Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:22]([O:24]CC)=[O:23])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:22]([OH:24])=[O:23])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(CC3CC3)C(=O)O)cc(Cl)c2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
A mixture of ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy) biphenyl-3-yl)-3-cyclopropylpropanoate (370 mg, 0.84 mmol) and lithium hydroxide monohydrate (282 mg, 6.7 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoic acid (200 mg) as a white solid. 1HNMR (CDCl3): 7.21-7.42 (m, 6H); 3.87 (q, 2H); 3.65 (t, 1H); 2.39 (s, 3H), 1.93 (m, 1H); 1.88 (m, 1H); 0.66 (m, 1H); 0.42 (m, 2H); 0.12 (m, 1H); 0.1 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[C:9]([CH3:14])[C:8]=1[CH3:15].[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:14][C:9]1[C:8]([CH3:15])=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:12]=[CH:11][N:10]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCOc1cc[n+]([O-])c(C)c1C
Product: COCCCOc1ccnc(COC(C)=O)c1C

Procedure:
20 ml of acetic anhydride was added to 760 mg (3.6 mmol) of 4-(3-methoxypropoxy)-2,3-dimethylpyridine N-oxide to carry out the reaction at 90° C. for one hour. The reaction mixture was distilled to remove the acetic anhydride, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was extracted with chloroform. The extract was concentrated to obtain 700 mg of 2-acetoxymethyl-4-(3-methoxypropoxy)-3-methylpyridine as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[OH:43][CH:44]1[CH2:47][NH:46][CH2:45]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[OH:43][CH:44]1[CH2:47][N:46]([C:18]([CH:14]2[CH2:15][CH2:16][CH2:17][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:12][CH2:13]2)=[O:20])[CH2:45]1
Reactant: OC1CNC1
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCC(C(=O)N2CC(O)C2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
To a stirred solution of 1-[(benzyloxy)carbonyl]azepane-4-carboxylic acid (317 mg, 1.14 mmol) in DMF (5 ml) was added HOBt (154 mg, 1.14 mmol) followed by EDCI (218 mg, 1.14 mmol). After 5 minutes, a solution of 3-hydroxyazetidine hydrochloride (138 mg, 1.26 mmol) and DIPEA (0.44 ml, 2.51 mmol) in DMF (1 ml) was added and the resulting solution was stirred for 12 hours at room temperature. The mixture was diluted with EtOAc (30 ml) and washed with saturated aqueous NaHCO3 (3×15 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica FCC (using a gradient of eluents; 99:1 to 92:8 DCM/MeOH) to give the title product as colourless oil (265 mg, 70%).
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH:13]([NH:15][C:16]1[S:17][CH:18]=[C:19]([C:21](=[N:27][O:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:20]=1)=[O:14].O>CN(C)C=O>[CH:13]([NH:15][C:16]1[S:17][C:18]([Cl:1])=[C:19]([C:21](=[N:27][O:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:20]=1)=[O:14]
Reactant: CCOC(=O)C(=NOC)c1csc(NC=O)n1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC)c1nc(NC=O)sc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 224.7 %

Procedure:
Trichloroisocyanuric acid (6.7 g.) was added portionwise to a chilled solution of ethyl 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 20.0 g.) in dry dimethylformamide (400 ml.) and stirred at room temperature for 2 hrs. The reaction mixture was poured into chilled water (2 l.), and the precipitates were collected by filtration, washed with water and dried to give ethyl 2-(2-formamido-5-chlorothiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 18.9 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:14]([NH:16][C:17](=[O:34])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[NH:30][CH2:31][CH2:32][CH3:33])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@H:14]([NH:16][C:17](=[O:34])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=2[NH:30][CH2:31][CH2:32][CH3:33])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCCNc1cc(C(F)(F)F)ccc1C=CC(=O)N[C@H](C)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: [Pd]
Product: CCCNc1cc(C(F)(F)F)ccc1CCC(=O)N[C@H](C)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 58.1 %

Procedure:
(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide (12 mg) was reduced with Pd/C (15 mg) under hydrogen atmosphere to yield title compound (7 mg, 60%).
Reaction SMILES: [O:1]=[C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[H][H]>C1COCC1>[OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(=O)Cc1ccccc1
Reactant: [H][H]
Solvent: C1CCOC1
Product: COC(=O)C(O)Cc1ccccc1

Procedure:
Methyl 2-oxo-3-phenylpropionate (16d, R18=Ph, R19=methyl) was hydrogenated according to General Procedure B in THF at 20.7 barg (300 psig) hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand (R,S)-1f (3.3 mg; 6 μmol; 0.012 equiv) for 6 hours to afford methyl 2-hydroxy-3-phenylpropionate (17d, R18=Ph, R19=methyl) with 86.0% ee as determined by chiral GC analysis.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].[BrH:15]>C(O)(=O)C>[BrH:15].[Br:15][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14]
Reactant: Cc1nc2n(c(=O)c1CCO)CCS2
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCBr)CCS2
Temperature: 25 °C
Reaction time: 17.25 h

Procedure:
To 79.6 parts of 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one were added dropwise successively 95 parts of acetic acid and 303 parts of a hydrobromic acid solution 30% in acetic acid at a temperature below 45° C. Upon completion, the whole was heated to reflux and stirring was continued for 17.25 hours at reflux temperature. The reaction mixture was cooled to room temperature. The precipitated product was filtered off and stirred in 152 parts of 2-propanol. The product was filtered off, washed with 40 parts of 2-propanol, dried in vacuo at 50° C. and recrystallized from methanol, yielding 102.3 parts of 6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide; mp. 237.2° C. (intermediate 4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:21]#[N:22])[CH2:17][CH2:16]1.Cl>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:20][CH2:19][C:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:21]#[N:22])[CH2:17][CH2:16]2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cc2)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
8.8 g of 1-bromo-4-fluorobenzene were dissolved in 50 ml of dry THF in a dried two-necked flask under an argon atmosphere, cooled to −70° C., and 32.2 ml of n-butyllithium solution (1.55 M in n-hexane) were slowly added dropwise so that the internal temperature did not exceed −65° C. The reaction mixture was stirred for 1 h at −70° C. Subsequently, 10.0 g of 4-oxo-1-phenylcyclohexanecarbonitrile in the form of a suspension in 50 ml of THF were slowly added dropwise so that the internal temperature did not exceed −65° C. The reaction solution was stirred further for 1 h at −70° C. and subsequently warmed to room temperature. It was stirred for 3 h at room temperature, the reaction mixture was added to ice water, cautiously acidified with 1 N hydrochloric acid and extracted three times with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product, a brown oil, was crystallized from toluene. 13.8 g of the title compound were obtained as a white solid.
Reaction SMILES: CC1(C=CCC)C(C)=CC=C(S([O-])(=O)=O)C1.[CH3:17][C:18](=[CH2:22])[CH2:19][CH2:20][OH:21].[Na].[Cl:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1O>CN(C)C=O>[Cl:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[O:21][CH2:20][CH2:19][C:18]([CH3:17])=[CH2:22]
Reactant: C=C(C)CCO
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: CCC=CC1(C)CC(S(=O)(=O)[O-])=CC=C1C
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(C)CCOc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C

Procedure:
3-Methyl-3-butenyltosylate derived from 12.9 g of 3-methyl-3-buten-1-ol by a conventional procedure was reacted with 31 g of sodium salt of 2-chloro-4-nitrophenol in 250 ml of dimethylformamide. The resultant mixture was stirred at 90°-100° C. for 2.5 hours and then poured into ice-water, followed by extraction with benzene. The solvent was removed under reduced pressure, and the precipitated crystals were subjected to filtration by a glass filter and washed with ether to give 29.3 g of 3-chloro-4-(3-methyl-3-butenyloxy)nitrobenzene. M.P. 38°-39° C.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[CH2:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2C(C(OC)=O)=CC=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:6]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:3]=[CH:2][C:1]([CH2:5][OH:4])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 ml of a THF solution of 32 g of methyl 4'-nonylbiphenylcarboxylate was slowly dropped to 300 ml of a THF solution of 3.5 g of lithium aluminum hydride while cooling with ice. After the completion of dropwise addition, the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was again cooled with ice, and 20 ml of ethyl acetate was slowly dropped thereto. Subsequently, 50 ml of water and 100 ml of 6 N hydrochloric acid were slowly dropped thereto. 300 ml of toluene was added thereto. An organic layer was washed with saturated saline water, with 6 N hydrochloric acid, with saturated saline water, with a 2 N sodium hydroxide aqueous solution and further with saturated saline water to make it neutral. The organic layer was dried over anhydrous magnesium sulfate, concentrated and then recrystallized from 200 ml of ethanol to obtain 28 g of 4'-nonyl-4-hydroxymethyl-biphenyl having a melting point of 101 to 102° C. Analysis of the above compound by HPLC showed that the purity was 99.9%. The total of the compound and 30 g of thionyl chloride were mixed and allowed to stand overnight. Then, the mixture was heated for 30 minutes on a water bath maintained at 70° C. and then allowed to cool. The mixture was poured into ice water and extracted with 300 ml of toluene. The extract thus obtained was washed with saturated saline water, with a saturated sodium hydrogencarbonate aqueous solution and further with saturated saline water, made neutral, dried over anhydrous magnesium sulfate, concentrated, and recrystallized from 300 ml of ethanol to obtain 25 g of 4'-nonyl-4-chloromethyl-biphenyl, having a melting point of 68.0 to 68.4° C. Analysis of the compound by HPLC showed that the purity was 99.8%.
Reaction SMILES: C[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:16](Cl)=[N:15][C:14]3[C:9]2=[CH:10][C:11]([Cl:19])=[C:12]([Cl:18])[CH:13]=3)[C@H:5]([OH:20])[C@@H:4]1[OH:21].[Br:22]C1NC2C=C(Cl)C(Cl)=CC=2N=1.C(OC1O[C@H](C)[C@@H](OC(=O)C)[C@H]1OC(=O)C)(=O)C>>[Br:22][C:16]1[N:8]([C@@H:6]2[O:7][C@H:3]([CH3:2])[C@@H:4]([OH:21])[C@H:5]2[OH:20])[C:9]2[CH:10]=[C:11]([Cl:19])[C:12]([Cl:18])=[CH:13][C:14]=2[N:15]=1
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Reactant: CC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O

Procedure:
2-bromo-5,6-dichloro-1-(5-deoxy-β-D-ribofuranosyl)benzimidazole (211) was prepared using the same method as that used for the preparation of compound 210, except that 2-bromo-5,6-dichlorobenzimidazole was condensed with the carbohydrate 206 instead of 207.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1F.O.[NH2:15][NH2:16]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[NH:15][NH2:16]
Reactant: Fc1cc(C(F)(F)F)cc(F)c1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1c(F)cc(C(F)(F)F)cc1F

Procedure:
A mixture of 1,2,3-trifluoro-5-(trifluoromethyl)benzene (300 g, 1.5 mmol) and hydrazine monohydrate (300 g, 6.0 mmol) in ethanol (1200 ml) was heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue was re-crystallised from 2-propanol to give Preparation 21 (194 g).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[N:23][CH:22]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][N:23]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 411.00 g/mol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:15]C)=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1>Br>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([OH:15])=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Agent: Br
Agent: Cl
Product: Oc1ccc(Cl)cc1N1CCNCC1

Procedure:
1-(5-chloro-2-methoxyphenyl)-piperazine hydrochloride (8 g) was heated in a solution of 48% aqueous HBr (200 ml) and the mixture was heated at reflux for 99 hours. The reaction mixture was concentrated in vacuo, the sub-title compound was used directly without any further purification.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:18])=[C:9]2[C:14]=1[C:13](=[O:15])[CH:12]([C:16]#[N:17])[CH2:11][CH2:10]2)(=O)C.[C:19](NC1CCC2C(=C(NC(=O)C)C=CC=2)C1=O)(=[O:21])[CH3:20]>>[C:19]([NH:17][CH2:16][CH:12]1[CH2:11][CH2:10][C:9]2[C:14](=[C:5]([NH2:4])[CH:6]=[CH:7][C:8]=2[Cl:18])[C:13]1=[O:15])(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Reactant: CC(=O)Nc1ccc(Cl)c2c1C(=O)C(C#N)CC2
Product: CC(=O)NCC1CCc2c(Cl)ccc(N)c2C1=O

Procedure:
The procedure of Example 1-(4) was followed by using 1.20 gm of the compound prepared in (3) above, instead of 2,8-diacetylamino-1-tetralone. The reaction product was post-treated to obtain 1.20 gm of the title compound.
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O:21]C)=O)=[CH:15][N:14]=2)[CH2:8][CH2:7]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([NH2:40])[NH:38][N:39]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>C1(C)C=CC=CC=1>[CH3:32][O:31][C:29]1[CH:28]=[C:27]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([NH:40][C:19]([C:16]3[CH:17]=[N:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][N:6]([CH3:5])[CH2:7][CH2:8]4)=[N:14][CH:15]=3)=[O:21])[NH:38][N:39]=2)[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=1
Reactant: COC(=O)c1cnc(N2CCCN(C)CC2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
Trimethylaluminium (1.35 ml, 2.70 mmol) was added dropwise to a stirred suspension of methyl 2-(4-methyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (270 mg, 1.08 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (267 mg, 1.08 mmol) in toluene (5.39 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was quenched into methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing pure desired compound were evaporated to dryness to afford the title compound (136 mg, 27%) as a cream solid. The fractions containing impure product were concentrated and purified by crystallisation from MeCN to afford the title compound (56.0 mg, 11%) as a beige solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:24]([CH2:27][CH2:28][OH:29])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>ClCCl>[OH:29][CH2:28][CH2:27][S:24]([C:20]1[CH:19]=[C:18]([NH:17][C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=3[N:3]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:25])=[O:26]
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Solvent: ClCCl
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cccc(S(=O)(=O)CCO)c3)nc21
Yield: 85 %

Procedure:
2-Chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (150 mg; 0.623 mmol) and 2-(3-Amino-phenylsulfonyl)-ethanol (120 mg; 0.600 mmol) were heated to 160° C. for 30 minutes. The reaction mixture was then suspended in dichloromethane and ethyl acetate then filtrated to yield 215 mg (0.530 mmol; 85% yield) as yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([O:7][CH3:8])[O:5][CH3:6].[CH3:9][CH:10]([CH3:26])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1)=[O:12]>>[CH3:6][O:5][CH:4]([O:7][CH3:8])[CH2:3][CH2:2][N:23]1[CH2:24][CH2:25][CH:20]([C:16]2[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH:10]([CH3:9])[CH3:26])[CH:19]=[CH:18][CH:17]=2)[CH2:21][CH2:22]1
Reactant: COC(CCBr)OC
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)OC

Procedure:
Prepared by Procedure G and Scheme B1 using 3-bromo-1,1-dimethoxypropane and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 349.2 (M+H)+.
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]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24]>Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CCCCCc1c(-c2cccnc2)n(C)c2ccc(Cl)cc12
Agent: Cl
Product: Cn1c(-c2cccnc2)c(CCCCCC(=O)O)c2cc(Cl)ccc21

Procedure:
A mixture of 1.0 g of 5-chloro-3-[5-(ethoxycarbonyl)pentyl]-1-methyl-2-(3-pyridyl)indole in 20 ml of 2N aqueous hydrochloride acid is stirred and heated at reflux overnight. The mixture is cooled and the solid formed collected and dried in vacuo to give 5-chloro-3-(5-carboxypentyl)-1-methyl-2-(3-pyridyl)indole hydrochloride, m.p. 186°-189°.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13]([CH3:21])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][C@@H:12]([C:13]([CH3:21])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:10]
Reactant: CC(=Cc1ccccc1)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=Cc1ccccc1)[C@H](N)CO
Yield: 87.4 %

Procedure:
A solution of (S)-2,2-dimethyl-4-(1-methyl-2-phenyl-vinyl)-oxazolidine-3-carboxylic acid tert-butyl ester (250 mg) in 4M HCl in dioxane (2 ml) was stirred at r.t. overnight. The reaction mixture was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give (S)-2-amino-3-methyl-4-phenyl-but-3-en-1-ol (122 mg, 87%) as light yellow oil. MS (ISP): 177.9 ([M+H]+))
Reaction SMILES: [K].[NH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[CH:11]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH:26]([F:28])[F:27])[C:19](Cl)=[O:20])[CH2:13][CH2:12]1.Cl>CN(C=O)C.O>[CH:22]1[C:18]([C:19]([NH:2][C:3]2[C:4]([Cl:10])=[CH:5][N:6]=[CH:7][C:8]=2[Cl:9])=[O:20])=[CH:17][C:16]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13]2)=[C:24]([O:25][CH:26]([F:27])[F:28])[CH:23]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C

Procedure:
The potassium salt suspension of the anion of 4-amino-3,5-dichloropyridine in DMF (2-2.5 equivalents) is introduced into a reaction vessel. A solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride (1 equivalent) in DMF is slowly added to this suspension while stirring vigorously at a temperature of 15 to 40° C., preferably 20 to 30° C. After the reaction is complete, water is slowly added while stirring at 15-25° C., and the pH is adjusted to 2-3 with hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])=[CH:24][CH:23]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCc1ccc(Br)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 4-bromophenethylamine (65 mg, 0.32 mmol). The title compound was obtained as a solid (30 mg, 21% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.88 (1H, m), 8.38 (1H, m), 7.47(2H, dd), 7.18 (2H, dd), 3.43 (2H, m), 2.78 (2H, m). MS m/z: 529.92, 531.95, 533.95 [M+H]+.