Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]3[CH2:23][N:22]([C:24](=[O:44])[C@@H:25]([NH:30][C:31](=[O:43])[C@@H:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])[C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:21]([C:45](=[O:57])[NH:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:50][CH2:49][CH2:48]4)[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:18][C@@H:19]1[CH2:23][N:22]([C:24](=[O:44])[C@@H:25]([NH:30][C:31](=[O:43])[C@@H:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH3:33])[C:26]([CH3:28])([CH3:29])[CH3:27])[C@H:21]([C:45](=[O:57])[NH:46][C@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][CH2:49][CH2:48]2)[CH2:20]1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of tert-butyl ((S)-1-(((S)-1-((2S,4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (6.14 g, 7.87 mmol) in CH2Cl2 (40 mL) was added piperidine (4.67 mL, 47.2 mmol) dropwise. The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was washed with methanol and the resulting solid was removed by filtration. The filtrate was concentrated in vacuo and purified by flash column chromatography (gradient elution from 0 to 10% MeOH/CH2Cl2) to give the title compound (3.48 g, 79%) as a light tan solid. MS(ESI+) m/z 558.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH3:19])=[N:15][N:16]([CH3:18])[CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[C:14]([CH3:19])=[N:15][N:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nn(C)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: Cc1nn(C)cc1NS(=O)(=O)c1ccc(Br)cc1
Yield: 91.6 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (396 mg, 1.55 mmol) and 4-amino-1,3-dimethyl-1H-pyrazole (228 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (469 mg, 1.42 mmol, 92%). OH (D-6 DMSO, 300K) 9.44 (1H, s), 7.79 (2H, d J 8.7 Hz), 7.57 (2H, d J 8.7 Hz), 7.39 (1H, s), 3.65 (3H, s), 1.70 (3H, s). m/z (ES+, 70V) 332.0 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:22]([C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:29][NH:30]2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[C:29]([CH:14]([C:3]3[C:4](=[O:13])[CH2:5][CH:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]=3[OH:1])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:30]2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: O=Cc1ccccc1
Reactant: CCc1ccc2c(CCNC(C)=O)c[nH]c2c1
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Product: CCc1ccc2c(CCNC(C)=O)c(C(C3=C(O)C(c4ccccc4)CC3=O)c3ccccc3)[nH]c2c1

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and N-[2-(6-ethyl-1H-indol-3-yl)-ethyl]-acetamide to give N-(2-{6-ethyl-2-[(2-hydroxy-5-oxo-3-phenyl-cyclopent-1-enyl)-phenyl-methyl]-1H-indol-3-yl}-ethyl)-acetamide as a pale brown solid. MS: 493.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.B(Br)(Br)[Br:18].O>C(Cl)Cl>[Br:18][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrB(Br)Br
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15.14 g (59.3 mmol) of bis(4-chlorophenyl)methanol in 100 mL of methylene chloride was added slowly a solution of 71.2 mL of BBr3 (71.2 mmol, 1M in CH2Cl2). The solution was stirred for at 0° C. for 1 h. Then 60 mL of water was added to quench the reaction and the reaction mixture was poured into 200 mL of methylene chloride. The water layer was extracted with methylene chloride (60 mL×2) and the combined organic layer was dried over Na2SO4 and concentrated to give the title compound; 1NMR (CDCl3) δ 6.24 (s, 1H), 7.36 (d, 4H, J=8.7 Hz), 7.41 (d, 2H, J=8.7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C@@H:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:11]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:39]([NH3+:43])[CH:40]([CH3:42])[CH3:41].C([BH3-])#N.[Na+]>CO>[CH2:39]([NH:43][CH2:11][C@@H:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)C[NH3+]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](C=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CNC[C@@H](OCc1ccccc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A solution of (S)-3-t-butoxycarbonylamino-(R)-2-benzyloxy-4-cyclohexylbutyraldehyde (600 mg.) and isobutylammonium p-toluenesulfonate (510 mg.) were stirred together in methanol for 30 minutes at 20° C. and then treated in one portion with sodium cyanoborohydride (105 mg.). After 45 minutes 28 mg. more sodium cyanoborohydride was added and 30 minutes later the mixture was filtered through Celite, concentrated, the residue dissolved in ethyl acetate which was washed twice with aqueous bicarbonate, brine and dried over sodium sulfate. After solvent removal 600 mg. (87%) of the title amine was obtained which was used without additional purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[NH:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH2:18]>C1(C)C(C)=CC=CC=1>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([N:17]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]3=[N:18]2)[CH:20]=1
Reactant: NNc1cnc2ccccc2c1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Solvent: Cc1ccccc1C
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1cnc2ccccc2c1
Reaction time: 16 h

Procedure:
A solution of 11.8 g of ethyl 4-chloroquinoline-3-carboxylate and 8.7 g of 3-hydrazinoquinoline is refluxed for 51/2 hours in 300 ml of xylene. The reaction mixture is allowed to stand for 16 hours at 23°. The solvent is decanted from an oily solid. This solid is slurried twice in 80 ml of xylene, the solvent is decanted and the residue is stirried for 1 hour in 150 ml of IN sodium hydroxide, 150 ml of water and 220 ml of xylene. The mixture is filtered, the aqueous layer is separated and 12 g of ammonium chloride is added while stirring. The resulting slurry is heated on the steam bath for one hour, allowed to cool down to 30° and then filtered. The solid is washed three times with water, twice with ether-acetone (2:1) and twice with ether. Recrystallization from dimethylformamide gives 2-(3-quinolyl)pyrazolo[4,3-c]quinolin-3(5H)-one, m.p. above 350°; IR (KBr) 802, 852, 858, 882, 895 cm-1.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([OH:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32]>C(Cl)Cl>[CH3:8][S:9]([O:33][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Et3N (1.50 mL, 10.8 mmol) and methanesulfonyl chloride (402 μL, 5.20 mmol) was added to a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol (1.15 g, 4.0 mmol) in CH2Cl2 (40 mL) held at 0° C. under nitrogen. The mixture was stirred at 0° C. for one hour, and poured into ice-water (100 g) and the water phase extracted with Et2O (50 mL). The combined organic extracts were added 0.5 M H2SO4 (35 mL), the organic phase washed with NaHCO3 (sat. aq.) (25 mL), before dried (Mg2SO4, gram). Filtration and concentration in vacuo afforded 1.24 gram of crude oil. Purification on Armen, SVP D26 column packed with 30 gram of 15-40 μm Merck silica, flow 20 mL/min, UV 210 nm and collecting 15 mL fraction, was performed using gradient elution: (starting heptane:EtOAc (100:0) and increasing during 10 min. to 10% EtOAc, then increasing 5 min. to 20% EtOAc (hold 10 min.), then increasing in 5 min. to 40% EtOAc (hold 0 min.). Fractions 6-14 afforded 1.16 g (79% yield) of the title compound as oil.
Reaction SMILES: [Cl-].[NH4+:2].[CH3:3][O:4][N:5]=[C:6]([C:9]#[N:10])[C:7]#[N:8].[CH2:11]([OH:13])[CH3:12]>N>[C:11]([O-:4])(=[O:13])[CH3:12].[C:7]([C:6](=[N:5][O:4][CH3:3])[C:9]([NH2:2])=[NH2+:10])#[N:8]
Reactant: CON=C(C#N)C#N
Reactant: [NH4+]
Reactant: CCO
Agent: N
Agent: [Cl-]
Product: CC(=O)[O-]
Product: CON=C(C#N)C(N)=[NH2+]
Reaction time: 24 h

Procedure:
To a solution of ammonium chloride (28.4 g 0.53 mole) in 28% aqueous ammonia (355 ml) and ethanol (180 ml) was added dropwise a solution of 2-methoxyiminopropanedinitrile (58.0 g, 0.53 mole) in ethanol (120 ml) at -15° to -10° C. over a period of 30 minutes, with stirring. The mixture was stirred at -10° C. overnight and then at ambient temperature (20°-25° C.) for one day. The reaction mixture was partitioned between water (350 ml) and CH2Cl2 (350 ml), and the aqueous phase was saturated with sodium chloride, and extracted again with CH2Cl2 (300 ml). The organic extracts were combined, dried over MgSO4 and evaporated in vacuo. A solution of the residue in ethyl acetate (1.6 L) was adjusted to pH 3-4 with acetic acid to precipitate the title compound as crystals, which were collected by filtration and washed with ethyl acetate. Yield 67.6 g (69%). M.p. 152°-4° C. (dec.). [Lit., m.p. 150°-155° C. (dec.)].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C(O)(=O)C(O)=O>C(O)(=O)C.O>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COc1ccc(CO)cc1
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)cc1

Procedure:
4,6-Di-t-butyl-2-(4-methoxybenzyl) phenol was prepared as follows: A solution of 2,4-di-t-butylphenol (57.5 g), 4-methoxybenzyl alcohol (34.5 g) and oxalic acid (2 g) in acetic acid (80 ml) and water (2 ml) was refluxed for 7 hours, diluted with water, and extracted with chloroform. Distillation of the chloroform extract gave an oil (b.p. 200°-210° C. at 2 mm Hg) which crystallized (58 g; 71.4%). The product was recrystallized from methanol to give glistening colorless needles, m.p. 84°-85°; (Found: C, 81.0; H, 9.21. Calc. for C22H30O2 : C, 80.9; H, 9.26%). The pmr spectrum exhibited the following: δ1.30, 9H, S; δ1.38, 9H, S; δ3.79, 3H, S; δ3.83, 2H, S; δ4.62, 1H, S; δ6.84, 2H, D (J=8 Hz); δ7.02, 1H, D (J=2 Hz); δ7.14, 2H, D (J=8 Hz); δ7.23, 1H, D (J=Hz).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.[OH-].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25]Br)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>C(Cl)Cl.C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:5]2[CH2:4][CH2:3][OH:2])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: OCCC1CCCCCN1
Reactant: COc1ccc(CCBr)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCCCCC2CCO)cc1OC

Procedure:
2.9 g (0.016 mol) of 2-(2-hydroxyethyl)-hexahydro-azepinehydrochloride are liberated with concentrated sodium hydroxide solution, taken up in methylene chloride and, after drying, evaporated down over magnesium sulphate. The residue is refluxed for 2 hours with 3.9 g (0.016 mol) of 2-(3,4-dimethoxy-phenyl)ethylbromide in 10 ml of triethylamine. After cooling, the reaction mixture is combined with 2 molar sodium hydroxide solution/methylene chloride. The alkaline phase is separated off and extracted twice with methylene chloride and the combined organic phases are dried over magnesium sulphate. The solvent is distilled off in vacuo and the residue is purified by column chromatography over aluminium oxide N (activity II, eluant: methylene chloride). Yield: 3.7 g (75.2% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:41][O:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45].C1COCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:44](=[O:45])[C:43]([O:42][CH3:41])([CH3:48])[CH3:47])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(C)(C)C(=O)Cl
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)C(C)(C)OC)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 295 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 6.6 mL of DCM was added 1.4 mL of NEt3, 81 mg of DMAP and 0.8 mL of 2-methoxy-2-methyl propanoyl chloride (prepared as in JOC, 1976, 41, 19, 3182-3187) at 0° C. The reaction mixture was allowed to warm up to rt and stirred for 5 min at rt before 0.3 mL of anh. THF was added. The reaction mixture was stirred overnight at 50° C., extracted with DCM and washed with sat. NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The crude product was purified by CC using DCM/MeOH/DIPEA 95/5/1 to yield 214 mg of rac-2-methoxy-2-methyl-propionic acid (1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as white foam.
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH:10]([C:17]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[O:18][C:17]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(NC(=O)C1CCCCC1)C(=O)c1ccco1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(C2CCCCC2)oc1-c1ccco1
Yield: 69.9 %

Procedure:
5.0 g of ethyl 3-cyclohexylcarbonylamino-3-(2-furylcarbonyl)propionate, 30 ml of chloroform and 16.0 g of phosphorus oxychloride are treated in the same manner as described in Example 2. 3.3 g of ethyl 2-[2-cyclohexyl-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained as an oil. Yield: 70.0%
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:41]=[CH:40][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[S:36](=[O:38])(=[O:37])[NH:35][C:34](=[O:39])[CH2:33]5)=[CH:28][CH:27]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:42]1([OH:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH:42]1([O:48][C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[CH:28][C:29]([N:32]6[S:36](=[O:38])(=[O:37])[NH:35][C:34](=[O:39])[CH2:33]6)=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:40][CH:41]=3)=[CH:4][CH:3]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: OC1CCCCC1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nc4)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OC5CCCCC5)nc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-[4-(6-Chloro-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (63 mg, 0.1 mmol) was treated as described in general procedure L using cyclohexanol (20 mg, 0.2 mmol) to give 5-{4-[2-[4-(6-cyclohexyloxy-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:14][CH:13]2[C:35]([O:37]C(C)(C)C)=[O:36])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[CH2:14][CH:13]2[C:35]([OH:37])=[O:36])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3cccc(C(F)(F)F)c3)CC2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3cccc(C(F)(F)F)c3)CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A mixture of 0.36 g (0.61 mmol) of 4-(4-methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, tert-butyl ester and 3 ml of trifluoroacetic acid in 3 ml of CH2Cl2 was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under vacuum and the residue extracted with CH2Cl2. The CH2Cl2 was washed with 1 N NaHCO3 and the aqueous layer (pH 8) was acidified with 2 N citric acid and extracted with ethyl acetate. The extract was dried (Na2SO4). The original CH2Cl2 extract was washed with 2 N citric acid, H2O, brine and dried with Na2SO4. The CH2Cl2 extract and the ethyl acetate extract were combined and the solvent removed under vacuum to give 0.31 g of solid, m.p. 105-110° C. Anal. for C25H21F3N2O6S: Calc'd: C,56.2; H,4.0; N,5.2; Found: C,55.1; H,3.7; N,5.0.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>ClCCl>[CH2:27]([O:26][C:24]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:5][CH2:6]1)=[O:25])[CH3:28]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CC=C(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h
Yield: 76.6 %

Procedure:
5 g of 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole prepared in Example 1 (part A) were dissolved in 25 mL of dichloromethane and 3.22 g of triethylamine were added to the solution. Keeping the temperature between 20 and 25° C., 3.14 g of ethyl chloroformate were added dropwise. The mixture was stirred for 2 hours and 20 mL of water were added. The organic layer was separated and the solvent was was removed under reduced pressure affording 5.22 g of a colourless oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:60])([C:54]([CH3:59])([CH3:58])[CH:55]([CH3:57])[CH3:56])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[O:28])[CH2:14][CH2:13][C@H:12]([CH2:29][O:30]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][O:10][C:9](=[O:50])[C:8]=2[C:7]([CH3:51])=[C:6]([O:52][CH3:53])[CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:60][Si:2]([CH3:1])([C:54]([CH3:58])([CH3:59])[CH:55]([CH3:56])[CH3:57])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[O:28])[CH2:14][CH2:13][C@H:12]([CH2:29][OH:30])[CH2:11][O:10][C:9](=[O:50])[C:8]=2[C:7]([CH3:51])=[C:6]([O:52][CH3:53])[CH:5]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)CCC(=O)N[C@H](c1nc(C)no1)CSC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](CO)CCC(=O)N[C@H](c1nc(C)no1)CSC2

Procedure:
(4R,9R)-16-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-9-trityloxymethyl-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione was treated with 4-toluenesulfonic acid monohydrate in methanol at 20° C. for 30 min to yield (4R,9R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-9-hydroxymethyl-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin6,12-dione as a white foam.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][OH:5].[H-].[Na+].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>C1COCC1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][O:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: COC(CO)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(COCC(OC)OC)OCC
Temperature: 25 °C

Procedure:
To a solution of glycolaldehyde dimethyl acetal (25 g, 236 mmol) in 750 mL of THF at 0° C. was added portionwise 14.1 g (353 mmol) of a 60% suspension of NaH in oil. The solution was warmed to room temperature, and then to 60° C. overnight. After cooling to room temperature, and then to 0° C., 69.9 g (353 mmol) of bromoacetaldehyde diethyl acetal in 200 mL of THF was added dropwise over 30 minutes. The reaction was warmed to room temperature, and then to reflux for 2 days. The reaction was cooled to room temperature, filtered through a pad of celite, and concentrated by rotary evaporation while keeping the bath temperature below 40° C. The residue was purified by column chromatography on silica gel (0 to 30% EtOAc in hexanes) to provide C-1 as a yellow oil. Data for C-1:1 H NMR (CDCl3, 500 MHz) δ 4.65 (m, 1H), 4.5 (m, 1H), 3.7 (m, 2H), 3.55 (m, 6H), 3.4 (s, 6H), 1.2 (M, 6H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:5])[CH3:2].[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH2:21])[CH3:17].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=[O:15])[NH:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:16][CH3:17])=[O:5])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN(CC)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 908.2 %

Procedure:
A stirred solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (2.11 g, 10 mmol) in N,N-dimethylformamide (5 ml) and dichloromethane (50 ml) was added with N1,N1-diethylethane-1,2-diamine (1.23 g, 11 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (5 g, 26 mmol) and 1-hydroxybenzotriazol (1.5 g, 11 mmol) in an ice-water bath. Upon completion of the addition, the mixture was stirred at room temperature overnight, added with cold water (50 ml), extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated sodium bicarbonate (50 ml), water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (28.1 g, 90.9%) as a colorless oil.