Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59]C(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@H:8]1[OH:57])=[O:6].C([O-])(O)=O.[Na+].OO>C1COCC1>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:59])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@]2(C)[C@H](O)C[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c3ccccc3)c3ccccc3)C(C)=C1C2(C)C
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Reaction of 7-epi-taxol with NaHCO3 : 10 mg (0.01 mmol) of 7-epi-taxol with NaHCO3 in 0.3 ml of THF were introduced into a 4 ml vial equipped with a magnetic stir bar. 0.5 ml of 30% H2O2 was added followed by 100 mg NaHCO3 and the mixture was then stirred at room temperature overnight. The mixture was then extracted with methylene chloride/water (50:50 by volume). The organic phase was collected and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure to obtain a crude product 7-epi-10-deacetyl taxol, that was subsequently purified. Following a 48 hour reaction 25.4% chromo. purity of starting material and 48.3% chrom. purity of 7-epi-10-deacetyl taxol resulted.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][C:13]([OH:15])=O)=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].[CH2:24]([O:26][C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[C:28]=1[NH2:29])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][C:13]([NH:29][C:28]1[C:30]([O:34][CH2:35][CH3:36])=[CH:31][CH:32]=[CH:33][C:27]=1[O:26][CH2:24][CH3:25])=[O:15])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23]
Reactant: COc1ccccc1-c1c(CC(=O)O)n(C)c2ccc(Cl)cc12
Reactant: CCOc1cccc(OCC)c1N
Product: CCOc1cccc(OCC)c1NC(=O)Cc1c(-c2ccccc2OC)c2cc(Cl)ccc2n1C

Procedure:
5-Chloro-3-(2-methoxyphenyl)-1-methylindole-2-acetic acid was reacted with 2,6-diethoxyaniline by a method similar to Example 6 to give the title compound as colorless crystals.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][CH:27]([C:29](=[O:36])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:28])[CH:24]=2)[N:19]([CH3:37])[CH:18]=1)[C:9]([O:11]C)=[O:10]>O.CO.O1CCCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][CH:27]([C:29](=[O:36])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:28])[CH:24]=2)[N:19]([CH3:37])[CH:18]=1)[C:9]([OH:11])=[O:10]
Reactant: CCCCCNC(=O)C(C)Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCNC(=O)C(C)Cc1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
A solution of lithium hydroxide monohydrate (0.29 g) in water (5 ml) was added to a solution of methyl 3-methoxy-4-[1-methyl-5-[2-(pentylcarbamoyl)propyl]indol-3-ylmethyl]benzoate (0.65 g) in methanol (25 ml) and tetrahydrofuran (5 ml). The mixture was stirred under an atmosphere of nitrogen for 48 hr, and the solvents evaporated. The residue was taken up in water (5 ml), acidified with 1M hydrochloric acid (10 ml), and the precipitate which formed isolated by filtration to give the title compound (0.63 g, 94%) as a white powder; mp 85°-95°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:31]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]3[CH:28]=[CH:27][N:26]([CH3:29])[C:25]3=[O:30])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl.[N:40]1([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][C:48]2[C:43](=[CH:44]C=CC=2)[CH2:42][C@H:41]1[C:50]([OH:52])=O.[CH:60]1[CH:65]=NC2N(O)N=NC=2[CH:61]=1.C(Cl)CCl>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:31][C:50]([C@@H:41]2[CH2:42][C:43]3[C:48](=[CH:61][CH:60]=[CH:65][CH:44]=3)[CH2:49][N:40]2[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:52])[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]3[CH:28]=[CH:27][N:26]([CH3:29])[C:25]3=[O:30])[CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cn1ccn(-c2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)OC(C)(C)C)CC2)c1=O
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: On1nnc2cccnc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1ccn(-c2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)[C@@H]3Cc4ccccc4CN3C(=O)OC(C)(C)C)CC2)c1=O
Yield: 39.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 10 (Step b) using N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(3-methyl-2-oxo(4-imidazolinyl))-phenyl]piperidyl}-2-oxoethyl)(tert-butoxy)carboxamide (Step b) (0.237 g, 0.44 mmol) and satd anhydrous HCl in EtOAc, followed by Boc-L-TicOH (Advanced ChemTech) (0.123 g, 0.44 mmol), HOAT (Aldrich) (0.06 g, 0.44 mmol), TEA (Aldrich) (0.06 mL, 0.44 mmol) and EDC (Advanced ChemTech) (0.126 g, 0.66 mmol) in DMF (10 mL). Purification by silica gel chromatography (EtOAc then 1:9 MeOH:EtOAc) provided the title compound as a pale yellow foam (0.12 g). MS (ESI, pos. ion) m/z: 698 (M+1). Calc'd for C39H44ClN5O5: 697.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:14][C:13]3([CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH3:23])=[O:21])[CH2:15]3)[O:12][C:11]2=[O:24])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:14][C:13]3([CH2:19][CH2:18][CH2:17][C:16]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:20]([O:22][CH3:23])=[O:21])[CH2:15]3)[O:12][C:11]2=[O:24])=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCCC2(C1)CN(Cc1ccc(OC)cc1)C(=O)O2
Reactant: ClCOCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(COCc2ccccc2)CCCC2(CN(Cc3ccc(OC)cc3)C(=O)O2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-{[4-(methyloxy)phenyl]methyl}-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-carboxylate (5.05 g, 15.15 mmol) in THF (38.7 mL) under nitrogen at −78° C. was added sodium bis(trimethylsilyl)amide, (1M in THF, 45.4 mL, 45.4 mmol) over 30 minutes. The reaction mixture was stirred at −78° C. for 1 h. Benzyl chloromethyl ether (7.12 g, 45.4 mmol) was then added. After 1 h, the reaction was quenched slowly with water (5 mL). Saturated aq NaCl (100 mL) was then added and the mixture was extracted with EtOAc (2×125 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The compound was then loaded onto florisil and purified using silica gel chromatography CISCO): 10-25% ethyl acetate/hexanes (30 min), 25% (5 min.), 25-45% (15 min), 45% (5 min), 120 g silica. The product eluted at 45 minutes. Methyl 3-{[4-(methyloxy)phenyl]methyl}-2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]decane-7-carboxylate was obtained as a light yellow oil (4.62 g, 64% yield) and NMR and LCMS were 95% clean for trans product. MS (m/z) 454.0 (M+H+).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:11].O1CCO[CH2:20]1.Cl>CC(OC)(C)C.C(OCC)(=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([CH:9]([CH2:20][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH3:8])=[O:11])=[CH:13][CH:14]=1.[ClH:1]
Reactant: CCC(=O)c1ccc(C)cc1
Reactant: C1CCNCC1
Reactant: C1COCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: Cc1ccc(C(=O)C(C)CN2CCCCC2)cc1

Procedure:
75 kg piperidine hydrochloride and 105 kg 4-methylpropiophenone are heated to 90° C. with 180 kg of 1,3-dioxolane and 12 kg of hydrochloric acid under a nitrogen atmosphere for 7 to 20 hours. With addition of 500 kg of ethyl acetate and 440 kg MTBE at a temperature in the range of (40-80° C.), a suspension of the product is produced. After that the solid is separated from the liquid as a damp product and then dried at 60-80° C. in the vacuum oven (200-500 mbar) over a period of 12-24 hours whereby 140 kg (81.5%) of colorless crystals are isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[CH2:9][N:10](C(=O)C(F)(F)F)[CH2:11][C:5]=2[C:4]=1[N+:21]([O-:23])=[O:22].N>CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[CH2:9][NH:10][CH2:11][C:5]=2[C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1ccc2c(c1[N+](=O)[O-])CN(C(=O)C(F)(F)F)CC(=O)N2
Agent: N
Solvent: CO
Product: COc1ccc2c(c1[N+](=O)[O-])CNCC(=O)N2
Temperature: 25 °C
Reaction time: 22 h
Yield: 90.9 %

Procedure:
A mixture of 7-Methoxy-6-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (1.70 g, 0.00510 mol) and 7.0 M of Ammonia in Methanol (30 mL) was stirred at room temperature for 22 hrs. The reaction was evaporated to give 7-Methoxy-6-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (1.10 g, 90%). Mp 220-222° C.; LCMS (m/e) 237 (M); 1H-NMR (DMSO, 400 MHz) δ 1H-NMR (DMSO, 400 MHz) δ 9.92 (s, 1H), 7.257-20 (q, 2H, J=3.79 Hz), 3.83 (s, 3H), 3.69 (d, 2H), 3.43 (d. 2H, J=4.29 Hz), 3.11 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[S:11])[NH:9][CH:10]=2)[CH:7]=1.[CH3:12][O-].[Na+].CI>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[CH:7]=1
Reactant: Fc1ccc2c[nH]c(=S)n2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1ncc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.5 %

Procedure:
In a round-bottomed flask, 6-fluoro-2H-imidazo[1,5-a]pyridine-3-thione (158 mg, 0.94 mmol) was suspended in methanol (1 ml) and sodium methoxide (0.5 M in MeOH, 2.0 ml, 1.0 mmol) was added dropwise. The reaction was stirred at room temperature for 10 min then methyl iodide (0.07 ml, 1.12 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane then the organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 179 mg of 6-fluoro-3-methylsulfanyl-imidazo[1,5-a]pyridine as a brown oil which was used without further purification. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.98-8.05 (m, 1H), 7.58 (s, 1H), 7.45 (dd, J=9.3, 4.8 Hz, 1H), 6.73 (ddd, J=9.6, 7.6, 2.0 Hz, 1H), 2.56 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:21])[N:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])[C:8](=[O:20])[CH:7]=[CH:6]2.[C:22]([N:26]1[CH2:31][CH:30]=[C:29]([Sn](C)(C)C)[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([N:26]1[CH2:27][CH:28]=[C:29]([C:2]2[CH:3]=[C:4]([Cl:21])[N:5]3[C:10]([CH:11]=2)=[C:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:8](=[O:20])[CH:7]=[CH:6]3)[CH2:30][CH2:31]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=c1ccn2c(Cl)cc(Br)cc2c1-c1c(Cl)cccc1Cl
Reactant: CC(C)(C)N1CC=C([Sn](C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(C)(C)N1CC=C(c2cc(Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
To a solution of 8-bromo-6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (Example 17, 132 mg) in THF was added 1-t-butyl-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine (process route disclosed in U.S. Pat. No. 6,809,199, 90 mg.), dichlorobis(triphenylphosphine) palladium (21 mg) and heated to reflux for 12 h. The mixture was concentrated and purified by silica gel (methylene chloride/acetone=1/2) to give title compound (57 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1([CH:30]2[CH2:36][CH2:35][C:34]3[CH:37]=[C:38]([NH2:41])[CH:39]=[CH:40][C:33]=3[CH2:32][CH2:31]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:41][C:38]2[CH:39]=[CH:40][C:33]3[CH2:32][CH2:31][CH:30]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:36][CH2:35][C:34]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
The title compound was prepared from (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine and 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner as Example 179. Product isolated as a white solid (46 mg, 60%). LCMS (m/e) 565 (M+H); 1H NMR (CDCl3, 400 MHz) δ 8.27 (d, 1H, J=7.6 Hz), 8.00 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.35 (d, 1H, J=9.3 Hz), 7.04 (d, 1H, J=8.1 Hz), 6.84 (s, 1H), 6.55 (s, 1H), 6.51 (d, 1H, J=9.3 Hz), 3.92 (s, 3H), 3.90 (m, 5H), 3.69 (m, 4H), 3.16 (m, 4H), 2.81 (2H, m), 2.67 (2H, m), 2.55 (m, 4H), 2.08 (m, 2H), 1.44 (m, 2H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]([OH:26])=O)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH2:44]>C1COCC1>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH:44][C:24]([C:19]1[C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:26]
Reactant: O=C(O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Reactant: CN(C)CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccccc1-c1ccc(CSCCOc2ccccc2)cc1
Yield: 85.7 %

Procedure:
Prepared in the same manner as described for example 1. A solution of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.38 g, 1.04 mmol, 1 eq.) in anhydrous THF was treated with 1,1′-carbonyldiimidazole (0.17 g, 1.06 mmol, 1.02 eq.) and warmed as described. The reaction was allowed to cool and then treated with 3-(dimethylamino)propylamine (0.13 g, 1.25 mmol, 1.2 eq.). The reaction was treated as described in example 1 to give a yellow oil. The oil was purified by silica gel flash chromatography using 10% 2M NH3 in methanol in diethyl ether as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (3-dimethylamino-propyl)-amide (0.40 g, 85% yield) as a light yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[S:13][CH3:14].CC(C[AlH]CC(C)C)C.CO>C1(C)C=CC=CC=1.CC(=O)OCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH:3]=[O:2])=[C:7]([S:13][CH3:14])[CH:8]=1
Reactant: COC(=O)CCc1ccc(F)cc1SC
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CSc1cc(F)ccc1CCC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 3-(4-fluoro-2-methylsulfanyl-phenyl)-propionic acid methyl ester (1 g, 4.3 mmol) in dry toluene was added DIBAL-H (5.2 ml in toluene, 1N) drop-wise at −78° C. After stirring at this temperature for 1 h, methanol (5 ml) was added dropwise to quench the reaction. The mixture was warmed to room temperature and diluted with EA. The mixture was washed with brine, dried and concentrated. The residue was purified by column chromatography to give the titled compound (804 mg, yield 92%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8]>CCO.[Pd]>[NH2:12][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution of 5-fluoro-N-methyl-2-nitrobenzamide (Compound 102B) in EtOH (10.0 mL) was charged with Palladium 10% wt on activated carbon (0.316 g, 0.297 mmol). The reaction mixture was evacuated and purged with hydrogen gas (3 times). The reaction mixture was allowed to stir under hydrogen at rt for 16 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to yield a light yellow semi-solid. The material was purified by silica gel chromatography using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 0.500 g (100% yield). 1H NMR (CDCl3, 400 MHz): δ=2.98 (d, J=4.80 Hz, 3H), 5.30 (d, J=5.31 Hz, 1H), 6.64 (dd, J=8.84, 4.80 Hz, 1H), 6.96 (ddd, J=8.91, 7.89, 2.91 Hz, 1H), 7.02 (dd, J=9.22, 2.91 Hz, 1H). MS (ES+): m/z 169.08 [MH+] (TOF, polar).
Reaction SMILES: Br.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[N:13]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: Nc1nc(-c2ccc3ccccc3c2)cs1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccc4ccccc4c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
A mixture of 0.5 g of 4-(2-naphthyl)-thiazol-2-ylamine hydrobromide with 0.34 g of 4-methoxy-benzenesulfonyl chloride was stirred for 3 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and freed from solvent. The residue was dissolved in a mixture of 25 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 10 ml of ethyl acetate and 15 ml of n-hexane yielded 0.19 g of 4-methoxy-N-(4-naphthalen-2-yl-thiazol-2-yl)-benzenesulfonamide as colorless crystals.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].N12CCN(CC1)CC2>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:18]=2[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1I
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2C1
Temperature: 110 °C
Yield: 17.3 %

Procedure:
General Method: A mixture of 2-iodoaniline (0.315 g, 1.44 mmol), 4-oxo-1-piperidinecarboxylic acid tert-butyl ester (0.860 g, 4.31 mmol), 1,4-diazabicyclo[2.2.2]octane (Dabco™) (0.483 mL, 4.31 mmol) and palladium acetate (0.016 g, 0.072 mmol) in dry DMF (7 mL) was degassed via vacuum/argon purging, and then it was heated to 110° C. for 3.5 h. The reaction mixture was subsequently cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed (SiO2/hexanes:ethyl acetate, 1:1) to give the title compound (0.068 g, 17%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.12 (m, 2H), 4.64 (s, 2H), 3.82 (s, 2H), 2.82 (s, 2H), 1.50 (s, 9H); LCMS: m/e 273 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@:13]1([CH2:23][C:24]#[N:25])[CH2:22][C:17]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>CCOCC>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@:13]1([CH2:23][CH2:24][NH2:25])[CH2:22][C:17]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: N#CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
LAH (1M in Et2O, 20 ml, 20 mmol) was added to a solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (2.56 g, 10 mmol) in Et2O (100 ml, 0.1M) at 0° C. under N2. The resulting mix was stirred and allowed to warm to room temperature. After 2 h, LCMS showed the reaction had completed. The reaction was cooled at 0° C. and quenched with water (1.12 ml), NaOH (10%, 2.24 ml) and another 3.36 ml of water. Solid was filtered and filter pad was washed with ether (3×20 ml). The combined organic was dried and concentrated to give 2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (2.44 g, 94% yield, m/z 260.6 [M+H]+ observed) as a light amber oil.
Reaction SMILES: B(F)(F)F.CCOCC.CSC.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30]CC2C=CC=CC=2)=[CH:26][CH:25]=1)=[O:23]>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1nc2ccccc2s1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1ccc(O)cc1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a 1 L round bottom flask was charged in a solution of boron trifluoride diethyl etherate (101.2 g, 312 mmol) and dimethylsulfide (112 g, 809 mmol) in dry methylenedichloride (300 ml). Benzo[d]thiazol-2-yl(4-(benzyloxy)phenyl)methanone (30 g, 86.9 mmol) was added slowly to the mixture and the resulting solution was stirred at room temperature for 72 h. The reaction mixture was then quenched with water and diluted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel column chromatography with hexane and ethyl acetate to give benzo[d]thiazol-2-yl(4-hydroxyphenyl)methanone. [M+H]=256.