Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.CC[O:12][CH2:13][CH3:14]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([C:14]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: Fc1ccc([Mg]Br)cc1
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution of nitrile 1 (900 mg, 5.02 mmol) in ether (45 mL) at 0° C. was added via syringe ρ-fluorophenylmagnesium bromide (5.0 mL, 2.0 M solution in ether 10 mmol). The resulting turbid mixture was stirred at 0° C. for 5 min then warmed to r.t. and stirred for 6 h. At that time, the reaction was quenched with H2O (3 mL) and then diluted with ether (25 mL) and H2O (25 mL). The organic phase was separated, and the aqueous phase was extracted with ether (80 mL×2). The organic portions were combined, washed with saturated aqueous NaCl, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (30 g short path, 1%→10% EtOAc/hexane) to give the desired product (700 mg, 2.53 mmol, 50%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.97 (m, 2 H), 7.11 (m, 2 H), 5.79 (d, J=2.0 Hz, 1 H), 3.41 (s, 3 H), 2.97-2.81 (m, 3 H), 2.00 (m, 2 H), 1.82 (m, 1 H), 1.74 (m, 2 H), 1.65 (m, 1 H), 1.53 (m, 3 H), 1.21 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 199.0, 165.3 (d, J=253 Hz), 140.4, 133.7 (d, J=3.0 Hz), 130.4 (d, J=9.1 Hz), 118.8, 115.3 (d, J=22.0 Hz), 59.0, 36.6, 32.5, 31.6, 28.2, 26.4, 25.7, 21.6.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(Br)cc1C(=O)O
Product: O=c1oc(-c2ccccc2)nc2ccc(Br)cc12
Temperature: 25 °C
Yield: 97.4 %

Procedure:
The 2-amino-5-bromobenzoic acid (5 g, 23.1 mmol) was treated with benzoyl chloride (237 mL, 2.04 mol) at 140° C. for 3 h. After the reaction mixture was cooled to rt, the crystals that formed were collected by filtration and were washed with hexanes to provide 64 as light brown needles (6.8 g, 97%): 1H NMR (CDCl3) δ 7.51-7.2 (m, 4H), 7.9 (dd, 1H, J=2.3, 8.6 Hz), 8.30-8.33 (m, 2H), 8.8 (d, 1H, J=2.2 Hz); 13C NMR (CDCl3) δ 158.19, 157.35, 145.75, 139.58, 132.82, 130.97, 129.77, 128.82, 128.73, 128.29, 121.37, 118.27; MS (EI) m/e (relative intensity) 303 (M+, 36), 301 (M+, 36), 259 (14), 257 (14), 226 (6), 224 (6), 178 (9), 170 (9), 168 (9), 151 (4), 105 (100).
Reaction SMILES: C(OC([C:6]1[N:7]([C@H:23]([CH3:33])[CH2:24][NH:25][C:26](OC(C)(C)C)=[O:27])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=2)=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.C(OCC)(=O)C>[OH:15][C:11]1[CH:10]=[CH:9][C:8]2[N:7]3[C@H:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:27])[C:6]3=[CH:14][C:13]=2[CH:12]=1
Reactant: CCOC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2n1[C@H](C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CNC(=O)c2cc3cc(O)ccc3n21
Temperature: 0 °C
Reaction time: 6 h
Yield: 55.1 %

Procedure:
The solution of 0.60 g (1.26 mmol) 1-((R)-2-tert-butoxycarbonylamino-1-methyl-ethyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole-2-carboxylic acid ethyl ester in 8 mL dichloromethane was cooled to 0° C. and 1.9 mL (2.8 g, 24.9 mmol) trifluoroacetic acid was added dropwise within 5 min. The cooling bath was removed and after 1.5 hours the volatile components were removed at a rotary evaporator. The residue was dissolved in methanol, cooled to 0° C. and 0.69 g (5.0 mmol) potassium carbonate was added. The suspension was stirred for 6 hours at room temperature, diluted with water and ethyl acetate and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give 0.15 g (57%) of the desired product as a light brown gum.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH:37]5[CH2:38][CH2:39][O:34][CH2:35][CH2:36]5)[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C1CCOCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol), tetrahydropyran-4-one (27 mg, 0.27 mmol) and AcOH (50 μL) in DCE (2 mL) was allowed to stir at r.t. for 20 min before the addition of sodium triacetoxyborohydride (104 mg, 0.49 mmol). The resulting mixture was allowed to stir for 18 h then partitioned between DCM and H2O. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) then triturated with MeCN and H2O and the resulting solid dried in vacuo affording 827 (92 mg, 82%). LCMS (method I): RT 2.65 min, [M+H]+ 555.3. 1H NMR (DMSO, 400 MHz): δ 8.04-8.04 (1 H, m), 7.65-7.62 (1 H, m), 7.25-7.24 (2 H, m), 4.40-4.10 (4 H, brd s), 3.91 (2 H, d, J=8.05 Hz), 3.80-3.79 (6 H, m), 3.71 (3 H, s), 3.41 (2 H, d, J=8.07 Hz), 3.28-3.26 (4 H, m), 3.02 (3 H, s), 2.37-2.28 (1 H, m), 1.67-1.63 (2 H, m), 1.34 (3 H, t, J=7.43 Hz), 1.23-1.10 (2 H, m)
Reaction SMILES: C(OC([N:11]1[CH:18]2[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:21][CH:12]1[CH2:13]3)[CH:17]2Br)=O)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:19][CH:18]([CH2:17]3)[NH:11]1)[CH2:13]2
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1C2CC3CC(C2)C(Br)C1C3
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C1C2CC3CC1CC(C2)N3

Procedure:
To 1.0 g of N-benzyloxycarbonyl-4-bromo-2-azaadamantane, 10 g of ethanol, 0.32 g of triethylamine and 0.5 g of 10 wt % Pd/C (containing 50% of water) were charged, followed by stirring at 20 to 30° C. for 5 hours while 0.5 MPa of a hydrogen pressure was applied. Filtration by Celite (registered trademark by Celite Corporation) was carried out to remove a solid, and the mother liquor was quantitatively analyzed, whereupon the yield of 2-azaadamantane was 85%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.CCOCC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([Cl:9])[CH:4]=1)[CH3:22]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CNc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a solution of 4-bromo-3-chloro-aniline (0.64 g, 3.10 mmol) in ethanol (7 ml) were added sodium carbonate (0.49 g, 4.65 mmol) and ethyl bromoacetate (0.38 ml, 3.41 mmol). The resulting suspension was stirred at room temperature for 10 min and was then heated at 100° C. for 30 min under microwave irradiation. The mixture was then cooled to room temperature, diluted with ether, and filtered. The filtrate was washed with 1 M aqueous hydrochloric acid, the phases separated, and the aqueous phase extracted with ether. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=gradient 100:0-70:30) to yield a brown oil (0.56 g, 62%); MS (ISP): 296.1, 294.1, 292.1 ([M+H]+.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C([O:27][CH2:28][C:29]1[C:34]([N:35]2[N:44]=[CH:43][C:42]3[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=3)[C:36]2=[O:50])=[CH:33][CH:32]=[CH:31][C:30]=1[B-](F)(F)F)(=O)C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCO>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[N:12]=[N:13][C:14]([CH:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[CH:15][CH:16]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:29]=1[CH2:28][OH:27])[N:44]=[CH:43]2)([CH3:48])([CH3:46])[CH3:47]
Reactant: CN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nn2)CC1
Reactant: CC(=O)OCc1c(-n2ncc3cc(C(C)(C)C)cc(F)c3c2=O)cccc1[B-](F)(F)F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Solvent: O
Product: CN1CCC(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nn2)CC1
Temperature: 110 °C
Yield: 20.4 %

Procedure:
In a 15 mL microwave reaction vial was added 6-chloro-2-methyl-4-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)pyridazin-3(2H)-one (160 mg, 478 μmol, Eq: 1.00), potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (272 mg, 573 μmol, Eq: 1.2) with n-BuOH (7.5 ml) and water (1.5 ml). Argon was bubbled through the solution for 5 min. To the mixture was added X-PHOS (34.2 mg, 71.7 μmol, Eq: 0.15) and potassium phosphate tribasic (304 mg, 1.43 mmol, Eq: 3). Argon was bubbled through the mixture for 5 min. To this mixture was added bis(dibenzylideneacetone)palladium (20.6 mg, 35.8 μmol, Eq: 0.075). The tube was sealed under argon and heated in oil bath at 110° C. for 3 hrs. The mixture was cooled to room temperature and treated with a solution of 220 mg NaOH in 1.5 mL water dropwise. The resultant mixture was heated in an oil bath at 50° C. for 3 hrs with strong stirring. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3×30 mL). The combined extracts were concentrated and purified by solid loading on a 40 g silica gel column and eluting with 5-10% (10% NH4OH in MeOH) in 1/1 EtOAc/hexane to afford 61 mg (20%) of the title compound as a yellow solid. mp: 260-265° C. 1H NMR (300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 1.80-2.20 (m, 6H), 2.37 (s, 3H), 2.90-3.07 (m, 3H), 3.85 (t, J=6.2 Hz, 1H), 3.92 (s, 3H), 4.45 (d, J=6.2 Hz, 2H), 7.15 (d, J=9 Hz, 1H), 7.35 (d, J=9 Hz, 1H), 7.43-7.65 (m, 5H), 8.28 (d, J=2.5, 1H), 8.32 (s, 1H), 8.78 (s, 1H). LCMS (ES): 625 (M+H), RT=2.21 min.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:21]1([NH:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:27]2[C:13]([C:10]3[C:9]([CH3:19])=[N:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[OH:12])=[CH:14][C:15]([CH3:16])=[N:28]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: NNC1CCCCC1
Agent: Cl
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(C2CCCCC2)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and cyclohexylhydrazine hydrochloride according to the procedure of Example 28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:16]([OH:18])=O)=[CH:6]2.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:16]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:16]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[C:10]=4[O:14][CH3:15])=[O:18])[CH2:21][CH2:20]1)=[O:18])=[CH:6]2
Reactant: C1CNCCNC1
Reactant: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Product: COc1cc2cc(C(=O)N3CCCN(C(=O)c4cc5cc(OC)c(OC)c(OC)c5[nH]4)CC3)[nH]c2c(OC)c1OC

Procedure:
5,6,7-Trimethoxyindole-2-carboxylic acid (300 mg) and homopiperazine (60 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:15]([O:19][CH2:20]C)(=[O:18])[CH2:16][SH:17].C([O-])([O-])=O.[K+].[K+]>C(O)C>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=2[S:17][C:16]=1[C:15]([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)CS
Reactant: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)c1sc2cc([N+](=O)[O-])ccc2c1N
Yield: 46 %

Procedure:
The product from Example 47B (3.73 g, 19.3 mmol) was treated with 1 equivalent ethyl thioglycolate and 1 equivalent K2CO3 in ethanol by the procedure described in Example 41A to yield the title compound (2.35 g, 46%). m.p. 169°-170° C. 1H NMR (300 MHz, DMSO) δ8.90 (d, 1H), 8.37 (d, 1H), 8.20 (dd, 1H), 7.29 (br s, 2H), 4.31 (q, 2H), 1.31 (t, 3H). MS (DCI/NH3) m/e 284 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][C:17](=[CH2:21])[C:18](Cl)=[O:19]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:21])=[CH2:16])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: C=C(C)C(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: C=C(C)C(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using 2-methyl-acryloyl chloride (53 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2-methylacrylamide (0.037 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([O:20]C)=O)([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7]>C1COCC1>[CH3:4][O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18](=[O:20])[N:2]([CH3:3])[CH3:1])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7]
Reactant: CNC
Reactant: COC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Solvent: C1CCOC1
Product: COC(=O)C12CC3CC(C1)CC(C(=O)N(C)C)(C3)C2
Yield: 80 %

Procedure:
1 mmole of 1,3-bis(methozxycarbonyl)adamantane obtained by the method of Example 84 was dissolved in 30 ml of THF. To the mixture, 0.5 mmole of dimethylamine and 0.1 mmole of aluminum chloride anhydride AlCl3 was added and reacted for 6 hours at 80° C. As a result, The conversion of 1,3-bis(methoxycarbonyl)adamantane was 90%, and 1-methoxycarbonyl-3-(N,N-dimethylcarbamoyl)adamantane (yield 80%) was formed.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4](OC)(=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.O.Cl>CS(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([CH2:2][C:1]#[N:3])=[O:13])=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 60 °C
Yield: 79.7 %

Procedure:
To a solution of acetonitrile (15 g) in DMSO (25 mL) was added methyl p-anisate (25 g) and the mixture was stirred with heating at 60° C. for 1 hour. The reaction mixture was allowed to cool and cold water (100 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give 4-methoxybenzoylacetonitrile (21 g) as colorless crystals. To a solution of the obtained crystals in toluene was added hydrazine monohydrate (13 g) and the mixture was heated under reflux for 3 hours. The mixture was cooled and the precipitated crystals were collected by filtration to give 5-amino-3-(4-methoxyphenyl)pyrazole (22 g). Subsequently, the title compound was prepared from methyl butyrate, 2-chlorobenzaldehyde and 5-amino-3-(4-methoxyphenyl)pyrazole in the same manner as in Example 94.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.O=[CH:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CO.[Pd]>[C:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1)=[O:36])([CH3:35])([CH3:34])[CH3:33]
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6, 15 mg) in MeOH (2 mL) was added tert-butyl 2-oxoethylcarbamate (20 mg). Pd/C (10% by weight, 10 mg) was added and the reaction mixture was stirred under H2 balloon overnight. The reaction mixture was filtrated and the solvent was then removed under reduced pressure and the residue was carried on to the next step without further purification. ESI-MS m/z 490.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-(4-Bromophenyl)-5-methyl-4-oxazoleethanol (10.0 g, 35.0 mmol) (see Ex. 1, Part G) and 2-thiophenyl boronic acid (38.0 mmol) were dissolved in n-propanol (120 ml) before adding triphenylphosphine (165.2 mg, 0.63 mmol), palladium acetate (46 mg, 2.1 mmol), and Na2CO3 (4.5 g, 42 mmol dissolved in 30 mL distilled H2O). The solution was heated to reflux and stirred for 1.5 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and then partitioned between CH2Cl2 (100 mL) and 1N NaOH (100 mL). The aqueous phase was extracted with CH2Cl2 (2×50 mL) and the combined organic phases were dried (MgSO4) and concentrated under reduced pressure to provide 2-(4-thiophen-2-yl-phenyl)-5-methyl-4-oxazoleethanol.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:3])[CH3:2].C([Li])CCC.Cl[P:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=[N:20][P:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:3])[CH3:2]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C(C)C)cc1
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(c2ccccc2)c2ccccc2)Nc2c(C)cccc2C(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.33 g of N1-(2-isopropyl-6-methylphenyl)-4-methylbenzamidine (Amidine V, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the residue was treated with 20 mL of pentane. Prolonged stirring deposited a beige solid which was collected and dried (1.62 g, 72%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[O:39])[CH2:34][CH2:33]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OCc5ccccc5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a suspension of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (2 g, 6.53 mmol, INTERMEDIATE 2) in dichloromethane (25 ml) were added oxalyl chloride (9.79 ml, 19.59 mmol) and a drop (ca. 10 μl) of dimethylformamide. The mixture was stirred for 1 h at 25° C., at which point a clear solution formed. The mixture was concentrated and then co-concentrated with 5 ml of toluene. To a solution of the residue in dichloromethane (25 ml) was added 4-aminomethyl-1-N-Cbz-piperidine (2 g, 8.05 mmol) and diisopropylethylamine (1.711 ml, 9.79 mmol). The mixture was stirred overnight at 25° C. and then concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 65i column, eluting with 1 column volume of 10% ethyl acetate in hexanes followed by a gradient of 10 to 100% ethyl acetate in hexanes over 10 column volumes to provide the title compound (2.53 g, 72.2%). Mass spectrum (ESI) 537.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.29 (m, 2H), 7.94 (d, J=8.5 Hz 2H), 7.90 (m, 1H), 7.49 (s, 1H), 7.27-7.35 (m, 4H), 6.69 (m, 1H), 5.11 (s, 2H), 4.09-4.30 (m, 2H), 3.31-3.49 (m, 3H), 2.79 (m, 2H), 1.86 (m, 1H), 1.77 (m, 2H), 1.45 (d, J=6.5 Hz, 6H), 1.18-1.30 (m, 2H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].Cl.C(=O)=O>ClCCl>[CH3:5][C:6]1([CH3:11])[CH2:9][O:10][C:1](=[O:2])[O:8][CH2:7]1
Reactant: CC(C)(CO)CO
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: O=C=O
Solvent: ClCCl
Product: CC1(C)COC(=O)OC1
Temperature: 110 °C
Yield: 45 %

Procedure:
198 g (2.00 mol) phosgene were introduced over a period of 1,5 h at 0° to 5° C. into a suspension of 208 g (2.00 mol) 2,2-dimethylpropane-1,3-diol and 600 ml dry dichloromethane, followed by stirring at that temperature until the initially vigorous evolution of hydrogen chloride had abated. The discharge of phosgene was prevented by an effective reflux condenser (dry ice). The solvent was then removed in vacuo, 500 mg (0.2% by weight) imidazole and 500 ml toluene were added and the reaction was completed by slowly increasing the temperature to 110° C. until the evolution of hydrogen chloride had stopped (3 hours). Residues of hydrogen chloride were then removed by application of a low vacuum. Removal of the toluene and fractionation of the residue in vacuo left 121 g (93%) of a solid product (boiling point 142° to 146° C./10 mbar). Recrystallization from ethyl acetate gave 117 g (90%) of product (Mp. 108° to 109° C.). Further working up is unnecessary.