Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([OH:24])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CC1(C)[O:41][CH:40]([CH2:42][CH2:43]OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:39][O:38]1.O>CN(C=O)C>[CH:1]([O:4][C:5](=[O:29])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:43][CH2:42][CH:40]([OH:41])[CH2:39][OH:38])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1
Reactant: CC1(C)OCC(CCOS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCC(O)CO)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (100 mg, 0.26 mmol) in DMF (3 mL) is added K2CO3 (43.2 mg, 0.312 mmole) and 4-nitrobenzenesulfonic acid 2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (129 mg, 0.39 mmole) and the reaction is stirred for 18 h at ambient temperature. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with EtOAc/hexane and dried in vacuo to afford 96 mg, 84% of the desired product, (4-{3-cyano-1-cyclobutyl-6-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-1H-indol-2-yl}carbamic acid isopropyl ester, compound 1428.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[CH2:14]([O:13][P:12]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C#N)c(F)c1)OCC
Temperature: 150 °C
Reaction time: 4 h

Procedure:
2.2 g 4-Bromomethyl-2-fluoro-benzonitrile were dissolved in 2.0 ml triethyl phosphite and stirred at 150° C. for four hours. Then the triethyl phosphite was removed in vacuo to obtain 2.5 g (4-Cyano-3-fluoro-benzyl)-phosphonic acid diethyl ester as an oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(OCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A solution of ethyl 2-[(5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)methoxy]propanoate (Example 51) (184 mg, 0.45 mmol) in 1,4-dioxan (4 ml) and water (2 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (2 mg, 0.48 mmol) and stirred at 0° C. for 2 hours. The solvent was partially removed under reduced pressure and diluted with water and washed with diethylether (×2). The aqueous layer was acidified to pH 1 with hydrochloric acid (2M) and washed with ethyl acetate (×2). The combined organic layers were washed with brine, dries over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a colourless oil (160 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]([N:25]1[CH:29]=[CH:28]N=[CH:26]1)(N1C=CN=C1)=[O:19].[CH3:30][O:31][C:32]1[CH:33]=[C:34]2C(=[CH:39][C:40]=1[C:41]([F:44])([F:43])[F:42])NCC2>>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:18]([N:25]3[C:26]4[C:34](=[CH:33][C:32]([O:31][CH3:30])=[C:40]([C:41]([F:43])([F:44])[F:42])[CH:39]=4)[CH2:28][CH2:29]3)=[O:19])[CH:7]=[CH:6][CH:5]=2)=[CH:9][N:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(-c2cncc3ccccc23)c1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(-c3cncc4ccccc34)c1)CC2
Yield: 25 %

Procedure:
The title compound was prepared by the method of Example 23, from 4-(3-aminophenyl)isoquinoline (0.41 g, 1.9 mmol), 1,1'-carbonyldiimidazole (0.33 g, 2 mmol) and 5-methoxy-6-trifluoromethylindoline (D11) (0.41 g, 1.9 mmol). Crude product was chromatographed on silica gel eluted with 5% methanol/dichloromethane and eluted material was recrystallised from dichoromethane to give the title compound (0.22 g, 25%), m.p. 211-5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]#[N:22])[N:5]([CH3:20])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:23][Sn](C)(C)C.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:17][C:12]1([CH3:18])[C:11]2[CH:19]=[C:7]([C:6]3[N:5]([CH3:20])[C:4]([C:21]#[N:22])=[CH:3][C:2]=3[CH3:23])[CH:8]=[CH:9][C:10]=2[NH:15][C:14](=[O:16])[O:13]1
Reactant: C[Sn](C)(C)C
Reactant: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cc(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Yield: 60.9 %

Procedure:
A solution of 4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (70 mg, 0.2 mmol), PhCNPdCl(PPh3)2 (cat., 7 mg) and tetramethyltin (10 eq, 0.35 g, 2 mmol) in HMPA (3 mL) was heated to 110° C. for 5 days. The solution was allowed to cool, poured into water (20 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile (36 mg, 63%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.64 (s, 6H), 1.97 (s, 3H), 3.56 (s, 3H), 6.87 (s, 1H), 7.00 (d, 2H, J=8.1 Hz), 7.28 (dd, 1H, J=8.1, 1.6 Hz), 7.32 (s, 1H), 10.40 (s, 1H). MS (ESI (−)) 294 (M−H)−. Anal. calcd for C17H17N3O2, C, 69.1, H, 5.8, N, 14.2. Found, C, 69.1, H, 5.72, N, 14.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1.[H][H]>C(O)C.[C].[Pd].O>[CH:26]1([CH2:29][NH:30][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[NH2:17])[CH2:28][CH2:27]1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: [H][H]
Reactant: NCC1CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NCC1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.8 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (176 mg, 1.28 mmol) and cyclopropylmethylamine (176 mg, 1.28 mmol), and this was heated to reflux for 7 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a tetrahydrofuran solution (5 mL) of the crystals obtained was added 10% palladium-carbon (50 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 6 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (142 mg, 44% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:25][O:24][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[CH:21][O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[C:26]1([N:32]2[C:36]3([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:35](=[O:42])[NH:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:43]S(C)=O>>[CH3:43][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:24][CH2:25][CH:13]([CH2:12][N:39]1[CH2:38][CH2:37][C:36]2([N:32]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:33][NH:34][C:35]2=[O:42])[CH2:41][CH2:40]1)[O:14]3
Reactant: CS(C)=O
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4ncoc4c3O2)cc1
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCC2(CC1)C(=O)NCN2c1ccccc1)CO3
Temperature: 77.5 °C

Procedure:
(8R)-7,8-Dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methyl-benzenesulfonate (0.79 g, 2.1 mmole) and 1-phenyl-1,3,8-triazaspiro[4.5]-decan-4-one (1.46 g, 6.3 mmole) were combined in 40 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen for 4 hours. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute 0.62 g of the desired free amine. This was recrystallized from ethanol with the addition of 0.20 g of fumaric acid to give 0.40 g of the (S)-enantiomer of the title compound as a white solid, m. p. 240° C.
Reaction SMILES: C([O:5][C:6](=[O:17])[C@H:7](C)[N:8]=CC1C=CC=CC=1)(C)(C)C.[S:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=2)=[CH:19]1.N1C=CC=CC=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[S:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C@@H:7]([C:6]([OH:17])=[O:5])[NH2:8])=[CH:25][CH:24]=2)=[CH:19]1
Reactant: C[C@H](N=Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccsc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(-c2ccsc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-(phenylmethylene)alanine t-butyl ester (210 mg, 0.90 mmol), 4-(3-thienyl)phenylmethyl bromide (250 mg, 0.99 mmol), and pyridine (7 ml, 0.09 mmol) in methylene chloride (1.8 ml) are added potassium hydroxide (505 mg, 9.0 mmol) and potassium carbonate (1.24 g, 9.0 mmol). The mixture is stirred at room temperature for 2 days, then filtered and washed with methylene chloride. The filtrate and washings are concentrated in vacuo to give a crude 3-[4-(3-thienyl)phenyl]alanine as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[O:28])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Reactant: O=C(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)c3cccs3)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
To a solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.50 g, 1.7 mmol) in tetrahydrofuran (10 mL) was added 2-thiophenecarbonyl chloride (0.36 mL, 3.4 mmol), and triethylamine (0.52 mL, 3.7 mmol) was added to the obtained mixture. The reaction mixture was stirred at room temperature for 10 min. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The residue was dissolved in conc. hydrochloric acid (5 mL) and the mixture was stirred at 40° C. for 14 hrs. The reaction mixture was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) and crystallized from isopropyl ether-hexane to give the title compound (0.56 g, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][C@@H:16]([CH3:30])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:17][C@@H:16]([OH:15])[CH3:30])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: C[C@H](O)CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: C[C@H](O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
150 mg of (S)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (S)-methyl 4-(2-hydroxypropylthio)benzoate. 650 mg of (S)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 350 mg of (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (S)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncn1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=C(c1ccncn1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.43 (s,1H), 7.53 (dd,1H, J=8.8 Hz, 2.4 Hz), 7.62 (m, 2H), 7.75 (m, 2H), 7.80 (m, 3H), 7.98 (s, 1H), 8.99 (d, 1H, J=5.2 Hz), 9.25 (b, 1H), 10.29 (b, 1H). MS: m/z 441.9 (M++1).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13](N)[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C[N:40]1CCOCC1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:55]([OH:57])=O)[CH:52]([CH3:54])[CH3:53])=[O:49].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([NH2:40])[N:13]([C:55](=[O:57])[C@H:51]([CH:52]([CH3:54])[CH3:53])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CN1CCOCC1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N(C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(N)c1ccc(-c2cncs2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere, 344 mg of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane and 191 μl (1.74 mmol) of NMM in 5.6 ml of DMF are added to 122 mg (0.696 mmol) of N-methoxycarbonyl-(L)-valine and 173 mg (0.58 mmol) of TPTU in 2.9 ml of DMF and the mixture is stirred at room temperature for 16 hours. The reaction mixture is poured into ice-water, stirred for 30 min and filtered. Column chromatography of the residue (SiO2 ; methylene chloride/THF 4:1) and stirring in ether yield the title compound: m.p: 134-135° C.; HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]([CH3:25])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[O:22][CH2:21][C@H:20]([CH2:23]O)[O:19][C:17]3=2)[CH:12]=[N:11]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:43]=[N+:44]=[N-:45].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CS(C)=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]([CH3:25])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[O:22][CH2:21][C@H:20]([CH2:23][N:43]=[N+:44]=[N-:45])[O:19][C:17]3=2)[CH:12]=[N:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)O[C@@H](CO)CO3)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C[C@@H](Cn1ncc2ccc3c(c21)O[C@@H](CN=[N+]=[N-])CO3)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 89.5 %

Procedure:
To a 0° C. stirred solution of the alcohol from Step A (0.69 g, 1.87 mmol) in anhydrous tetrahydrofuran (30 mL) was added triethylamine (0.38 g, 0.52 mL, 3.7 mmol) and methanesulfonic anhydride (0.49 g, 2.81 mmol) under a nitrogen atmosphere. After 1 h the volatiles were evaporated. To the residue was added anhydrous DMSO (40 mL) and sodium azide (2.43 g, 37 mmol). The resulting mixture was heated at 90° C. for 1 h, cooled, mixed with a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (50 mL×3). Chromatography on silica eluting with a gradient of 0% to 25% ethyl acetate/hexane gave an oil (0.65 g, 88%), that solidified on standing. Crystallization from ethyl acetate/hexane gave a crystalline solid (0.48 g, 65%): mp 134-135° C. LCMS (+APCI) 395 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3[O:21][C:20]([CH3:23])(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[N:2]1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([C@H:37]2[CH2:42][CH2:41][C@H:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[N:28]=1.C(=O)([O-])[O-:51].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([OH:51])(=[O:21])[CH3:23].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:27]3[C:35]4[C:30](=[N:31][CH:32]=[N:33][C:34]=4[NH2:36])[N:29]([C@H:37]4[CH2:38][CH2:39][C@H:40]([N:43]5[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]5)[CH2:41][CH2:42]4)[N:28]=3)=[CH:15][CH:16]=2)=[N:2]1
Reactant: CC1(C)OB(c2ccc(Nc3n[nH]c4ccccc34)cc2)OC1(C)C
Reactant: O=C([O-])[O-]
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(Nc5n[nH]c6ccccc56)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of N-(1H-3-indazolyl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.064 g, 0.000191 mol), trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.070 g, 0.000159 mol), tetrakis(triphenylphosphine)palladium (0.011 g, 0.0000095 mol) and sodium carbonate (0.042 g, 0.000398 mol) was heated in a mixture of ethylene glycol dimethyl ether (4 mL) and water (2 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[4-(1H-3-indazolylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.035 g, 0.000060 mol) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[CH2:55][CH2:54]1>CN(C=O)C>[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH:68][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[CH2:55][CH2:54]1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3c(c2)CCO3)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 79.5 %

Procedure:
DIEA (0.014 mL, 0.078 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.020 g, 0.071 mmol) and HATU (0.030 g, 0.078 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzofuran-5-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.026 g of product in 76% yield: LCMS (ESI) m/z 484 (MH+).
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[CH2:31]([N:6]1[C:5]([C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])[CH:30]([CH3:33])[CH3:32]
Reactant: CC(C)(C)I
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC(C)C)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (Compound 1) (1.19 g, 4 mmol) and powdered anhydrous potassium carbonate (662 mg, 4.8 mmol) in DMF (20 mL), was added 2-iodo-2-methylpropane (460 μL, 4 mmol). The mixture was then stirred in an oil bath (50-60° C.) for overnight and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 500 mg (35%) of 3-(3-isobutyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (78) as a white solid. m.p. 200-201° C.; 1H-NMR (200 MHz, CDCl3) δ 0.80 (3H, d, J=3.2 Hz), 0.83 (3H, d, J=3.2 Hz), 1.12 (3H, d, J=7.0 Hz), 1.23 (3H, d), J=7.0 Hz), 1.90 (1H, m), 2.25 (1H, m), 2.53 (3H, s), 2.93 (1H, dd, J=14.2 Hz, J=7.4 Hz), 3.75 (1H, dd, J=14.2 Hz, J=7.4 Hz), 7.80 (1H, s), 7.92 (1H, s), 8.03 (1H, s), 9.03 (1H, s); m/z (EI) 353 (M+).