Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=O.[CH3:16][C:17]([CH3:19])=[O:18].CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:16]/[C:17](=[O:18])[CH3:19])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)/C=C/c1ccc(C2CCCCC2)c(Cl)c1
Yield: 40 %

Procedure:
222.72 Gm (1.0 mol) of 3-chloro-4-cyclohexyl-benzaldehyde, 3,500 gm (60.3 mols) of acetone and 200 ml of methanol were charged into a 6-liter three-necked flask equipped with a stirrer, dropping funnel and internal thermometer. While thoroughly stirring the contents of the flask, a solution of 2.805 gm (0.05 mol) of potassium hydroxide in 16 ml of water was added dropwise thereto, while an internal temperature of 20° to 25°C was maintained. The mixture was then stirred for 3 hours more. The precipitate solid by-product was filtered off, and the filtrate was neutralized by dropwise addition of glacial acetic acid, and concentrated by evaporation in vacuo. The residue was shaken with a mixture of water and ether. The ether phase separated, dried over sodium sulfate, clarified with charcoal, and evaporated. The residual oil was distilled in a high vacuum (b.p. 162°-175°C at 0.2 mm Hg), crystallized by trituration with a small quantity methanol, and finally recrystallized once from methanol. The colorless crystals melted at 48°-49°C. Yield: 40 % of theory.
Reaction SMILES: C([C:8]1[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(OC(C)(C)C)=O.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C(O)(C(F)(F)F)=O>O>[NH2:18][CH2:17][C:15]1[CH:16]=[CH:8][C:9]([C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([Cl:19])=[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:22]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)c1cc(CN)ccc1C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Procedure G was used to couple BOC-4-(aminomethyl)benzoic acid (48 mg) with 4-chloro-3-(pyridin-2-yl)aniline (35 mg). The crude reaction mixture was treated with TFA (1 mL) containing trace amounts of water for 1 h. The reaction mixture was concentrated to yield 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[C:21]([F:23])[N:22]=2)[CH:7]=1)=[O:5])[CH3:2].[C:24]([O:28][C:29]([NH:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:34]3[CH2:35][CH2:36][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:33]3)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[C:21]([F:23])[N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cn(-c2nc(F)cs2)c2nc(Cl)ccc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2nc(F)cs2)c2nc(N3CCC(NC(=O)OC(C)(C)C)C3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A mixture composed of 7-chloro-1-(4-fluoro-2-thiazoly)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (30 mg) obtained in Example A-2, 3-(t-butoxycarbonylamino)pyrrolidine (19 mg), triethylamine (26 mg) and acetonitrile (10 ml) was stirred at room temperature for 30 minutes. Solvent was distilled off under reduced pressure, and water was added, and then, the resulting mixture was extracted with chloroform. The obtained extract was dried over anhydrous sodium sulfate, and solvent was distilled off under reduced pressure. The resulting residue was subjected to recrystallization with use of ethyl acetate, and thus, there was obtained 7-(3-t-butoxycarbonylamino-1-pyrrolidinyl)-1-(4-fluoro-2-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (40 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Sc1ccccc1Br
Reactant: CCOC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCSc1ccccc1Br
Yield: 80.7 %

Procedure:
A mixture of 2-bromobenzenethiol (6 g, 30 mmol), ethyl 3-chloropropanoate (13 g, 96 mmol), K2CO3 (8.8 g, 64 mmol) and acetone (150 mL) was refluxed for 15 h. The reaction mixture was filtered and the filter cake washed with acetone (50 mL). The filtrate was concentrated to dryness and subjected to FCC to give ethyl 3-(2-bromophenylthio)propanoate (7 g, 78%). MS (ESI): mass calcd. for C11H13O2S, 287.98; m/z found, 288.8 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1>>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:24]2[CH:25]=[C:20]([Cl:19])[N:21]=[CH:22][N:23]=2)=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: Clc1cc(Cl)ncn1
Product: O=[N+]([O-])c1cc(Nc2cc(Cl)ncn2)ccc1OCc1ccccc1

Procedure:
The reaction of 4-benzyloxy-3-nitro-aniline with 4,6-dichloropyrimidine to afford 4-(4′benzyloxy-3-nitrophenyl)amino-6-chloro-pyrimidine is performed according to Preparation method 1. δH (d6DMSO): 5.34 (2H, s, CH2Ar), 6.84, (1H, s, HetH), 7.30-7.75 (7H, m, ArH), 8.30 (1H, m, ArH), 8.55 (1H, s, Het H), 10.10 (1H, s, NH)
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH:70]([CH3:72])[CH3:71])=[CH:65][CH:64]=1)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:62][C:63]3[CH:64]=[CH:65][C:66]([O:69][CH:70]([CH3:72])[CH3:71])=[CH:67][CH:68]=3)[C:57]([N:59]([CH3:60])[CH3:61])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: CC(C)Oc1ccc(C[C@H](N)C(=O)N(C)C)cc1
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: CN(C)C=O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)c2ccc3c(N4CCN(C)CC4)nc(N)nc3c2)C(=O)N(C)C)cc1
Reaction time: 0.17 h
Yield: 19.2 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (42 mg, 0.11 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (24 uL, 0.14 mmol). The reaction was stirred for 10 min, and the (2S)-2-amino-3-(4-isopropoxyphenyl)-N,N-dimethylpropanamide (35 mg, 0.14 mmol) was added. The reaction was stirred for 2 h. at r.t., and was purified by RP-HPLC (pH=2) to afford the desired product (7 mg, 20%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=520.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:26])[C:19]([CH3:25])([CH3:24])[CH:20]([Br:23])[CH2:21][Br:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:26])[C:19]([CH3:25])([CH3:24])[CH:20]([Br:23])[CH2:21][Br:22])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C(=O)CCl)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C(=O)COc1ccc(Cl)cc1)C(Br)CBr
Temperature: 100 °C
Reaction time: 5 h
Yield: 63.3 %

Procedure:
70.7 g (0.55 mole) of 4-chlorophenol and 75.9 g (0.55 mole) of potassium carbonate are heated under reflux in 500 ml of toluene for 2 hours, using a water separator. 133 g (0.433 mole) of 1-chloro-4,5-dibromo-3,3-dimethyl-2-pentanone in 100 ml of toluene are then added at 70° C. The reaction mixture is stirred at 100° C. for 5 hours and is then allowed to cool, and is washed with water and dilute sodium hydroxide solution, dried over sodium sulphate and concentrated. 109.2 g (63.3% of theory) of 1-(4-chlorophenoxy)-4,5-dibromo-3,3-dimethyl-2-pentanone of refractive index nD20 1.5363 are obtained. ##STR108##
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[NH:14])=[CH:11][C:10]=1[CH:18]=[CH:19][C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][CH:33]=2)=[CH:28][CH:27]=1>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[NH:14])=[CH:11][C:10]=1[CH2:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25](=[O:39])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][CH:33]=2)=[CH:28][CH:27]=1
Reactant: N=C(N)c1ccc(O)c(C=C[C@H]2CCCN2C(=O)c2ccc(-c3ccc(=O)[nH]c3)cc2)c1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(O)c(CC[C@@H]2CCCN2C(=O)c2ccc(-c3ccc(=O)[nH]c3)cc2)c1
Yield: 50.6 %

Procedure:
4-Hydroxy-3-(2-{1-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoyl]pyrrolidin-2-(R)-yl}-vinyl)benzamidine trifluoroacetate (0.0065 g, 0.01198 mmol) in MeOH (10 mL) and 5% Pd/C (catalytic amt.) is hydrogenated using a balloon filled with H2 gas for 4 h. The reaction is filtered, evaporated and the residue is diluted with H2O (10 mL). The aqueous solution is lyopholized to give the title compound as a white solid (0.0033 g, 0.00606 mmol). 1H NMR (DMSO-d6, 300 MHz) 8.97(s, 2H), 8.60(s, 2H), 7.93-7.26(m, 8H), 6.93(d, 1H), 6.42(d, 1H), 4.15(m, 1H), 3.61-3.35(m, 1H), 2.70-2.51(m, 2H), 2.45-1.98(m, 4H), 1.93-1.55(m, 3H). MS m/z: [M+H]+=431.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][NH2:22])=[O:20])(=[O:15])=[O:14]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:22]/[NH:21][C:19](=[O:20])[C:18]2[CH:23]=[CH:24][CH:25]=[C:16]([S:13]([CH3:12])(=[O:14])=[O:15])[CH:17]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CS(=O)(=O)c1cccc(C(=O)NN)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(C)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 63.5 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (55 mg, 0.322 mmol) and 3-(methylsulfonyl)benzohydrazide (69.1 mg, 0.322 mmol) were dissolved in methanol (5 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (3% CH3OH/CH2Cl2) affording the title compound (75 mg, 63.4% yield) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.49 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=7.6 Hz), 7.80 (t, 1H, J=7.6 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.27 (m, 1H), 6.93 (d, 1H, J=8.8 Hz), 3.19 (s, 3H), 2.49 (s, 3H). ESI-MS: 367.8 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:14][C:2]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([F:1])[F:13]
Reactant: FC(F)(F)Oc1ccc2cc[nH]c2c1
Reactant: Ic1ccccc1
Product: FC(F)(F)Oc1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-(trifluoromethoxy)-1H-indole and iodobenzene: ESMS m/e: 278.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH2:22][CH2:23][CH3:24])=[C:8]([C:16]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH:25][C:26]1[C:31]([CH2:32][CH2:33][CH3:34])=[C:30]([SH:35])[CH:29]=[CH:28][C:27]=1[C:36](=[O:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[C:36]([C:27]1[CH:28]=[CH:29][C:30]([S:35][CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:7]([CH2:22][CH2:23][CH3:24])=[C:8]([C:16]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:18]=2)[O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:31]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:25])(=[O:38])[CH3:37]
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCCl)ccc(C(C)O)c1OCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(SCCCOc2ccc(C(C)O)c(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 25.4 %

Procedure:
A mixed solution of 42.6 mg of (+)-4-[3-(3-chloropropoxy)-6-(1-hydroxyethyl)-2-propylphenoxy] butanoic acid, 30.0 mg of (2-hydroxy-4-mercapto-3-propylphenyl) ethanone, 39.4 mg of potassium carbonate and 1 ml of dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. After washed with water and saturated aqueous solution of sodium chloride, the organic layer was dried over anhydrous sodium sulfate and subjected to distillation off of the solvent under reduced pressure to afford residue. The residue was purified through silica gel column chromatography (methylene chloride: ethanol=20:1) and further through preparative thin layer chromatography (methylene chloride: methanol=1.5:1) to afford 16.1 mg of yellow oily water as the title compound (yield 25.4%). [α]D20 +13.3° (c=1.56, ethanol)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:19]Br)=[O:5])[CH3:2].[CH2:21]([O:23][C:24](=[O:38])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:19][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(OC)cc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 226.4 %

Procedure:
A mixture of 4-bromomethyl-2-(4-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.70 g, 4.78 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (1.21 g, 4.78 mmol) and potassium carbonate (992 mg, 7.18 mmol) in anhydrous dimethylformamide (15 mL) was stirred at room temperature for 18 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (5.72 g): MS: (+) m/z 529.10 (M+H+), 551.20 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:21]([O-])=O)=[CH:4][C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[C:6]([OH:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:34][O:35][CH3:36].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:34][O:35][CH3:36])[C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[CH:4][C:3]=1[NH2:21]
Reactant: COCCl
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitrophenol (0.52 g) and N,N-diisopropylethylamine (0.52 mL) in methylene chloride (5 mL) was added (chloromethyl)methyl ether (0.17 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (7.5 mL). To the solution were added methanol (7.5 mL) and nickel(II) bromide (17 mg). To the mixture was added sodium borohydride (0.17 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−1/1) to give the title compound (0.4 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[Cl:9][CH2:10]OCCl.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[Cl:9][CH2:10][C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1
Reactant: ClCOCCl
Reactant: O=C(O)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc(CCl)s1

Procedure:
2-Thiophenecarboxylic acid is treated in a solution of chloroform with chloromethyl ether in the presence of 0.9 to 2.2 equivalents of aluminum chloride to give 5-chloromethyl-2-thienylcarboxylic acid. Treatment of the obtained acid with excess thionyl chloride at room temperature for about 16 hours yields the acid chloride which is reacted with diazomethane to give the corresponding diazoketone. A methanol solution of the diazoketone is irradiated under nitrogen for about one hour with a high pressure mercury lamp using a Quartz filter. The methyl 5-chloromethyl-2-thienylacetate is obtained upon work up and column chromatography on silica gel. The acetate is hydrolyzed by treatment of a 1:1 mixture of acetic acid and concentrated hydrochloric acid at room temperature overnight to give 5-chloromethyl-2-thienylacetic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH:7]1([C:13]2[S:14][C:15]3[C:21](=[O:22])[CH:20]=[C:19](NCCN(C)C)[C:18](=[O:29])[C:16]=3[N:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[CH:7]1([C:13]2[S:14][C:15]3[C:21](=[O:22])[C:20]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:19][C:18](=[O:29])[C:16]=3[N:17]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CN(C)CCN
Reactant: CN(C)CCNC1=CC(=O)c2sc(C3CCCCC3)nc2C1=O
Product: CN(C)CCNC1=CC(=O)c2nc(C3CCCCC3)sc2C1=O

Procedure:
The experimental protocol used is identical to that described for Stage 15.4 of Example 15, intermediate 101.4 replacing intermediate 15.3 and N,N-dimethylethylene diamine replacing aniline. A mixture of 80% and 9% of 2-cyclohexyl-5-{[2-(dimethylamino)ethyl]amino}-1,3-benzothiazole-4,7-dione and of 2-cyclohexyl-6-{[2-(dimethylamino)ethyl]amino}-1,3-benzothiazole-4,7-dione is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][C:6]2=[CH2:13].[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH:11]2[CH:5]([CH:6]([CH3:13])[CH2:7][C:8](=[O:12])[CH2:9][CH2:10]2)[CH2:4][CH2:3]1
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CCC2C(C)CC(=O)CCC12

Procedure:
176 mg of 1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene were hydrogenated in 15 ml of ethanol with 175 mg of palladium-on-carbon (5%). After hydrogen uptake was completed the mixture was filtered off from the catalyst, the filtrate evaporated and distilled in vacuum. There was obtained pure 1,4-dimethyl-6-oxo-perhydroazulene; b.p.0.05 60°; IR(film):νmax = 1700, 1460, 1375, 1335, 1250, 1180, 980, 850 cm-1. The compound has a camphorous, herby, woody odour.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29](COCC[Si](C)(C)C)[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[F:17])[CH2:5]1)#[N:2].Cl.[F:41][C:42]([F:47])([F:46])[C@H:43]([NH2:45])[CH3:44]>>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:45][C@H:43]([CH3:44])[C:42]([F:47])([F:46])[F:41])=[O:14])=[CH:10][C:9]=2[F:17])[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5F)C4)c3)ncnc21
Reactant: C[C@@H](N)C(F)(F)F
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)c(F)c1)C(F)(F)F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5, Step 3 starting from 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluorobenzoic acid and (2R)-1,1,1-trifluoropropan-2-amine hydrochloride. LCMS (M+H)+: m/z=513.2. 1H NMR (400 MHz, DMSO-d6): δ 12.66 (br, 1H), 9.11 (s, 1H), 8.86 (s, 1H), 8.64 (d, J=8.9 Hz, 1H), 8.58 (s, 1H), 7.80 (br, 1H), 7.71 (s, 1H), 7.69 (dd, J=4.0, 1.6 Hz, 1H), 7.26 (br, 1H), 6.78 (t, J=8.7 Hz, 1H), 4.89-4.78 (m, 1H), 4.71 (d, J=7.7 Hz, 2H), 4.45 (dd, J=9.4, 1.8 Hz, 2H), 3.78 (s, 2H), 1.35 (d, J=7.0 Hz, 3H).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(=O)=O)=CC=1.[F:22][C:23]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25][CH2:26]O.CC(C)([O-])C.[K+].C(O)C>O1CCCC1>[F:22][C:23]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25][CH2:26][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OCCCC(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCOCCCC(F)(F)C(F)(F)F
Temperature: 200 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To a stirred solution of the product of step (a) (500 mg) and 4,4,5,5,5-pentafluoropentan-1-ol (284 mg) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (1M in tetrahydrofuran; 1.6 ml) and the reaction was stirred at 200° C. for 2 hours. An additional charge of potassium tert-butoxide (1M in tetrahydrofuran; 1.6 ml) was added and the reaction was stirred for a further 18 hours. Ethanol (5 ml) was added and the reaction was stirred for 30 mlnutes. The reaction mixture was partitioned between dichloromethane (300 ml) and water (300 ml). The organic layer was dried over magnesium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel (5 g Bond Elut cartridge) eluting with 20% ethyl acetate in cyclohexane gave the title compound as a clear oil (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[N:10]2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.O.NN>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)=[C:4]([C:25]([F:26])([F:28])[F:27])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of crude 2-(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (6.14 g, 15.1 mmol) in THF (50 ml) was added hydrazine hydrate (3.67 ml, 76 mmol, Aldrich). The resulting colourless solution was stirred at 50° C. for 1 h. A white solid precipitated. The reaction was cooled down to ambient temperature and filtered through a sinter funnel. The filtrate was then passed through a hydrophobic frit and concentrated under reduced pressure. The sample was pre-absorbed on florosil (15 ml of DCM:MeOH=1:1) and purified on silica 100 g using 0-50% ethyl acetate-dichloromethane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (1.57 g); LCMS: (System 3) MH+=276, tRET=0.90 min.