Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[OH:12])=[CH:5][CH:4]=1
Reactant: O=C1CCc2ccc(C(F)(F)F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2ccc(C(F)(F)F)cc21
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of 6-(trifluoromethyl)indan-1-one (2.20 g, 11 mmol) in THF (30 mL) was added sodium borohydride (0.50 g, 13 mmol). After being stirred for 30 min, methanol (10 mL) was added slowly. Stirring was continued for 2 hrs. The reaction was quenched by addition of an aqueous ammonium chloride solution. The two layers were separated and the water layer was extracted by ether. The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. Column chromatography on silica (10-15% EtOAC in hexane) gave the title compound (1.52 g, 68%) as an oil. MS calculated for C10H9F3O: (M+H)+ 203. found 185.0 (M−H2O+1)+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[N:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=[C:9](O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=[N:11][C:10]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1
Reactant: Oc1cc(-c2ccccc2)nnc1N1CCN(c2ncccn2)CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc(-c2ccccc2)nnc1N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazin-4-ol 1 h (22.0 g, 66 mmol) was suspended in 75 ml phosphorus oxychloride and heated with stirring at 100 for 3 h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over filter funnel to provide white solid. (21.3 g, 60.3 mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+). 1H NMR (CDCl3): d 8.377 (d, J=4.5, 2H), 8.036 (d, J=7.5, 2H), 7.833 (s, 1H), 7.508 (m, 3H), 6.564 (t, J=4.5, 1H), 4.073 (t, J=4.0, J=4.5, 4H), 3.672 (t, J=4.0, J=4.5, 4H).
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(COC)OC.[Pd]>[OH:1][C:2]([CH3:33])([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[CH2:3][CH2:4][NH:5][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(CCCCC#CCOC1CCCCO1)NCCC(C)(O)CC1CCCCC1
Agent: [Pd]
Solvent: COCCOC
Product: CCOC(=O)C(CCCCCCCOC1CCCCO1)NCCC(C)(O)CC1CCCCC1
Yield: 99.1 %

Procedure:
Ethyl 2-(3'-hydroxy-3'-methyl-4'-cyclohexyl-n-butyl)amino-9-tetrahydropyranyloxy-non-7-ynoate (7 g) was hydrogenated over 10% Pd/C (1.4 g) in dry dimethoxyethane (100 ml) at atmospheric pressure and room temperature. When hydrogen absorption was completed, the mixture was filtered through Kieselguhr, and the filtrate was evaporated in vacuo to give ethyl 2-(3'-hydroxy-3'-methyl-4'-cyclohexyl-n-butyl)amino-9-tetrahydropyranyloxy-nonanoate (7 g) as a pale yellow oil.
Reaction SMILES: N#N.[OH:3][CH:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)[CH3:5]>C(C#N)(C)=O.O=[Mn]=O>[C:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)(=[O:3])[CH3:5]
Reactant: CC(O)c1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-oxazole-4-carboxylic acid {2-[2-(1-hydroxy-ethyl)-oxazol-5-ylmethyl]-2H-[1,2,3]triazol-4-yl}-amide (60 mg, 0.16 mmol) in AcCN (1.6 mL) was treated at rt with MnO2 (114 mg, 1.18 mmol) and the reaction mixture was stirred at rt overnight before being filtered through Celite. The solvent was removed under reduced pressure and the residue was dissolved in EA (10 mL), washed with water (10 mL), and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a white foam. LC-MS-conditions 02: tR=0.97 min; [M+H]+=379.06.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:32]([O:34][CH:35]([O:42][CH2:43][CH3:44])[C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH3:33]>C1COCC1.O>[CH2:43]([O:42][CH:35]([O:34][CH2:32][CH3:33])/[C:36](/[O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)=[CH:37]/[C:38]([O:40][CH3:41])=[O:39])[CH3:44]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCOC(C#CC(=O)OC)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)/C(=C/C(=O)OC)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 2.43 g (15 mmol) of 4-trifluoromethylphenol in 40 mL of THF was added 1.12 g (20 mmol) of powdered KOH and 5.28 g (20 mmol) of 18-crown-6. The solution was heated to 50° C. for 15 minutes, whereupon 3.73 g (20 mmol) of methyl 4,4-diethoxy-2-butynoate was added. The mixture was stirred for 30 minutes, then allowed to cool to room temperature. The solution was then poured into water, and extracted 3 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude oil was subjected to column chromatography on SiO2. Elution with 20% ethyl acetatehexane yielded 2.31 g (65%) of an oil, used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[C:12]([C:14]1[C:21]([Cl:22])=[CH:20][C:17]([CH2:18]Cl)=[CH:16][C:15]=1[Cl:23])#[N:13]>CN(C)C=O>[NH2:1][C:2]1[N:6]([CH2:18][C:17]2[CH:16]=[C:15]([Cl:23])[C:14]([C:12]#[N:13])=[C:21]([Cl:22])[CH:20]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: N#Cc1c(Cl)cc(CCl)cc1Cl
Reactant: NC(=O)c1nn[nH]c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cc(Cn2nnc(C(N)=O)c2N)cc1Cl
Reaction time: 0.17 h
Yield: 23.4 %

Procedure:
A stirred, ambient temperature solution of 5-amino-1,2,3-triazole-4-carboxamide (630 mg, 5.0 mmol) in dry N,N-dimethylformamide (20 ml) was treated with sodium hydride (250 mg of a 50% dispersion in mineral oil, 125 mg NaH, 5.2 mmol). The resulting suspension was stirred 10 min., 4-cyano-3,5-dichlorobenzyl chloride (1.1 g, 5.0 mmol) was added, and the mixture was stirred 2 hours. The reaction was quenched by pouring into ice and water (80 ml). The suspension was filtered and washed three times with water. The solid was suspended in 19:1 (v/v) dichloromethane-methanol and filtered to provide 364 mg (23%) 5-amino-1-(4-cyano-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide. Recrystallization from ethanol provided material of m.p. 238°-239.5° C.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26])=O)(C)(C)C.Cl.C(Cl)[Cl:29].[NH4+].[OH-]>C(OCC)(=O)C.CO>[ClH:29].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Reaction time: 3 h

Procedure:
To a solution of the compound of Example 38 (4.00 g, 0.0110 mole) in 10 mL of ethyl acetate at room temperature was added 5N HCl in ethyl acetate (50 mL, freshly prepared, 0.25 mole) in one portion. The solution was stirred for 3 hrs, solvent was evaporated, CH2Cl2 was added and the solvents were reevaporated. The residue was pumped at <1 mm Hg on a vacuum pump for 24 hours to afford 3.37 g (~Quantitative crude yield) of product as a colorless foam. TLC (silica gel; CH2Cl2, methanol, conc. NH4OH: 27:3:1): Rf=0.32.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=3[CH:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH2:5][CH2:4][O:3]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:71]1[CH:76]=[C:75]([F:77])[CH:74]=[C:73]([F:78])[CH:72]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[F:77][C:75]1[CH:76]=[C:71]([N:24]2[CH2:25][CH2:26][CH2:27][CH:23]2[C:11]2[CH:12]=[C:13]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=[C:15]3[C:10]=2[O:9][C:8]([N:6]2[CH2:5][CH2:4][O:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:17][C:16]3=[O:18])[CH:72]=[C:73]([F:78])[CH:74]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COC(=O)c1cc(C2CCCN2)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 60.7 %

Procedure:
Diacetoxypalladium (4.58 mg, 0.02 mmol) was added to a stirred mixture of methyl 2-((R)-2-methylmorpholino)-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (190 mg, 0.51 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (25.09 mg, 0.04 mmol), 1-bromo-3,5-difluorobenzene (73.4 μl, 0.64 mmol) and cesium carbonate (249 mg, 0.77 mmol) suspended in 1,4-dioxane (5 mL). The resulting suspension was degassed with argon and then stirred at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature, the insoluble were removed by filtration and the filtrate concentrated. The crude product was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 0 to 6% MeOH in EtAc. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (150 mg, 61%) as a beige foam.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C@H:27]([OH:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:22](OCC)=[O:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].Cl>O.C1COCC1>[C:1]([NH:20][C@H:21]([C@H:27]([OH:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][OH:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C(=O)OCC)[C@H](O)CCCCCCCCCCCCCCC
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)CCCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Ethyl (2R,3R)-2-octadecanoylamino-3-hydroxyoctadecanoate (5.00 g, 8.17 mmol) synthesized in the same manner as Example 17 was added to a THF suspension (48 mL) containing sodium borohydride (0.62 mg, 16.34 mmol) at 0° C. for 5 hour. After completion of the dropwise addition, calcium chloride (1.82 mg, 16.40 mmol) was added for 1 hour. After water was added to the reaction mixture, concentrated hydrochloric acid was added thereto to adjust pH of the mixture to be 1.5. The mixture was further stirred at 50° C. for 1 hour, and the organic layer was separated. It was confirmed by comparative analysis of the organic layer with sample product using HPLC that the organic layer contained 4.41 g of the title compound (yield: 95%). It was also found that anti-form:syn-form was 98:2 and the optical purity of the anti-form was 99% ee.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]=1[F:24].[AlH4-].[Li+]>O1CCCC1>[F:24][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc(CO)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To 2-fluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoic acid methyl ester (32. 3.34 g, 8.85 mmol) in 71 mL of tetrahydrofuran, lithium tetrahydroaluminate (17.7 mL, 1.00 M in tetrahydrofuran, 17.7 mmol) was added under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature for 8 hours, followed by addition of 10 g of NaSO4.10H2O. After 12 hours, the reaction was filtered, the filtrate concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (33, 1.79 g, 58%). MS(ESI) [M−H+]−=348.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[CH2:13]([CH:15]([CH2:19][CH3:20])[C:16](Cl)=[O:17])[CH3:14].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH2:13]([CH:15]([CH2:19][CH3:20])[C:16]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[C:8]=1[CH3:11])=[O:17])[CH3:14]
Reactant: COc1ccc2occ(C)c2c1
Reactant: CCC(CC)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC(CC)C(=O)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized above, 2-ethylbutanoyl chloride (1.85 mL) and nitromethane (30 mL) was added aluminum chloride (3.28 g), and the mixture was stirred at room temperature for 1.5 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (6% ethyl acetate/hexane) to give the title object compound (3.12 g, 97%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1.O>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:20][C:9]2[CH:8]=[CH:7][C:6]3[C@@H:5]4[C@H:14]([C@H:15]5[C@@:2]([CH2:3][CH2:4]4)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]5)[CH2:13][CH2:12][C:11]=3[CH:10]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]23)cc1

Procedure:
Oestrone (2 g., 7.4 mmole) in pyridine (10 ml.) was treated at room temperature for 3 days with toluene-p-sulphonyl chloride (2 g., 1.4 equiv.). The stirred mixture was slowly diluted with water (40 ml.). The precipitated oil slowly crystallized on agitation. Recrystallisation from methanol -- methylene cloride gave the title compound plates (2.65 g., 85%), m.p. 143°-145° , [α]D + 105°. (c, 1.00).
Reaction SMILES: BrC1C=CC([C@@H](N)C)=CC=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([N:20]2[CH2:26][CH2:25][CH2:24][C:23]([CH2:33][C:34]([CH3:36])=[CH2:35])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:22]C2=O)[CH3:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C@@H:18]([NH:20][CH2:26][CH2:25][CH2:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([OH:22])[CH2:33][C:34]([CH3:36])=[CH2:35])[CH3:19])=[CH:16][CH:17]=1
Reactant: C=C(C)CC1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)CC(O)(CCCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Yield: 30.4 %

Procedure:
To a solution of (S)-1-(4-bromo-phenyl)-ethyl amine (3.58 g, 0.018 mol) in dry CH3CN (350 mL) was added 3-((1S)-1-(4-bromophenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one (4.2 g, 0.018 mol), KI (3.19 g, 0.019 mol), and K2CO3 (3.73 g, 0.027 mol). The mixture was stirred at reflux overnight, filtered, and concentrated to give the crude product, which was purified by column chromatography to give 7-((1S)-1-(4-bromophenyl)ethylamino)-2-methyl-4-phenylhept-1-en-4-ol (2.2 g, 30%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([O:26]CC)=[O:25].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Temperature: 0 °C
Yield: 91 %

Procedure:
A mixture of ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate (4.31 g, 10.5 mmol) and 1 N aqueous sodium hydroxide solution (60 mL, 60 mmol) in ethanol (120 mL) was stirred at reflux for 1.5 h, then cooled to 0° C. and acidified with 10% aqueous hydrochloric acid to pH ˜2. The white precipitate was filtered, washed with water and ethanol, and then dried in vacuo to afford the title compound as a colorless solid in 91% yield (3.68 g): 1H NMR (300 MHz, DMSO-d6) δ 12.37 (br s, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.30 (s, 1H), 4.50 (s, 2H), 3.90-3.81 (m, 2H), 3.52-3.44 (m, 2H), 2.40 (s, 3H); MS (ES+) m/z 385.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[N:3]=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:5]3[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)[CH:28]=[N:29][CH:30]=1
Reactant: CC(C)n1ccc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Reactant: OB(O)c1cncc(F)c1
Product: CC(C)n1ccc2c(NCCc3ccc(O)cc3)nc(-c3cncc(F)c3)nc21

Procedure:
Following the procedure of Example 15d, 4-(2-(2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl)phenol (20 mg, 0.06 mmol) was reacted with 5-fluoropyridin-3-ylboronic acid. The crude residue was purified by reverse-phase HPLC (C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=1[I:1])[CH2:8][CH2:7][CH2:6]3)[N:13]2[CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28]
Reactant: CC(C)(C)S(=O)NCCCBr
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)CCC4)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)NCCCn1c(Sc2cc3c(cc2I)CCC3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a solution of 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine (13 mg, 0.03 mmol) in DMF (1.5 mL) was added N-(3-bromopropyl)-2-methlpropane-2-sulfinamide (23 mg, 0.1 mmol) and Cs2CO3 (21 mg, 0.06 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS63 as a white solid (5 mg, 27%). 1H NMR (600 MHz, CDCl3): δ 8.22 (s, 1H), 7.68 (s, 1H), 7.05 (s, 1H), 5.70 (br s, 2H), 4.83 (t, J=6.7 Hz, 1H), 4.28-4.36 (m, 1H), 4.17-4.27 (m, 1H), 2.99-3.07 (m, 1H), 2.85-2.93 (m, 1H), 2.81 (t, J=7.4 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 1.83-2.08 (m, 4H), 1.20 (m, 9H); HRMS (ESI) m/z [M+H]+ calcd. for C21H28IN6OS2, 571.0811. found 571.0809.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].Cl.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][C@@H:26]([NH:28][C@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH3:27])=[CH:24][C:19]=2[CH2:18][CH2:17]1.C(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C.C(N(CC)CC)C>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][C@@H:26]([N:28]([C@H:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH3:30])[CH2:1][CH3:2])[CH3:27])=[CH:24][C:19]=2[CH2:18][CH2:17]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@H](N[C@@H](C)Cc1ccc2c(c1)CCO2)c1ccccc1
Agent: CC=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCN([C@@H](C)Cc1ccc2c(c1)CCO2)[C@@H](C)c1ccccc1
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
Sodium triacetoxyborohydride (26 grams, 0.123 mole) was added to a suspension of (S,S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-1-phenylethylamine hydrochloride (26 grams, 0.08 mole) in dichloroethane (300 ml) and triethylamine (11.5 ml). After stirring for 5 minutes, acetaldehyde (4.8 ml, 0.086 mole) was added and the mixture was stirred for another 2 hours. Aqueous 5% sodium carbonate (400 ml) was added and the mixture was extracted with methylene chloride. Evaporation of the solvent gave (S,S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-phenylethyl)amine as an oil (23 grams, 91%), M+ 309.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([CH:10]=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH2:12](O)[CH2:13][OH:14].CCCP(=O)=O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[C:7]1[N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]2=[CH:9][CH:8]=1
Reactant: O=Cc1ccc2cc[nH]c2n1
Reactant: OCCO
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: c1cc2ccc(C3OCCO3)nc2[nH]1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridine-6-carbaldehyde (840 mg, 5.60 mmol), ethylene glycol (3.13 ml, 56.0 mmol) and propylphosphonic anhydride (50% in EtOAc, 3.34 ml, 5.60 mmol) in EtOAc (15 ml) was stirred at 80° C. After 18 h, the reaction mixture was cooled to room temperature, diluted with sat. aq. NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The crude material was applied to a 120 g RediSep® silica column and purified by normal phase chromatography, eluting with EtOAc. Product-containing fractions were combined and evaporated. The residue was triturated with Et2O to give the title compound as an white solid. (UPLC-MS 6) tR 0.66; ESI-MS 191.1 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23]Br)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23][N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8](=[O:9])[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:6][CH2:5]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)NCCBr
Product: CC(C)(C)OC(=O)NCCN1CCN(CC(=O)N2CCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (commercially available from CHESS GmbH) and (2-Bromo-ethyl)-carbamic acid tert-butyl ester analogously to the preparation of Intermediate 269.2 as a colorless oil; ES-MS: M+H=341.3: CtRet=4.08.