Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[O:14][C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=1)=[CH:12][C:11]2=[O:34])=[O:5])C.C1COCC1.[OH-].[Li+].Cl>CO>[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[O:14][C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=1)=[CH:12][C:11]2=[O:34])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc2c(=O)cc(-c3ccc(OCc4ccc5ccccc5n4)cc3)oc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c(=O)cc(-c3ccc(OCc4ccc5ccccc5n4)cc3)oc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
8-Ethoxycarbonyl-4'-(2-quinolinylmethoxy)flavone was dissolved in a mixed solvent of methanol:THF:5% aqueous solution of lithium hydroxide (1:1:1 V/V), followed by stirring at room temperature for 2 days. The reaction mixture was acidified with 3 N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and methanol, and then recrystallized from DMF, whereby the title compound represented by the following formula was obtained (yield: 89%). ##STR31##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C@H:11]([NH:13][S@](C(C)(C)C)=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CC(S(OC)=O)(C)C>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C@H:11]([NH2:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H](CCc1ccc(Cl)c(Cl)c1)N[S@@](=O)C(C)(C)C
Agent: COS(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 195 %

Procedure:
(S)-N-((R)-4-(3,4-Dichlorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (600 mg, 1.862 mmol) was stirred in MeOH (10 mL) at rt. 4N HCl in dioxane (5 mL) was added. The resulting mixture was stirred at rt for 20 min. The solvents were evaporated and CH2Cl2 (3×) was added and evaporated. The resulting white solids were vacuum dried for 5 h to give (R)-4-(3,4-dichlorophenyl)butan-2-amine hydrochloride (462 mg, 1.815 mmol, 97% yield) as off-white solids and methyl 2-methylpropane-2-sulfinate. The HCl salt was used without further purification. LC-MS (ESI) m/z 218.0 (M+H), RT=1.61 min (Method B).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Br:15]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:15][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH:4]=1
Reactant: CC(C)(C)C(=O)Oc1ccccc1O
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cc(Br)ccc1O
Yield: 97 %

Procedure:
2,2 dimethylpropionic acid 2-hydroxyphenylester (6 g) was dissolved in dichloromethane and bromine (4 ml) was added slowly at 0° C. Then, the blended solution was reacted for 30 minutes at −75° C. After completing the reaction, sodium thiosulfate was added to remove bromine, water was added to dilute, and extracted with ethylacetate. A resulting organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. As a result, the present compound (2.2 g, productive yield 97%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O>[CH:21]1([C:2]2[C:3]3[N:4]([CH:18]=[CH:19][N:20]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:7]=2)[CH2:23][CH2:22]1
Reactant: FC(F)(F)c1ccc(-c2cc(Br)c3nccn3c2)cc1
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)c3nccn3c2)cc1
Yield: 66.5 %

Procedure:
To a Schlenk flask was added 8-bromo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.25 step 3) (3.026 g, 8.9 mmol), cyclopropyl boronic acid (103 mg, 13 mmol), tri(cyclohexyl)phosphine (101 mg, 4 mol %), potassium phosphate (6.53 g, 31 mmol), 50 mL of toluene and 2.5 mL of water. The reaction mixture was degassed under Ar for 5 min, then palladium acetate (41 mg, 2 mol %) was added and continued to bubble in Ar, then placed into a 100° C. oil bath for 23 h. The cooled reaction mixture was decanted and filtered through a pad of celite/Si Gel, washed aqueous material with EtOAc and combined organic layers were concentrated to give a green-colored mixture. This residue was purified by silica gel column chromatography with heptane/EtOAc followed by trituration with heptane and very little ether to give the title compound as a green solid (1.79 g, 67%). MS (ISP) 303.1 [(M+H)+].
Reaction SMILES: [OH-].[K+].[C:3]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1>CN(C)C=O>[CH2:6]([O:5][C:3]([C:8]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:4])[CH3:7]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCOC(=O)C(C)c1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(CC2(C(=O)OCC)CCCC2=O)cc1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To 200 ml of dimethyl formamide containing 6.0 g of potassium hydroxide was added 15.6 g of 2-carboethoxycyclopentanone with stirring at room temperature to give a homogeneous solution. Under ice-cooling, 25 g of ethyl 2-(p-chloromethylphenyl)propionate was added dropwise thereto, and the mixture was heated at 80° C. with stirring for 2 hours. After completion of the reaction, the reaction mixture was poured into an ice-water, extracted with ether, the extract washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give 28 g of an oily substance, which was subjected to a vacuum distillation affording 21 g of the desired compound, b.p. 175°-178° C. at 0.5 mm Hg.
Reaction SMILES: [C:1]([CH:4]([C:9](=O)[CH3:10])[CH2:5][C:6]([OH:8])=[O:7])(=O)[CH3:2].[CH:12]1[C:17]([NH:18][NH2:19])=[CH:16][CH:15]=[C:14]([Cl:20])[CH:13]=1.OS(O)(=O)=O.C([O-])(=O)C.[Na+]>C([O-])(=O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([OH:8])=[O:7])=[C:9]([CH3:10])[N:18]([C:17]2[CH:16]=[CH:15][C:14]([Cl:20])=[CH:13][CH:12]=2)[N:19]=1
Reactant: CC(=O)C(CC(=O)O)C(C)=O
Reactant: NNc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nn(-c2ccc(Cl)cc2)c(C)c1CC(=O)O
Temperature: 60 °C
Yield: 102 %

Procedure:
4.0 grams 3,3-diacetyl-propionic acid, 4.9 grams p-chlorophenylhydrazine-sulfate, 2.1 grams anhydrous sodium acetate and 30 milliliters glacial acetate acid were mixed and the mixture was heated to 60° C. for 3 hours. The reaction mixture was evaporated and water was added to the residue. The precipitate formed thereby was separated by filtration and recrystallized from a mixture of ethanol and of water. 5.5 grams 3,5-dimethyl-1-(p-chlorophenyl)-pyrazol-4-acetic acid, melting at 176°-177° C., were obtained, representing a yield of 82%.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C@@H:11]([CH3:25])[CH2:10][C@H:9]2[N:26]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:27](=[O:30])[CH2:28][CH3:29].[OH-].[Na+]>CO>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([N:26]([C:27](=[O:30])[CH2:28][CH3:29])[C@H:9]2[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])[CH:7]=3)[N:12]([C:16](=[O:24])[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@@H:11]([CH3:25])[CH2:10]2)=[CH:36][CH:35]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(=O)O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
(±)-Cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid was prepared from (±)-cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid methyl ester. To a solution of (±)-cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid methyl ester (83 mg, 0.155 mmol) in methanol (3 mL) was added sodium hydroxide (1 M in water, 310 uL, 0.310 mmol). The reaction was stirred at room temperature 3 h and concentrated under reduced pressure to remove methanol. The pH of the remaining aqueous solution was adjusted to 6 with 1 M hydrochloric acid. The suspension was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the carboxylic acid (76 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11]O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[Cl:24]CCl>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11][Cl:24])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: ClCCl
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CO)C(=O)OC
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CCl)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(S)-dimethyl 2-((7-bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (2.25 g, 5.8 mmol) was dissolved in 2M thionyl chloride in dichloromethane (42 mL, 84 mmol). Reaction stirred at room temperature for 2.0 hours. Mixture was concentrated. Residue was treated with toluene and then concentrated by roto-vap. Residue was dissolved in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as amber solid in 99% yield. MS m/e (M+H)+=404.9, 403.0, 406.9.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1.[C:19]1(C)[C:20](S(O)(=O)=O)=CC=C[CH:24]=1>C(O)CC>[CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH2:24][CH2:19][CH3:20])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1
Reactant: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCCO
Product: CCCOC1CCN(CCC)C(=O)N1c1nnc(SC)s1

Procedure:
Tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), propyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-propoxy-2(1H)-pyrimidinone.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[Cu][C:23]#[N:24]>CN1CCCC1=O.[Cu]I>[CH:15]1([N:12]2[CH2:13][CH2:14][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:23]#[N:24])[CH:21]=[CH:20][C:5]=4[N:6]=3)[CH2:10][CH2:11]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Brc1ccc2nc(N3CCN(C4CCCC4)CC3)sc2c1
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2nc(N3CCN(C4CCCC4)CC3)sc2c1
Temperature: 160 °C
Yield: 29.9 %

Procedure:
To a solution of 6-bromo-2-(4-cyclopentylpiperazin-1-yl)benzothiazole (0.54 g, 1.50 mmol) in N-methylpyrrolidin-2-one (100 mL) was added copper(I)iodide (344 mg, 1.80 mmol) and copper(I)cyanide (270 mg, 3.0 mmol). The mixture was heated at 160° C. for 4 h, then allowed to cool to room temperature and filtered. The filtercake was washed with ethyl acetate and the filtrate was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 140 mg (30%) of 2-(4-cyclopentylpiperazin-1-yl)benzothiazole-6-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.Cl.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:10]([C:7]1[CH:6]=[C:5]([CH2:4][C:3]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: NCCc1c[nH]c2ccc(Br)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Br)cc12)c1cc(Cc2cc(F)ccc2F)on1
Yield: 59.9 %

Procedure:
A solution of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.104 g, 0.435 mmol), 2-(5-bromo-1H-indol-3-yl)ethanamine hydrochloride (0.120 g; 0.435 mmol), HATU (0.166 g; 0.435 mmol) and N,N diisopropylethylamine (0.201 mL; 1.09 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.120 g (60%) of N-(2-(5-bromo-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]2.[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>CC(N(C)C)=O>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][CH2:2][C:3]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=2[O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1
Reaction time: 2 h

Procedure:
To a 4.1° C. solution of 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol (71.55 g, 237 mmol) in DMA (350 mL) was added a DMA (350 mL) solution of phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (80.5 g, 230 mmol). The temperature rose to 18.4° C. and stabilized. The ice bath was removed and the reaction was stirred for 2 hours. An additional portion of 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol was added and the reaction was stirred for 2 hours. The reaction mixture was partitioned between isopropyl acetate (1.6 L) and water (2.4 L). The aqueous layer was removed and the organic layer was washed with 0.5 N NaOH (2×2.4 L) and then saturated brine (1×2.4 L). The organic layer was dried over Na2SO4 (300 g) and concentrated to yield 110.8 g (86.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:18]([C:22](O)=[O:23])[CH:19]([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>ClCCl>[NH2:16][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C@H:18]([NH:17][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]([CH3:21])[CH3:20])[CH2:10][C:9]1([CH3:14])[CH3:15]
Reactant: CC1(C)CNCCC1(N)c1ccc(Cl)cc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(N)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A mixture of 4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-amine (488 mg, 2.044 mmol), Boc-D-Val-OH (444 mg, 2.044 mmol), HOBT (626 mg, 4.09 mmol), and triethylamine (1.140 mL, 8.18 mmol) in dichloromethane (5 mL) was treated with EDC (784 mg, 4.09 mmol), and the mixture was stirred overnight at room temperature. The mixture was concentrated in-vacuo, and the residue was taken up in ethyl acetate. The organic phase was washed 3× with WATER, 3× with sat. sodium carbonate, and 1× with sat sodium chloride, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with ethyl acetate/hexanes (25%-50%-100% EtOAc) to yield the title compound (845 mg, 1.929 mmol, 94% yield) as a colorless glass. MS (ESI+)=438.36, M+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:5].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(Cl)cc1)NC(c1ccccc1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[phenyl-(4-trifluoromethyl-phenyl)-methyl]-acetamide hydrochloride (example 3.2) and 4-chlorobenzoic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1>C(O)(C)C>[Cl:7][C:8]1[CH:13]=[C:12]([NH:1][CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4])[N:11]=[C:10]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1
Reactant: CC(C)(C)CNc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)CN
Solvent: CC(C)O
Product: CC(C)(C)CNc1cc(Cl)nc(NCC(C)(C)C)n1

Procedure:
After adding 5 ml of 1-amino-2,2-dimethylpropane to a solution of 5.0 g of 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine in 25 ml of isopropanol the reaction mixture is boiled under reflux for 20 hours, then evaporated. The residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. After recrystallization from hexane the title compound is obtained in a yield of 2.994 g (49.4%), m.p.:95°-98° C.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:3]([O:4][CH3:5])[CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CON(C)C(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (5.5 g, 56.4 mmol) was added to a suspension of 4-iodobenzoyl chloride (10.0 g, 37.5 mmol) and toluene (60 mL) at 0° C. After 10 min, a solution of sodium carbonate (16.0 g, 151 mmol) and water (250 mL) was added over 50 min via addition funnel. With vigorous stirring, the reaction was maintained at 0° C. for 2 h and then partitioned. The toluene layer was washed with water (125 mL), washed with brine (125 mL), and then concentrated. The residue was redissolved in toluene and filtered to remove trace solids. This solution was concentrated to give 10.5 g of 4-iodo-N-methoxy-N-methylbenzamide as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.32 (d, 2H), 3.53 (s, 3H), 3.25 (s, 3H); LCMS: 292.4 (M+H)+. Step 2: 1-(4-Iodophenyl)-2-(4-methoxyphenyl)ethanone
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:14][S:15]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
(S)-Tetrahydrofuran-3-ol 2a (300 mg, 3.40 mmol) and triethylamine (687 mg, 6.80 mmol) were dissolved in 20 mL of dichloromethane in an ice bath, followed by addition of methanesulfonyl chloride (908 mg, 7.93 mmol). The reaction solution was warmed up to room temperature and stirred for 2 hours. The resulting solution was mixed with 10 mL of dichloromethane, washed with water (30 mL×2), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-tetrahydrofuran-3-yl methanesulfonate 2b as a yellow oil (522 mg, yield 92.5%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][N-:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[K+].[CH:32](O)([CH3:34])[CH3:33]>>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:22]([C:23]4[N:27]=[N:26][N:25]([C:32]([C:34]5[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=5)([C:12]5[CH:11]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:33]5[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=5)[N:24]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Reactant: CC(C)O
Agent: [K+]
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Yield: 82 %

Procedure:
Surprisingly it was found that if the suspension of Losartan potassium in isopropyl alcohol, obtained by deprotection of trityl Losartan, kept at a temperature of 25-30 degree for a period of 6-13 hours preferably 12 hours and is cooled slowly to a temperature of 0-5° C. in 2-12 hours, then the precipitated and dried crystals isolated in 82-92% yield are identical with the polymorphic Form I of Losartan potassium. The crystal form was found to be identical with the Polymorph Form I disclosed in the patent U.S. Pat. No. 5,608,075 by differential scanning calorimetry and X-Ray powder diffraction patterns studies.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].O.N([O-])=O.[Na+].[N-:20]=[N+:21]=[N-].[Na+]>Cl>[NH2:7][C@@H:6]([CH2:5][C:4]1[CH:11]=[CH:12][C:13]([OH:14])=[C:2]([N:1]=[N+:20]=[N-:21])[CH:3]=1)[C:8]([OH:10])=[O:9]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cc(C[C@H](N)C(=O)O)ccc1O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc(C[C@H](N)C(=O)O)ccc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-amino-L-tyrosine.2HCl.H2O (2.50 g, 8.8 mmol) in 0.5 N HCl (28 mL) at 0° C., an aqueous solution of NaNO2 (0.724 g, 10.5 mmol, in 10 mL H2O) was added slowly. The reaction mixture was stirred for 10 min at 0° C., in the dark, and then a solution of NaN3 (1.43 g, 21.9 mmol, in 10 mL H2O) was added and stirring was continued for 1 h at 0° C. The white solid formed was filtered and dried to give (S)-2-amino-3-(3-azido-4-hydroxy-phenyl)-propionic acid (1.16 g) as of a beige solid. This amino acid was coupled to the carboxylic acid of example 2 in the usual manner to give the title compound of example 146 after purification by preparative C18 reversed-phase HPLC.