Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([O:38]CC2C=CC=CC=2)=[O:37])=[CH:32][CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C(=O)O)cc1
Yield: 88 %

Procedure:
Next, 1.40 g (2.22 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[4-(benzyloxycarbonyl)phenyl(methyl)phosphono]butanoate was dissolved in 28 mL of a solvent mixture of acetic acid and water at 2:1 and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced at room temperature for 2.2 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated, and the residue was freeze-dried from water to obtain 2-amino-4-[4-carboxyphenyl(methyl)phosphono]butanoic acid (0.62 g, yield 89%) as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.Cl[C:24]1[C:29]([O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:28][CH:27]=[CH:26][N:25]=1>CC(N(C)C)=O>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([CH:11]3[CH2:12][N:9]([C:24]4[C:29]([O:30][CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[N:28][CH:27]=[CH:26][N:25]=4)[CH2:10]3)=[N:14][C:15]=2[CH:21]=1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: Clc1nccnc1OC1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Clc1ccc2[nH]c(C3CN(c4nccnc4OC4CCOCC4)C3)nc2c1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
A mixture of cesium carbonate (0.63 g, 1.94 mmol), 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride (as described in Preparation 5) (0.14 g, 0.49 mmol), and 2-chloro-3-(tetrahydro-2H-pyran-4-yloxy)pyrazine (0.10 g, 0.49 mmol) in DMA (1 mL) was heated to 100° C. for 16 h, then cooled to RT. The resulting suspension was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed with water (2×), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 5-chloro-2-(1-(3-(tetrahydro-2H-pyran-4-yloxy)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.16 g, 0.40 mmol, 83% yield) as a white solid. [M+1] 386. IC50 (uM) 0.9004.
Reaction SMILES: CO[C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Mg]Br.[C:20](=[O:23])(O)[O-].[Na+].Cl>C1COCC1>[O:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:23][CH3:20])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH3:10])[OH:4]
Reactant: O=C([O-])O
Reactant: COc1ccccc1[Mg]Br
Reactant: COC(=O)c1ccco1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)(c1ccco1)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
Methyl-2-furoate (1.58 g, 0.0125 mol) was dissolved in 100 mL of dry THF. A dropping funnel containing 50 mL of a 0.5 M solution of 2-methoxyphenylmagnesium bromide in THF (Aldrich) was attached to the reaction flask and the system was purged with argon. The reaction flask was submerged in an ice bath for 5 minutes, at which time the Grignard solution was added drop-wise over 15 minutes. After addition was complete, the reaction was allowed to warm to room temperature and was stirred overnight. A brown solution resulted. This solution was added to 150 g crushed ice and the slush was stirred with ˜0.5 g sodium bicarbonate during drop-wise addition of conc. HCl. A lavender color was observed upon addition of acid, which was continued until effervescence was observed. The resulting neutral suspension was extracted into ˜400 mL EtOAc and the organic layer was dried over MgSO4. Removal of solvent in vacuo gave a clear/yellow oil. The oil was purified by silica gel column chromatography and the product eluted using a 50:50 (vol:vol) mixture of EtOAc:hexanes. The purified product was evaporated to a solid gum yielding 3.1 grams/82% yield. The product was characterized by HPLC, 1H NMR, and FAB mass spectroscopy FAB+311 m/e.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([C:11]1C(C(C)C2C=CC=CC=2)=C(C)C(C)=CC=1)[C:5]1C=CC=C[CH:6]=1.[CH3:27][CH:28]([CH:35]([CH:43]([CH3:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1C=CC=CC=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH2:51]=[CH:52][C:53]1C=CC=[CH:55][CH:54]=1>>[CH:29]1([CH:28]([C:35]2([CH:43]([CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[CH3:50])[CH2:36][CH2:37][C:4]([CH3:11])([CH3:3])[CH2:5][CH2:6]2)[CH3:27])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[CH:44]1([CH:43]([C:35]2([CH:28]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH3:27])[CH2:36][CH2:37][CH:53]([CH2:54][CH3:55])[CH2:52][CH2:51]2)[CH3:50])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccc(C(C)c2ccccc2)c(C(C)c2ccccc2)c1C
Reactant: CC(c1ccccc1)C(Cc1ccccc1)C(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C1CCCCC1)C1(C(C)C2CCCCC2)CCC(C)(C)CC1
Product: CCC1CCC(C(C)C2CCCCC2)(C(C)C2CCCCC2)CC1
Temperature: 14 °C

Procedure:
Twenty-one (21) Kl/hr of the distillate (a mixture of α-methylbenzylxylene and α-methylbenzylethylbenzene) boiling in the range of 300°-319° C. obtained in Example 2, 0.1 Kl/hr of styrene and 0.4 Kl/hr of sulphuric acid (92%) were supplied into a 17-Kl reactor (average residence time: about 48 minutes) and so cooled from outside as to maintain the reaction temperature at 14° C. The resulting effluent from the autoclave was allowed to stand still thereby to separate the lower layer (sulphuric acid) for re-circulation and obtain the upper layer (oil layer). The upper layer so obtained was neutralized with an aqueous solution of sodium hydroxide, washed with water and distilled to recover the unreacted α-methylbenzylxylene/α-methylbenzylethylbenzene mixture for re-circulation and then obtain 270 Kg/hr of a distillate boiling in the range of 193°-220° C. at 3 mm Hg. This distillate was found to be a mixture corresponding to the bis-(α-methylbenzyl) xylene/bis-(α-methylbenzyl) ethylbenzene mixture (9:1) obtained in Example 4. As the residue (after the distillation), 3 Kg/hr of styrene polymers was obtained. Thus, it was found that 95% of the styrene was consumed for the alkylation. Four hundred (400) grams of the aforesaid distillate boiling in the range of 193°-220° C. at 3 mm Hg were hydrogenated to obtain 440 cc of a bis-(α-cyclohexylethyl) dimethylcyclohexane/bis-(α-cyclohexylethyl) ethylcyclohexane mixture (traction fluid (II) of this invention) having a specific gravity (15/4° C.) of 0.90, a refractive index (nD20) of 1.490, a kinetic viscosity of 10.9 cSt (98.9° C.), and a traction coefficient of 0.093 (25° C.) or 0.075 (80° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([OH:17])(=O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([Cl:20])(=[O:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NCCS(=O)(=O)O)OCc1ccccc1
Product: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of taurine (12.5 g, 100 mmol), benzyl chloroformate (15.1 mL, 105 mmol) and sodium carbonate (10.6 g, 100 mmol) in water (250 mL) was stirred at room temperature for overnight. The product mixture was extracted with diethyl ether. The organic extract was concentrated under vacuum to provide 2-{[(benzyloxy)carbonyl]-amino}ethanesulfonic acid. Without further purification, the sulfonic acid was treated with thionyl chloride (15 mL, 206 mmol) with external ice-water bath cooling. The resultant mixture was stirred at room temperature for 1 hour, and poured into ice water. The mixture was extracted with diethyl ether. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16](I)[CH:15]=1.[CH3:23][OH:24].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN([CH:64]=[O:65])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:15]=1)[C:23]([O:65][CH3:64])=[O:24])=[O:22]
Reactant: CO
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2F)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)Nc2cc(C(F)(F)F)ccc2F)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stainless steel cylinder equipped with a glass liner was charged with N-(2-fluoro-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide 34 (1.089 g, 2.57 mmol), methanol (20 mL), and a magnetic stir bar. Argon gas was bubbled through this solution for one minute, and then triethylamine (0.358 ml, 2.57 mmol), 1,3-bis(diphenylphosphino)propane (0.0584 g, 0.142 mmol), and palladium(II) acetate (0.0289 g, 0.129 mmol) were added. The cylinder was sealed, charged to 200 psi of CO gas, placed into an oil bath at 75° C. and stirred for 2 hours. The reaction was cooled to room temperature, and palladium(II) acetate (0.0289 g, 0.129 mmol), DMF (2 mL), 1,3-bis(diphenylphosphino)propane (0.0584 g, 0.142 mmol), and triethylamine (0.358 ml, 2.57 mmol) were added. The cylinder was sealed, charged to 200 psi of CO gas, placed into an oil bath at 75° C. and stirred 48 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromoatography on silica gel (gradient elution 0 to 100% ethylacetate in hexane) to afford methyl 5-((2-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-2-methylbenzoate 35 as pale yellow solid. MS m/z found 356 [MH+]; calc. for C17H13F4NO3=355.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.C(O)C.C(O[CH:27](OCC)[N:28]([CH3:30])[CH3:29])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9](=[CH:27][N:28]([CH3:30])[CH3:29])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Solvent: CCO
Product: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Temperature: 130 °C

Procedure:
A suspension of 50 gm of 7-chloro-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 100 ml of N,N-dimethyl-formamide diethylacetal was heated to 130°C in a vessel equipped with a descending condenser, whereby a clear solution was formed after a short time. The temperature of the reaction solution was maintained at 130°C for 40 minutes, during which time the ethanol formed by the reaction slowly distilled over. Thereafter, the reaction solution was allowed to cool, and the red precipitate was collected by vacuum filtration, washed with petroleum ether and recrystallized from methanol, whereupon it had a melting point of 239°-241°C. It was identified to be the compound of the formula ##SPC6##
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:23]2[O:24][C:25]([CH3:26])=[C:21]([CH2:20][N:11]3[C:12]4[C:8](=[CH:7][C:6]([CH2:5][C@H:4]([O:15][CH2:16][CH3:17])[C:3]([OH:2])=[O:18])=[CH:14][CH:13]=4)[CH:9]=[CH:10]3)[N:22]=2)[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=1
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3cc(OC)cc(OC)c3)oc2C)c1)C(=O)O
Yield: 43 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole, the title compound was obtained in 43% yield as a pale red solid. MS: (M−H)− 463.2.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]>CO.[Pd]>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)#[N:3]
Reactant: N#Cc1ccc(-c2cccc3cncn23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 54 mg of 5-(p-cyanophenyl)imidazo[1,5-a]pyridine hydrochloride in 5.0 ml methanol is hydrogenated at room temperature and atmospheric pressure for 30 min with 0.1 g of 10% palladium on charcoal. The catalyst is filtered and 0.21 ml of 1N sodium hydroxide is added. The filtrate is evaporated, taken up in 10 ml of methylene chloride and filtered through Celite®. Evaporation yields an oil which is chromatographed on silica gel with ethyl acetate to yield the title compound, m.p. 117°-118°.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[OH:16][C:17]1[CH:41]=[CH:40][C:20]([C:21]([NH:23][CH2:24][C@H:25]([N:30]2[CH2:35][CH2:34][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[C:26]([O:28][CH3:29])=[O:27])=[O:22])=[CH:19][CH:18]=1>CN(C)C=O>[CH3:39][S:36]([N:33]1[CH2:32][CH2:31][N:30]([C@@H:25]([CH2:24][NH:23][C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:41][CH:40]=2)[C:26]([O:28][CH3:29])=[O:27])[CH2:35][CH2:34]1)(=[O:37])=[O:38]
Reactant: ClCc1ccncc1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCc2ccncc2)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
1 g (3.2 mmol) of caesium carbonate and 280 mg (1.7 mmol) of 4-chloromethylpyridine hydrochloride are added to a solution of 560 mg (1.4 mmol) of methyl (S)-3-(4-hydroxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoate (prepared as described in example 4-4) diluted in 20 ml of dimethylformamide. The reaction medium is stirred at 80° C. for 24 h. The reaction medium is cooled, hydrolysed and extracted with ethyl acetate. The organic phase is washed once with water and once with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product is purified by chromatography over silica gel eluted with a 30/70 heptane/ethyl acetate mixture+10% methanol. 430 mg (62%) of methyl (S)-2-(4-methane-sulphonylpiperazin-1-yl)-3-[4-(pyridin-4-ylmethoxy)-benzoylamino]propanoate are obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].O>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:3]=1
Reactant: CCC(=O)Cl
Reactant: CNc1c(N)cc(Br)nc1Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1cc(Br)nc(Cl)c1NC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-bromo-2-chloro-N3-methylpyridine-3,4-diamine 2.59 (410 mg, 2.74 mmol) was dissolved in pyridine (10 mL). Mixture was cooled down to 0° C. and then propanoyl chloride (207 mg) was added portion wise. Mixture was stirred at 0° C. for 1 h. Reaction mixture was poured into water and extracted with ethyl acetate. Organic phase was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Resulting residues were purified by silica gel chromatography (5% MeOH in DCM) to provide N-(6-bromo-2-chloro-3-(methylamino)pyridin-4-yl)propionamide (2.78). LC/MS found for C9H11BrClN3O as (M+H)+ 291.9.
Reaction SMILES: C[Si](C)(C)C1C=C(Br)C=C([Si](C)(C)C)C=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].S(Cl)([Cl:33])=O>CN(C)C=O.C(Cl)Cl.C(C1C=CC(CCC(O)=O)=CC=1)(C)(C)C>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([Cl:33])=[O:30])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(CCC(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: C[Si](C)(C)c1cc(Br)cc([Si](C)(C)C)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CCC(=O)Cl)cc1
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A 2 L 3 neck round bottom flask fit with a condenser, thermometer, nitrogen inlet, and overhead stirrer was charged with 3-(4-t-butylphenyl)propionic acid (118.7 g, 0.576 mol),thionyl chloride (210 mL, 2.88 mol), dimethylformamide (3 drops), and methylene chloride solvent. The reaction was refluxed for 3 hours and additional 3-(4-t-butylphenyl)propionic acid (8.17 g, 0.040 mol) was added to the reactor and refluxed for an additional hour. After allowing to stand overnight, the reaction was stripped of volatiles to yield the crude 3-(4-t-butylphenyl)propionyl chloride (99.0 g). 1HNMR (CDCl3, 500 MHz) δ7.33 (d, JAB=8 Hz, 2H); 7.12 (d, JAB=8 Hz, 2H); 3.20 (t, J=7.5 Hz, 2H); 2.98 (t, J=7.5, 2H); 1.31 (s, 9H).
Reaction SMILES: COC(=O)C.[CH2:6]([O:8][C:9](=[O:24])[CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19](Cl)(=O)=O)=[CH:14][C:13]=1[CH3:23])[CH3:7].S(=O)(=O)(O)O>C(O)C>[CH2:6]([O:8][C:9](=[O:24])[CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([SH:19])=[CH:14][C:13]=1[CH3:23])[CH3:7]
Reactant: CCOC(=O)COc1cc(C)c(S(=O)(=O)Cl)cc1C
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: COC(C)=O
Product: CCOC(=O)COc1cc(C)c(S)cc1C

Procedure:
(4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester was prepared as described for 2,6-difluoro-4-mercapto-phenoxy)acetic acid methyl ester (compound 21) in Eur. J. Med. Chem., 1995, 30, 403 (Kawashima, M. S.) except that (4-chlorosulfonyl-2,5-dimethyl-phenoxy)acetic acid ethyl ester was reduced with 4 eq. of zn (dust) in a mixture of konc. sulfuric acid and ethanol at 80° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:5]=2[CH:4]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[ClH:18].[Cl:18][C:17]1[C:5]2[CH:4]=[C:3]([CH2:2][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccc2c1C=C(CBr)c1ccccc1O2
Reactant: C1CCNC1
Product: Cl
Product: Clc1cccc2c1C=C(CN1CCCC1)c1ccccc1O2
Yield: 51 %

Procedure:
Preparation analogous to Example 2 from 10-bromomethyl-1-chloro-dibenz[b,f]oxepine with pyrrolidine. Yield: 51%, yellow foam; melting point: not determined, (yellow foam); 1H-NMR (CDCl3, 200 MHz): 1.78 (m, 4H); 2.65 (m, 4H); 3.65 (s, 2H); 7.10-7.45 (m, 7H) 7.68 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][N:28]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: COCC(=O)Cl
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNC2)C[C@H]1c1ccc(Cl)cc1
Product: COCC(=O)N1CCC(C(=O)N2C[C@@H](N(C)C(=O)Oc3ccc(F)cc3)[C@H](c3ccc(Cl)cc3)C2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 73, the title [(3S,4R)-4-(4-chloro-phenyl)-1-(1-(2-methoxy-acetyl)-pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-1-(pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using methoxyacetyl chloride instead of propionyl chloride and was obtained as a light yellow oil. MS m/e: 518.3 [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([C:33](O)=O)[N:24]=2)=[CH:19][CH:18]=1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:37])([F:36])[F:15])=[CH:18][CH:19]=2)[N:24]=[C:25]([C:33]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=3)[N:14]=2)[N:26]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)cc1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.75 mmol) and 4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.026 g, 10%). MS (ISN) 514.2 [(M−H)−]; mp 302° C.
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11][NH2:12].[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>>[Cl:13][CH2:14][CH2:15][NH:16][C:17]([N:12]([CH3:11])[CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4])=[O:18]
Reactant: O=C=NCCCl
Reactant: CN
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Product: CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 74.5 %

Procedure:
3.0 g of D-ribose, 1.0 g of methylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 1-(1). 4.0 g of 1-(2-chloroethyl)-3-methyl-3-D-ribofuranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[NH2:16][NH2:17].[N:18]([O-])=O.[Na+].Cl>C(O)C>[NH:16]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[N:2][N:18]=[N:17]1
Reactant: NN
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 48 h

Procedure:
First, 26.9 mmol of 2-cyano-4'-methyl-1,1'-biphenyl was dissolved in 150 ml of ethanol, and 270 mmol of hydrazine and 77.7 mmol of 28% methylate were added thereto, followed by keeping at 50° C. for 48 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethanol, and 55 mmol of sodium nitrite and 110 mmol of concentrated hydrochloric acid were added to the solution at 0° C. After keeping at 0°-5° C. for 2 hours, the reaction mixture was concentrated to give 2-(tetrazol-5-yl)-4'-methyl-1,1'-biphenyl. Yield, 46%