Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](I)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C1COCC1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:30]3[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: OB(O)c1cccnc1F
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(-c3cccnc3F)c3ccccc32)cc1

Procedure:
Reflux a mixture of 4-(3-iodo-indole-1-sulfonyl)-benzoic acid methyl ester (1.33 g, 3.01 mmol, 1 equiv), 2-fluoropyridine-3-boronic acid (Frontier Scientific®; 0.47 g, 3.3 mmol, 1.1 equiv), sodium carbonate (2M in H2O; 3.0 mL, 6.0 mmol, 2.0 equiv), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (62 mg, 0.080 mmol, 0.025 equiv) in THF (15 mL) under N2 for 2 h (reaction mixture turned very dark when heated). Rotary evaporate the reaction mixture. Dissolve the resultant residue in Et2O (15 mL) and wash with H2O (5 mL). Back-extract the aqueous layer is with Et2O (5 mL). Dry the combined organic layers with (anhydr Na2SO4), and rotary evaporate (40° C.) giving the crude 4-[3-(2-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzoic acid methyl ester as a brown foam. Dissolve this material in THF (10 mL) and add 5M aq NaOH (2 mL). After 18 h, add H2O (25 mL) and Et2O (25 mL). Separate the aqueous layer and extract the organic layer with H2O (25 mL). Combine the aqueous layers and wash with Et2O (25 mL). Acidify this aqueous layer with 1M aq HCl (8 mL) to pH 5 causing much precipitation. Extract this mixture with CHCl3 (1×50 mL, 2×25 mL). Dry the combined organic layers (anhydr Na2SO4) and rotary evaporate (40° C.) yielding 673 mg (56.3%) of 4-[3-(2-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzoic acid as a brown powder. MS (m/e): 396.94 (M+1); 394.99 (M−1).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].[Cl-].[Mg+2].[Cl-].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1.[Cu]Br.O>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[CH2:2][CH2:3][CH:4]2[O:8][CH2:7][CH2:6][O:5]2)=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: BrCCC1OCCO1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCC1OCCO1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (40 ml) was added dropwise within 15 minutes under argon and while stirring at a maximum 30° C. to a suspension of Rieke magnesium, prepared from 45.0 g of magnesium chloride, in 1500 ml of absolute tetrahydrofuran. The suspension was stirred at room temperature for 15 minutes, cooled to 0° C. and, after the addition of 43.5 g of copper(I) bromide, stirred at 5° C. for 15 minutes. After cooling to -70° C., 33 ml of 4-chlorobenzoyl chloride was added dropwise within 10 minutes. The reaction mixture was stirred at -70° C. for 15 minutes and at room temperature for 2 hours and subsequently hydrolyzed with 1000 ml of saturated ammonium chloride solution while cooling at a maximum 20° C. After the addition of 500 ml of water the mixture was extracted three times with 1000 ml of ethyl acetate each time. The combined organic extracts were washed with 1000 ml of saturated sodium chloride solution, dried over MgSO4 and freed from solvent. 63.0 g of residue were chromatographed on 2000 g of silica gel with ethyl acetate/hexane (1:1) as the eluent. 36.5 g (59%) of 4'-chloro-3(1,3-dioxolan-2-yl)propiophenone were isolated as a yellow, amorphous solid.
Reaction SMILES: [NH2:1][C@:2]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:40])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:29][CH2:28][C@@H:27]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Br[CH2:48][CH2:49]Cl.P(=O)(O)(O)O.[K]>C(#N)C>[N:1]1([C@:2]23[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:40])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH2:29][CH2:28][C@@H:27]([C:30]([O:32][CH2:33][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])[CH2:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:49][CH2:48]1
Reactant: ClCCBr
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P(O)(O)O
Agent: [K]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C

Procedure:
To a sealable vial was added (R)-benzyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.075 g, 0.120 mmol), 1-bromo-2-chloroethane (0.100 mL, 1.202 mmol), and phosphoric acid, potassium salt (0.128 g, 0.601 mmol). The mixture was diluted with acetonitrile (1.5 mL), flushed with nitrogen, then the vial was sealed and heated to 120° C. After 24 h of heating, the mixture was cooled to rt and was filtered to remove solids. The solids were washed with dichloromethane and the filtrate was concentrated under reduced pressure to give (R)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate as an off-white solid that was used in the next step with no additional purification. LCMS: m/e 650.7 (M+H)+, 2.22 min (method 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[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]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCC(=O)Cl
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Product: COCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and methoxyacetyl chloride (16 mg, 150 μmol). Yield 17 mg (69%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:29][C:30]1[C:31]([F:40])=[C:32]2[C:38]([NH2:39])=[CH:37][NH:36][C:33]2=[N:34][CH:35]=1.[Li+].[OH-].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:29][C:30]1[C:31]([F:40])=[C:32]2[C:38]([NH:39][C:4](=[O:6])[CH2:3][O:2][CH3:1])=[CH:37][NH:36][C:33]2=[N:34][CH:35]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: COCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
2-Methoxyacetic acid (313 mg, 3.5 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (885 mg, 3.5 mmol) and triethylamine (880 mg, 8.7 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.7 mmol, Example 1, Step H) in DCM (50 mL). The reaction was stirred at room temperature for 1 hour, and then 3M aqueous LiOH (4 mL) was added. The reaction was stirred for 1 hour, and then saturated aqueous Na2CO3 was added (200 mL). The aqueous phase was extracted 3 times with DCM (200 mL), and then the combined organic phases were dried over MgSO4 and concentrated to dryness. N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide (236 mg, 45% yield) was isolated as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.[C:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:38]3[CH:39]=[C:34]([NH:33][C:30](=[O:32])[CH3:31])[CH:35]=[CH:36][CH:37]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-c2nn(Cc3oc4ccccc4c(=O)c3-c3ccccc3)c3ncnc(N)c23)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 31.8 %

Procedure:
To a solution of Example 57a (0.250 g, 0.50 mmoles) in DMF (5 ml), ethanol (2.5 ml) and water (2.5 ml), 3-Acetamidophenyl boronic acid (0.116 g, 0.65 mmoles) and sodium carbonate (0.264 g, 2.50 mmoles) were added and the system is degassed for 30 min Tetrakis triphenylphosphine Palladium (0.109 g, 0.095 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as yellow solid (0.080 g, 23% yield). MP: 122-123° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 10.13(s,1H), 8.06(dd, J=7.7, 1.4Hz, 1H),7.90(s, 1H),7.77(m,1H), 7.57-7.47(m,3H), 7.48(m,3H), 7.37-7.29(m, 6H), 5.52(s,2H), 2.05(s, 3H). Mass: 503.05(M++1).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([F:20])=[C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:23]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Reactant: O=Cc1ccc(F)c(-c2ccccn2)c1
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1ccc(F)c(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with 4-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.58 min.; [M+H]+: 421.83 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:39]2[CH:51]=[CH:50][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:40]=[CH:41][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:50][CH:51]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Temperature: 100 °C
Yield: 73 %

Procedure:
A solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-2-methylbenzamide (800 mg, 1.629 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (740 mg, 2.443 mmol), sodium carbonate (621 mg, 5.86 mmol) in 20 ml of dioxane was degassed with argon for 20 min, Pd(PPh3) (188 mg, 0.16 mmol) was added to the mixture and heated to 100° C. overnight. The reaction was cooled to room temperature and diluted with water, compound was extracted in 10% MeOH in DCM, dried over Na2SO4, concentrated and crude was purified by silica gel (100-200) chromatography to obtain the title compound (700 mg, 73.0%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:12]=[C:13]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([C@H:27]5[CH2:32][CH2:31][C@H:30]([C:33]([O:35]CCCC)=[O:34])[CH2:29][CH2:28]5)([OH:26])[CH3:25])=[N:22][CH:23]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl.CC(O)C>CO.C(Cl)(Cl)Cl.O>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:12]=[C:13]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([C@H:27]5[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]5)([OH:26])[CH3:25])=[N:22][CH:23]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ccc(-c3cc(C)cc(Nc4nccc(C5CC5)n4)c3)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2ccc(C(C)(O)[C@H]3CC[C@H](C(=O)O)CC3)nc2)c1
Temperature: 25 °C

Procedure:
A solution of trans-butyl 4-(1-(5-(3-(4-cyclopropylpyrimidin-2-ylamino)-5-methylphenyl)pyridin-2-yl)-1-hydroxyethyl)cyclohexanecarboxylate (61.0 mg, 0.095 mmol) and NaOH (1 M, 0.480 ml, 0.480 mmol) in MeOH (1 mL) was heated to 80° C. for 1 hour. The reaction mixture was cooled to room temperature, acidified with aqueous 1N HCl and diluted with 9:1 CHCl3:IPA. The mixture was then diluted with water and extracted with 9:1 CHCl3:IPA (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford trans-4-(1-(5-(3-(4-cyclopropylpyrimidin-2-ylamino)-5-methylphenyl)pyridin-2-yl)-1-hydroxyethyl)cyclohexanecarboxylic acid. MS ESI calc'd for C28H33N4O3 [M+H]+ 473. found 473. 1H NMR (500 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.75 (s, 1H), 8.49 (br s, 1H), 8.27 (d, J=5.0 Hz, 1H), 8.00 (br s, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.19 (s, 1H), 6.82 (d, J=5.0 Hz, 1H), 5.74 (s, 1H), 2.35 (s, 3H), 2.04-1.73 (m, 5H), 1.56 (s, 3H), 1.30-1.22 (m, 5H), 1.05-1.01 (m, 5H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=O)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.B.C1COCC1>C1COCC1>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][NH2:12])=[CH:13][CH:14]=2)=[CH:4][N:3]=[CH:2]1
Reactant: NC(=O)c1ccc(-c2cnco2)cc1
Agent: B
Solvent: C1CCOC1
Product: NCc1ccc(-c2cnco2)cc1
Temperature: 0 °C
Yield: 32.4 %

Procedure:
A suspension of 4-(5-oxazolyl)benzamide (500 mg, 2.657 mmol) in 10 mL of dry THF was cooled to 0° C. and 10 mL of 1 M BH3.THF (10.00 mmol) was added. The contents were refluxed overnight and the excess borane was destroyed by dropwise addition of methanol. The solvent was evaporated and the residue was treated with methanolic HCl to decompose the amine-borane complex. After evaporation of the methanol, the residue was taken in water, basified to pH 10 and the product was extracted in to DCM. The DCM layer was dried (K2CO3) and the solvent was removed to provide 150 mg (32%) of 4-(5-oxazolyl)benzylamine: 1H NMR (CDCl3) δ 7.90 (s, 1H), 7.60 (d, 2H), 7.40 (d, 2H), 7.30 (s, 1H), 3.90 (s, 2H).
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)C1)=O)(C)(C)C.[C:33]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][CH2:47][CH:41]1CNC2)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][CH2:47][CH:41]1[CH2:11][N:12]([CH2:16][C:17]1[S:18][C:19]3[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[C:24]=3[N:25]=1)[CH2:13]2)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(Cc1nc3c(N4CCOCC4)nc(Cl)nc3s1)C2

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (91 mg, 95%).
Reaction SMILES: ClCCl.[Sn](Cl)(Cl)(Cl)Cl.[CH3:9][C:10]([CH3:14])([OH:13])[C:11]#[N:12].[Br:15][CH2:16][CH2:17]O>O>[Br:15][CH2:16][CH2:17][O:13][C:10]([CH3:14])([CH3:9])[C:11]#[N:12]
Reactant: OCCBr
Reactant: CC(C)(O)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C#N)OCCBr
Temperature: 2.5 °C
Reaction time: 22 h
Yield: 31.6 %

Procedure:
Dichloromethane (42 mL) and tin tetrachloride (64.9 g, 249 mmol) were added to a 250 mL round bottom flask equipped with a magnetic stirrer, temperature probe, condenser and Argon inlet-outlet. The mixture was cooled to 0-5° C. Acetone cyanohydrin (21.2 g, 249 mmol) was added over 15 min, followed by slow addition of 2-bromoethanol (46.69 g, 373.6 mmol). The reaction mixture was stirred at 20-25° C. for 22 h. The mixture was cooled to 0-5° C., diluted with water (148 mL), and extracted with dichloromethane (3×64 mL). The combined CH2Cl2 extracts were dried (MgSO4), filtered and concentrated under vacuum to afford the crude product as a yellow liquid. The material was purified by vacuum distillation (10 mm Hg) using a Vigreux column. The fraction boiling between 75-85° C. was collected to afford 2-(2-Bromoethoxy)-2-methylpropanenitrile as a colorless oil (15.09 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:17]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[O:8][N:9]=2.[Li]CCCC.CON(C)[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>C1COCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C:7]2[O:8][N:9]=[C:5]3[CH:4]=[CH:3][C:2]([C:26]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:35])=[CH:17][C:6]=23)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(C(=O)N(C)OC)cc1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.13 m) was added at −70° C. to THF (300 ml ) under N2 flow. A solution of BuLi (0.143 mol) was added dropwise. The mixture was stirred at −70° C. for 10 minutes. A solution of N,4-dimethoxy-N-methyl-benzamide (0.117 mol) in THF (100 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour, poured out on ice/EtOAc and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried under a vacuo, yielding 19.5 g (41%) of [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-methoxyphenyl)- methanone (intermediate 10).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH:12]2[CH2:25][OH:26])[CH:7]=[CH:8][C:9]=1[Cl:10].[CH3:27]I>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13][CH:12]2[CH2:25][O:26][CH3:27])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of sodium hydride (10.5 mg) in THF (1 mL) was added a solution of tert-butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (65.7 mg) in THF (1 ml), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added methyl iodide (49.7 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (58.4 mg).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.Cl.[CH3:18][NH:19][O:20][CH3:21]>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7]([N:19]([O:20][CH3:21])[CH3:18])=[O:8]
Reactant: CNOC
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)sc1Cl
Reaction time: 18 h
Yield: 90.8 %

Procedure:
To a stirred solution of 2,5-dichloro-3-thiophenecarbonylchloride (1.08 g, 5.0 mmol) and pyridine (2 mL) in CH2Cl2 (10 mL) was added N,O-dimethylhydroxylamine hydrochloride (490 mg, 5.0 mmol) at room temperature, and the mixture was stirred for 18 hours. CH2Cl2 (10 mL) was added to the mixture. The combined organic layers were washed with 1N HCl solution, saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo to give light yellow oil (1.09 g, 91% yield). The compound was used for next reaction without purification.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[O:22]([C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:39][CH2:40][N:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:30]=3)[CH2:36][CH2:37]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: c1ccc(Oc2cccc(N3CCNCC3)c2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(Oc4ccccc4)c3)CC2)c(OC)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-phenoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6]([NH:22]C(=O)C(C2C=CC=CC=2)C)=[N:5]1)(=[O:3])[CH3:2].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>>[C:1]([N:4]1[N:5]=[C:6]([NH2:22])[S:7][C:8]1([CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(NC(=O)C(C)c2ccccc2)SC1(CCNS(C)(=O)=O)c1ccccc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)N1N=C(N)SC1(CCNS(C)(=O)=O)c1ccccc1
Yield: 50.9 %

Procedure:
In the same manner as that in Step 2 of Reference Example 20, from another diastereomer of N-[4-acetyl-5-(2-methanesulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2-phenylpropanamide (0.632 g, 1.33 mmol) eluted later obtained in Step 3 mentioned above, cerium chloride heptahydrate (0.496 g, 1.33 mmol) and sodium borohydride (0.503 g, 13.3 mmol), optically active N-[2-(3-acetyl-5-amino-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methanesulfonamide (232 mg, 51%) was obtained.