration, washed with EtOAc (10 ml) and dried in vacuo at 50° C. to afford 0.29 g (31%) of the title compound as a tan solid. Physical characteristics: 1H NMR (CDCl3) δ 1.58-1.82, 3.49, 3.60, 3.89, 4.50, 4.56, 4.86, 7.30, 7.42, 7.71, 15.62; IR (diffuse reflectance) 3353, 2945, 1615, 1581, 1541, 1493, 1431, 1366, 1345, 1308, 1296, 1276, 1183, 1119, 1031 cm−1; MS (EI) m/z 522 (M+). Anal. Found: C, 53.17; H, 4.49; N, 5.67.
Reaction SMILES: ClCl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:32](=[O:33])[CH2:31][C@@:12]3([CH2:16][N:15](C(OC(C)(C)C)=O)[C@H:14]([C:24]([O:26][C:27](C)(C)C)=[O:25])[CH2:13]3)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1>C(#N)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:32](=[O:33])[CH2:31][C@@:12]3([CH2:16][NH:15][C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]3)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(CC(=O)N(c3cccc(Cl)c3)C2)CN1C(=O)OC(C)(C)C
Agent: ClCl
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@H]1C[C@@]2(CN1)CC(=O)N(c1cccc(Cl)c1)C2
Yield: 105.9 %

Procedure:
The arylated lactam (3S,5S)-di-tert-butyl-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-2,3-dicarboxylate (A7a) (45.7 mg, 101 μmol) was taken up in 1M HCl in ethyl acetate (1.0 ml, 10 eq). The reaction was aged at room temperature overnight. The reaction was purged by bubbling N2 gas through it, until dry. The product was then taken up in a saturated solution of hydrochloric acid in methanol (2 ml), and aged at room temperature overnight. The reaction was blown dry with nitrogen gas and dried in-vacuo to give (3S,5R) methyl-7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (B7a) (35.2 mg, 102 μmol). LCMS for C15H17N2O3Cl 308.09 [M], found ES+ 309.2 [M+H]+ and 311.1 [M+H]+ (for the chlorine isotope) at 2.0 minutes retention time, using 5-45% acetonitrile/water (with 0.1% formic acid buffer) gradient over 7 minutes. The minor diastereomer (3S,5R)-di-tert-butyl 7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-2,3-dicarboxylate (A7b) (15.2 mg, 34 μmol) was treated similarly to give (3S,5S)-methyl 7-(3-chlorophenyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (B7b) (12.4 mg, 36 μmol). LCMS for C15H17N2O3Cl 308.09 [M], found ES+ 309.2 [M+H]+ and 311.1 [M+H]+ (for the chlorine isotope) at 2.2 minutes retention time, using 5-45% acetonitrile/water (with 0.1% formic acid buffer) gradient over 7 minutes.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][C@@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4]([CH2:17][OH:18])=[CH:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][C:4]1[C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:6][CH2:7][C@H:2]([CH3:1])[CH:3]=1)(=[O:29])=[O:28]
Reactant: CCCCCCCCC[C@@H]1OC[C@H](C)C=C1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC[C@@H]1OC[C@H](C)C=C1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (2S,5R)-(5,6-dihydro-5-methyl-2-nonyl-2H-pyran-3-yl)methanol (10 mg) and triethylamine (17 ml) in dry dichloro-methane (0.5 ml) was added methanesulfonyl chloride (10 ml) at 0° C. The mixture was allowed to warm to room temperature, and stirred for 30 min. The reaction was quenched by the addition of aqueous saturated sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography gave (2S,5R)-(5,6-dihydro-5-methyl-2-nonyl-2H-pyran-3-yl)methyl methanesulfonate (10.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1
Reactant: COc1cnc(CO)cc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cnc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (5-methoxy-4-nitropyridin-2-yl)methanol (4 g, 0.021 mol) in DCM (30 mL), was added Dess-Martin Periodinane (18.43 g, 0.043 mol, Spectrochem, India) and reaction was stirred for 3 h at rt. The reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, sat'd NaHCO3 (20 mL) was added and the product was extracted with DCM (3×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s, 1H), 9.02 (s, 1H), 8.36 (s, 1H), 4.19 (s, 3H). MS (ESI, positive ion) m/z: 182.9 (M+H).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([OH:25])[CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2].Cl[C:27]1[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)[O:25][C:27]3[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2]
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Reactant: CC[C@@H]1COC(c2ccc(-c3cc(O)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC[C@@H]1COC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105.4 %

Procedure:
3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (272 mg, 0.79 mmol) synthesized in Example (108b) was dissolved in acetonitrile (5.0 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (220 mg, 1.14 mmol) synthesized in Example (97c) and cesium carbonate (640 mg, 1.96 mmol) were added at room temperature, followed by stirring at room temperature for 3.5 hours under nitrogen atmosphere. To this reaction solution, water (20 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-3%) to afford the desired compound (417 mg, yield ˜100%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)=[O:8])[CH3:2].Cl.[NH2:19]O>CO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[O:8][N:19]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)on1
Yield: 67.3 %

Procedure:
A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.0 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol) in methanol (60 ml) was heated at 80° C. for 4 h. After cooling, the mixture was filtered and washed with cold methanol to afford 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (2.0 g, 71%, white solid). 1H NMR (CDCl3) d (ppm): 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H). Mixture of both methyl and ethyl ester (mostly methyl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:24])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([NH:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])=[O:35])[CH:6]=[C:7]([Cl:24])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2nccc(Oc3c(Cl)cc(N)cc3Cl)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3c(Cl)cc(NC(=O)Nc4ccc(F)cc4F)cc3Cl)c2cc1OC
Yield: 74 %

Procedure:
3,5-Dichloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]-aniline (53 mg) was dissolved in chloroform (5 ml), and 2,4-difluorophenyl isocyanate (34 μl) was added to the solution. The mixture was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 56 mg (yield 74%) of the title compound.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[CH:6]([CH:8]=[CH2:9])=[O:7]>N1CCCCC1>[CH2:1]([S:5][CH2:9][CH2:8][CH:6]=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC=O
Reactant: CCCCS
Solvent: C1CCNCC1
Product: CCCCSCCC=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
n-Butyl mercaptan (1 mole) was stirred with 80-100 petroleum ether (150 ml) at 10° C and piperidine catalyst (0.02 gm) was added. To this, acrolein (1 mole) was added dropwise over a period of 2 hours. The reaction mixture was allowed to warm up to room temperature whereupon stirring was continued for a further 36 hours. The mixture was then distilled under reduced pressure to yield a β-n-butylmercaptopropionaldehyde fraction (0.92 mole) having a boiling range 55°-57° C at a pressure of 1-2 mm of Hg. The reaction mixture was maintained under a blanket of nitrogen at all time throughout the preparation.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[Na].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(COS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate was dissolved in tetrahydrofuran (200 ml). 2.0 g (50 mmol) of a 60% sodium hydrode was added thereto under cooling with ice, followed by stirring for one hour. A solution of 8.65 g (45.4 mmol) of p-toluenesulfonyl chloride in tetrahydrofuran (50 ml) was dropwise added thereto. Then, the reaction was effected at room temperature for 2 hours and further reflux by heating was effected for 4 hours. The reaction liquid was cooled and added to a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with chloroform (200 ml). After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 13.4 g of the title compound as a was (yield 82%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-3-(4-chloro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.98 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.92 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes. Yield 362 mg, 86%; HPLC (60/40) 5.06 minutes (97%); mp 227-229° C.; TSPMS 460/462 (MH+, 100%);
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:32]=[CH:31][CH:30]=[CH:29][C:7]=1[CH2:8][C:9]1[S:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[C:16]=2[N:17]=1)=[CH2:5])C.Cl>C1COCC1.CCOC(C)=O>[F:27][C:25]([F:26])([F:28])[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15]2[C:16]3[N:17]=[C:9]([CH2:8][C:7]4[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=4[C:4](=[O:3])[CH3:5])[S:10][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:20][CH:21]=1
Reactant: C=C(OCC)c1ccccc1Cc1nc2c(Nc3ccc(C(F)(F)F)cc3)ncnc2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccccc1Cc1nc2c(Nc3ccc(C(F)(F)F)cc3)ncnc2s1
Yield: 86.6 %

Procedure:
{2-[2-(1-Ethoxy-vinyl)-benzyl]-thiazolo[5,4-d]pyrimidin-7-yl}-(4-trifluoromethyl-phenyl)-amine (230 mg, 0.62 mmol) was dissolved in THF (5 mL) and 2 N HCl (2 mL) and the reaction mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with EtOAc (20 mL), washed with satd. aq. NaCl (2×5 mL), dried (Na2SO4), and concentrated to provide a white solid (0.23 g, 69%). MS (ESI): mass calcd. for C21H15F3N4OS, 428.4; m/z found, 429.1 [M+H]+. 1H NMR (CDCl3): 8.61 (s, 1H), 8.08 (s, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.91 (dd, J=8.0, 1.2 Hz, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.58-7.54 (m, 1H), 7.50-7.46 (m, 2H), 4.75 (s, 2H), 2.64 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[NH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[NH2:18].CCCCCCC>C(O)CCC>[O:5]=[C:4]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]2=[N:18][N:17]1[C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Solvent: CCCCO
Solvent: CCCCCCC
Product: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 60 °C
Yield: 8.5 %

Procedure:
A solution of 4-chloro-quinoline-3-carboxylic acid ethyl ester (11.8 mg, 0.5 mmol) and 4-hydrazino-benzoic acid (7.6 mg, 0.5 mmol) in n-butanol (0.5 mL) was stirred at 115° C. over night in a sealed tube. After cooling to 50-70° C., heptane (1.0 mL) was added and the product was allowed to crystallize upon further cooling to room temperature. The solvent was removed and the product was washed with heptane and dried under vacuum to yield 4-(3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (13 mg). 1H NMR (400 MHz, DMSO-d6) δ 12.9 (1H, s), 8.77 (1H, d), 8.38 (2H, d), 8.25 (1H, d), 8.03 (2H, d), 7.65-7.77 (2H, m), 7.58 (1H, t).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([Cl:11])=[N:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2>C(O)(=O)C>[Cl:11][C:8]1[S:9][C:10]2[C:2]([N:1]3[C:17](=[O:18])[C:16]4[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=4[C:14]3=[O:19])=[C:3]([F:13])[CH:4]=[C:5]([Cl:12])[C:6]=2[N:7]=1
Reactant: Nc1c(F)cc(Cl)c2nc(Cl)sc12
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: 0 °C

Procedure:
A solution of 6 g 7-amino-2,4-dichloro-6-fluoro-benzothiazole and 4.3 g 3,4,5,6-tetrahydrophthalic anhydride in 50 ml acetic acid was heated under reflux for 5 hours. After cooling, the reaction solution was poured into 200 ml ice-water and the resulting crystals were separated off. They were dried at 50° C. in vacuo and then purified by column chromatography. Yield: 6.6 g=70% of theory m.p.: 139°-141° C.