Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CO
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 100 g of 4-bromophenylacetic acid in 1.5 l of methanol is mixed with 232 g of Amberlyst 15, and the suspension is stirred for 48 hours at room temperature. The reaction mixture is suctioned off on diatomaceous earth, the filter residue is washed with dichloromethane, and the filtrate is concentrated by evaporation. The residue is taken up in ethyl acetate, washed with 10% sodium bicarbonate solution and saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 106 g of 4-bromophenylacetic acid methyl ester is obtained as oil.
Reaction SMILES: C(OC(C[N:9]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C@@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12])=O)(C)(C)C.F[C:36](F)(F)[C:37]([OH:39])=[O:38]>ClCCl>[C:37]([CH2:36][S:14][C:11]([CH3:13])([CH3:12])[C@H:10]([C:15]([OH:17])=[O:16])[NH:9][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:19])=[O:20])([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)CN([C@@H](C(=O)O)C(C)(C)S)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(SCC(=O)O)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1)C(=O)O
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of S--(t-Butoxycarbonyl)methyl--N--[4-(4-fluorophenoxy)benzenesulfonyl]-D-penicillamine (188.8 mg, 0.367 mmol) in 3.4 mL of dichloromethane at 20° C. was added trifluoroacetic acid (0.85 mL). The solution was stirred for 16 h and concentrated in vacuo. The residue was partitioned between ethyl acetate (25 mL) and 1 M aq. phosphate buffer (pH 7). The aqueous layer was extracted with two additional portions of ethyl acetate (25 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was triturated with diethyl ether (5 mL) to give 67 mg (40%) of S-Carboxymethyl--N--[4-(4-fluorophenoxy)benzenesulfonyl]-D-penicillamine as an off-white solid: mp 69° C.; 1H--NMR (DMSO-d6) δ 1.32 (br s, 6H), 3.25-3.5 (br m, 3H), 7.12 (d, J=8 Hz, 2H), 7.2-7.5 (m, 4H), 7.82 (d, J=8 Hz, 2H), 8.00-8.40 (br s, 1H), 12.5-13.2 (v br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(OCc2ccccc2)cc1OC1CCNCC1

Procedure:
Using methods substantially equivalent to those described in Example 1-C, methyl 4-benzyloxy-2-hydroxybenzoate (2.0 g, 8.1 mmol), N-tert-butoxycarbonyl-4-hydroxy-piperidine (1.6 g, 8.1 mmol), triphenylphosphine (2.1 g, 8.1 mmol), and diethyl azodicarboxyalte (1.3 mL, 8.1 mmol) afforded, after purification by chromatography (SiO2: 5 to 15% EtOAc in hexanes), 2.57 g (74%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)[N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12.C(OCC)(=O)C.O.C[C:35]([N:37](C)C)=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-]#N.[Zn+2].[C-]#N>[C:35]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)[N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12)#[N:37]
Reactant: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(Br)cnc(OC)c32)cs1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(C#N)cnc(OC)c32)cs1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl 4-(4-bromo-3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxylate (65 mg), tetrakis(triphenylphosphine)palladium(0) (34.4 mg) and zinc cyanide (26.2 mg) in DMA (3 mL) was stirred under microwave irradiation at 120° C. for 30 min. To the reaction mixture were added ethyl acetate and water, and the mixture was filtered through Celite. The filtrate was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (40 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].C1(C)C=CC(S(O[C@H:23]2[CH2:30][CH2:29][CH2:28][C@@H:27](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][CH2:25][CH2:24]2)(=O)=O)=CC=1>CN(C=O)C>[NH2:1][C:2]1[N:6]([C@H:23]2[CH2:24][CH2:25][CH2:26][C@@H:27]([N:3]3[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]3[NH2:1])[CH2:28][CH2:29][CH2:30]2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCC[C@@H](OS(=O)(=O)c3ccc(C)cc3)CCC2)cc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2n1[C@H]1CCC[C@@H](n2c(N)nc3ccccc32)CCC1
Reaction time: 0.5 h

Procedure:
To a hot (60° C.) solution of 2-aminobenzimidazole (0.22 g; 1.65 mmol) in DMF (25 ml) was added sodium hydride (70 mg; 60% dispersion in mineral oil), and the mixture was stirred for 30 minutes prior to addition of cis-1,5-bis(p-toluenesulfonyloxy) cyclooctane. The resulting mixture was stirred at 100° C. for four days, cooled and filtered. The filtrate was diluted with water and the precipitate was filtered off, washed with water and dried to yield the desired product (9 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][NH:6][C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.[CH2:22]=[N:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CO>>[F:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([F:1])[CH:20]=1)[CH2:5][NH:6][C:7]([C:8]1[CH2:22][N:23]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: C=NCCN1CCOCC1
Reactant: CC1(C)OC(=O)C(=CC(=O)NCc2cc(F)cc(F)c2)O1
Solvent: CO
Product: O=C(NCc1cc(F)cc(F)c1)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Temperature: 25 °C
Yield: 22 %

Procedure:
A mixture of N-(3,5-difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide (60 mg, 0.2 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.25 mL, 0.25 mmol) was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a white powder (22 mg, 22% yield). 1H NMR (500 MHz, DMSO) δ: 11.95 (1H, br s), 9.54 (1H, br s), 8.08 (1H, t, J=6.1 Hz), 7.12–7.08 (1H, m), 7.00–6.94 (2H, m), 4.45 (2H, d, J=6.1 Hz), 4.05 (2H, s), 4.02–3.94 (2H, m), 3.83–3.77 (2H, m), 3.69–3.38 (6H, m), 3.16–3.05 (2H, m). HRMS calcd for C18H20F2N3O4 (M−H): 380.1422. found: 380.1422.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[CH3:32][C:33]([CH3:35])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:6][N:3]([CH:33]([CH3:35])[CH3:32])[CH2:4]2)[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH:27]([F:29])[F:28])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.9 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (45 mg, 0.090 mmol), acetone (37 mg, 0.63 mmol) and triethylamine (63 μL, 0.45 mmol) in methylene chloride (0.9 mL) was added sodium triacetoxyborohydride resin (0.12 g, 0.27 mmol). The mixture was stirred at room temperature for 2 h, then filtered, concentrated and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.5 mg, 6.8%). The product was isolated as a racemic mixture. LCMS calculated for C21H25ClF3N6O (M+H)+: m/z=469.2; Found: 469.2.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[CH:7][S:8][CH:9]=2)[NH:5][C:4](=[O:11])[C:3]=1[C:12]#[N:13].[N:14]1([C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:11]=[C:4]1[C:3]([C:12]#[N:13])=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[CH2:15][CH2:16]2)[C:10]2[C:6](=[CH:7][S:8][CH:9]=2)[NH:5]1
Reactant: N#Cc1c(Cl)c2cscc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O

Procedure:
To yield a compound of structure (II) with R2 as carbonitrile, R3 as thiophene, and R1 as defined above, the intermediate 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (33), was reacted with piperazin-1-yl-thiophene-2-yl-methanone to yield 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (34), which was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield target compounds of structure (II) with R2 as carbonitrile, R3 as thiophene, and R1 as defined above, as shown in Scheme 16.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[C:25](Cl)(=[O:36])[O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1>O1CCCC1>[N+:33]([C:30]1[CH:31]=[CH:32][C:27]([O:26][C:25]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[O:36])=[CH:28][CH:29]=1)([O-:35])=[O:34]
Reactant: NCCC(=O)OCc1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: O=C(CCNC(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1

Procedure:
200 mg (0.57 mmol) of commercially available 4-methylbenzenesulphonic acid-benzyl beta-alaninate and 229 mg (1.14 mmol) of 4-nitrophenyl chlorocarbonate were taken up in 15 ml of tetrahydrofuran and the reaction mixture was then heated to reflux for 30 min. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was purified by means of preparative HPLC. After concentration of the corresponding fractions and drying of the residue under high vacuum, 86 mg (44% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:14]2[N:15]=[C:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[C:17]([C:18]([NH2:20])=[O:19])=[C:13]2[NH:12][CH2:11][CH2:10]1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:14]2[N:15]=[C:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[C:17]([C:18]([NH2:20])=[O:19])=[C:13]2[NH:12][CH2:11][CH2:10]1)[C:34](=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)Cl
Reactant: CNc1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21
Product: C=CC(=O)N(C)c1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21

Procedure:
The desired product was prepared from 7-(2-(methylamino)phenyl)-2-(4-phenoxy phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and acryloyl chloride using the procedure similar to that for compound 8. 1H NMR (DMSO-d6) δ 7.45-7.37 (m, 6H), 7.29-7.24 (m, 1H), 7.15 (t, J=7.6 Hz, 1H), 7.06-7.00 (m, 5H), 6.81 (d, J=7.6 Hz, 1H), 6.25-6.16 (m, 2H), 5.94-5.87 (m, 1H), 5.63-5.51 (m, 1H), 5.41-5.35 (m, 1H), 3.41-3.22 (m, 5H), 2.41-1.97 (m, 2H). MS (ESI) m/e [M+1]+ 493.9.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:16][C@H:17]1[CH2:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=[C:21]([Br:40])[C:20]=2[CH2:19][CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[Br:40][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:28]2)=[C:25]2[C:20]=1[CH2:19][CH2:18][C@@H:17]([NH:16][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)c3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)c3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
4-Morpholinobenzoic acid (0.50 g, 2.4 mmol; described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) was dissolved in thionyl chloride (10 mL). After 2 min, the thionyl chloride was evaporated in vacuo and the residue was treated with toluene and again the solvent was evaporated in vacuo. Crude acid chloride (81 mg, 0.36 mmol) was dissolved in methylene chloride (10 mL) and added dropwise to a solution of tert-butyl (R)-4-(7-amino-4-bromo-5,6,7,8-tetrahydro-1-naphthyl)piperazin-1-carboxylate (140 mg, 0.34 mmmol) and triethylamine (71 μL, 0.51 mmol) in methylene chloride (10 mL). After the addition, the reaction was stirred at ambient temperature for 15 min and was then washed with a diluted aqueous solution of sodium hydrogen carbonate and the phases were separated. The organic phase was dried (Na2SO4), filtered and evaporated in vacuo and the residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent. Yield: 160 mg (79%) of a viscous colorless oil: [α]21D−11° (c=1, chloroform); TSPMS m/z (relative intensity)-599 and 601 (35, M+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Cl[C:15]1[C:16]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)[CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][N:20]=1.CN(C)C(=O)C.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:33][N:31]1[CH:32]=[C:28]([CH2:27][N:24]2[CH2:23][CH2:22][N:21]([C:16]3[C:15]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=4)=[N:20][CH:19]=[CH:18][N:17]=3)[CH2:26][CH2:25]2)[CH:29]=[N:30]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(CN2CCN(c3nccnc3-c3cccc(C(F)(F)F)c3)CC2)cn1
Temperature: 110 °C
Yield: 57.8 %

Procedure:
Charge a carousel tube with 3-trifluoromethylbenzeneboronic acid (136 mg, 0.66 mmol), 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (160 mg, 0.55 mmol) and N,N-dimethylacetamide (1 mL). Add N,N-dimethylacetamide (3 mL) and potassium carbonate (185 mg, 1.32 mmol) and purge with nitrogen for about 45 min. Add water (2 mL, purged with nitrogen for 1 hr.) then tetrakis(triphenylphosphine)palladium(0) (0.003 g, 0.0025 mmol) and purge the reaction vessel for about 30 min. Heat at 110° C. overnight. Cool to room temperature, add water and extract with DCM (3×30 mL), and then concentrate the combined DCM extracts. Purify using silica gel chromatography, followed by reverse phase HPLC, to give the title compound (128 mg, 58%). MS (ES): m/z=403.1 [M+H]+.
Reaction SMILES: C(C1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[CH:5]=1)(=O)C.C[Si](O[Si](C)(C)C)(C)C.[C:37]([O:40][CH2:41]C)(=[O:39])[CH3:38].CO>>[OH:27][C:14]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:38]([C:37]([O:40][CH3:41])=[O:39])[CH:13]=[CH:12]2)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc2cc(C(O)(c3ccccc3)c3cccnc3)ccc2c1
Reactant: CCOC(C)=O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: CO
Product: COC(=O)c1ccc2cc(C(O)(c3ccccc3)c3cccnc3)ccc2c1

Procedure:
Methyl 6-[1-hydroxy-1-phenyl-1-(3-pyridyl)methyl]-2-naphthoate is prepared from 2-acetyl-6-(1-hydroxy-1-phenyl-1-(3-pyridyl) methyl)naphthalene in analogy to 3a without intermediate protection of the hydroxyl group as the trimethylsilyl ether. RF (ethyl acetate/methanol): 0.53.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[C:13](Cl)=[C:12]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11]([Cl:23])=[N:10][C:9]=12)=[O:4]>C(O)C.O.C1COCC1.[Zn]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11]([Cl:23])=[N:10][C:9]=12)=[O:4]
Reactant: COC(=O)c1cnn2c(Cl)c(-c3c(F)cccc3F)c(Cl)nc12
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(Cl)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5 g (13.96 mmol) 5,7-Dichloro-6-(2,6-difluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester are dissolved in a mixture of 355 mL ethanol, 253 mL water and 136 mL THF. After addition of 5.8 g (89 mmol) zinc in portions, the mixture is vigorously stirred at rt for three hours. Stirring is continued over night. The reaction mixture is filtered via a glass microfibre filter and washed with plenty of ethanol. The solvent has been removed and the residue redissolved in ethyl acetate. After washing twice with brine and drying over Na2SO4, the solvent is evaporated and the residue is used in the next step as the crude contaminated product (2.3 g=51%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5](=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:3]1=[O:20].O.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:3](=[O:20])[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: CN1C(=O)CC(=O)N(c2cccc(C(F)(F)F)c2)C1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(=O)cc(Cl)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 0 °C

Procedure:
To a solution of 1-methyl-3-(3-(trifluoromethyl)phenyl)pyrimidin-2,4,6(1H, 3H, 5H)-trione (2.74 g) (prepared in Reference Example 55) in phosphorus oxychloride (22 ml) was added water (0.55 ml) slowly and the resulting mixture was stirred with heating under reflux for one hour. After concentration under reduced pressure, the reaction solutions were cooled to 0° C. and to the residue was added water (50 ml) slowly with stirring. The resulting mixture was extracted with ethyl acetate (50 ml×3), and the resulting extracts were dried and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (1.54 g).
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH4+].[Cl-]>C1COCC1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([N:2]([O:3][CH3:4])[CH3:1])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNOC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of N,O-dimethylhydroxylamine (1.51 mmol; 147 mg) in dry THF (3 mL), under argon, was added at −78° C. nbutyllithium 2.5M (3.02 mmol; 1.21 mL). The mixture was stirred minutes at −78° C., before addition of 4-fluorobenzoyl chloride (1.26 mmol; 150 μL). The reaction was stirred overnight at room temperature, then treated with saturated NH4Cl and extracted with ethyl acetate. Combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo, to give the title compound (66%; 173 mg) as a yellow oil used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:13]([CH2:17][C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:49]([O:53][NH2:54])([CH3:52])([CH3:51])[CH3:50].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[C:49]([O:53][NH:54][C:14](=[O:16])[CH:13]([N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](Cc2nnn(C)n2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(Cc2nnn(C)n2)C(=O)NOC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetic acid (0.96 g, 2.24 mmol), 1-hydroxybenzotriazole (0.30 g, 2.24 mmol), 4-methylmorpholine (0.86 mL, 7.89 mmol), and O-t-butylhydroxylamine hydrochloride (0.30 g, 2.24 mmol) are dissolved in methylene chloride (75.0 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (0.86 g, 4.48 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (50% ethyl acetate/hexane) to give N-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](benzyl)-amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetamide.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](=O)[CH3:11].[NH3:13].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH:10]([NH2:13])[CH3:11]
Reactant: N
Reactant: CC(=O)C1Cc2ccccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)C1Cc2ccccc2C1
Reaction time: 14 h

Procedure:
1-(2,3-dihydro-1H-inden-2-yl)ethanone (44 mg, 0.275 mmol) was dissolved in methanol (2 mL), and 7 M methanolic ammonia was added (1 mL, 7 mmol). This was allowed to stir at rt for 4 h, at which time sodium borohydride (31 mg, 0.824 mmol) and a catalytic drop of glacial acetic acid was added. Stirring continued for 14 h at rt, after which time the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with a small amount of 10% aqueous sodium carbonate, dried with magnesium sulfate, and concentrated. The residue was then taken on in subsequent reactions without further purification or characterization.