Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[O:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[O:37][NH2:38]>C(Cl)CCl.CN(C=O)C>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:38][O:37][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)=[O:21])=[CH:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Reactant: NOC1CCCCO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1

Procedure:
Starting materials: (E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compound B3) (0.150 g), HOBtH2O (0.072 g), triethylamine (259 μl), DMF (10 ml), EDC?HCl (0.269 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.049 g). Reaction conditions: room temperature, 1 hour; room temperature, 17 hours.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCNC1
Yield: 91.2 %

Procedure:
A solution of (R)-tert-butyl 3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (100 mg) in 20% TFA/CH2Cl2 was stirred at 0° C. for 30 min. The mixture was neutralized by addition of sat'd aq NaHCO3, extracted with CH2Cl2 (3×) and dried over Na2SO4. Evaporation of the solvent gave (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (70 mg, 91%), which was used without further purification. 1H NMR (400 MHz, CDCl3): 0.90 (m, 1H), 1.52-1.24 (m, 6H), 1.78 (m, 1H), 1.83 (m, 1H), 1.93 (m, 1H), 2.21 (m, 1H), 2.40 (m, 1H), 2.83 (m, 1H), 3.00 (m, 1H), 3.12 (s, 3H), 3.31 (m, 2H), 3.63 (m, 1H), 7.06 (m, 1H), 7.30 (m, 1H), 7.55 (t, 1H). MS (E/Z): 330 (M+H+).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[NH:18]1[CH2:21][CH2:20][CH2:19]1>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:18]3[CH2:21][CH2:20][CH2:19]3)[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: C1CNC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCC1)OC2

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), azetidine (0.1 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 301 (M+, 2), 141 (7), 95 (7), 75 (7), 71 (6), 70 (bp).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.O=[C:13]([CH3:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>CC(O)=O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:13]([CH3:20])=[C:14]2[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COc1ccc(NN)cc1
Reactant: COC(=O)CCC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Reaction time: 16 h

Procedure:
A suspension of 4-methoxyphenyl hydrazine hydrochloride (50 g, 0.286M) and methyl 4-oxo-pentanoate (40 mL, 0.315M) in HOAc (500 mL) was stirred for 16 h at reflux. The solvent was removed under vacuum, and the brown residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with H2O and brine, and was then dried (MgSO4) and filtered. Following removal of the solvent, the crude product was purified by flash chromatography (1:20 EtOAc/toluene), to give 48 g of the title compound as a pale brown syrup.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]([CH3:63])[S:39]([N:42]1C2=C3C(=CC=C2[CH:44]=[N:43]1)C(=O)C(I)=C(C1C=CC=CC=1)O3)(=[O:41])=[O:40]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:42]([S:39](=[O:41])(=[O:40])[N:38]([CH3:63])[CH3:37])[N:43]=[CH:44][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: CN(C)S(=O)(=O)n1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Product: CN(C)S(=O)(=O)n1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 87 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-6-oxo-8-phenyl-6H-9-oxa-1,2-diaza-cyclopenta[a]naphthalene-1-sulfonic acid dimethylamide was reacted to give the title compound as a gummy solid (65 mg, 87%). LCMS (Method A): RT=4.81 min, [M+H]+=615.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15](C(OC(C)(C)C)=O)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:27]=[C:28]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:27]=[C:28]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c(OCc3ccccc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(NS(C)(=O)=O)c(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Ethyl 5-(benzyloxy)-6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.32 g, 0.54 mmol, 1 eq) was dissolved in dichloromethane and cooled to 0° C. Then added trifluoroacetic acid (3.2 ml). The above mixture was stirred at room temperature for 12 h. The solution was concentrated and the pH was brought to 8 and extracted with dichloromethane. The organic layer was concentrated yielding the desired product and was taken to the next step without further purification. Yield: 0.23 g (88%). 1HNMR (400 MHz, DMSO-d6): δ 1.21-1.24 (t, 3H), 3.33 (s, 3H), 4.1-4.23 (q, 2H), 5.39 (s, 2H), 7.27 (t, J=5 Hz, 2H), 7.38 (d, J=2 Hz, 1H), 7.43 (m, 2H), 7.53 (s, 1H), 7.61 (d, J=2 Hz, 2H), 7.78 (t, J=6 Hz, 2H), 8.73 (s, 1H), 9.58 (s, 1H). LCMS: (ES+) m/z=484.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26].[NH4+].[Cl-]>CN(C=O)C>[CH3:24][CH:25]([CH3:27])[CH2:26][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])[CH:6]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)CBr
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (4 g, 16.2 mmol) was dissolved in 50 mL anhydrous DMF and NaH (60% wt. in oil, 0.846 g, 21.1 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and isobutyl bromide (2.12 mL, 19.5 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 4-methyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)pentanoate (1.5 g) as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:5]=1/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][C:22](=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>C(O)C.O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:5]=1/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][CH:22]([OH:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1-c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1-c1ccc(F)cc1

Procedure:
Sodium tetrahydridoborate (1.55 g, 41.1 mmole) is added with stirring to a cooled solution (5° C.) of methyl (E)-7-(2,4-dichloro-6-(4-fluorophenyl)phenyl)-5-hydroxy-3-oxo-6-heptenoate (82.3 mmole) in ethanol (200 ml) at a rate sufficient to maintain the internal temperature at 15°-20° C. The resulting solution is stirred with ice-bath cooling for 15 min. and then acidified with 6 N hydrochloric acid. The resulting mixture is diluted with water (500 ml) and extracted with ether (3×250 ml). The organic extracts are combined, washed with brine (4×100 ml), dried over magnesium sulfate and filtered. The filtrate is evaporated in vacuo, leaving the title compound as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@:23]2([CH3:24])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[O:25]C(=O)C)[CH2:9][C:8](=[O:29])[CH2:7]1)(=[O:3])[CH3:2].BrBr>C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[C@@:23]2([CH3:24])[C:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:25])=[CH:9][C:8](=[O:29])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1CC(=O)C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: BrBr
Solvent: CC(=O)O
Product: CC(=O)OCC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
9.1 g of 1α-acetoxymethyl-17β-acetoxy-5α-androstan-3-one (mp 193°-194° C.) [prepared from 3,3-ethylenedioxyl-1-methylene-5α-androstan-17β-ol ("Naturwissenschaften" [Natural Sciences 51: 86 (1963)) by hydroboration, acetylation, and ketal cleavage] is dissolved in 90 ml of glacial acetic acid. To this solution is added dropwise 3.2 ml of bromine in 25 ml of glacial acetic acid, and the mixture is agitated for 10 minutes. After precipitation in ice water which contains sodium sulfite, the product is suctioned off, washed with water, and dried. 16.5 g of crude dibromide is stirred in 100 ml of dimethylformamide with 10 g of lithium bromide and 20 g of calcium carbonate for 3.5 hours at a bath temperature of 120° C. After cooling, the inorganic salts are suctioned off and washed with 150 ml of methanol. The filtrate is combined with 6 g of potassium hydroxide in 20 ml of water and stirred for 16 hours at room temperature. The reaction solution is poured into ice water, the product is suctioned off and dried. The crude 1-hydroxymethyl-17β-hydroxyandrosta-1,4-dien-3-one (7.5 g) is dissolved in 100 ml of dimethylformamide, combined with 1 g of lead diacetate and 15 ml of acetic anhydride and stirred for 6.5 hours at room temperature. After precipitating in water and removal of the product by vacuum filtering, oxidation is carried out with chromic acid as described in Example 1. Recrystallization from acetone/hexane yields 2.3 g of 1-acetoxymethylandrosta-1,4-diene-3,17-dione, mp 121°-123° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](O)[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:18])=O>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([Cl:18])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccccc2)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc(-c2ccccc2)c(Cl)n1

Procedure:
Prepared from 2-methylsulphenyl-4-hydroxy-5-phenyl-pyrimidine by reacting with phosphorus oxychloride at reflux temperature, melting point: 99° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:56])[C:10]2=[CH:11][C:12]3[N:13]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:34]6[C:46]7[CH:45]=[C:44]8[C:47]([CH3:55])([CH3:54])[C:48]9[C:53]([C:43]8=[CH:42][C:41]=7[C:40]7[C:35]6=[CH:36][CH:37]=[CH:38][CH:39]=7)=[CH:52][CH:51]=[CH:50][CH:49]=9)=[CH:30][CH:29]=5)=[CH:24][CH:23]=4)[C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.C1C(=O)N([Br:64])C(=O)C1.O>C1COCC1>[Br:64][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:22]1[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([N:34]4[C:46]5[CH:45]=[C:44]6[C:47]([CH3:55])([CH3:54])[C:48]7[C:53]([C:43]6=[CH:42][C:41]=5[C:40]5[C:35]4=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:52][CH:51]=[CH:50][CH:49]=7)=[CH:32][CH:33]=3)=[CH:24][CH:23]=1)[C:12]1[CH:11]=[C:10]3[C:2]([CH3:56])([CH3:1])[C:3]4[C:8]([C:9]3=[CH:21][C:20]2=1)=[CH:7][CH:6]=[CH:5][CH:4]=4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccccc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(Br)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21
Reaction time: 4 h

Procedure:
9.42 g (13.1 mmol) of 4,4′-bis(12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)biphenyl are initially introduced in 77 ml of THF. A solution of 2.36 g (13.2 mmol) of NBS in 25 ml of THF is subsequently added dropwise at −15° C. with exclusion of light, allowed to come to room temperature and stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot ethanol and filtered off with suction. The yield is 7.5 g (9.4 mmol, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.[ClH:21]>>[ClH:1].[ClH:21].[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][NH:11]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Cl)c1
Agent: Cl
Product: Clc1cncc(OC[C@@H]2CCN2)c1
Yield: 80 %

Procedure:
The compound from step 39a (0.130 g, 0.44 mmol) was treated with saturated ethanolic HCl (5 mL) for 16 hr. The volatiles were removed in vacuo, and the dihydrochloride was recrystallized (EtOH/Et2O) to yield the title compound (0.094 g, 80%) as a white solid. mp 158-157° C. MS (DCI/NH3) m/e: 199 (M+H)+, 216 (M+NH4)+. 1H NMR (D2O, 300 MHz) d: 8.41 (d, J=5.1 Hz, 1H), 8.39 (d, J=4.4 Hz, 1H), 7.94 (t, J=2.1 Hz, 1H), 5.01-4.93 (m, 1H), 4.50 (d, J=4.0 Hz, 2H), 4.20-4.03 (m, 2H), 2.69 (q, J=8.45 Hz, 2H). Anal. calc. for C9H13Cl3N2O.0.5H2O: C, 38.53; H, 5.03; N, 9.98 Found: C, 38.51; H, 5.16 N, 9.96. [α]D23 =-3.23° (c=0.16 in MeOH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13]C(=O)C)=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20].Cl>>[NH2:13][C:11]1[S:12][C:8]([C:5]2[CH:4]=[C:3]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:2]([Cl:1])=[N:7][CH:6]=2)=[C:9]([CH3:17])[N:10]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(C)(=O)=O)c2)s1
Agent: Cl
Product: Cc1nc(N)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1

Procedure:
Using an analogous procedure to that described in Example 61, N-[5-(6-chloro-5-methylsulfonylaminopyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide was hydrolysed with aqueous hydrochloric acid solution to give the title compound; 1H NMR Spectrum: (DMSOd6) 2.22 (s, 3H); 3.13 (s, 3H); 7.23 (s, 2H); 7.76 (d, 1H); 8.21 (d, 1H); 8.79 (br s, 1H); Mass Spectrum: M+H+ 319.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][OH:15])=[C:12]([C:16]([F:19])([F:18])[F:17])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:15][CH2:14][C:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)=[N:10][S:11][C:12]=1[C:16]([F:19])([F:18])[F:17])(=[O:30])=[O:29]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (50 mg, 0.17 mmol, 1.00 equiv), triethylamine (53 mg, 0.52 mmol, 3.01 equiv), dichloromethane (2.0 mL), MsCl (40 mg, 0.35 mmol, 2.02 equiv). The resulting solution was stirred for 0.5 h at 25° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 75 mg of [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate as a light yellow solid. The crude could be used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C14H14F3NO3S2, 366.0 (M+H). found 366.0.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8](Cl)=[O:9].[Na].[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26]>O1CCCC1>[CH3:24][S:25]([NH:28][C:8](=[O:9])[CH:7]([O:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:22])([F:21])[F:1])[CH:4]=1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=[O:27])=[O:26]
Reactant: CS(N)(=O)=O
Reactant: O=C(Cl)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Agent: [Na]
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
(3-Trifluoromethylphenoxy)(4-chlorophenyl)acetyl chloride (0.02 mole) in tetrahydrofuran (50 ml.) is added over a 15-minute period to a solution of the sodium salt of methanesulfonamide (2.5 g., 0.021 mole) in tetrahydrofuran (50 ml.) at 0°-5° C., under a nitrogen atmosphere. The mixture is stirred at 20° C. for 20 hours and then the solvent is evaporated under vacuum. The residue is dissolved in chloroform and the solution is extracted with water. The chloroform solution is dried over anhydrous magnesium sulfate, filtered and the solvent removed to afford N-methanesulfonyl (3-trifluoromethylphenoxy)(4-chlorophenyl)acetamide.
Reaction SMILES: C(O[N:6]([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])C=O)(C)(C)C.[ClH:25]>CO.C(OCC)(=O)C>[ClH:24].[ClH:25].[NH2:6][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(C)(C)ON(C=O)CC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butoxy-N-[2-[4-(4-chlorophenyl)-1-piperazinyl]-2-oxoethyl]formamide (31 g) in methanol (60 ml) was added 4N hydrogen chloride in ethyl acetate (219 ml) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour and diluted with ethyl acetate. The resulting solid was collected by filtration and washed with ethyl acetate. The solid was dried to give the title compound (29 g).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:5]=1.[OH-].[Na+]>CCO>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][O:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([OH:17])=[O:2]
Reactant: COCCCOc1cc(C(=O)OC)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1cc(C(=O)O)ccc1C

Procedure:
A solution of 3-(3-methoxy-propoxy)-4-methyl-benzoic acid methyl ester (7.12 g, 32.86 mmol) and NaOH (1 N in water, 100 mL, 100 mmol) in EtOH (100 mL) is refluxed for 1 h. The reaction mixture is allowed to reach RT, and the solvent is concentrated under reduced pressure. The residue is dissolved in water (200 mL) and washed with ether (50 mL×3). The pH is adjusted to 2 by addition of cc HCl and the aqueous layer extracted with AcOEt (150 mL×2). The combined organic extracts are dried over Na2SO4, filtered and concentrated in vacuo. The crude material is recrystallized in diethyl ether/hexane to afford the desired title product. TLC, Rf (hexane/AcOEt 2:1)=0.15. MS (LC-MS): 224.0 [M−H]+. 1H-NMR (CDCl3, 300 MHz): δ=2.10 (p, 2H), 2.3 (s, 3H), 3.38 (s, 3H), 3.62 (t, 2H), 4.15 (t, 2H), 7.2 (d, 1H), 7.55 (s, 1H), 7.65 (d, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9](I)[CH:10]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[C:3]2[C:4]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([C:48]2[N:47]([CH3:46])[CH:51]=[CH:50][CH:49]=2)[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(I)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cccc1-c1cc(Br)c2c(Sc3ccc(Cl)cc3)c3n(c2c1)CCC3CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (+/−)-methyl {8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate (see Example 30, 145 mg, 0.25 mmol) in DMF (3 mL) were added tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol), triphenyl arsine (31 mg, 0.1 mmol) and 1-methyl-2-(tributylstannyl)-1H-pyrrole (111 mg, 0.3 mmol). The mixture was degassed and stirred at r.t. for 2 hours. The reaction mixture was poured into 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 15% EtOAc/hexane to give methyle ester of the title compound which was hydrolyzed following the procedures described in Step 10 of Example 7.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CCO>[F:11][C:10]([F:12])([F:13])[CH2:9][N:8]([CH2:14][C:15]([F:16])([F:18])[F:17])[C:6]([C:5]1[CH:19]=[CH:20][C:2]([NH:24][CH2:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ccc(C(=O)N(CC(F)(F)F)CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (200 mg, 0.574 mmol) and tert-butyl (2S)-2-(aminomethyl)piperidine-1-carboxylate (150 mg, 0.689 mmol) in 10 mL of EtOH containing TEA (0.120 mL, 0.861 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent Yield: 311 mg (99%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.47 (s, 9H), 1.52 (m, 1H), 1.66 (m, 1H), 1.71 (s, 2H), 1.74 (s, 2H), 2.79 (m, 1H), 3.36 (m, 1H), 3.65 (m, 1H), 4.09 (s, 1H), 4.26 (q, J=8.33 Hz, 4H), 4.64 (m, 1H), 7.07 (d, J=8.98 Hz, 1H), 7.55 (dd, J=8.89, 2.05 Hz, 1H), 8.30 (d, J=2.15 Hz, 1H), 8.39 (m, 1H); MS (ESI) 542.81 (MH+).