Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[O:23]1[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:23]1[CH:27]=[CH:26][C:25]([CH2:28][N:12]2[C:13](=[O:21])[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:11]2=[O:22])=[CH:24]1
Reactant: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Reactant: OCc1ccoc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccoc3)C2=O)cc1
Temperature: 130 °C
Yield: 26.7 %

Procedure:
To a solution of 3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione (0.17 mmol, 50 mg), 3-furanmethanol (0.19 mmol, 18 mg), diethyl azodicarboxylate (0.19 mmol, 33 mg) in dry THF (1 mL) was added triphenylphosphine (0.19 mmol, 49 mg) in dry THF (1 mL). The mixture was heated in a microwave reactor at 130° C. for six min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 17 mg (27%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.61 (bs, 1H), 7.35 (bs, 1H), 7.16 (bs, 1H), 7.15-7.05 (m, 3H), 7.00-6.95 (m, 2H), 6.62-6.51 (m, 4H), 6.48 (bs, 1H), 4.63 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][N+:8]1([CH3:29])[CH2:12][CH:11]([O:13][C:14]([C:16]([OH:28])([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:15])[CH2:10][CH2:9]1.C([O-])(=O)C>CO>[CH3:7][N+:8]1([CH3:29])[CH2:12][CH:11]([O:13][C:14]([C:16]([OH:28])([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:15])[CH2:10][CH2:9]1.[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3]
Reactant: O=C(O)C(=O)O
Agent: CC(=O)[O-]
Agent: C[N+]1(C)CCC(OC(=O)C(O)(c2ccccc2)C2CCCC2)C1
Solvent: CO
Product: O=C([O-])C(=O)[O-]

Procedure:
Glycopyrrolate oxalate was prepared using process (2) from Example 1. Equimolar amounts of oxalic acid and glycopyrrolate acetate were dissolved in methanol then fast evaporated and dried under vacuum. The resulting glassy, gel-like material was recrystallized by slurrying in ethyl acetate to produce grey solids that were then dried under vacuum before analysis by XRPD and proton NMR spectroscopy. The XRPD pattern can be found in FIG. 16.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4]([Sn](CCCC)(CCCC)CCCC)=[N:3]1.[C:23]([CH:25]1[CH2:28][N:27]([C:29](=[O:53])[C@H:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41](Br)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:36]=2)=[O:34])[CH3:31])[CH2:26]1)#[N:24]>CN(C=O)C.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.[Cu]I>[C:23]([CH:25]1[CH2:26][N:27]([C:29](=[O:53])[C@H:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([C:4]4[C:5]5[S:9][CH:8]=[CH:7][C:6]=5[N:2]([CH3:1])[N:3]=4)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:36]=2)=[O:34])[CH3:31])[CH2:28]1)#[N:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccsc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccsc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
To a solution of 1-methyl-3-tributylstannanyl-1H-thieno[3,2-c]pyrazole (111 mg, 0.26 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (120 mg, 0.24 mmol) in DMF (1.2 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.05 mmol). The yellow reaction mixture was purged with argon then heated at 80° C. for 1.5 h then cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to provide 131 mg (98%) of 2-(1-methyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as an off-white solid.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][Mg]Br)[CH2:19][CH2:18]1)[CH3:16].Cl[SiH]1CCC(C2C=CC(F)=C(F)C=2)CC1.C([C@H]1CC[C@H](CC[Mg]Br)CC1)CCC>>[CH2:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][Si@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[CH2:19][CH2:18]1)[CH3:16]
Reactant: Fc1ccc(C2CC[SiH](Cl)CC2)cc1
Reactant: CC[C@H]1CC[C@H](CC[Mg]Br)CC1
Agent: CCCC[C@H]1CC[C@H](CC[Mg]Br)CC1
Agent: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Product: CC[C@H]1CC[C@H](CC[Si@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 18, except that 22.8 g (100 mmol) of 1-chloro-4-(p-fluorophenyl)-1-silacyclohexane and 2-(trans-4-ethylcyclohexyl) ethylmagnesium bromide were used instead of 24.6 g (100 mmol) of 1-chloro-4-(3,4-difluorophenyl)-1-silacyclohexane and 2-(trans-4-n-butylcyclohexyl)ethylmagnesium bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1.[CH3:28][C@H:29](O)[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:28][C@H:29]([O:26][C:25]([C:22]1([C:20]2[N:21]=[C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[C:14](=[O:18])[O:13][CH2:12]5)[N:5]3[N:19]=2)[CH2:23][CH2:24]1)=[O:27])[CH2:30][CH3:31]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Reactant: CC[C@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)OC(=O)C1(c2nc3c(OC)ccc(-c4ccc5c(c4)COC5=O)n3n2)CC1
Temperature: 50 °C

Procedure:
A mixture of 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (10 mg, 27 μmol), (1S)-1-methylpropanol (10 μL, 108 μmol), DMAP (6.7 mg, 54 μmol) and EDCI.HCl (10.5 mg, 54 μmol) in DCM (0.5 mL) was stirred in a sealed vial at RT overnight before more (1S)-1-methylpropanol (10 μL, 108 μmol) and DMAP (6.7 mg, 54 μmol) was added and the mixture was heated to 50° C. for 3 hours. Evaporated to dryness and acidic prepHPLC purification afforded the title compound. HPLC-Retention time (XE Metode 7 CM): 2.35 minutes. Detected “M+1”-mass: 422.16. Calculated “M+1”-mass: 422.17. 1H NMR (DMSO, 600 MHz): δ=8.25-8.21 (m, 1H), 8.14 (dd, 1H, J=8.0, 1.2 Hz), 8.01-7.97 (m, 1H), 7.41 (d, 1H, J=8.2 Hz), 7.23 (d, 1H, J=8.2 Hz), 5.51 (s, 2H), 4.78 (h, 1H, J=6.3 Hz), 4.04 (s, 3H), 1.61-1.40 (m, 6H), 1.13 (d, 3H, J=6.2 Hz), 0.78 (t, 3H, J=7.4 Hz) ppm.
Reaction SMILES: C([O:4][C:5]1[CH:24]=[CH:23][C:8]([C:9]([O:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=2[F:22])=[O:10])=[CH:7][CH:6]=1)(=O)C.Cl>O1CCCC1>[OH:4][C:5]1[CH:24]=[CH:23][C:8]([C:9]([O:11][C:12]2[C:13]([F:22])=[C:14]([F:21])[C:15]([F:20])=[C:16]([F:19])[C:17]=2[F:18])=[O:10])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Pentafluorophenyl 4-acetoxybenzoate (10 g) in tetrahydrofuran was treated with 50 ml of 5M hydrochloric acid and 150 ml of tetrahydrofuran and stirred at room temperature overnight. The solvents were evaporated in vacuo to give a product which was purified by column chromatography (silica; ethyl acetate/hexane mixtures as eluant) to afford the title compound (8 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[C:20]=1[C:29]([O:31]C)=[O:30])(=[O:17])=[O:16])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[C:20]=1[C:29]([OH:31])=[O:30])(=[O:17])=[O:16])[CH3:34]
Reactant: CCN(CC)CCC/C=C\c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCN(CC)CCC/C=C\c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2

Procedure:
A solution of Example 595C (205 mg, 0.4 mmol), and LiI (214 mg, 4 equiv.) in 4 mL of pyridine was reacted in a microwave at 150° C. for 35 minutes, concentrated, and purified by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 95% acetonitrile/10 mM aqueous ammonium acetate over 12 minutes (15 minute run time) at a flow rate of 70 mL/min. in 143 mg (76%) yield. MS (ESI(+)) m/e 471 (M+H)+; MS (ESI(−)) m/e 469 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 0.99 (t, J=7.21 Hz, 6H) 1.56 (m, 6H) 2.10 (m, 2H) 2.58 (m, 4H) 2.68 (q, J=7.09 Hz, 4H) 2.90 (m, 2H) 5.71 (dt, J=11.55, 7.06 Hz, 1H) 6.79 (d, J=8.31 Hz, 1H) 6.93 (d, J=11.74 Hz, 1H) 7.12 (d, J=8.31 Hz, 1H) 7.32 (m, 2H) 7.48 (td, J=7.46, 1.22 Hz, 1H) 7.79 (dd, J=7.83, 1.22 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1)=[O:24].N1C=C(C2C(C3C=CC=CC=3)=NOC=2C(F)(F)F)N=C1.FC1C=CC(C(F)(F)F)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:28]4[CH:29]=[CH:30][C:25]([C:23](=[O:24])[CH3:22])=[CH:26][CH:27]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1onc(-c2ccc(Cl)cc2)c1-c1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Agent: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: Fc1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)cc1
Yield: 44 %

Procedure:
As described for Example 4, 3-(4-chloro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.32 mmol) and 4-fluoroacetophenone, instead of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole and 4-fluorobenzotrifluoride, was converted to the title compound (60 mg, 44%) which was obtained as a light brown solid. MS: m/e=432.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(OC1C=CC=CC=1O)C1C=CC=CC=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([O-:3])=[O:2]
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1OCc1ccccc1
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Yield: 96 %

Procedure:
To a stirred solution of 2-nitrophenol. (1) (1.4 g, 10 mM) and ethyl 4-bromobutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry acetone is added 2 g (14.5 mM) of anhydrous, ground potassium carbonate. The resultant colored mixture is then heated under a nitrogen atmosphere at gentle reflux until the color due to the phenol anion has dissipated and a yellow mixture remains. Concentration of the cooled and filtered mixture yields an oil which on flash chromatography (silica gel, ethyl acetate/hexane- or methylene chloride as eluant) yields 2.4 g (96% yield) of the title compound (3) as an oily liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C@@:9]([C:24](=[O:37])[NH:25][CH2:26][C:27]([O:29]CC1C=CC=CC=1)=[O:28])([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].CO>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C@@:9]([C:24](=[O:37])[NH:25][CH2:26][C:27]([OH:29])=[O:28])([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)N[C@](CCC(=O)OC(C)(C)C)(Cc1cccc(C#N)c1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: COC(=O)N[C@](CCC(=O)OC(C)(C)C)(Cc1cccc(C#N)c1)C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
To a round bottom flask containing a suspension of Pd—BaSO4 (47 mg) and MeOH (10 mL) was added compound 7 (527 mg, 1.01 mmol). The reaction flask was evacuated and back filled with H2 (1 atm, balloon) several times before being stirred for 30 minutes (the reaction was followed by TLC). The Pd catalyst was filtered off and rinsed several times with MeOH. The filtrate was concentrated to give the title compound a colorless solid (383 mg, 88%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([C:14](=[O:21])[CH2:15][NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[Br:22].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:7]([CH:14]([OH:21])[CH2:15][NH:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:6][C:5]=1[Br:22]
Reactant: CC(C)(C)NCC(=O)c1cc(Br)c(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)NCC(O)c1cc(Br)c(N)c(C(F)(F)F)c1

Procedure:
m.p. 85°-87° C., m.p. of the hydrochloride: 205°-206° C. (decomp.), was prepared from 4'-amino-3'-bromo-2-tert. butylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH4+:20].[OH-]>CCO>[NH2:20][CH2:3][C@@H:2]([OH:1])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (1.5 g, 5.7 mmol) in EtOH (35 mL) was added, with stirring, over 1 h to NH4OH (35 mL) at 0° C. NH3 gas was bubbled through the reaction mixture during the addition and for 1 h afterward. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting slurry was diluted with EtOAc (80 mL), and the organic layer was washed with brine and dried (MgSO4). Concentration in vacuo, followed by trituration with 10% i-PrOH-EtOAc (overnight stirring), afforded tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (0.44 g) as a white solid. The mother liquors were concentrated in vacuo and triturated again as above to give an additional quantity of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (0.57 g; 64% total yield): 1H NMR (CD3OD) d: 1.29 (s, 9H), 2.55 (m, 1H), 2.63 (m, 1H), 2.76 (m, 1H), 3.11 (m, 1H), 3.40 (m, 1H), 3.65 (m, 1H), 7.10-7.30 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][CH2:10]O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:12]
Reactant: OCCCc1cc(Cl)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(Cl)cc1CCCBr
Yield: 88.8 %

Procedure:
Compound 64-2 (2.28 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.50 g) and N-bromosuccinimide (2.37 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.70 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:17])O[C:11](C)(C)[O:12][C:13]=1[CH3:14].C=[N:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:17])[N:19]([C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:11][O:12][C:13]=1[CH3:14]
Reactant: C=NC(C)(C)C(=O)OCC
Reactant: CC1=C(c2ccccc2F)C(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(C)N1COC(C)=C(c2ccccc2F)C1=O
Yield: 62.5 %

Procedure:
A mixture of 5-(2-fluorophenyl)-2,2-dimethyl-6-methyl-4H-1,3-dioxin-4-one (2.0 g) and ethyl 2-(N-methyleneamino)-2-methylpropionate (1.45 g) was heated under reflux in xylene for 10 hours. After evaporation to dryness the residue was purified by dry column chromatography on silica gel eluting with cyclohexane/ethyl acetate to give ethyl [5-(2-fluorophenyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate as a pale yellow oil (1.7 g), NMR 1.24(t,3H), 1.42(s,6H), 1.57(s,3H), 4.15(q,2H), 5.3(s,2H), 7. 74(m,4H).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[CH3:23][N:24]([C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:25][CH2:26][OH:27]
Reactant: CNCCO
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N(C)CCO
Yield: 92 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 2.4 ml of N-methylethanolamine were used. 6.6 g (yield 92%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Reactant: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Cl)cc1S(N)(=O)=O

Procedure:
10 g of 4-methyl-3-sulfamoylbenzoic acid were boiled under reflux for 8 hours in 50 ml of thionyl chloride and the reaction mixture was allowed to stand over night at 0° C. The crystals were collected on a sinter glass frit and washed with petroleum ether and diisopropyl ether. Melting point: 180° C (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH3:13].CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][C@@H:24]2[CH2:25][CH2:26][N:28]([CH3:27])[CH2:23]2)=[O:8])=[CH:4][C:3]=1[O:11][CH2:12][CH3:13]
Reactant: CCOc1cc(C(=O)O)ccc1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1N
Reaction time: 2 h
Yield: 68 %

Procedure:
4-amino-3-ethoxybenzoic acid (Intermediate 164; 400 mg, 2.21 mmol), HATU (1.26 g, 3.31 mmol) and (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 453 mg, 3.31 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (1.7 ml, 9.95 mmol) added. The mixture was stirred for 2 hours and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% ammonia in methanol/DCM) to yield the title compound as a yellow foam (396 mg, 68%).
Reaction SMILES: [Cl-].[Li+].[CH2:3]([Mg]Br)[CH:4]=[CH2:5].Cl[Si](C)(C)C.[C:13]1(=[CH:16][C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:14]1.N.[Cl-].[NH4+]>C1COCC1.C(OCC)C.C1CCCCC1.C(OCC)(=O)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:13]1([CH2:5][CH:4]=[CH2:3])[CH2:15][CH2:14]1
Reactant: C=CC[Mg]Br
Reactant: COC(=O)C=C1CC1
Agent: C[Si](C)(C)Cl
Agent: N
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C=CCC1(CC(=O)OC)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
45.69 g (222.2 mmol) of copper(I) bromide/dimethyl sulfide complex and 9.42 g (222.2 mmol) of anhydrous lithium chloride were dissolved in 300 ml of THF, the mixture was cooled to −78° C. and 100 ml (200 mmol) of a 2 M solution of allylmagnesium bromide in diethyl ether were added slowly. 28.2 ml (222.2 mmol) of chlorotrimethylsilane and 11.21 g (100 mmol) of methyl cyclopropylideneacetate [CAS Registry No. 110793-87-8] were then added dropwise in succession to the reaction solution, and the mixture was stirred for about 5 min (monitored by TLC, mobile phase cyclohexane/ethyl acetate 20:1). 50 ml of an aqueous solution of ammonia/ammonium chloride (1:9) were then added, and the reaction solution was filtered through kieselguhr. The organic phase was separated off and the aqueous phase was extracted two more times with diethyl ether. The combined organic phases were then washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 100 ml of THF, and 222 ml (222 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF were added. The reaction solution was stirred for another 10 min and then concentrated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 6.92 g (45 mmol, 45% of theory) of the title compound.
Reaction SMILES: COC1C=CC=CC=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.[NH2:35][C:36]1[CH:46]=[CH:45][C:44](I)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39].C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C>[NH2:35][C:36]1[CH:46]=[CH:45][C:44]([C:15]2[CH:16]=[C:17]3[CH:9]=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[C:12]3=[N:13][CH:14]=2)=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]
Reactant: CN(C)C(=O)c1cc(I)ccc1N
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)C(=O)c1cc(-c2cnc3c(cnn3COCC[Si](C)(C)C)c2)ccc1N
Yield: 55 %

Procedure:
To a mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.0 g, 2.1 mmol) and 2-amino-5-iodo-N,N-dimethylbenzamide (0.67 g, 2.3 mmol) in a 20 mL microwave reaction flask was added THF (6 mL), acetonitrile (6 mL), and 1 N aqueous sodium carbonate (6 mL, 6 mmol). The resulting suspension was degassed with nitrogen for 2 minutes. dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (106 mg, 0.13 mmol) was added and degas was continued for another minute. The flask was capped and irradiated in a microwave reactor to 150° C. for 30 min. The reaction mixture was partitioned between aqueous saturated sodium chloride and ethyl acetate (50 mL:50 mL). The aqueous layers were extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel with a gradient of ethyl acetate in hexane to afford 2-amino-N,N-dimethyl-5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzamide as a pale yellow solid (55%). MS: m/z 518 (M+H+).