Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]3[C:20]4[CH2:21][NH:22][CH2:23][CH2:24][C:25]=4[C:26]([CH3:29])([CH3:28])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]3[C:20]4[CH2:21][N:22]([CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:23][CH2:24][C:25]=4[C:26]([CH3:28])([CH3:29])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)N(C)C)CC1

Procedure:
The above-titled compound was prepared by reacting 8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N,N-dimethylacetamide according to the method of Example 3.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH2:8]([O:15][C:16](ON1C(=O)CCC1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>O1CCCC1>[CH2:8]([O:15][C:16]([NH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(CN)CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-amino-2,2-dimethyl-1-propanol (2 g) in tetrahydrofuran (20 mL) was added N-(benzyloxycarbonyloxy)-succinimide (7.25 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-1/1) to give 3-benzyloxycarbonylamino-2,2-dimethyl-1-propanol (4.6 g) To this material were added carbon tetrachloride (40 mL), acetonitrile (40 mL), water (48 mL), sodium periodate (11.6 g) and ruthenium trichloride (0.2 g) successively, and the mixture was stirred at room temperature overnight. To the reaction mixture were added sodium periodate (11.6 g) and ruthenium trichloride (0.2 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in a saturated aqueous potassium carbonate solution. The solution was washed with ethyl acetate, and the aqueous layer was acidified with 2 mol/L hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid (3.6 g). This material was dissolved in tetrahydrofuran (25 mL). To the solution was added 1,1′-carbonylbis-1H-imidazole (3.39 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (25 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-benzyloxycarbonylamino-2,2-di(methyl)-propionamide (3.35 g). The obtained 3-benzyloxycarbonylamino-2,2-di(methyl)propionamide (0.13 g) was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (61 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NOC(CCCC=O)C2)cc1OC
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCCN3CCN(c4ccccc4OC)CC3)C2)cc1OC
Yield: 67.2 %

Procedure:
4-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]butanal (26.7 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 26.5 mg (62.5%) of the target compound was obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH:10]=[CH2:11]>>[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[CH:10]=[CH2:11]
Reactant: C=CCOc1ccccc1O
Reactant: CC(C)N1CC(O)C1
Product: C=CCOc1ccccc1OCC(O)CNC(C)C
Yield: 48 %

Procedure:
When 1-(iso-propyl)-3-azetidinol and 2-allyloxyphenol were reacted in the same manner as in Example 6, 1-(2-allyloxyphenoxy)-3-(iso-propylamino)-2-propanol melting at 76°-79° C was obtained. The yield was 48%.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.CON(C)[C:9]([C:11]1[C:16]([NH2:17])=[N:15][CH:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24](=[O:31])(=[O:30])[NH:25][CH2:26][CH2:27][O:28][CH3:29])[CH:19]=2)[N:12]=1)=[O:10].Cl>C1COCC1>[NH2:17][C:16]1[N:15]=[CH:14][C:13]([C:18]2[CH:19]=[C:20]([S:24]([NH:25][CH2:26][CH2:27][O:28][CH3:29])(=[O:30])=[O:31])[CH:21]=[CH:22][CH:23]=2)=[N:12][C:11]=1[C:9]([CH:1]1[CH2:2][CH2:3]1)=[O:10]
Reactant: COCCNS(=O)(=O)c1cccc(-c2cnc(N)c(C(=O)N(C)OC)n2)c1
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1cccc(-c2cnc(N)c(C(=O)C3CC3)n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1M solution of cyclopropyl magnesium bromide in THF (1.3 ml, 1.3 mmol) is added to a solution of 3-amino-6-[3-(2-methoxy-ethylsulfamoyl)-phenyl]-pyrazine-2-carboxylic acid methoxy-methyl-amide (Intermediate CB) (0.49 g, 1.24 mmol) in anhydrous THF (15 ml) under N2. The orange solution is stirred at room temperature for 18 hours after which time a 1M solution of cyclopropyl magnesium bromide in THF (1.3 ml, 1.3 mmol) is added. The orange solution is stirred at room temperature for 1 hour. 1M HCl (45 ml) is added and the product extracted into EtOAc (120 ml), dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (SiO2, 50-100% EtOAc in iso-hexane) yields the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-6) δ 9.08 (1H, s), 8.51 (1H, m), 8.39 (1H, d), 8.22-7.90 (2H, br), 7.88 (2H, m), 7.76 (1H, t), 3.73 (1H, m) 3.37 (2H, t), 3.21 (3H, s), 3.02 (2H, q), 1.19 (2H, m), 1.14 (2H, m); MS m/z 377 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](Cl)=[O:10])[CH:3]=1.[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:10])[CH:3]=1
Reactant: Cc1nc(Cl)cc(C(=O)Cl)n1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.48 g (13.0 mmol) 6-chloro-2-methyl-pyrimidine-4-carboxylic acid chloride, 1.94 g (13.0 mmol) 4-methyl-3H-benzoxazol-2-one and 6.93 g (52.0 mmol) aluminium trichloride were heated to 125° C. with stirring for 1.5 h. The mixture was combined with ice water and the precipitate formed was suction filtered and washed with water. Then the precipitate was dissolved in MeOH/DCM and suction filtered through silica gel. The filtrate was evaporated down and the residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down and triturated with diethyl ether. The precipitate was suction filtered, washed with diethyl ether and dried i. vac.
Reaction SMILES: [Cl:1][CH:2]([CH2:11][CH2:12][CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N+:14]([O-])([OH:16])=[O:15]>>[Cl:1][CH:2]([CH2:11][CH2:12][CH2:13][N+:14]([O-:16])=[O:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CCCC(Cl)C(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Product: O=C(c1ccccc1)C(Cl)CCC[N+](=O)[O-]
Temperature: 0 °C

Procedure:
133 g of 2-chlorovalerophenone are added dropwise to 715 ml of fuming HNO3 at -15° C. and the mixture is poured onto 4 kg of ice. The aqueous phase is then extracted with chloroform and the organic phase is washed, dried and concentrated. The oily compound is further processed as the crude product.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)#[CH:12].N>>[F:19][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1cccc(F)c1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Fc1cccc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-3-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.51 (m, 1H), 7.67 (td, J=8.1, 5.9 Hz, 1H), 7.73-7.82 (m, 2H), 7.86 (s, 1H), 9.32 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1>C(OCC)(=O)C.CN(C=O)C>[NH2:19][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: COCCN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCN1CCN(c2ccc(N)cc2F)CC1=O

Procedure:
3-Fluoro-4-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)nitrobenzene (4 g) was dissolved in a mixture of ethyl acetate (200 ml) and DMF (5 ml), and the solution flushed with argon. Palladium (10% on carbon, 200 mg) was added, and the mixture hydrogenated under ambient pressure. After gas uptake had ceased, the mixture was filtered through celite and solvent was evaporated to give 5-amino-2-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)fluorobenzene which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][OH:15])=[CH:5][CH:4]=1)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH:12]([CH3:16])[CH2:13][CH:14]=[O:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(CCO)CC(=O)Nc1ccc(C#N)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(CC=O)CC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
To a solution of the compound obtained in Step 1 (435 mg, 1.87 mmol) in acetonitrile (10 mL) was added Dess-Martin Periodinane (953 mg, 2.25 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 80% ethyl acetate/hexane) to give crude N-(4-cyanophenyl)-3-methyl-5-oxopentanamide (113 mg, 0.492 mmol, 26.3%) as a white powder.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].CCN(CC)CC.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([C:19]([NH:21][C:22]2[CH:44]=[CH:43][C:25]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:24][CH:23]=2)=[O:20])[C:15](=[O:45])[N:14]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN1C(=O)CCC1>[CH2:2]([NH:4][C:34](=[O:35])[NH:33][C:29]1[CH:28]=[C:27]([O:26][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:19]([C:16]3[C:15](=[O:45])[N:14]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:13]([CH3:12])[C:17]=3[CH3:18])=[O:20])=[CH:44][CH:43]=2)[CH:32]=[CH:31][N:30]=1)[CH3:3]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
To a solution of ethylamine hydrochloride (29 mg, 0.356 mmol) was in NMP (3 mL) was added Et3N (0.1 mL). The solution was stirred at rt for 10 minutes, followed by the addition of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridin-2-yl)carbamate (100 mg, 0.187 mmol). The reaction was stirred at 40° C. overnight, then concentrated in vacuo at 40° C., and diluted with water (10 mL). The precipitate was collected by filtration, and then purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v/v)=80/40/1) to give the title compound as a white solid (46 mg, 50%).
Reaction SMILES: [CH:1]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=[C:4]([CH3:5])[C:2]=1[OH:3].[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([O:3][C:2]3[CH:1]=[C:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[CH:6][C:4]=3[CH3:5])[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Cc1ccc(C(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(C)C)cc1Oc1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Yield: 73.7 %

Procedure:
Carvacrol (25 mg, 0.16 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted using K2CO3 (50 mg, 0.36 mmol) as described above to give the title compound (40 mg, 77%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([SH:8])[CH:7]=1.[C:13]1([S:19]([C:22]2[CH:27]=[CH:26][C:25](F)=[C:24]([F:29])[CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([S:8][C:25]2[CH:26]=[CH:27][C:22]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[F:29])[CH:7]=1
Reactant: O=C(O)Cc1cc(S)cc(Cl)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Product: O=C(O)Cc1cc(Cl)cc(Sc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The title compound was prepared as described in example 1 step vi) but instead using the product from example 71 step (i) and the product from example 24 step (i).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([CH2:15][NH2:16])[OH:14]>C1COCC1.CC(=O)OCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:16][CH2:15][CH2:13][OH:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(S(=O)(=O)NCCO)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 112.3 %

Procedure:
To a solution of 4-cyano-benzenesulfonyl chloride (1.00 g, 4.96 mmol) in THF, ethanolamine (454 mg, 7.44 mmol) is added. The mixture becomes slightly warm (30° C.) and turbid. The mixture is stirred at rt for 3 h before it is diluted with EA, washed with sat. aq. NH4Cl solution and water, dried over MgSO4, filtered and concentrated to give crude 4-cyano-N-(2-hydroxy-ethyl)-benzenesulfonamide (1.26 g) as a white solid; LC-MS: tR=0.34 min, [M+1+CH3CN]+=268.13. b) A mixture of 4-cyano-N-(2-hydroxy-ethyl)-benzenesulfonamide (1.25 g, 5.56 mmol), hydroxylamine hydrochloride (773 mg, 11.1 mmol) and NaHCO3 (934 mg, 11.1 mmol) in methanol is stirred at 60° C. for 7 h. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in EA (250 mL) and washed with water (5 mL). The organic extract is dried over MgSO4, filtered, concentrated and dried to give the title compound (720 mg) as a white solid; LC-MS: tR=0.23 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:24]([CH:26]=[CH2:27])=[O:25].O>O1CCCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:24]([OH:25])[CH:26]=[CH2:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
10.3 g (40 mmol) of 1-(phenylsulfonyl)indole (synthesized analogous to T. Sakamoto; Y. Kondo; N. Takazawa; H. Yamanaka; J. Chem.Soc.Perkin Trans. 1; 16; 1996; 1927–1934) in 110 ml tetrahydrofuran were cooled to −20° C. To the stirred solution 30 ml of 1.6 M n-butyllithium were added at −20° C. within 20 min. The resulting suspension was warmed to 10° C. and stirred at 10° C. for 4 hours. The mixture was again cooled to −20° C. and a solution of 3.4 g acrolein (61 mmol) in 20 ml THF was added dropwise within 20 min at −20° C. The solution was stirred at 20° C. for 16 hours. 150 ml water was added dropwise, the mixture was vigorously stirred for 10 min. The phases were separated, and the water phase was extracted with 3×100 ml of methyl-t-butyl-ether. The combined organic phases were washed with 100 ml of brine, dried on sodium sulfate and rotary evaporated (35° C., 20 mbar). The residue was purified by liquid chromatography (eluent toluene/ethyl acetate 6:1), the pure fractions were collected and rotary evaporated (40° C./15 mbar).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:16]2[CH:17]=[C:12]([Cl:11])[N:13]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[N:15]=2)=[C:4]([F:10])[CH:3]=1
Reactant: Nc1cc(F)c(O)cc1F
Reactant: CC(=O)Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(Cl)cc(Oc2cc(F)c(N)cc2F)n1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A solution of 4-amino-2,5-difluoro-phenol (3.5 g, 24 mmol), N-(4,6-dichloro-pyrimidin-2-yl)-acetamide (5.30 g, 24 mmol) and potassium carbonate (3.4 g, 24 mmol) in DMF (100 mL) was stirred at 50° C. under nitrogen overnight. After cooling to room temperature the reaction mixture was suspended in water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (15%-20% ethyl acetate in petroleum ether) to give N-[4-(4-amino-2,5-difluoro-phenoxy)-6-chloro-pyrimidin-2-yl]-acetamide (3.3 g, 44% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.20-7.24 (dd, J=11.2 Hz, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.64 (dd, J=12.0 Hz, J=8.4 Hz, 1H), 5.48 (s, 2H), 2.03 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH2:3].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:15]=1
Reactant: C=C(C)CCCCCCCCC
Reactant: Oc1ccc(Br)cc1
Product: CCCCCCCCCC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-1-undecene (35.6 g, 211 mmoles), parabromphenol (36.6 g, 211 mmoles) and Dowex 50×12 resin (100-200 mesh) previously washed with water, rinsed with acetone and oven dried for 3 hours at 80° C., is heated at 100°-110° C. for 48 hours. The mixture is then cooled to ambient temperature and chromatographed on a silica column (eluant: a mixture of dichloromethane, 40% and hexane, 60%), yielding 4-bromo-2-(1,1-dimethyldecyl)-phenol in the form of a pale yellow oil. (30.85 g, 43%).
Reaction SMILES: I[CH3:2].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][OH:25])[N:22]=3)[CH2:17][C@@:11]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:12]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+]>>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][O:25][CH3:2])[N:22]=3)[CH2:17][C@@:11]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:12]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:40])([F:41])[F:39])[CH:29]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: OCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Product: COCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Iodomethane, 85 mg, 0.6 mmol was added to suspension of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Compound 3a in Table 3; 250 mg, 0.4 mmol) and sodium hydride (24 mg, 0.6 mmol, 60% in oil). The reaction mixture was stirred at 50° C. for 2 hours then quenched by addition of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:2 ethyl acetate/iso-hexanes to yield the title compound (246 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c([N+](=O)[O-])ccc(CO)c1Cl
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
To a solution of 2-chloro-3-methoxy-4-nitrobenzaldehyde (Compound 54I, 1.6 g, 7.44 mmol) in methanol (25 mL) at 0° C. was added sodium borohydride (330 mg, 8.91 mmol). After stirring for 1.5 h, water (15 mL) was added. The solid obtained was filtered and dried to obtain the desired intermediate (1.1 g, 69%). 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=4.8 Hz, 1H), 7.47 (d, J=5.1 Hz, 1H), 4.83 (d, J=3.6 Hz, 2H), 4.02 (s, 3H), 2.25 (t, J=3.6 Hz, 1H).